Tricyclic derivative inhibitor, and preparation method and use therefor

Abstract

A tricyclic derivative inhibitor, and a preparation method and use therefor. In particular, the present invention relates to a tricyclic derivative compound, a preparation method therefor and a pharmaceutical composition containing the compound, and a use thereof in treating cancer.

Description

Tricyclic derivative inhibitors, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular relates to 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 structure represented by general formula (I) is as follows:

[0007] M1 is selected from -N- or -CR a -;

[0008] M2 is selected from -N- or -CR b -;

[0009] M3 is selected from N or C;

[0010] 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;

[0011] 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; more 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;

[0012] L1 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 C(S)-、-(CR aa R bb ) m2 C(NR cc )-、-(CR aa R bb ) m2 NR cc C(O)-、-(CR aa R bb ) m2 S(O) m1 -、-(CR aa R bb ) m2 NR cc -、-(CR aa R bb ) m2 P(O)2-、-(CR aa R bb ) m2 P(O)(OR cc )-、C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1- 6 alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents in aryl and 5-12 membered heteroaryl; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0013] L2 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[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, -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)Re (=NR f ) or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-10 Aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -ORe 、-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 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)Ree 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 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 1-3Alkoxy, 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;

[0016] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12 membered heterocyclic group, -Y1-C 6-12 Aryl, -Y1-5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h 、-C(=NR i )NR g R h or =R g R h , the amino group, C1-6 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 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents;

[0017] Or any two R3 atoms are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0018] R a 、R b 、R c 、R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, 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, 5-12 membered heteroaryl and =CR gg R hh Preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, 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;

[0019] or R a With R b Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0020] Y1 is selected from a bond, -O-, -S-, -C(O), -NR j -、-C(O)NR j -、-NR j C(O)-、-S(O)2NR j -、-NR j S(O)2-、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -NR j -C 1-6 Alkylene-, -C 1-6 Alkylene-NR j -、C 2- 6 alkenylene or C 2-6 Alkynylidene, the C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0021] R g 、R h 、R i and R j are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1- 6 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0022] R aa 、R bb 、R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1- 6 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 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, 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;

[0023] R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 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 gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 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, C1-3 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;

[0025] x is selected from 0, 1, 2, 3, 4, 5 or 6;

[0026] y is selected from 0, 1, 2, 3, 4, 5 or 6;

[0027] m1 is selected from 0, 1 or 2;

[0028] m2 is selected from 0, 1 or 2;

[0029] n1 is selected from 0, 1, 2, 3 or 4; and

[0030] n2 is selected from 0, 1, 2, 3 or 4.

[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 by being further represented by general formula (II):

[0033] R 1-2 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 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents;

[0034] R 1-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, 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, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents;

[0035] Or, R 1-2 With R 1-3 The 3-10 membered heterocyclic group is linked to form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is 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, cyano substituted C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents;

[0036] 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 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0037] R gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 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 1-6Deuterated 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;

[0038] n2 is selected from 0, 1, 2, 3 or 4;

[0039] n3 is selected from 0, 1, 2, 3 or 4;

[0040] Ring A, Ring B, M1, M2, M3, L2, R2, R3, R c , x and y are as defined in any of the above embodiments.

[0041] The present invention also provides a compound represented by general formula (III) or (III-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the structure of which is shown below:

[0042] X1 is selected from O or CH2;

[0043] X2 is selected from C or N;

[0044] X3 is selected from C or N;

[0045] X4 is selected from CH or N;

[0046] X5 is selected from CH or N;

[0047] X6 selected from CR 4a NR 4a or N; preferably CR 4a or N;

[0048] X7 selected from CR 4b NR 4b or N; preferably CR 4b or N;

[0049] Or, R 4a With R 4b Linked to form ring A;

[0050] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R 2c replaced by;

[0051] Ring F is selected from C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0052] R 2c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 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, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0053] R 3e and R 3g 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 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -OR a1 、-NR a1 R a2 、-C(O)R a1 、-C(O)NR a1 R a2 、-N=S(O)R a1 R a2 、-S(O)R a1 (=NR a2 ),-P(O)R a1 R a2 or =R a1 R a2 , 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 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 1-6Halogenated 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 a3 R a4 is substituted by one or more substituents;

[0054] Or, two R 3e Link Form C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, =N-OR a5 、=CR a5 CR a6 、-S(O)R a5 (=NR a6 ) and -N=S(O)R a5 R a6 One or more substitutions in ;

[0055] R 3f Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -(CR b1 R b2 ) n6-C 3-8 Cycloalkyl, -(CR b1 R b2 ) n6 -3-8 membered heterocyclic group, -(CR b1 R b2 ) n6 -C 6-10 Aryl, -(CR b1 R b2 ) n6 -5-10 membered heteroaryl, -SF5, -OR b1 、-NR b1 R b2 、-C(O)R b1 、-C(O)NR b1 R b2 、=N-OR b1 、=CR b1 CR b2 、-S(O)R b1 (=NR b2 ) and -N=S(O)R b1 R b2 , the 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl and 5-10 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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 b3 CR b4 Preferably, the alkyl group is substituted by one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -OR b1 、-NR b1 R b2 、-C(O)R b1 、-C(O)NR b1 R b2 、=N-OR b1 、=CR b1 CR b2 、-S(O)R b1 (=NR b2 ) and -N=S(O)R b1 R b2 ;

[0056] Or, two R 3f Link Form C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0057] R 4a 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, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0058] R 4b 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-14 Aryl, 5-14 membered heteroaryl, -OR c1 、-C(O)R c1 、-C(O)OR c1 、-NR c1 R c2 、-P(O)R c1 R c2 、-NR c3 C(O)R c1 、-C(O)NR c1 R c2 、-S(O)2R c1 、-S(O)2NR c1 R c2 、-NR c3 S(O)2R c1 、-S(O)R c1 (=NR c3 ) or -N=S(O)R c1 R c2 , 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0059] R a1 、R a2 、R a3 、R a4、R a5 and R a6 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0060] R b1 、R b2 、R b3 and R b4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0061] R c1 、R c2 and R c3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1- 6-alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0062] a is selected from 0, 1, 2, 3 or 4;

[0063] b is selected from 0, 1, 2, 3 or 4;

[0064] c is selected from 0, 1, 2, 3 or 4; and

[0065] n6 is selected from 0, 1, 2, 3 or 4;

[0066] M1, M2, R1, R c 、R ee 、R ff and n2 are as defined in any of the above embodiments.

[0067] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (IV) or (IV-1):

[0068] R1-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents;

[0069] R 1-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents;

[0070] Or, R 1-2 With R 1-3 The 3-10 membered heterocyclic group is linked to form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is 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, cyano substituted C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents;

[0071] Ring F, M1, M2, M3, X1, X2, X3, X4, X5, X6, X7, R 3e 、R 3g 、R 3f 、R 1-2 、R 1-3 、R c 、R ee 、R ff 、R gg 、R hh , x, a, b, c and n2 are as defined in any of the above embodiments.

[0072] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (V) or (V-1):

[0073] Ring A, Ring F, X2, X3, M1, M2, M3, R 2c 、R 3e 、R 3g 、R 3f 、R 1-2 、R 1-3 、R c , x, a, b and c are as defined in any of the above embodiments.

[0074] 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

[0075] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (V-2):

[0076] Ring A' is selected from 3-8 membered heterocyclyl or 5-10 membered heteroaryl; preferably 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl;

[0077] R 2d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0078] 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, C6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0079] n2 is selected from 0, 1, or 2;

[0080] d is selected from 0, 1, 2, 3 or 4;

[0081] R a 、R b 、R c and R1, Ring F, X1, X2, X3, X4, X5, R 3e 、R 3f 、R 3g , a, b and c are as defined in any of the above embodiments.

[0082] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (VI):

[0083] 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

[0084] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from a 6-14 membered tricyclic heterocyclic group; preferably a 6-14 membered tricyclic spiro heterocyclic group or a 6-14 membered tricyclic fused heterocyclic group; more preferably

[0085] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (VI-A) or (VI-B):

[0086] M4 is selected from N or R 3a ;

[0087] X2 and X3 are selected from C or N;

[0088] R 3a 、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, 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, 5-12 membered heteroaryl and -SF5, 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, 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 is substituted by one or more substituents;

[0089] R 3b 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 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and -SF5, 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 Rf is substituted by one or more substituents;

[0090] n5 is selected from 0, 1 or 2.

[0091] In a preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is characterized in that R2 or R 2c 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, 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;

[0092] 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;

[0093] Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl,

[0094] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that Ra 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.

[0095] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R b Selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, --(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C1-3 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- 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 heterocyclyl and =CR gg R hh Preferably, hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, 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 substituted by one or more substituents in a cycloalkyl group or a 3-8 membered heterocyclic group;

[0096] R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 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;

[0097] n2 is selected from 0, 1 or 2;

[0098] Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy,

[0099] In a preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is characterized in that R3 and R 3f 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, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or -SF5, the amino, 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, C 6-10 Aryl and 5-10 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;

[0100] R 3e and R 3gare 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, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 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, C 6-10 Aryl and 5-10 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 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0101] The present invention also provides a compound represented by general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the structure of which is shown below:

[0102] Preferably, the general formula (VII) is further represented by formula (VII-1):

[0103] n4 is selected from 0 or 1;

[0104] X2, X3, R 1-2 、R 1-3 、R 3e 、R3f 、R 3g , a, b, c and n4 are as defined in any of the above embodiments.

[0105] The present invention also provides a method for preparing a compound represented by general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that:

[0106] The compound represented by general formula (III-I) reacts with the compound represented by general formula (III-II) in the presence of a condensing agent and a base to obtain the compound represented by general formula (III-III), and the protecting group is further removed to obtain the compound represented by general formula (III);

[0107] Preferably, the method is a method for preparing a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0108] The compound represented by the general formula (IV-I) reacts with the compound represented by the general formula (IV-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV);

[0109] More preferably, the method is a method for preparing a compound represented by general formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0110] The compound represented by general formula (VI) reacts with the compound represented by general formula (V-II) in the presence of a condensing agent and a base to obtain the compound represented by general formula (V-III), and the protecting group is further removed to obtain the compound represented by general formula (V);

[0111] Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0112] Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably hydrogen, benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0113] X2, X3, R 1-2 、R 1-3 、R 2c 、R 3e 、R 3f 、R 3g 、M1、M2、M3、R a 、R b 、R c , a, b, c, x and n4 are as defined in any of the above embodiments.

[0114] In a preferred embodiment of the present invention, the condensing agent in the preparation method is selected from thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, ethyl chloroformate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; preferably phosphorus oxychloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate.

[0115] The base is selected from potassium carbonate, methylamine, triethylamine, diisopropylamine, pyridine, imidazole, N-methylimidazole or N-methylmorpholine.

[0116] 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.

[0117] 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.

[0118] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer; preferably, the cancer is a cancer with MTAP gene deletion.

[0119] The present invention further relates to a method for preparing a method for treating cancer using the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition; preferably, the cancer is a cancer with MTAP gene deletion.

[0120] In some embodiments, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0121] 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.

[0122] 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.

[0123] 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%.

[0124] 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.

[0125] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] In some embodiments, the present method relates to the treatment of conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, biliary tract cancer, or bile duct cancer.

[0130] 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.

[0131] Detailed Description of the Invention

[0132] 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.

[0133] 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 (C3-6 ) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6 Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0134] 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.

[0135] 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 (C2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2- 10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0136] 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.

[0137] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3- 20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0138] 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.

[0139] 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.

[0140] 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 (C7-10 ) (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:

[0141] 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:

[0142] 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:

[0143] 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.

[0144] 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.

[0145] 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:

[0146] 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:

[0147] 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:

[0148] The term "tricyclic heterocyclic group" refers to a heterocyclic group having three rings in the system, wherein the three rings may be a paracyclic system, a spirocyclic system or a bridged ring system. In one embodiment, the tricyclic heterocyclic group is a system in which at least one of the three rings is a heterocyclic group, and the other two rings may be cycloalkyl, heterocyclic, aryl or heteroaryl. The definitions of cycloalkyl, heterocyclic, aryl or heteroaryl are as described above. Non-limiting examples thereof are preferably the following tricyclic heterocyclic groups:

[0149] wait.

[0150] 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.

[0151] 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),

[0152] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aromatic group, wherein the arylene group is optionally substituted or unsubstituted, and the aromatic group is as defined above.

[0153] 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,

[0154] 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.

[0155] 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.

[0156] 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.

[0157] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0158] 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,

[0159] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0160] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0161] 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.

[0162] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0163] 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.

[0164] The term "aminocarbonyl" refers to NH2-C(O)-.

[0165] 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.

[0166] 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.

[0167] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0168] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0169] The term "oxo" or "oxo" refers to =0.

[0170] 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

[0171] 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.

[0172] 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.

[0173] 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.

[0174] "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.

[0175] 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.

[0176] "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.

[0177] "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';

[0178] 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.

[0179] 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.

[0180] 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.

[0181] "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.

[0182] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0183] "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.

[0184] "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.

[0185] "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.

[0186] "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.

[0187] 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

[0188] 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.

[0189] Example

[0190] 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.

[0191] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0192] HPLC determination was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0193] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0194] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0195] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0196] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0197] Unless otherwise specified in the examples, reactions can be carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of approximately 1 L. Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of approximately 1 L.

[0198] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0199] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0200] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0201] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0202] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0203] 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.

[0204] 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.

[0205] The conditions for chiral preparative HPLC separation in the embodiment of the present invention are as follows: R Indicates retention time:

[0206] Condition 1:

[0207] Chiral preparation conditions

[0208] Chiral analysis conditions:

[0209] Condition 2:

[0210] Chiral preparation conditions

[0211] Chiral analysis conditions

[0212] Condition 3:

[0213] Chiral preparation conditions

[0214] Chiral analysis conditions

[0215] The compounds in the embodiments of the present invention are prepared by referring to the following example preparation steps:

[0216] Example 1

[0217] (4-Amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0218] Step 1: Dissolve 2-methyl-1H-imidazole 1a (5 g, 60.89 mmol) in DMSO (50 mL). Slowly add DBU (13.91 g, 91.35 mmol, 14 mL) and methyl 3-fluoro-4-nitrobenzoate (13.34 g, 66.99 mmol). Stir the reaction at 25°C for 2 hours. Add water (200 mL) and extract with ethyl acetate (200 mL x 3). Combine the organic phases, wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System C to afford 1b (9 g) in a 56.6% yield. MS m / z (ESI): 262 [M+1].+

[0219] Step 2: 1b (2 g, 7.66 mmol) was dissolved in methanol (20 mL), and Pd / C (816 mg, 766 μmol, 10% purity) was added. The atmosphere was replaced with hydrogen three times. Under hydrogen protection, the reaction was stirred at 50°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the filter cake was stirred with a 1:10 methanol:EA mixture (10 mL) for 15 minutes, filtered, and dried under reduced pressure to obtain 1c (1.45 g). Yield: 81.9%. MS m / z (ESI): 232 [M+1]. +

[0220] Step 3: 1c (1 g, 4.32 mmol) was dissolved in DCM (15 mL), and DMAP (265 mg, 2.16 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (1.06 g, 6.49 mmol, 926 μL) were added. The reaction was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) and methyl tert-butyl ether (10 mL) were added to the residue. The mixture was stirred for 15 minutes, filtered, and the filter cake was collected and dried under reduced pressure to afford 1 g (750 mg). Yield: 45.8%. MS m / z (ESI): 380 [M+1] +

[0221] Step 4: Dissolve 1g (600mg, 1.52mmol) in pyridine (2mL) and add phosphorus oxychloride (280mg, 1.83mmol, 171μL). Stir the reaction at 120°C for 16 hours. Concentrate the reaction mixture under reduced pressure, add water (50mL) to the residue, and extract with ethyl acetate (50mL x 3). Combine the organic phases, wash with saturated brine (50mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System C to afford 1d (250mg) in a 43.7% yield. MS m / z (ESI): 377[M+1]. +

[0222] Step 5: 1d (250 mg, 664 μmol) was dissolved in water (2 mL) / methanol (2 mL) / tetrahydrofuran (6 mL). Lithium hydroxide (32 mg, 1.33 mmol) was added and stirred at 80°C for 3 hours. The pH was adjusted to 5 with 0.5 M hydrochloric acid, filtered, and the filter cake was stirred with ethanol (5 mL) for 0.5 hours, filtered, and dried under reduced pressure to afford 1h (110 mg). Yield: 45.7%. MS m / z (ESI): 363 [M+1]. +

[0223] Step 6: 1h (50 mg, 138 μmol) and N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyran-[3,4-b]pyridin-5-amine (39 mg, 166 μmol, synthesized by the known method "Patent WO2021163344") were dissolved in DMF (2 mL), and N-methylimidazole (46 mg, 552 μmol, 44 μL) and TCFH (58 mg, 207 μmol) were added. The reaction was stirred at 25 ° C for 1.5 hours; the reaction solution was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue, and extracted with ethyl acetate (20 mL×3); the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was separated by high performance liquid chromatography to obtain 1i (55 mg), with a yield of 68.9%. MS m / z(ESI):576[M+1] +

[0224] Step 7: 1i (45 mg, 78 μmol) was dissolved in trifluoroacetic acid (3 mL). The reaction was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by HPLC to afford Example 1 (20 mg). Yield: 56.2%. MS m / z (ESI): 458 [M+1]. +

[0225] 1 H NMR (400MHz, DMSO-d6) 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).

[0226] Example 1 Preparation of Chiral Isomers

[0227] First step chiral isomer preparation

[0228] Example 1 (20 mg, 0.044 mmol) was separated by Chiral-HPLC to give 1-P1: (R)-(4-amino-1-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (9.5 mg), yield: 47.5%; 1-P2: (S)-(4-amino-1-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (9.8 mg), yield: 49.0%.

[0229] The preparation of the following examples is described in Example 1:

[0230] Example 8

[0231] 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

[0232] Step 1: Disperse 6-bromo-2-chloro-3-methylquinoxaline 8a (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. Pour the reaction mixture into 50 mL of ethyl acetate, wash with saturated sodium chloride solution (50 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by silica gel column chromatography with eluent System A to afford 8b (1.5 g) in a 71.9% yield. MS m / z (ESI): 358 [M+1]. +

[0233] Step 2: Dissolve 8b (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 8c (1.43 g) in a 91.7% yield. MS m / z (ESI): 372 [M+1]. +

[0234] Step 3: Dissolve 8c (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 solution, 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 8d (1.43 g) in a 96.2% yield. MS m / z (ESI): 386 [M+1] +

[0235] Step 4: Dissolve 8d (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 solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 8e (560 mg) in a 41.2% yield. MS m / z (ESI): 384 [M+1] +

[0236] Step 5: Dissolve 8e (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. Add water (50 mL) to the reaction mixture, extract 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 8f (91 mg) in a 37.1% yield. MS m / z (ESI): 363 [M+1]. +

[0237] Referring to the synthesis method of steps 5 to 7 of Example 1, Example 8 (6 mg) was obtained from 8f (91 mg) with a yield of 5.6%. MS m / z (ESI): 444 [M+1] +

[0238] 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.44(d,1H),8.17(d,1H),7.86(d,3H),7.7 5(s,1H),7.55(d,1H),5.84(s,1H),5.02-4.71(m,2H),4.18(d,2H),2.76(d,3H).

[0239] Example 9

[0240] 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

[0241] Step 1: Disperse methyl 6-methoxy-2-methylnicotinate 9a (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 9b (30.50 g, crude product). MS m / z (ESI): 338 [M+1] +

[0242] Step 2: Disperse 9b (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 for 25 min. ℃ The reaction was stirred 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 9c (12.00 g) in a 55.9% yield. MS m / z (ESI): 260 [M+1] +

[0243] 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 9c (12.00 g, 46.33 mmol) and stir at 25°C for 16 hours. The reaction mixture is poured into 2000 mL of water and extracted with ethyl acetate (300 mL x 3). The organic phases are combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 9d (22.00 g, crude product). MS m / z (ESI): 238 [M+1] +

[0244] Step 4: Disperse 9d (22.00 g, crude product) in 100 mL of ethanol and 100 mL of concentrated hydrochloric acid. ℃ The reaction was stirred 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 obtain 9e (4.00 g) in a yield of 52.3%. MS m / z (ESI): 166 [M+1] +

[0245] Step 5: Disperse 9e (4.00 g, 24.24 mmol) in 30 mL of phosphorus oxychloride and stir at 90°C for 2 hours. Concentrate under reduced pressure, and the residue is dispersed in 300 mL of dichloromethane. Wash with saturated sodium bicarbonate solution (200 mL x 2) and sodium chloride solution (200 mL x 2), sequentially, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to afford 9f (4.30 g) in a 96.9% yield. MS m / z (ESI): 184 [M+1] +

[0246] Step 6: Disperse 9f (300 mg, 1.64 mmol), 3,3-difluorotrimethyleneimine hydrochloride (260 mg, 2.02 mmol), and N,N-diisopropylethylamine (800 mg, 6.20 mmol) in 5 mL of acetonitrile and stir at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System B to yield 9g (240 mg), in a 61.0% yield. MS m / z (ESI): 241 [M+1] +

[0247] Step 7: Disperse 9g (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 resulting residue was purified by silica gel column chromatography with eluent System A to afford 9h (150 mg) in a 58.8% yield. MS m / z (ESI): 256 [M+1] +

[0248] Referring to the synthesis method of step 7 of Example 1, Example 9 (9 mg) was obtained by 9h (50 mg, 0.20 mmol) with a yield of 9.3%. MS m / z (ESI): 480 [M+1] +

[0249] Example 10

[0250] 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

[0251] Step 1: Disperse methyl 2-hydroxy-4-nitrobenzoate 10a (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 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 10b (330 mg) in a 23.9% yield. MS m / z (ESI): 248 [M+1]. +

[0252] Step 2: Dissolve 10b (330 mg, 1.34 mmol) in 8 mL of methanol, add palladium on carbon (284 mg, 5% purity, 0.13 mmol), and stir at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite to remove the palladium on carbon, and then concentrated under reduced pressure to obtain 10c (250 mg) in an 86.2% yield. MS m / z (ESI): 218 [M+1] +

[0253] Step 3: Dissolve 10c (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 afford 10d (160 mg) in a 47.0% yield. MS m / z (ESI): 296 [M+1] +

[0254] Step 4: Dissolve 10d (160 mg, 0.54 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (40 mg, 0.05 mmol), potassium acetate (106 mg, 1.08 mmol), and bis(pinacol)boronic acid ester (292 mg, 1.15 mmol) in 5 mL of dioxane. Stir the reaction at 90°C for 16 hours. Filter the reaction solution, 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 10e (71 mg) in a 38.3% yield. MS m / z (ESI): 344 [M+1]. +

[0255] Step 5: Dissolve 10e (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 solution, 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 10f (37 mg) in a 55.5% yield. MS m / z (ESI): 323 [M+1]. +

[0256] Referring to the synthesis method of steps 5 to 6 of Example 1, Example 10 (7.1 mg) was obtained from 10f (37 mg, 0.11 mmol) in an 11.8% yield. MS m / z (ESI): 523 [M+1] +

[0257] The preparation of Example 11 is described in reference to Example 10:

[0258] Example 12

[0259] 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

[0260] Step 1: 4-Amino-3-nitro-benzoic acid methyl ester 12a (5 g, 25.49 mmol) was dissolved in dichloromethane (50 mL), and DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), and di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) were added in sequence. The reaction was stirred at 25° C. for 2 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent System C to afford 12b (6.5 g) in a yield of 86.0%.

[0261] Step 2: 12b (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 12c (4 g) in an 89.0% yield. MS m / z (ESI): 267 [M+1] +

[0262] Step 3: 12c (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate 12d (575.05 mg, 5.63 mmol, 559 μL) was added. The reaction was stirred in a microwave at 100°C for 10 minutes. After the reaction was completed, the product was used directly in the next step.

[0263] Step 4: Methyl 4-(tert-butoxycarbonylamino)-3-[(E)-(2-methoxy-2-oxo-ethylidene)amino]benzoate 12e (600 mg, 1.78 mmol) was dissolved in N,N-dimethylformamide (7 mL), and tosylmethyl isocyanate 12f (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 obtain 12 g (700 mg), which was used directly in the next step.

[0264] Step 5: Dissolve 12g (600mg, 1.54mmol) in 1,2-dichloroethane (6mL) / trifluoroacetic acid (0.6mL) and stir in a microwave at 80°C for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was stirred with dichloromethane (10mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 12h (200mg). Yield: 53.4%. MS m / z (ESI): 244[M+1] +

[0265] Step 6: Dissolve 12h (200 mg, 822 μmol) in phosphorus oxychloride (3 mL) and stir at 180°C for 8 hours. The reaction mixture was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue to separate the organic phase. The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 12i (100 mg), which was used directly in the next step. MS m / z (ESI): 262 [M+1] +

[0266] Step 7: 12i (100 mg, 383 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 organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 12j (200 mg), which was used directly in the next step. MS m / z (ESI): 363 [M+1] +

[0267] Step 8: 12j (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 12k (60 mg). Yield: 62.4%. MS m / z (ESI): 349 [M+1]. +

[0268] Step 9: 12k (50 mg, 144 μmol) and N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 12l (40 mg, 172 μmol) were dissolved in N,N-dimethylformamide. N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to obtain 12m (18 mg) in a yield of 22.3%. MS m / z (ESI): 563 [M+1]. +

[0269] Step 10: 12m (18 mg, 32 μmol) was dissolved in trifluoroacetic acid (2 mL). The reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC (acid method) to give Example 12 (6 mg) in a 42.4% yield. MS m / z (ESI): 443 [M+1]. +

[0270] 1H NMR(400MHz,DMSO-d6)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).

[0271] Example 13

[0272] 4-Amino-N,1-dimethyl-N-(2-(trifluoromethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0273] Step 1: Dissolve methyl 2-methylthiophene-3-carboxylate 13a (8.00 g, 51.22 mmol) in carbon tetrachloride (100 mL). Add NBS (10.03 g, 56.34 mmol) and AIBN (841 mg, 5.12 mmol). Stir the reaction at 80°C for 16 hours. Add water (100 mL) and extract with dichloromethane (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 using eluent System C to afford 13b (8.60 g) in a 71.4% yield. MS m / z (ESI): 235 [M+1]. + .

[0274] 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, 13b (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 with eluent System C to afford 13c (430 mg) in a 47.6% yield. MS m / z (ESI): 213 [M+1] + .

[0275] Step 3: Dissolve 13c (3.10 g, 14.61 mmol) 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 13d (1.80 g) in a yield of 79.9%. MS m / z (ESI): 155 [M+1] + .

[0276] Step 4: Dissolve 13d (800 mg, 5.19 mmol) and NIS (1.20 g, 6.75 mmol) in acetonitrile (20 mL) and acetic acid (5 mL). Stir the reaction at 30°C for 6 hours. Dilute the reaction with ethyl acetate, wash with water and brine, and concentrate the organic phase. The residue is purified using eluent System C to afford 13e (680 mg) in a 54.6% yield. MS m / z (ESI): 281 [M+1] + .

[0277] Step 5: Disperse 13e (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) in DMF (10 mL), replace with nitrogen, and stir at 90°C for 16 hours. The reaction solution was diluted with ethyl acetate, and the solid matter was removed by filtration. The organic phase was washed with water and brine, and concentrated. The concentrated residue was purified with eluent system C to give 13f (520 mg) in a yield of 77.1%.

[0278] Step 6: 13f (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 13 g (58 mg) in a yield of 46.9%. MS m / z (ESI): 238 [M+1] + .

[0279] Step 7: Dissolve 13 g (20 mg, 0.08 mmol) and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (39 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL). Add N-methylpyrazole (20 mg, 0.24 mmol) and TCFH (45 mg, 0.16 mmol). Stir the reaction at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to obtain Example 13 (16 mg) in a 42.0% yield. MS m / z (ESI): 462 [M+1]. +

[0280] 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).

[0281] Example 14

[0282] 4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide

[0283] Step 1: Dissolve 2-(trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 14a (500 mg, 2.30 mmol) and cyclopropylmethylamine (1.31 g, 18.42 mmol, 1.6 mL) in methanol (15 mL). Add tetraisopropyl titanate (1.96 g, 6.91 mmol, 2 mL). The reaction is stirred at 25°C for 16 hours. Sodium acetate borohydride (732.02 mg, 3.45 mmol) is added and stirred at 25°C for 30 minutes. Saturated aqueous sodium bicarbonate (8 mL) is added to the reaction mixture, which is filtered, collected, and concentrated under reduced pressure. The residue is separated by Pre-TLC to afford 14b (52 mg) in an 8.3% yield. MS m / z (ESI): 273 [M+1]. +

[0284] Step 2: 4-Amino-3-nitro-benzoic acid methyl ester 14c (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 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 afford 14d (6.5 g) in 86.0% yield.

[0285] Step 3: 14d (5 g, 16.88 mmol) was dissolved in methanol (60 mL) and Pd / C (2.05 g, 1.69 mmol, 10% wt) was added. The reaction was stirred at 50°C for 16 hours. A filtration funnel was covered with celite and the reaction mixture was filtered. The filtrate was collected and concentrated under reduced pressure to afford 14e (4 g) in an 89.0% yield. MS m / z (ESI): 267 [M+1] +

[0286] Step 4: 14e (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate (575.05 mg, 5.63 mmol, 559 μL) was added. The reaction was stirred in a microwave at 100°C for 10 minutes. After the reaction was completed, the product was used directly in the next step.

[0287] Step 5: Methyl 4-(tert-butoxycarbonylamino)-3-[(E)-(2-methoxy-2-oxo-ethylidene)amino]benzoate 14f (500 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (7 mL), and 1-methyl-1-toluenesulfonylmethyl isocyanate (373.30 mg, 1.78 mmol) and potassium carbonate (410.92 mg, 2.97 mmol) were added. The reaction was stirred in a microwave at 80°C for 10 minutes; water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL×3); the organic phases were combined, washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14 g, which was directly used in the next step.

[0288] Step 6: Dissolve 14g (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 14h (200mg). Yield: 52.3%. MS m / z (ESI): 258[M+1] +

[0289] Step 7: 14h (200 mg, 778 μmol) was dissolved in phosphorus oxychloride (3 mL), and 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, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14i (100 mg), which was used directly in the next step. MS m / z (ESI): 276 [M+1] +

[0290] Step 8: 14i (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 organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14j (200 mg), which was used directly in the next step. MS m / z (ESI): 377 [M+1] +

[0291] Step 9: 14j (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, and the mixture was filtered. The filter cake was rinsed with water (5 mL) and dried under reduced pressure to afford 14k (60 mg). Yield: 62.3%. MS m / z (ESI): 363 [M+1]. +

[0292] Step 10: 14k (50 mg, 138 μmol) and 14b (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 14l (18 mg) in a yield of 21.2%. MS m / z (ESI): 617 [M+1]. +

[0293] Step 11: 141 (18 mg, 29 μmol) was dissolved in trifluoroacetic acid (2 mL) and the reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC (acid method) to give Example 14 (6 mg) in a 41.4% yield. MS m / z (ESI): 497 [M+1] +

[0294] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.25(d,2H),7.81(d,1H),7.41(s,2H),6.88(s,2H),5.32(t,1H),4.9 4–4.63(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).

[0295] The preparation of the following examples is shown in Example 1:

[0296] Example 28

[0297] 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

[0298] Step 1: Dissolve methyl 4-fluoro-2-methyl-5-nitrobenzoate 28a (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 mixture is concentrated under reduced pressure to give a 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 give 28b (22 g, crude product). MS m / z (ESI): 211 [M+1] +

[0299] Step 2: 28b (22 g, 104.67 mmol) was dissolved in DMF (150 mL), and the reaction system was cooled to 0°C. Boc2O (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, and 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 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 purified with eluent system C to give 28c (18 g) in a yield of 55.4%.

[0300] 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.42(s,1H),7.80(s,1H),3.85(s,3H),2.58(s,3H),1.48(s,9H).

[0301] Step 3: 28c (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 with tetrahydrofuran (THF). To hydrofuran (120 mL) were added diethyl phosphite (7.03 g, 51.27 mmol, 6.6 mL) and DIEA (6.63 g, 51.27 mmol, 9.0 mL), and the mixture was stirred at 25°C for 1 hour. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (120 mL × 3). The organic phases were combined, 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 compound 28d (9 g) in a yield of 90.2%.

[0302] 1H NMR (400MHz, DMSO-d6) δ9.93(s,1H),8.44(s,1H),8.03(s,1H),5.05(s,2H),3.89(s,3H),1.47(s,9H).

[0303] Step 4: 28d (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 organic phases were combined, washed with saturated brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent System C to give 28e (1.3 g) in a yield of 31.0%.

[0304] Referring to the synthesis method of steps 3 to 11 of Example 14, Example 28 (5.5 mg) was obtained from 28e (500 mg). Yield: 1%. MS m / z (ESI): 487 [M+1] +

[0305] 1 H NMR(400MHz,DMSO-d6)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).

[0306] The preparation of the following table examples refers to Example 13:

[0307] Example 32

[0308] 4-Amino-7-fluoro-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide

[0309] Step 1: Dissolve methyl 2,4-difluoro-5-nitrobenzoate 32a (12 g, 55.27 mmol) in tetrahydrofuran (50 mL). Add ammonia (2 M, 10.4 mL) under ice-cooling. Stir the reaction at 0°C for 0.5 h. Add tetrahydrofuran (50 mL) and stir the reaction at 25°C for 16 h. Concentrate the reaction mixture under reduced pressure. Add water (100 mL) to the residue, stir for 15 min, filter, and dry the filter cake under reduced pressure to obtain 32b (12 g, crude product). MS m / z (ESI): 214 [M+1] +

[0310] Referring to the synthesis method of steps 1 to 10 of Example 12, Example 32 (10 mg) was obtained from 32b (500 mg, 2.33 mmol) in a yield of 0.9%. MS m / z (ESI): 461 [M+1] +

[0311] 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.32(s,1H),8.19–7.68(m,3H),7.38(s ,1H),7.24(d,1H),5.89(s,1H),4.83(d,2H),4.32–3.99(m,2H),2.78(s,3H).

[0312] Example 33

[0313] 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

[0314] Step 1: Dissolve methyl 4-fluoro-2-methyl-5-nitrobenzoate 33a (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 mixture is concentrated under reduced pressure to give 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 give 33b (11 g, crude product). MS m / z (ESI): 211 [M+1] +

[0315] Referring to the synthesis method of steps 1 to 10 of Example 12, Example 33 (9.8 mg) was obtained from 33b (500 mg, 1.78 mmol) in a yield of 1.2%. MS m / z (ESI): 458 [M+1] +

[0316] 1 H NMR(400MHz,DMSO-d6)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).

[0317] Example 34

[0318] 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

[0319] Step 1: 2-Chloro-6-methoxy-pyridine-3-carboxylic acid methyl ester 34a (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 × 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 34b (6 g) in a yield of 69.6%. MS m / z(ESI):194[M+1] +

[0320] Step 2: Dissolve 34b (6 g, 31.06 mmol) in methanol (100 mL). The atmosphere was purged with nitrogen three times. Palladium on carbon (377 mg, 0.31 mmol, 10% purity) was added. The reaction system was stirred at 25°C under a hydrogen balloon for 2 hours. The reaction mixture was filtered and concentrated to afford 34c (5.90 g, crude product). MS m / z (ESI): 196 [M+1] +

[0321] Step 3: Dissolve 34c (5.9 g, 30.22 mmol), azobisisobutyronitrile (496 mg, 3.02 mmol), and N-bromosuccinimide (8.61 g, 48.36 mmol) in carbon tetrachloride (60 mL). The atmosphere was purged with nitrogen three times and heated to 90°C for reaction. The reaction mixture was cooled to room temperature, concentrated, and water was added. The mixture was washed with ethyl acetate (100 mL x 3), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 34d (7.50 g) in a 90.5% yield. MS m / z (ESI): 275 [M+1]. +

[0322] Referring to the synthesis method of steps 3 to 4 of Example 9, 34f (2.60 g) was obtained from 34d (7.80 g, 28.46 mmol) in a yield of 51.0%. MS m / z (ESI): 180 [M+1] +

[0323] Step 6: Dissolve 34f (0.5 g, 2.79 mmol) in dichloromethane (40 mL), purge the nitrogen atmosphere three times, cool to 0°C, add triethylamine (339 mg, 3.35 mmol, 0.47 mL) and trifluoromethanesulfonic anhydride (866 mg, 3.07 mmol), and react at 25°C for 2 hours. Sodium iodide (2.09 g, 13.95 mmol) and concentrated hydrochloric acid (12 M, 0.28 mL) were then added and the reaction continued at 20°C for 15 hours. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 34f (0.35 g) in a 43.4% yield. MS m / z (ESI): 290 [M+1]. +

[0324] Step 7: Dissolve 34g (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 the nitrogen atmosphere three times, and heat to 100°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and water was added. The mixture was washed with ethyl acetate (5mL x 3), washed with brine (3mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to give 34h (0.14g) in a yield of 54.7%. MS m / z (ESI): 232 [M+1] +

[0325] Step 8: Dissolve 34h (0.14 g, 0.61 mmol) and methylamine alcohol solution (314 mg, 3.03 mmol, 30% wt) in trifluoroethanol (10 mL). The atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at 25°C for 2 hours. Sodium cyanoborohydride (76 mg, 1.21 mmol) was added and the reaction was allowed to proceed at 25°C for 1 hour. 10 mL of saturated sodium bicarbonate solution was added to the reaction, and the system was stirred at room temperature for one hour. The product was extracted with dichloromethane / methanol (10 / 1) (50 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 34i (80 mg) in a 53.6% yield. MS m / z (ESI): 247 [M+1]. +

[0326] With reference to the synthesis method of steps 9 to 10 of Example 12, 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 34A (23 mg) was obtained by using 4-[(3,5-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 34j (160 mg, 0.41 mol) and 34i (100 mg, 0.41 mmol). MS m / z (ESI): 471 [M+1] + and 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 34B (10 mg), yield: 9.5%. MS m / z (ESI): 471 [M+1] + .

[0327] 34A: 1 H NMR(400MHz,DMSO-d6)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).

[0328] 34B: 1H NMR(400MHz,DMSO-d6)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).

[0329] The preparation of the following table examples refers to Example 12:

[0330] Example 37

[0331] 4-Amino-N-(2-bromo-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0332] Step 1: 2-Chloro-3-methyl-pyridine-4-carboxylic acid methyl ester 37a (5 g, 26.94 mmol), diphenylmethaneimine (5.37 g, 29.63 mmol), tris(dibenzylideneacetone)dipalladium (2.47 g, 2.69 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.12 g, 5.39 mmol), cesium carbonate (13.17 g, 40.41 mmol), and dioxane (25 mL) were reacted at 100°C for 16 hours. The reaction solution turned yellow. H2O was added to quench the reaction. Then, 50 mL of water and 300 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 30 mL of saturated brine, dried, and spin-dried. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 37b (1.9 g) in a 42.2% yield. MS m / z(ESI):167[M+1] +

[0333] Step 2: 37b (1.4 g, 8.42 mmol), 2-bromo-1,1-dimethoxyethane (1.42 g, 8.42 mmol), p-toluenesulfonic acid (725 mg, 4.21 mmol), and N,N-dimethylformamide (15 mL) were reacted at 100°C for 16 hours. The reaction solution turned yellow. 10 mL of saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 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 37c (0.64 g) in a 39.8% yield. MS m / z (ESI): 191 [M+1].+

[0334] Step 3: 37c (60 mg, 0.315 mmol), N-bromosuccinimide (56 mg, 0.31 mmol), azobisisobutyronitrile (15 mg, 0.094 mmol), and carbon tetrachloride (4 mL) were reacted at 80°C for 16 hours. The reaction solution turned yellow. The solution was cooled, concentrated, and quenched with 10 mL of water. The solution 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 37d (0.06 g) in a 70.8% yield. MS m / z (ESI): 269 [M+1]. +

[0335] Step 4: 37d (30 mg, 0.11 mmol), N-bromosuccinimide (20 mg, 0.11 mmol), azobisisobutyronitrile (6 mg, 0.034 mmol), and carbon tetrachloride (3 mL) were reacted at 80°C for 16 hours. The reaction solution turned yellow. The reaction was stirred at 90°C for 16 hours. The solution was cooled, filtered, and dried to afford 37e (25 mg) in a 65.1% yield. MS m / z (ESI): 349 [M+1] +

[0336] Step 5: 37e (380 mg, 1.09 mmol), methyl glycolate (216 mg, 2.40 mmol), sodium hydride (65 mg, 2.73 mmol), and N,N-dimethylformamide (8 mL) were reacted at 20°C for 16 hours. The mixture was quenched by the addition of 10 mL of water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 37f (180 mg) in a 46.3% yield. MS m / z (ESI): 357 [M+1]. +

[0337] Step 6: 37f (50 mg, 0.14 mmol), lithium bis(trimethylsilyl)amide (46 mg, 0.28 mmol) and tetrahydrofuran (2 mL) were reacted at -55°C for 1 hour. The reaction solution turned yellow. The crude product was treated with C 18 The resulting residue was purified by column chromatography using eluent system A to give 37 g (35 mg) of the compound in a 76.9% yield. MS m / z (ESI): 325 [M+1] +

[0338] Step 7: 37g (26mg, 0.08mmol), hydrochloric acid (2mL) and ethanol (2mL) were reacted at 80℃ for 16 hours. The reaction solution turned yellow. Cool, concentrate, spin dry, and the crude product was purified by C 18 The resulting residue was purified by column chromatography using eluent system A to afford 37h (8 mg) in a 37.5% yield. MS m / z (ESI): 267 [M+1] +

[0339] Step 8: 37h (30 mg, 0.11 mmol), methylamine (7 mg, 0.225 μmol) and trifluoroethanol (2 mL) were reacted at 60 ° C for 2 hours. The reaction solution turned yellow. Cool, concentrate, and dry the crude product with C 18 The resulting residue was purified by column chromatography using eluent system A to afford 37i (15 mg) in a 48.3% yield. MS m / z (ESI): 282 [M+1] +

[0340] Step 9: 37i (24 mg, 0.086 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol), N-methylimidazole (21 mg, 0.26 mmol), and N,N-dimethylformamide (4 mL) were reacted at 40°C for 1 hour. The reaction solution turned yellow. 10 mL of water was added to quench the reaction. The mixture was 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 Example 37 (16.8 mg) in a 38.6% yield. MS m / z (ESI): 506 [M+1]. +

[0341] 1 HNMR(400MHz,DMSO-d6)δ8.35(d,1H),8.27(d,2H),7.72-7.61(m,3H),7.15 (s,3H),4.94(d,3H),4.42(s,3H),4.30(dd,1H),4.16(s,1H),2.84(s,3H).

[0342] Example 37 Preparation of Chiral Isomers

[0343] Example 37 (16 mg, 0.032 mmol) was separated by Chiral-HPLC (Condition 1) to give 37-P1: (S)-4-amino-N-(2-bromo-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (7.3 mg), yield: 45.6%; 37-P2: (R)-4-amino-N-(2-bromo-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (7.6 mg), yield: 47.5%.

[0344] 37-P1(t R :6.687min): 1 HNMR(400MHz,DMSO-d6)δ8.35(d,1H),8.27(d,2H),7.72-7.61(m,3H),7.15 (s,3H),4.94(d,3H),4.42(s,3H),4.30(dd,1H),4.16(s,1H),2.84(s,3H).

[0345] 37-P2(t R :9.125min): 1 HNMR(400MHz,DMSO-d6)δ8.35(d,1H),8.27(d,2H),7.72-7.61(m,3H),7.15 (s,3H),4.94(d,3H),4.42(s,3H),4.30(dd,1H),4.16(s,1H),2.84(s,3H).

[0346] The preparation of the following table examples refers to Example 37:

[0347] Alternatively, Examples 39, 48, 62, and 68 were prepared using the following method:

[0348] Example 39

[0349] 4-amino-N,7-dimethyl-N-(2-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0350] Step 1: Disperse 2-amino-3-methylisothiazolinone 39a (3 g, 18.07 mmol) and 3-bromo-1,1,1-trifluoroacetone (3.43 g, 18.07 mmol) in 50 mL of acetonitrile and stir at 80°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 39b (2.71 g) in a 57.9% yield. MS m / z (ESI): 259 [M+1] +

[0351] The synthesis method of steps 3 to 8 of Example 34 was followed to obtain 39g (100 mg) from 39b (1.45 g, 5.62 mmol). Yield: 5.1%. MS m / z (ESI): 350 [M+1] +

[0352] Step 7: Disperse 39g (100 mg, 0.29 mmol) and palladium on carbon (100 mg, 5% wt) in 10 mL of methanol and stir under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to afford 39h (70 mg) in a 90.1% yield. MS m / z (ESI): 272 [M+1]

[0353] Referring to the synthesis method of steps 9 to 10 of Example 12, Example 39 (5 ​​mg) was obtained from 39h (20 mg, 0.07 mmol) with a yield of 14.4%. MS m / z (ESI): 496 [M+1] +

[0354] 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.40(d,1H),8.16(d,1H),7.98(broad s,2H),7.74(m,2H),7.44(d,1H),7.37(d,1H),5.82(s,1H),5.01(d,2H),4.24(s,2H),2.69(s,3H),2.43–2.30(m,3H).

[0355] Example 39 Preparation of Chiral Isomers

[0356] Example 39 (21 mg, 0.042 mmol) was separated by Chiral-HPLC (Condition 2) to give 39-P1: (S)-4-amino-N,7-dimethyl-N-(2-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (10.1 mg), yield: 48.1%; 39-P2: (R)-4-amino-N,7-dimethyl-N-(2-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (10.2 mg), yield: 48.2%.

[0357] 39-P1(t R :1.562min): 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.40(d,1H),8.16(d,1H),7.98(broad s,2H),7.74(m,2H),7.44(d,1H),7.37(d,1H),5.82(s,1H),5.01(d,2H),4.24(s,2H),2.69(s,3H),2.43–2.30(m,3H).

[0358] 39-P2(t R :1.943min): 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.40(d,1H),8.16(d,1H),7.98(broad s,2H),7.74(m,2H),7.44(d,1H),7.37(d,1H),5.82(s,1H),5.01(d,2H),4.24(s,2H),2.69(s,3H),2.43–2.30(m,3H).

[0359] Example 48

[0360] 4-amino-N,7-dimethyl-N-(8-(trifluoromethyl)-3,4-dihydro-1H-imidazo[1,2-a]pyrano[4,3-e]pyridin-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0361] Step 1: 2-chloro-7,8-dihydro-6H-quinolin-5-one 48a (1.7 g, 9.36 mmol, synthesized using the known method "Patent WO2021163344"), diphenylmethaneimine (1.70 g, 9.36 mmol), Pd2(dba)3 (0.86 g, 0.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.08 g, 1.87 mmol), cesium carbonate (6.10 g, 18.72 mmol) and dioxane (20 mL) were reacted at 100°C for 16 hours. The reaction solution was yellow. After the reaction was completed, the reaction solution was filtered, and a methanolic hydrochloric acid solution was added to the filtrate and reacted at 20°C for 3 hours. The reaction solution was yellow. After quenching with NaHCO 3 solution, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 48b (1.1 g) in a 71.2% yield. MS m / z (ESI): 165 [M+1] +

[0362] Step 2: 48b (400 mg, 2.44 mmol), 3-bromo-1,1,1-trifluoro-propan-2-one (465 mg, 2.44 mmol), and acetonitrile (6 mL) were reacted at 80°C for 3 hours. The reaction solution turned yellow. NaHCO₃ solution was added to quench the reaction, followed by 10 mL of water. The mixture was extracted with ethyl acetate (40 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 48c (30 mg) in a 4.8% yield. MS m / z (ESI): 257 [M+1]. +

[0363] Step 3: Compound 48c (70 mg, 0.273 mmol), methylamine (8.5 mg, 0.273 mmol), sodium cyanoborohydride (51 mg, 0.819 mmol), acetic acid (3.3 mg, 0.054 mmol), and methanol (3 mL) were reacted at 60°C for 4 hours. The reaction solution turned yellow. The mixture was quenched by the addition of NaHCO₃ solution and 2 mL of water. The mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 48d (28 mg) in a 37.7% yield. MS m / z (ESI): 272 [M+1] +

[0364] Step 4: 48d (17 mg, 0.062 mmol), 4-amino-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 48e (15 mg, 0.062 mmol, refer to Steps 1 to 11 of Example 28), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (26 mg, 0.093 mmol), N-methylimidazole (15 mg, 0.186 mmol) and N,N-dimethylformamide (2 mL) were reacted at 20°C for 2 hours. The reaction solution turned yellow. After quenching with H2O, the mixture was quenched with 10 mL of water and extracted with ethyl acetate (40 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 Example 417 (10 mg) in a 32.5% yield. MS m / z (ESI): 496 [M+1]. +

[0365] 1 HNMR(400MHz,DMSO-d6)δ9.15(s,1H),8.48(d,1H),8.16(d,1H),7.98(d,1H),7.80–7.68(m,2H),7.44(d,1H),7.37(s,1H), 5.86(s,1H),5.13(d,1H),4.87(d,1H),4.18(m,1H),3.49(t,1H),3.42(t,1H),2.88–2.84(m,1H),2.64(s,2H),2.34(s,3H).

[0366] Example 62

[0367] 4-amino-N,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0368] Step 1: Disperse 2-amino-3-methylisothiazolinone 62a (5 g, 30.12 mmol) and bromoacetaldehyde dimethyl acetal (10.12 g, 60.24 mmol) in 50 mL of ethanol and 10 mL of 2 M / L hydrochloric acid. Stir and react at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 62b (3.2 g) in a 55.9% yield. MS m / z (ESI): 191 [M+1] +

[0369] Step 2: Disperse 62b (3.2 g, 16.84 mmol) in 50 mL of acetonitrile and add N-iodosuccinimide (4.5 g, 20 mmol). Stir and react for 1 hour. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System A to afford 62c (2.80 g) in a 52.6% yield. MS m / z (ESI): 317 [M+1] +

[0370] Step 3: Disperse 62c (2.80 g, 8.86 mmol), cuprous iodide (8.42 g, 44.30 mmol), and potassium fluoride (1.54 g, 26.58 mmol) in 30 mL of N,N-dimethylformamide. Add (trifluoromethyl)trimethylsilane (3.77 g, 26.58 mmol). Stir and react at 90°C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 62d (830 mg) in a 36.3% yield. MS m / z (ESI): 259 [M+1]. +

[0371] Referring to the synthesis method of steps 3 to 8 of Example 34 and steps 9 to 10 of Example 12, Example 62 (19 mg) was obtained from 62d (400 mg, 1.55 mmol) in a yield of 2.5%. MS m / z (ESI): 496 [M+1] +

[0372] 1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.87(s,2H),8.31(dd,4H),7.50(s,1 H),7.16(s,1H),5.93–4.56(m,3H),4.27(s,2H),2.79(d,3H),2.42(s,3H).

[0373] Example 62 Preparation of Chiral Isomers

[0374] Example 62 (19 mg, 0.042 mmol) was separated by Chiral-HPLC (Condition 2) to give 62-P1: (S)-4-amino-N,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (9.1 mg), yield: 47.8%; 62-P2: (R)-4-amino-N,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (8.8 mg), yield: 46.3%.

[0375] 62-P1(t R :1.982min): 1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.87(s,2H),8.31(dd,4H),7.50(s,1 H),7.16(s,1H),5.93–4.56(m,3H),4.27(s,2H),2.79(d,3H),2.42(s,3H).

[0376] 62-P2(t R :1.436min): 1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.87(s,2H),8.31(dd,4H),7.50(s,1 H),7.16(s,1H),5.93–4.56(m,3H),4.27(s,2H),2.79(d,3H),2.42(s,3H).

[0377] Example 68

[0378] 4-amino-N,1-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-pyrano[4,3-h]quinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0379] Step 1: Dissolve 3-amino-2-methyl-benzoic acid 68a (20 g, 132.31 mmol), sodium iodide (500 mg, 3.33 mmol), and glycerol (12.18 g, 132.31 mmol, 20 mL) in water (30 mL) and concentrated sulfuric acid (40 mL). The reaction system was stirred at 150°C for 1 hour. The reaction was cooled to room temperature, the pH was adjusted to 3 with 12 M aqueous sodium hydroxide solution, and extracted with ethyl acetate (500 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 68b (15 g, crude product). MS m / z (ESI): 188 [M+1] +

[0380] Step 2: Dissolve 68b (0.7 g, 3.74 mmol) in methanol (10 mL) and add thionyl chloride (1.33 g, 11.22 mmol, 0.81 mL). The reaction system is stirred at 70°C for 15 hours. Cool to room temperature, quench with water, and extract with ethyl acetate (80 mL x 3). Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is purified by silica gel column chromatography using eluent System B to afford 68c (350 mg) in a 46.5% yield. MS m / z (ESI): 202 [M+1]. +

[0381] Step 3: Dissolve 68c (2.9 g, 14.41 mmol) and N-iodosuccinimide (3.89 g, 17.29 mmol) in acetic acid (10 mL). The nitrogen atmosphere was purged three times, and the reaction system was stirred at 100°C for 18 hours. The reaction was concentrated, quenched with water, and extracted with ethyl acetate (100 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 B to afford 68d (3.0 g) in a 63.6% yield. MS m / z (ESI): 328 [M+1]. +

[0382] Step 4: Dissolve 68d (2.9 g, 8.87 mmol) and cuprous iodide (4.22 g, 22.16 mmol) in N,N-dimethylformamide (20 mL). Add methyl fluorosulfonyldifluoroacetate (4.26 g, 22.16 mmol, 2.82 mL). Purge the nitrogen atmosphere three times and heat the reaction at 100°C for 2 hours. The reaction mixture is cooled to room temperature, filtered, concentrated, and dried. Water is added and extracted with ethyl acetate (100 mL x 3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography using eluent System B to afford 68e (2.1 g) in an 88.0% yield. MS m / z (ESI): 270 [M+1]. +

[0383] Referring to the synthesis method of steps 1 to 4 of Example 9, 68j (520 mg) was obtained from 68e (2.5 g, 9.29 mmol) with a yield of 21.0%. MS m / z (ESI): 268 [M+1] +

[0384] Referring to the synthesis method of step 7 of Example 9, 68k (320 mg) was obtained from 68j (520 mg, 1.95 mmol) with a yield of 58.3%. MS m / z (ESI): 283 [M+1] +

[0385] Referring to the synthesis method of step 7 of Example 1, Example 68 (44 mg) was obtained from 68k (58 mg, 0.20 mmol) with a yield of 42.1%. MS m / z (ESI): 507 [M+1] +

[0386] 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.63(s,1H),9.23(d,1H),9.00(d,1H),8.71–8.43(m,3H),8.18(t,1H),8 .00(dd,1H),7.87(q,2H),5.92(s,1H),5.45(dd,1H),5.15(t,1H),4.51(d,3H),4.39–4.10(m,2H),2.79(d,3H).

[0387] Example 79

[0388] 4-Amino-N-(7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide

[0389] From the ninth to the tenth steps of Reference Example 12, 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 79a (90 mg, from the first to the eleventh steps of Reference Example 28) and 3-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-amine 79b (40 mg, from the first to the eighth steps of Reference Example 37) were used to give 79d (47 mg) in a yield of 40.5%.

[0390] Step 3: 79d (15 mg, 0.029 mmol), Pd / C (3 mg, 20% weight), and methanol (2 mL) were reacted at 20°C under a H2 atmosphere for 4 hours. The reaction solution turned yellow. The reaction solution 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 provide Example 79 (2.1 mg) in a 16% yield. MS m / z (ESI): 428 [M+1] +

[0391] 1 HNMR(400MHz,DMSO-d6)δ9.12(d,1H),8.53(d,1H),8.13(s,1H),7.99(d,1H),7.88(s,1H),7.56–7.51(m,1H), 7.32(s,2H),5.77(s,1H),5.10(d,1H),4.83(d,1H),4.17(s,2H),2.85(s,1H),2.68–2.62(m,3H),2.33(d,3H).

[0392] Example 80

[0393] 4-amino-N,1-dimethyl-N-(8-(trifluoromethyl)-3,4-dihydro-1H-imidazo[1,2-a]pyrano[4,3-e]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0394] In the first and third steps of Reference Example 79, 2-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-amine 80a (20 mg, from the first to third steps of Reference Example 48) and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 80b (20 mg, synthesized using the known method "Patent WO2022169948") were used to obtain Example 80 (2.2 mg) in a yield of 5.6%. MS m / z (ESI): 428 [M+1] +

[0395] 1 HNMR(400MHz,DMSO-d6)δ8.50(s,1H),8.35(d,1H),8.25(s,1H),7.97(s,1H),7.66(s,1H),7.63(s,1H),7 .54(s,1H),7.22(s,1H),7.16(s,2H),6.68(s,1H),5.32(t,2H),4.42(s,3H),4.28(dd,2H),2.83(s,3H).

[0396] Example 81

[0397] 4-amino-N,1-dimethyl-N-(8-(trifluoromethyl)-3,4-dihydro-1H-imidazo[1,2-a]pyrano[4,3-e]pyridin-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0398] N-methyl-4-(trifluoromethyl)-12-oxa-2,5-diazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7-tetraen-10-amine 81a (11 mg, 0.041 mmol, synthesized from the first to third steps of Reference Example 48), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 81b (10 mg, 0.041 mmol, synthesized using the well-known method "Patent WO2022169948"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (2 mg, 0.066 mmol) and N-methylimidazole (10 mg, 0.124 mmol) were dissolved in 2 mL of N,N-dimethylformamide and stirred at 20°C for 2 hours. 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 Example 81 (2 mg) in a 9.8% yield. MS m / z (ESI): 496 [M+1] +

[0399] 1 HNMR(400MHz,DMSO-d6)δ8.41(d,2H),8.21(d,1H),7.73–7.60(m,2H),7.50(s,1H),7.13(s,1H),5.08(s,1H),4.8 3(s,1H),4.56(d,1H),4.42(s,2H),4.37–4.30(m,1H),4.15(s,1H),3.96(d,1H),3.64–3.41(m,2H),2.75(d,3H).

[0400] Example 82

[0401] 4-Amino-N-(2-chloro-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide

[0402] Step 1: Disperse 2-amino-3-methylisothiazolinone 82a (5 g, 30.12 mmol) and ethyl bromoacetate (5.03 g, 30.12 mmol) in 50 mL of tetrahydrofuran and stir at 25°C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and 20 mL of phosphorus oxychloride was added. The mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent System A to afford 82b (3.31 g) in a 49.1% yield. MS m / z (ESI): 225 [M+1]. +

[0403] Referring to the synthesis methods of steps 2 to 3 of Example 62, steps 3 to 8 of Example 34, and steps 9 to 10 of Example 12, Example 82 (20 mg) was obtained from 82b (1.21 g, 5.40 mmol) in a 0.7% yield. MS m / z (ESI): 530 [M+1] +

[0404] Example 83

[0405] 4-amino-N,1-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0406] Referring to the synthesis method of step 7 of Example 1, Example 83 (10 mg) was obtained from N-methyl-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-amine 83a (30 mg, 0.11 mmol) in an 18.4% yield. MS m / z (ESI): 496 [M+1]. +

[0407] 1 H NMR (400MHz, DMSO-d6) δ8.35(dd,6H),7.89–7.75(m,2H),7.23(s,1H),5.01(d,3H),4.48(d,3H),4.26(d,2H),2.86(d,3H).

[0408] Example 84

[0409] 4-amino-N,1-dimethyl-N-(2-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0410] Referring to the synthesis method of step 7 of Example 1, Example 84 (10 mg) was obtained from N-methyl-2-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-amine 84a (40 mg, 0.11 mmol) in an 18.4% yield. MS m / z (ESI): 496 [M+1]. +

[0411] 1 H NMR (400MHz, DMSO-d6) δ8.36(dd,6H),7.83(d,2H),7.11(s,1H),4.96(dd,3H),4.48(d,3H),4.23(d,2H),2.85(d,3H).

[0412] The preparation of the following table examples refers to Example 37:

[0413] The preparation of the following table examples refers to Example 62:

[0414] The preparation of the following table examples refers to Example 82:

[0415] The preparation of Examples 192, 193, and 194 is described in reference to Example 33; the preparation of Examples 195 and 196 is described in reference to Example 14:

[0416] Alternatively, Examples 144 and 146 were prepared using the following method:

[0417] Example 144

[0418] 4-Amino-N-[3-(difluoromethylene)cyclobutyl]-7-methyl-N-[5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]tridec-1(9),2,4,7-tetraen-10-yl]imidazo[1,5-a]quinoxaline-8-carboxamide

[0419] Step 1: Dissolve 3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-ol 144a (200 mg, 774.60 μmol) and triethylamine (391.91 mg, 3.87 mmol, 540.19 μL) in dichloromethane (4 mL) and cool to 0°C. Add methanesulfonic anhydride (404.80 mg, 2.32 mmol). Stirring is continued at room temperature for 2 h. The solvent is removed under reduced pressure, and the residue is purified by column chromatography using petroleum ether / ethyl acetate (1:1) as eluent to isolate 144b (100 mg, 297.37 μmol) in a 38.4% yield. MS m / z (ESI): 337 [M+1]. +

[0420] Step 2: 144b (100 mg, 297.37 μmol), 3-(difluoromethylene)cyclobutaneamine (70.84 mg, 594.73 μmol), cesium carbonate (290.66 mg, 892.10 μmol), and sodium iodide (44.57 mg, 297.37 μmol) were added to acetonitrile (1.5 mL) and stirred at 60°C for 16 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate (1:2) as eluent to afford 144c (50 mg, 139.16 μmol) in a 46.7% yield. MS m / z (ESI): 360 [M+1] +

[0421] Step 3: 144c (55.17 mg, 153.08 μmol) was dissolved in dichloromethane (1.5 mL), and oxalyl chloride (97.15 mg, 765.39 μmol) and N,N-dimethylformamide (0.01 mL) were added at 0°C. The reaction mixture was stirred at 0°C for 3 h. The reaction solution was spin-dried. N-[3-(difluoromethylene)cyclobutyl]-5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]tridec-1(9),2,4,7-tetraen-10-amine (55 mg, 153.08 μmol) was dissolved in DCM (1.5 mL), and oxalyl chloride and triethylamine (31 mg, 306.16 μmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using petroleum ether / ethyl acetate (10:1) as eluent to obtain compound 144d (25 mg, 35.63 μmol) in a yield of 22.2%. MS m / z (ESI): 734 [M+1] +

[0422] Step 4: 144d (20 mg, 28.50 μmol) was added to trifluoroacetic acid (200 μL) and stirred at 90°C for 2 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by HPLC to obtain Example 144 (4.2 mg, 7.20 μmol) in a 25.2% yield. MS m / z (ESI): 584 [M+1] +

[0423] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.41(d,1H),8.11(s,2H),7.90(d,1H),7.37(s,1H),7.25-7.0 3(m,3H),5.10-4.77(m,3H),4.42-4.02(m,3H),3.67-3.27(m,2H),2.96–2.62(m,2H),2.41(s,3H).

[0424] Example 146

[0425] 4-amino-N-(3-((dimethyl(carbonyl)-16-sulfaneylidene)amino)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide

[0426] Step 1: Dissolve 3-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine 37i (220 mg, 0.78 mmol), di-tert-butyl dicarbonate (218 mg, 1.17 mmol), and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to afford compound 146a (240 mg) in 80.5% yield. MS m / z (ESI): 382 [M+1]. +

[0427] Step 2: 146a (100 mg, 0.26 mmol), imino-dimethyl-carbonyl-sulfane (37 mg, 0.39 mmol), cesium carbonate (127 mg, 0.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.5 mmol), and tris(dibenzylideneacetone)palladium (24 mg, 0.03 mmol) were dissolved in 5 mL of dioxane and stirred at 80°C under nitrogen for 2 hours. The reaction mixture was extracted with ethyl acetate (50 mL) and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 146b (57 mg) in a 55.1% yield. MS m / z (ESI): 395 [M+1]. +

[0428] Step 3: Dissolve 146b (57 mg, 0.13 mmol) in 5 mL of 2M hydrochloric acid in dioxane and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to afford 146c (33 mg) in an 85.7% yield. MS m / z (ESI): 295 [M+1] +

[0429] Referring to the ninth step of Example 37, Example 146 (4.2 mg) was obtained from 146c (33 mg, 0.11 mmol) in a yield of 7.4%. MS m / z (ESI): 519 [M+1] +

[0430] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.13–8.06(m,2H),7.88(s,1H),7.34(d,2H),7.32(s,1H),7.00(d,1H),6.78 (d,1H),5.74(s,1H),5.07(d,1H),4.78(d,1H),4.23(d,1H),4.15(dd,1H),3.30(d,6H),2.63(s,3H),2.33(s,3H).

[0431] Example 197

[0432] 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

[0433] Step 1: THF (70 mL) was added to a three-necked flask, replaced with nitrogen three times, and cooled to 0°C. Dibromo(difluoro)methane (20.72 g, 98.74 mmol, 9.02 mL) was quickly added and stirred in an ice bath for 10 minutes. HMPT (16.12 g, 98.74 mmol, 18 mL) was slowly added dropwise, and white solid was formed. After the addition was completed, stirring was continued at 0°C for 1 hour. Tert-butyl 3-oxocyclobutanecarboxylate 197a (3.86 g, 22.7 mmol) / 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 the mixture was added. HMPT, 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 obtain 197b (2 g) in a yield of 43.1%.

[0434] Step 2: 197b (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 h. The reaction solution was directly concentrated under reduced pressure to afford 197c (1 g, crude product).

[0435] Step 3: 197c (1 g, crude) 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 purged with nitrogen three times and protected with nitrogen. The reaction was stirred at 25°C for 16 h. Water (20 mL) was added to the reaction solution, and 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 residue was isolated and purified using Purification System C to afford 197d (1.92 g) in a 96.9% yield. MS m / z (ESI): 294 [M+1]. +

[0436] Step 4: 197d (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), the atmosphere was replaced with nitrogen three times, and nitrogen protection was applied. The mixture was stirred for 15 h under a blue light reactor (18w, 456 nm). Pinacol (3.10 g, 26.19 mmol) and TEA (4.18 g, 41.32 mmol, 5.8 mL) were then added in sequence. The atmosphere was replaced with nitrogen three times, and nitrogen protection was applied. The reaction was stirred at 25 °C for 1 h. 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 isolated and purified using Purification System C to obtain 197e (540 mg) in a yield of 35.9%.

[0437] Referring to the synthesis method of steps 1 to 10 of Example 32, methyl 2-bromo-4-fluoro-5-nitrobenzoate 197f (2 g, 3.60 mmol) was used to obtain compound 197o (600 mg) in a 0.1% yield. MS m / z (ESI): 671 [M+1] +

[0438] Step 14: 197o (100 mg, 149 μmol) and 197e (137.05 mg, 596 μmol) were dissolved in DMF (5 mL). 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 give 197p (100 mg, crude product). MS m / z (ESI): 695 [M+1] +

[0439] Step 15: 197p (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 residue was purified by Pre-HPLC to give Example 197 (7.5 mg). MS m / z (ESI): 545 [M+1] +

[0440] 1H NMR(400MHz,DMSO-d6)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).

[0441] Example 198

[0442] 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

[0443] Referring to the synthesis method from the first step to the second step of Example 28, tert-butyl 4-oxopiperidine-1-carboxylate 198a (5 g, 25.09 mmol) was used to obtain 198c (1.5 g) in a yield of 44.9%.

[0444] Referring to the synthesis method of steps 1 to 10 of Example 32, methyl 4-fluoro-2-methyl-5-nitrobenzoate 198e (2 g, 9.38 mmol) was used to obtain 198n (600 mg) in a 12% yield. MS m / z (ESI): 617 [M+1] +

[0445] Step 12: 198n (120 mg, 195 μmol) and 198c (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 h. 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 give 198o (100 mg, crude product). MS m / z (ESI): 670 [M+1] +

[0446] Step 13: 198o (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 Example 198 (18 mg). MS m / z (ESI): 520 [M+1] +

[0447] 1 H NMR(400MHz,DMSO-d6)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).

[0448] Example 199

[0449] 4-amino-N-methoxy-7-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0450] Step 1: Dissolve 2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one (500 mg, 2.30 mmol, synthesized using the known method from Patent WO2022169948) in methanol. Add sodium borohydride (435 mg, 11.51 mmol) portionwise under ice-cooling, and stir at 0°C for 1 hour. The reaction mixture was quenched by adding saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 199b (470 mg) in a 93.1% yield. MS m / z (ESI): 220 [M+1]. +

[0451] Step 2: Dissolve 199b (470 mg, 2.14 mmol) and triethylamine (651 mg, 6.43 mmol) in 10 mL of dichloromethane. Add methylsulfonic anhydride (560 mg, 3.22 mmol) and stir at room temperature for 1 hour. Quench the reaction mixture with saturated ammonium chloride solution (30 mL) and extract with ethyl acetate (30 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford 199c (430 mg) in a 66.8% yield. MS m / z (ESI): 298 [M+1]. +

[0452] Step 3: Dissolve 199c (220 mg, 0.74 mmol) in 10 mL of acetonitrile, add potassium carbonate (511 mg, 3.7 mmol), and stir at 80°C in a sealed tube for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 199d (139 mg) in a 75.7% yield. MS m / z (ESI): 249 [M+1] +

[0453] Step 4: Dissolve 199d (139 mg, 0.56 mmol) and 4-((3,4-dimethylbenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 199e (241 mg, 0.62 mmol) in 5 mL of dichloromethane. Phosphorus oxychloride (257 mg, 1.68 mmol) and pyridine (265 mg, 3.36 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding 2M hydrochloric acid (30 mL) and extracted with dichloromethane (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 199f (67 mg) in a 19.2% yield. MS m / z (ESI): 623 [M+1]. +

[0454] Referring to the seventh step of Example 1, Example 199 (20.2 mg) was obtained from 199f (67 mg, 0.11 mmol) in a yield of 38.9%. MS m / z (ESI): 473 [M+1] +

[0455] 1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.32(s,1H),8.20(s,1H),8.13(d,1H),7.90(d,1H),7.3 8(s,1H),5.70(s,1H),4.90(d,1H),4.78(d,1H),4.37–4.15(m,2H),3.43(s,3H),2.38(s,3H).

[0456] Example 200

[0457] 4-amino-N-methyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)benzofuro[3,2-c]pyridine-8-carboxamide

[0458] Step 1: A mixture of methyl 3-bromo-4-hydroxybenzoate 200a (5.00 g, 21.64 mmol), 3-bromo-4-chloro-5-nitropyridine (5.65 g, 23.81 mmol), and cesium carbonate (10.55 g, 32.46 mmol) in N,N-dimethylformamide (50 mL) was stirred at 35°C for 16 hours. The reaction mixture was filtered to remove solids and concentrated. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to afford 200b (7.60 g) in 81.3% yield. MS m / z (ESI): 433 [M+1] +

[0459] Step 2: A reaction mixture of 200b (5.00 g, 11.55 mmol) and iron powder (6.48 g, 115.51 mmol) in methanol (100 mL) and saturated aqueous ammonium chloride (50 mL) was stirred at 50°C for 16 hours. After the reaction, the reaction mixture was filtered to remove solids. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to afford 200c (3.92 g) in an 84.2% yield. MS m / z (ESI): 403 [M+1] +

[0460] Step 3: The reaction mixture of 200c (20 mg, 0.050 mmol), bis(pinacol boronate) (18.95 mg, 0.074 mmol), potassium phosphate (15.82 mg, 0.075 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (3.64 mg, 0.005 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was sealed with nitrogen and placed in a microwave tube and stirred at 90°C for 16 hours. The reaction mixture was filtered to remove solids and concentrated. The organic phase was concentrated and the residue was purified by silica gel column chromatography to give 200d (8 mg) in a yield of 66.4%. MS m / z (ESI): 243 [M+1] +

[0461] Step 4: A reaction mixture of 200d (50 mg, 0.21 mmol) and lithium hydroxide (17 mg, 0.42 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The organic phase was concentrated, and the residue was purified by reverse phase column chromatography to afford 200e (22 mg) in a 46.7% yield. MS m / z (ESI): 229 [M+1] +

[0462] Step 5: A solution of 200e (15 mg, 0.066 mmol), N-methyl-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-amine (27 mg, 0.099 mmol), N-methylimidazole (16 mg, 0.197 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (28 mg, 0.099 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The organic phase was concentrated, and the residue was purified by prep-HPLC column chromatography to afford Example 200 (5 mg) in a 15.8% yield. MS m / z (ESI): 482 [M+1] +

[0463] 1 H NMR (400MHz, CD3OD) δ8.83(s,1H),8.42(m,2H),8.10(d,2H),7.90(m,2H),7.28(d,1H),5.88(s,1H),5.23(d,1H),4.30(m,3H),2.94(s,3H).

[0464] Example 201

[0465] 4-amino-7-fluoro-N-methoxy-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0466] Referring to the fourth step of Example 199 and the seventh step of Example 1, 4-((3,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 201a (88 mg, 0.24 mmol) was used to obtain Example 201 (20 mg) in a 17.4% yield. MS m / z (ESI): 477 [M+1]. +

[0467] 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.44(d,1H),8.07(d,1H),7.95–7.89(m,2H),7.65 (s,2H),7.23(d,1H),5.68(s,1H),4.89(d,1H),4.78(d,1H),4.25(qd,2H),3.47(s,3H).

[0468] Example 202

[0469] 4-amino-N-(2-(cyclohexylidenefluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0470] Step 1: Cyclohexanone 202a (2 g, 20.38 mmol, 2.11 mL), tribromofluoromethane (6.62 g, 24.45 mmol, 2.39 mL), and triphenylphosphine (6.41 g, 24.45 mmol) were dissolved in tetrahydrofuran (60 mL). The atmosphere was purged with nitrogen three times. Diethylzinc (3.02 g, 24.45 mmol, 24.5 mL, 1 M) was added dropwise at 25°C. After addition, the system was incubated at 25°C for 1 hour. The reaction was monitored for completion by TLC. The reaction was quenched with 50 mL of methanol, concentrated, and filtered. The residue was purified by silica gel column chromatography using eluent System B to afford compound 202b (1.20 g) in a 30.5% yield.

[0471] 1 H NMR (400MHz, CDCl3) δ2.27(td,2H),2.15–2.10(m,2H),1.59–1.49(m,6H).

[0472] Step 2: Dissolve 202b (2 g, 10.36 mmol), pinacol diboronate (5.26 g, 20.72 mmol), and potassium acetate (3.05 g, 31.08 mmol) in 1'4-dioxane (20 mL). The atmosphere was purged with nitrogen three times. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (758 mg, 1.04 mmol) was added to the mixture and the reaction was stirred at 90°C for 5 hours. The mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (80 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 202c (0.55 g) in a 22.1% yield.

[0473] 1 H NMR (400MHz, CDCl3) δ2.39(d,2H),2.31(d,2H),1.56(d,6H),1.30(s,12H).

[0474] Step 3: tert-Butyl N-(2-bromo-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl)-N-methylcarbamate 202d (0.13 g, 0.38 mmol), 202c (455 mg, 1.89 mmol), and sodium carbonate (200 mg, 1.89 mmol) were dissolved in 1'4-dioxane (8 mL) and water (1.5 mL). The atmosphere was purged with nitrogen three times. Tetrakistriphenylphosphine palladium (44 mg, 38 μmol) was added to the system, and the reaction system was reacted at 100°C for 15 hours. The mixture was cooled to room temperature, concentrated, and extracted with ethyl acetate (50 mL × 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 B to afford 202e (130 mg) in a 91.2% yield. MS m / z (ESI): 377 [M+1]. +

[0475] Step 4: Dissolve 202e (130 mg, 0.35 mmol) in 1'4-dioxane (4 mL). The nitrogen atmosphere was purged three times. Hydrochloric acid / 1'4-dioxane (4 M, 4 mL) was added to the system. The reaction system was reacted at 25°C for 1 hour. Concentration afforded 202f (0.10 g, crude product). MS m / z (ESI): 277 [M+1]. +

[0476] Step 5: 4-Amino-7-fluoro-imidazo[1,5-a]quinoxaline-8-carboxylic acid 202g (40 mg, 0.16 mmol), 202f (54 mg, 0.19 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (55 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (5 mL). N-methylimidazole (45 mg, 0.49 mmol, 39 μL) was added, and the atmosphere was purged with nitrogen three times. The reaction system was stirred at 25°C for 1 hour. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The mixture was 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 Example 202 (36 mg) in a 43.9% yield. MS m / z (ESI): 505 [M+1]. +

[0477] 1 H NMR(400MHz,DMSO-d6)δ9.14(d,1H),8.37(d,1H),7.95(d,1H),7.83–7.63(m,3H),7.51(d,1H),7.27(t,1H),5.83(t,1H ),4.86–4.75(m,1H),4.62(dd,1H),4.19–3.99(m,2H),2.76(d,3H),2.65(dt,2H),2.42–2.32(m,2H),1.64–1.46(m,6H).

[0478] The preparation of the following table examples refers to Example 34:

[0479] The preparation of the following examples is shown in Table 146:

[0480] The preparation of the following examples is shown in Table 201:

[0481] Example 204

[0482] 4-amino-N-(2-(4-(difluoromethylene)piperidin-1-yl)-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0483] Step 1: 2-Amino-3-methylisothiazolinone 204a (15 g, 90.36 mmol) and ethyl bromoacetate (15.09 g, 90.36 mmol) were dispersed in 70 mL of tetrahydrofuran and stirred at 25°C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was dispersed in 800 mL of acetonitrile. Phosphorus oxybromide (64.16 g, 225.90 mmol) was added and stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent System A to afford 204b (5.41 g) in a 22.3% yield. MS m / z (ESI): 269 [M+1] +

[0484] Referring to the synthesis method of steps 2 to 8 of Example 62, 204h (490 mg) was obtained from 204b (5.41 g, 20.19 mmol) in a yield of 6.9%. MS m / z (ESI): 350 [M+1] +

[0485] Step 8: Disperse 204h (490 mg, 1.40 mmol) and triethylamine (202 mg, 2.00 mmol) in 10 mL of dichloromethane, and add di-tert-butyl dicarbonate (436 mg, 2.00 mmol). Stir and react at 25°C for 1 hour. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography with eluent System A to afford 204i (610 mg) in a 96.8% yield. MS m / z (ESI): 450 [M+1] +

[0486] Referring to the synthesis method of step 12 of Example 198, 204k (62 mg) was obtained from 204i (100 mg, 0.22 mmol) in a yield of 55.5%. MS m / z (ESI): 503 [M+1] +

[0487] Step 10: Disperse 204k (62 mg, 0.12 mmol) in 2 mL of trifluoroacetic acid. Stir and react at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to afford 204l (49 mg) in a 98.7% yield. MS m / z (ESI): 403 [M+1] +

[0488] Referring to the synthesis method of steps 9 and 10 of Example 12, Example 204 (18 mg) was obtained from 2041 (49 mg, 0.12 mmol) in a yield of 23.4%. MS m / z (ESI): 631 [M+1] +

[0489] Example 205

[0490] 4-amino-N-(2-((dimethyl(carbonyl)-16-sulfaneylidene)amino)-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0491] Referring to the synthesis methods of step 12 of Example 198, step 10 of Example 204, and steps 9 and 10 of Example 12, tert-butyl (2-bromo-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)(methyl)carbamate 205a (100 mg, 0.22 mmol) was used to obtain Example 205 (18 mg) in a 13.7% yield. MS m / z (ESI): 591 [M+1]. +

[0492] Alternatively, Examples 206 and 234 were prepared using the following method:

[0493] Example 206

[0494] 4-amino-N-(4-(difluoromethylene)-3,4,7,10-tetrahydro-2H,8H-pyrano[4,3-h]chroman-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoline-8-carboxamide

[0495] Step 1: Disperse 206a (8.00 g, 32.79 mmol), triethylamine (5.05 g, 50.00 mmol), and bromomethyl methyl ether (6.25 g, 50.00 mmol) in 100 mL of dichloromethane and stir at 25°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to afford 206b (9.00 g) in a 95.3% yield. MS m / z (ESI): 289 [M+1] +

[0496] Referring to the first to fourth and seventh steps of Example 9, 206f (4.50 g) was obtained from 206b (9.00 g, 31.25 mmol) in a 56.0% yield. MS m / z (ESI): 258 [M+1] +

[0497] Step 6: Disperse 206f (1.00 g, 3.89 mmol) and di-tert-butyl dicarbonate (1.09 g, 5.00 mmol) in 10 mL of dichloromethane and stir at 25°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to yield 206f (1.51 g crude product). MS m / z (ESI): 358 [M+1] +

[0498] Step 7: Disperse 206g (1.51g crude product), tributyl(1-ethoxyethylene)tin (1.44g, 4.00mmol), and bistriphenylphosphine palladium dichloride (280mg, 0.40mmol) in 20mL of 1,4-dioxane and stir at 100°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to yield 206h (1.21g crude product). MS m / z (ESI): 322[M+1] +

[0499] Step 8: Disperse 206h (1.21 g crude product) and N,N-dimethylformamide dimethyl acetal (952 mg, 8.00 mmol) in 10 mL of toluene and stir at 80°C for 2 hours. Add 5 mL of concentrated hydrochloric acid and stir at 50°C for 1 hour. The reaction solution is concentrated to dryness under reduced pressure to obtain 206i (2.21 g crude product). MS m / z (ESI): 232 [M+1] +

[0500] Step 9: Disperse 206i (2.21 g crude product) and di-tert-butyl dicarbonate (3.27 g, 15.00 mmol) in 20 mL of dichloromethane and stir at 25°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to afford 206j (270 mg) in a 21.0% yield. MS m / z (ESI): 332 [M+1] +

[0501] Step 10: Compound 206j (270 mg, 0.82 mmol), tris(triphenylphosphine)ruthenium dichloride (77 mg, 0.08 mmol), potassium carbonate (113 mg, 0.82 mmol), and paraformaldehyde (123 mg, 4.10 mmol) were dispersed in 5 mL of toluene and 0.5 mL of water. The mixture was stirred at 110°C for 16 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford compound 206k (160 mg) in a 58.6% yield. MS m / z (ESI): 334 [M+1]. +

[0502] Step 11: Disperse 206k (160 mg, 0.48 mmol) and difluoromethyl (2-pyridyl) sulfone (139 mg, 0.72 mmol) in 10 mL of N,N-dimethylformamide. Add potassium tert-butoxide (108 mg, 0.96 mmol) and stir at -40°C for 1 hour. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford 206l (80 mg) in a 45.4% yield. MS m / z (ESI): 368 [M+1] +

[0503] Step 12: Disperse 206l (80 mg, 0.22 mmol) in 2 mL of trifluoroacetic acid and 2 mL of dichloromethane. Stir and react at 25°C for 1 hour. Concentrate the reaction mixture to dryness under reduced pressure to obtain 206m (100 mg crude product). MS m / z (ESI): 268 [M+1] +

[0504] Referring to the synthesis method of steps 9 to 10 of Example 12, Example 206 (36 mg) was obtained from 206m (100 mg crude product) with a yield of 33.1%. MS m / z (ESI): 496 [M+1] +

[0505] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.36(d,1H),7.97(s,1H),7.77(s,2H),7.46(d,1H),7.28(t,1H),6.93( d,1H),5.70(s,1H),4.83–4.61(m,1H),4.49(dd,1H),4.24(dd,2H),4.06–3.86(ddd,2H),2.79–2.61(m,5H).

[0506] Example 234

[0507] 4-amino-N-(2-(3-(difluoromethylene)azetidine-1-carbonyl)-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0508] Step 1: Methyl 2-chloro-3-methylisonicotinate 234a (10 g, 53.88 mmol) was weighed and added to a reaction flask. Carbon tetrachloride (200 mL) was added and stirred at room temperature. N-bromosuccinimide (19.18 g, 107.75 mmol) and azobisisobutyronitrile (1.77 g, 10.78 mmol) were weighed and added to the reaction flask. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 77°C for 16 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to afford 234b (14 g, 52.93 mmol) in a 98.2% yield. MS m / z (ESI): 265 [M+1] +

[0509] Step 2: Methyl glycolate (10.01 g, 111.15 mmol) was weighed and added to a reaction flask. Ultra-dry tetrahydrofuran (150 mL) was added and mixed thoroughly. The mixture was cooled to 0°C and sodium hydride (6.35 g, 158.79 mmol, 60% purity) was added portionwise. After complete addition, the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was cooled to 0°C and 234b (14 g, 52.93 mmol) was dissolved in ultra-dry tetrahydrofuran (30 mL) and slowly added dropwise to the reaction mixture. The reaction was maintained at 0°C for 30 minutes. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched by adding glacial acetic acid (4 mL) and water (100 mL). The mixture was extracted with ethyl acetate (100 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 B to give 234c (9.45 g, 38.89 mmol) in a 73.5% yield. MS m / z (ESI): 243 [M+1] +

[0510] Step 3: 234c (12 g, 49.66 mmol) was dissolved in 1,4-dioxane (50 mL) and concentrated hydrochloric acid (50 mL). The reaction system was stirred at 100°C for 2 hours. The reaction solution was concentrated to remove the 1,4-dioxane. Water (100 mL) was added to the residue, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The residue was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to give 234d (5.08 g, 27.67 mmol) in a 55.7% yield. MS m / z (ESI): 184 [M+1] +

[0511] Step 4: 234d (8.6 g, 46.84 mmol) was weighed and dissolved in trifluoroethanol (60 mL). Methylamine methanol solution (23.28 g, 187.37 mmol) was added and the reaction system was allowed to react at room temperature for 16 hours. Sodium borohydride (3.54 g, 93.69 mmol) was added portionwise in an ice bath and the reaction system was allowed to react at room temperature for 2 hours. The mixture was quenched with aqueous ammonium chloride (5 mL) and concentrated. Water (50 mL) was added to the residue and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was 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 234e (4.04 g, 20.34 mmol) in a 43.4% yield. MS m / z (ESI): 199 [M+1] +

[0512] Step 5: 234e (4.04 g, 20.34 mmol) was weighed and dissolved in dichloromethane (40 mL). Triethylamine (6.17 g, 61.01 mmol, 8.51 mL) was added, and benzyl chloroformate (5.20 g, 30.51 mmol) was added dropwise under ice-cooling. The reaction system was allowed to react at room temperature for 1 hour. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography using eluent system A to obtain 234f (5.6 g, 16.83 mmol) in an 82.7% yield. MS m / z (ESI): 334 [M+1] +

[0513] Step 6: Weigh 234f (5.6 g, 16.83 mmol) and dissolve it in 1,4-dioxane (120 mL). Add tris(dibenzylideneacetone)dipalladium (1.54 g, 1.68 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.95 g, 3.37 mmol), cesium carbonate (8.22 g, 25.24 mmol) and benzophenone imine (3.05 g, 16.83 mmol). Nitrogen is replaced three times. The reaction system is reacted at 100 ° C for 16 hours. The reaction solution is cooled to room temperature, filtered through celite, the solid is washed with 1,4-dioxane, and the filtrate is concentrated and used directly in the next step. MS m / z (ESI): 478 [M+1] +

[0514] Step 7: Methanol (40 mL) and hydrochloric acid (25 mL, 4 M in 1,4-dioxane) were added directly to the crude product from the previous step, and the reaction system was allowed to react at room temperature for 6 hours. The reaction solution was concentrated, adjusted to a weak base by adding aqueous sodium bicarbonate solution, and extracted with dichloromethane (20% methanol). The organic phase was 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 obtain 234h (4.12 g, 13.15 mmol) in a yield of 78.1%. MS m / z (ESI): 314 [M+1] +

[0515] Step 8: 234h (4 g, 12.77 mmol) was dissolved in ethanol (40 mL), and ethyl 3-bromo-2-oxopropanoate (3.73 g, 19.15 mmol) and sodium bicarbonate (2.14 g, 25.53 mmol) were added. The reaction system was reacted at 70°C for 18 hours. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography with eluent System B to obtain 234i (3.88 g, 9.48 mmol) in a yield of 74.2%. MS m / z (ESI): 410 [M+1] +

[0516] Step 9: 234i (3.88 g, 9.48 mmol) was dissolved in acetonitrile (40 mL) and N-iodosuccinimide (2.56 g, 11.37 mmol) was added. The reaction was allowed to react at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using eluent System B to afford 234j (3.94 g, 7.36 mmol) in a 77.7% yield. MS m / z (ESI): 536 [M+1] +

[0517] Step 10: 234j (3.84 g, 7.17 mmol) was dissolved in N,N-dimethylformamide (40 mL), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.13 g, 21.52 mmol) and cuprous iodide (4.10 g, 21.52 mmol) were added. The reaction system was reacted at 100°C for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 234k (1.42 g, 2.97 mmol) in a yield of 41.5%. MS m / z (ESI): 478 [M+1]. +

[0518] Step 11: 234k (1.42 g, 2.97 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL). Lithium hydroxide (213.70 mg, 8.92 mmol) was added and the reaction system was allowed to react at room temperature for 2 hours. The tetrahydrofuran was removed by distillation under reduced pressure. The residue was acidified with 3N hydrochloric acid. The aqueous phase was extracted with dichloromethane (10% methanol), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude 234l (1.15 g, 2.56 mmol) in an 86.0% yield. MS m / z (ESI): 450 [M+1]. +

[0519] Step 12: 234l (500 mg, 1.11 mmol) was dissolved in acetonitrile (5 mL). 3-Oxoazetidine (143.58 mg, 1.34 mmol, CL), N,N-diisopropylethylamine (359.50 mg, 2.78 mmol, 484.50 μL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (629.65 mg, 1.67 mmol) were added. The reaction system was allowed to react at room temperature for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 234m (213 mg, 423.93 μmol) in a 38.1% yield. MS m / z (ESI): 503 [M+1]. +

[0520] Step 13: 234m (200 mg, 398.06 μmol) was dissolved in 1,4-dioxane (10 mL), and 2,2-difluoro-2-triphenylphosphonic acid ester (283.66 mg, 796.11 μmol) was added. The atmosphere was purged with nitrogen three times, and the reaction system was reacted at 80°C for 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to obtain 234n (106 mg, 197.60 μmol) in a yield of 49.6%. MS m / z (ESI): 537 [M+1] +

[0521] Step 14: 234n (100 mg, 186.41 μmol) was added to trifluoroacetic acid (5 mL), and the reaction system was incubated at 80°C for 2 hours. The reaction solution was directly concentrated, and sodium bicarbonate aqueous solution was added to adjust the base. The aqueous phase was extracted with dichloromethane (10% methanol), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 234o (55 mg, 136.71 μmol) in a yield of 73.3%. MS m / z (ESI): 403 [M+1] +

[0522] Step 15: 234o (55 mg, 136.71 μmol) was dissolved in acetonitrile (5.02 mL), and 4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (65.02 mg, 164.05 μmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (77.36 mg, 205.06 μmol), and N,N-diisopropylethylamine (44.17 mg, 341.77 μmol, 59.53 μL) were added. The reaction system was reacted at room temperature for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to give 234p (62 mg, 79.42 μmol) in a 58.1% yield. MS m / z (ESI): 781 [M+1] +

[0523] Step 16: 234p (62 mg, 79.42 μmol) was added to trifluoroacetic acid (5 mL), and the reaction system was incubated at 90°C for 2 hours. The reaction solution was directly concentrated, and the base was adjusted with aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (10% methanol), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used to prepare Example 234 (39 mg, 61.86 μmol) in a 77.9% yield. MS m / z (ESI): 631 [M+1] +

[0524] 1 H NMR(400MHz,DMSO-d6)δ9.13(d,1H),8.62(d,1H),8.37(d,1H),7.93(d,1H),7.63(s,2H),7.33– 7.00(m,2H),5.79(s,1H),5.22–4.99(m,3H),4.94–4.72(m,3H),4.28–4.02(m,2H),2.82(s,3H).

[0525] Example 237

[0526] 4-amino-N-(2-(4-(difluoromethylene)azetidin-1-yl)-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0527] Referring to the synthesis methods of step 12 of Example 198, step 10 of Example 204, and steps 9 and 10 of Example 12, Example 237 (8 mg) was obtained from tert-butyl (2-bromo-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)(methyl)carbamate 237a (100 mg, 0.22 mmol) in a 6.0% yield. MS m / z (ESI): 603 [M+1]. +

[0528] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.29(s,2H),7.94(s,1H),7.40(s,2H),7.2 4(d,1H),6.96(s,1H),5.77(s,1H),5.13–4.64(m,6H),4.19(s,2H),2.76(t,3H).

[0529] Example 240

[0530] 4-amino-N-(3-(cyclohexylidenefluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0531] Referring to the synthesis method of steps 3 to 5 of Example 202, Example 240 (30 mg) was obtained from 2-(cyclohexylidenefluoromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 240a (943 mg, 3.92 mmol) and tert-butyl (3-bromo-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)(methyl)carbamate 240b (300 mg, 0.78 mmol) in a yield of 27.8%. MS m / z (ESI): 544 [M+1]. +

[0532] 1H NMR(400MHz,DMSO-d6)δ9.14(d,1H),8.33(dd,2H),7.93(s,1H),7.72(dd,1H),7.62(s,2H),7.27(dd,1H),6.91(d,1H),5.76( s,1H),5.10(dd,1H),4.88–4.70(m,1H),4.27–4.00(m,2H),2.86(s,1H),2.76(s,2H),2.44(d,2H),2.06(d,2H),1.59(d,6H).

[0533] Example 276

[0534] 4-Amino-N',N',7-trimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0535] Step 1: 4-((3,5-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 276a (0.5 g, 1.27 mmol), 1,1-dimethylhydrazine (115 mg, 1.91 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (721 mg, 1.91 mmol) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (494 mg, 3.82 mmol, 0.66 mL) was added, and the atmosphere was purged with nitrogen three times. The reaction system was stirred at 25°C for 1 hour. The mixture was quenched with water, extracted with ethyl acetate (50 mL × 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 B to give 276b (0.51 g) in 92.1% yield. MS m / z (ESI): 435 [M+1] +

[0536] Step 2: 276b (0.40 g, 0.92 mmol), [2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]methanesulfonate 276c (410 mg, 1.38 mmol), and cesium carbonate (900 mg, 2.76 mmol) were dissolved in N,N-dimethylformamide (10 mL). The nitrogen atmosphere was purged three times, and the reaction system was stirred at 60°C for 15 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate (80 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent System B to afford 276d (30 mg) in a 5.1% yield. MS m / z (ESI): 636 [M+1] +

[0537] Step 3: Dissolve 276d (24 mg, 38 μmol) in TFA (3 mL). The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 90°C for 3 hours. Cool to room temperature and concentrate. The residue was purified by silica gel column chromatography using eluent System A to afford Example 276 (5 mg) in a 27.3% yield. MS m / z (ESI): 486 [M+1] +

[0538] 1 H NMR(400MHz,CD3OD)δ8.99(s,1H),8.31(d,1H),8.04(s,1H),7.94(s,1H),7.76(d,1H),7.34(s,1H),6. 25(d,1H),4.61(s,2H),4.41(dd,1H),4.22(d,1H),3.60(q,1H),3.35(s,1H),2.43(s,6H),2.35(s,3H)

[0539] Example 277

[0540] 4-amino-N'-ethyl-7-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0541] Referring to the synthesis method of Steps 1 to 3 of Example 276, Example 277 (35 mg) was obtained from 4-((3,5-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 277a (200 mg, 0.51 mmol) in a 14.1% yield. MS m / z (ESI): 486 [M+1]. +

[0542] 1 H NMR(400MHz,DMSO-d6)δ9.05(d,1H),8.12(d,2H),7.92(s,1H),7.81(d,1H),7.28(d ,3H),5.04(s,1H),4.89–4.61(m,2H),4.36–4.08(m,2H),2.39(s,3H),0.67(s,3H).

[0543] Example 278

[0544] 4-Amino-N',7-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0545] Referring to the synthesis method of Steps 1 to 3 of Example 276, Example 278 (26 mg) was obtained from 4-((3,5-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 278a (200 mg, 0.51 mmol) in a 10.9% yield. MS m / z (ESI): 472 [M+1]. +

[0546] 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.41–8.16(m,1H),8.12(d,1H),8.00(d,,1H),7.87(d,1H),7.82(d,1H),7.34(d,1H),5.53–5 .41(m,1H),5.29(d,1H),4.93–4.82(m,1H),4.77–4.59(m,1H),4.29(qd,1H),4.03(s,1H),2.57(s,1H),2.44(s,2H),2.29(d,3H).

[0547] Example 278 Preparation of Chiral Isomers

[0548] Example 278 (26 mg, 0.055 mmol) was separated by Chiral-HPLC (Condition 1) to give 278-P1: (S)-4-amino-N',7-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide (12.6 mg), yield: 48.5%; 278-P2: (R)-4-amino-N',7-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide (13.0 mg), yield: 50.0%.

[0549] 278-P1(t R :5.897min): 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.41–8.16(m,1H),8.12(d,1H),8.00(d,1H),7.87(d,1H),7.82(d,1H),7.34(d,1H),5.53–5 .41(m,1H),5.29(d,1H),4.93–4.82(m,1H),4.77–4.59(m,1H),4.29(qd,1H),4.03(s,1H),2.57(s,1H),2.44(s,2H),2.29(d,3H).

[0550] 278-P2(t R :5.240min): 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.41–8.16(m,1H),8.12(d,1H),8.00(d,1H),7.87(d,1H),7.82(d,1H),7.34(d,1H),5.53–5 .41(m,1H),5.29(d,1H),4.93–4.82(m,1H),4.77–4.59(m,1H),4.29(qd,1H),4.03(s,1H),2.57(s,1H),2.44(s,2H),2.29(d,3H).

[0551] Example 279

[0552] 4-Amino-7-fluoro-N'-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-hydrazide

[0553] Referring to the synthesis method of Steps 1 to 3 of Example 278, methyl 2,4-difluoro-5-nitrobenzoate 279e (500 mg, 2.35 mmol) was used to obtain Example 279 (11 mg) in a 0.2% yield. MS m / z (ESI): 476 [M+1] +

[0554] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.26(s,1H),8.04(s,1H),7.92(s,1H),7.79(dd,1 H),7.34(s,2H),7.19(d,1H),5.21(s,1H),4.91–4.68(m,2H),4.25(s,2H),2.42(s,3H).

[0555] Example 280

[0556] 4-Amino-7-fluoro-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0557] Step 1: 2-Aminoisoindoline-1,3-dione 280a (184 mg, 1.14 mmol) and 4-((3,4-dimethylbenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (300 mg, 0.76 mmol) were dissolved in 10 mL of dichloromethane. Pyridine (239 mg, 3.03 mmol) and phosphorus oxychloride (348 mg, 2.27 mmol) were added sequentially. The mixture was stirred at room temperature 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 280b (162 mg) in a 39.6% yield. MS m / z (ESI): 541 [M+1]. +

[0558] Step 2: Compound 280b (162 mg, 0.30 mmol), sodium iodide (89 mg, 0.60 mmol), cesium carbonate (292 mg, 0.90 mmol), and 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl methanesulfonate (133 mg, 0.45 mmol) were dissolved in 10 mL of acetonitrile and microwave-treated at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was added to 100 mL of ethyl acetate and washed with saturated brine (100 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 compound 280c (66 mg) in a 29.7% yield. MS m / z (ESI): 742 [M+1]. +

[0559] Step 3: Dissolve 280c (66 mg, 0.09 mmol) in 2 mL of tetrahydrofuran and 2 mL of ethanol, add hydrazine hydrate (16 mg, 0.27 mmol, 85% purity), and react at 80°C in a sealed tube 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 280d (16 mg) in a 29.4% yield. MS m / z (ESI): 612 [M+1] +

[0560] Step 4: Dissolve 280d (16 mg, 0.02 mmol) in 2 mL of dichloromethane and 1 mL of water, add 2,3-dichloro-5,6-dicyanobenzoquinone (10.91 mg, 0.05 mmol, 60% purity), and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by HPLC (BASE) to afford Example 280 (2 mg) in a 16.1% yield. MS m / z (ESI): 462 [M+1] +

[0561] 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.32(d,1H),7.97(d,1H),7.91(d,2H),7.5 5(s,2H),7.16(d,1H),5.88(d,1H),4.85–4.79(m,2H),4.62(s,2H),4.20(d,2H).

[0562] Example 281

[0563] 4-Amino-N',7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0564] Reference Example 276: From the first step to the second step, tert-butyl 2-(4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carbonyl)-1-methylhydrazine-1-carboxylate 281b (200 mg, 0.38 mmol) and 3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl methanesulfonate (260 mg, 0.76 mmol) were reacted to give 281c (60 mg) in a 20% yield. MS m / z (ESI): 761 [M+1] +

[0565] Step 3: Dissolve 281c (20 mg, 0.026 mmol) in 2 mL of trifluoroacetic acid and stir at 90°C for 1 hour. Concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography using eluent System A to afford Example 281 (6.7 mg) in a 49% yield. MS m / z (ESI): 511 [M+1]. +

[0566] 1 HNMR(400MHz,DMSO-d6)δ9.08(s,1H),8.50(d,1H),8.19(s,1H),8.10(d,1H),7.88(s,1H),7.38(d,1H),7.32–7.23(m,2H),5.46(d ,1H),5.14–5.04(m,1H),4.99(d,1H),4.88(q,1H),4.72(d,1H),4.30(dq,1H),4.09(s,1H),2.74–2.52(m,2H),2.45–2.16(m,4H).

[0567] Example 282

[0568] 4-Amino-7-fluoro-N'-methyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0569] Reference Example 279 Step 1 to Step 2: tert-butyl 2-(4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carbonyl)-1-methylhydrazine-1-carboxylate 282b (200 mg, 0.38 mmol) and 3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl methanesulfonate (260 mg, 0.76 mmol) were used to give 282c (200 mg) in a 68% yield. MS m / z (ESI): 765 [M+1] +

[0570] Step 3: Dissolve 282c (50 mg, 0.065 mmol) in 2 mL of trifluoroacetic acid and stir at 90°C for 1 hour. Concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography using eluent System A to afford Example 282 (15.3 mg) in a 45% yield. MS m / z (ESI): 515 [M+1]. +

[0571] 1 HNMR(400MHz,DMSO-d6)δ9.16(d,1H),8.48(dd,1H),8.27(d,J=6.5Hz,1H),8.16(d,1H),7.93(d,1H),7.60(d,2H),7.33 –7.12(m,2H),5.50–5.21(m,1H),5.04(q,1H),4.91(td,2H),4.29(dt,1H),4.21–3.94(m,1H),2.58(d,1H),2.35(d,2H).

[0572] Example 283

[0573] 4-Amino-N-[2-[(1R,4S)-5-(difluoromethylene)-2-azabicyclo[2.2.2]oct-2-yl]-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0574] Step 1: 4-Amino-N,7-dimethyl-N-[5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraen-10yl]imidazo[1,5-a]quinoxaline-8-carboxamide 283a (50 mg, 101 μmol, Example 62) was dissolved in 1'4-Dioxane (3 mL). Lawesson's Reagent (122.45 mg, 303 μmol) was added. The atmosphere was purged with nitrogen three times and protected with nitrogen. The reaction was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by Pre-HPLC to give Example 283 (14 mg) in a yield of 27.1%. MS m / z (ESI): 512 [M+1] +

[0575] 1 H NMR(400MHz,DMSO-d6)δ9.18–8.98(m,1H),8.57–8.44(m,1H),8.23–8.08(m,1H),8.03–7.83(m,2H),7 .33(dt,3H),7.18–7.00(m,1H),5.30–4.70(m,3H),4.51–4.17(m,2H),2.87(d,3H),2.42–2.16(m,3H).

[0576] Example 284

[0577] 4-Amino-6-fluoro-N',7-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxylic acid hydrazide

[0578] Step 1: Methyl 4-amino-2-methyl-5-nitrobenzoate 284a (3 g, 14.27 mmol) was dissolved in 50 mL of acetonitrile. 1-Chloromethyl-4-fluoro-1,4-diazidebicyclo[2.2.2]octane bistetrafluoroborate (6.07 g, 17.13 mmol) was added and stirred at 50°C for 3 hours. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System C to afford 284b (1.03 g) in a 31.6% yield. MS m / z (ESI): 229 [M+1] +

[0579] Referring to the first through ninth steps of Example 12, the second step of Example 280 and the tenth step of Example 12 were followed by 284b (1.03 g, 4.51 mmol) to afford Example 284 (29 mg) in a 1.3% yield. MS m / z (ESI): 490 [M+1]. +

[0580] The preparation of the following examples is shown in Table 284:

[0581] Alternatively, Examples 285 and 286 were prepared as follows:

[0582] Example 285

[0583] 4-Amino-N'-methyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide

[0584] Step 1: 3-(Trifluoromethyl)-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7(10H)-one 285a (1.3 g, 5.07 mmol) and tert-butyl N-amino-N-methylcarbamate (1.48 g, 10.15 mmol) were dissolved in 10 mL of methanol and 10 mL of tetrahydrofuran. Acetic acid (305 mg, 5.07 mmol) and sodium cyanoborohydride (1.59 g, 25.37 mmol) were added, and the reaction was stirred at 20°C for 48 hours. The reaction mixture was quenched by adding 100 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to afford 285b (1.6 g) in 81.6% yield. MS m / z(ESI):387[M+1] +

[0585] Step 2: Compound 285b (400 mg, 1.04 mmol), 4-(2,4-dimethoxybenzylamino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid (395 mg, 1.04 mmol), POCl3 (456 mg, 2.97 mmol), and pyridine (392 mg, 4.95 mmol) were dissolved in 20 mL of N,N-dimethylacetamide and stirred at 20°C for 2 hours. The reaction mixture was concentrated, added with 50 mL of ethyl acetate, and washed with 2M hydrochloric acid to remove pyridine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent System B to afford compound 285c (220 mg) in a 28.3% yield. MS m / z (ESI): 750 [M+1]. +

[0586] Referring to the eleventh step of the synthesis method of Example 14, Example 285 (90 mg) was obtained from 285c (220 mg, 0.29 mmol) in a yield of 61.7%. MS m / z (ESI): 499 [M+1] +

[0587] Example 285 Preparation of Chiral Isomers

[0588] Example 285 (90 mg, 0.18 mmol) was separated by chiral preparative HPLC (Condition 2) to obtain (S)-4-amino-N'-methyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylate Hydrazine 285-P1 (38 mg), yield: 42.2% and (R)-4-amino-N'-methyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide 285-P2 (42 mg), yield: 46.7%.

[0589] 285-P1(t R :0.765min): 1H NMR(400MHz,DMSO-d6)8.87(d,1H),8.47(dd,1H),8.16(d,3H),7.96(d,1H),7.22–7.04(m,3H),6.18(d ,1H),5.57(d,1H),5.41(d,2H),5.32(d,1H),5.05(t,2H),5.01(d,1H),4.93(s,1H),4.31–4.03(m,2H).

[0590] 285-P2(t R :0.974min): 1 H NMR(400MHz,DMSO-d6)δ8.86(d,1H),8.47(dd,1H),8.16(d,3H),7.93(s,1H),7.23–7.03(m,3H),6.17(d ,1H),5.56(d,1H),5.41(s,2H),5.32(d,1H),5.05(t,2H),5.01(d,1H),4.93(s,1H),4.31–4.04(m,2H).

[0591] Example 286

[0592] 4-Amino-N'-methyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide

[0593] Step 1: Dissolve 2-trifluoromethyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 286a (640 mg, 2.95 mmol) and tert-butyl N-amino-N-methylcarbamate (430.86 mg, 2.95 mmol) in 5 mL of 1,1,1-trifluoroethanol and stir at 20°C for 3 hours. The system was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to afford 286b (1 g) in a 98.3% yield. MS m / z (ESI): 346 [M+1] +

[0594] Step 2: Dissolve 286b (900 mg, 2.61 mmol) in 20 mL of methanol, replace the atmosphere with hydrogen, and stir at 20°C for 3 hours. Filter and concentrate the filtrate under reduced pressure to obtain 286c (900 mg) in a 99.4% yield. MS m / z (ESI): 348 [M+1] +

[0595] Step 3: 286c (227 mg, 0.59 mmol), 4-(2,4-dimethoxybenzylamino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid (172 mg, 0.50 mmol), POCl3 (456 mg, 2.97 mmol), and pyridine (392 mg, 4.95 mmol) were dissolved in 20 mL of 1,2-dichloroethane and stirred at 20°C for 6 hours. The reaction was quenched by the addition of 1 mL of triethylamine, concentrated to dryness, and thoroughly dissolved in 20 mL of ethyl acetate. The filtrate was filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 286d (150 mg) in a 42.6% yield. MS m / z (ESI): 711 [M+1]. +

[0596] Step 4: Dissolve 286d (150 mg) in TFA (20 mL) and react at 90°C for 1 h. The reaction was quenched by cooling, concentrated to dryness, and the residue purified by reverse-phase chromatography using eluent System D to afford Example 286 (92 mg) in a 94.7% yield. MS m / z (ESI): 461 [M+1] +

[0597] 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.09-8.00(m,1H),7.99-7.91(m,1H),7.89-7.79(m,1H),7.14(s,2H),6.18(s,0.5H),5. 65(m,1H),5.40(s,2H),5.37-5.30(m,0.5H),5.05(t,2H),4.79(m,2H),4.26(td,1H),4.09(dt,1H),2.47(d,2H),2.17(d,1H).

[0598] Example 286 Preparation of Chiral Isomers

[0599] Example 286 (50 mg, 0.108 mmol) was separated by Chiral-HPLC (Condition 2) to give 286-P1: (S)-4-amino-N'-methyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide (23.8 mg), yield: 47.6%; 286-P2: (R)-4-amino-N'-methyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide (24.0 mg), yield: 48.0%.

[0600] 286-P1(t R :2.521min): 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.09-8.00(m,1H),7.99-7.91(m,1H),7.89-7.79(m,1H),7.14(s,2H),6.18(s,0.5H),5. 65(m,1H),5.40(s,2H),5.37-5.30(m,0.5H),5.05(t,2H),4.79(m,2H),4.26(td,1H),4.09(dt,1H),2.47(d,2H),2.17(d,1H).

[0601] 286-P2(t R :2.818min): 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.09-8.00(m,1H),7.99-7.91(m,1H),7.89-7.79(m,1H),7.14(s,2H),6.18(s,0.5H),5. 65(m,1H),5.40(s,2H),5.37-5.30(m,0.5H),5.05(t,2H),4.79(m,2H),4.26(td,1H),4.09(dt,1H),2.47(d,2H),2.17(d,1H).

[0602] The preparation of the following examples is shown in Table 277:

[0603] The preparation of the following examples is shown in Table 281:

[0604] The preparation of the following examples is shown in Table 276:

[0605] Alternatively, the following examples are prepared using the following method:

[0606] Example 298

[0607] 4-Amino-N'-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide

[0608] Referring to the synthesis method of Steps 1 to 4 of Example 277, 7-(trifluoromethyl)isochroman-4-one 298a (100 mg, 0.46 mmol) was used to obtain Example 298 (12.2 mg) in a 5.7% yield. MS m / z (ESI): 460 [M+1] +

[0609] 1 HNMR(400MHz,DMSO-d6)δ8.85(s,1H),7.94(d,1H),7.62(dd,1H),7.55–7.46(m,2H),7.13(s,1H),5.58(dt,1H),5 .39(d,2H),5.24(d,1H),5.04(t,2H),4.85–4.73(m,2H),4.21(ddd,1H),4.10–3.97(m,1H),2.29(dd,4.7Hz,3H).

[0610] Example 301

[0611] 4-Amino-N',1-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]pyrazolo[4,3-c]quinoline-8-hydrazide

[0612] Referring to the synthesis method of Steps 1 to 3 of Example 276, 4-amino-1-methylpyrazolo[4,3-c]quinoline-8-carboxylic acid 301d (500 mg, 2.05 mmol) was used to obtain Example 301 (42 mg) in a 4.3% yield. MS m / z (ESI): 472 [M+1] +

[0613] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.25(s,1H),8.12(d,1H),7.87–7.67(m,2H),7.59(d,1H),7.18(s,2H),6.65(broad s,1H),5.32(s,3H),4.80(t,2H),4.40(s,2H),4.30(m,1H),4.19(s,2H).

[0614] Example 301 was separated by Chiral-HPLC to give 301-P1 and 301-P2.

[0615] Example 306

[0616] 4-Amino-7-fluoro-N'-methyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide

[0617] Referring to the synthesis method from steps 3 to 4 of Example 286, tert-butyl 1-methyl-2-(2-trifluoromethyl-6H-pyrano[3,4-b]pyridin-5-yl)hydrazine-1-carboxylate 286c (208 mg, 0.60 mmol) was used to obtain Example 306 (6 mg) in a 2.1% yield. MS m / z (ESI): 478 [M+1]. +

[0618] 1 H NMR(400MHz,DMSO-d6)δ8.06(d,1H),7.87(d,1H),7.53(d,1H),7.23(d,1H),6.89(s,1H),6 .75(s,2H),5.42(s,1H),5.33(d,3H),4.98(d,2H),4.77(m,2H),4.25(m,2H),2.31(d,2H).

[0619] Example 307

[0620] 4-Amino-7-methyl-N'-methyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide

[0621] Referring to the synthesis method from steps 3 to 4 of Example 286, Example 307 (4 mg) was obtained in 8.4% yield from tert-butyl 1-methyl-2-(2-trifluoromethyl-6H-pyrano[3,4-b]pyridin-5-yl)hydrazine-1-carboxylate 286c (35 mg, 0.10 mmol). MS m / z (ESI): 474 [M+1]. +

[0622] 1 H NMR(400MHz,DMSO-d6)δ8.15(m,1H),7.87(d,1H),7.82(d,1H),7.50(s,1H),7.45(s ,1H),5.38(m,4H),5.03(s,2H),4.76(m,2H),4.27(m,2H),2.37(s,3H),2.22(d,2H).

[0623] Example 324

[0624] 4-Amino-N-[5-deuterio-2-(trifluoromethyl)-6,8-dihydropyrano[3,4-b]pyridin-5-yl]-1-methyl-N'-(trideuteriomethyl)pyrazolo[4,3-c]quinoline-8-hydrazide

[0625] Referring to the synthesis method of Steps 1 to 3 of Example 276, 4-amino-1-methylpyrazolo[4,3-c]quinoline-8-carboxylic acid 324d (200 mg, 826 μmol) was used to obtain Example 324 (20 mg) in a 5.0% yield. MS m / z (ESI): 476 [M+1] +

[0626] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.34(s,1H),8.03(d,2H),7.74(d,2H),4.80(s,3H),4.53–4.46(m,2H),4.44–4.21(m,2H).

[0627] Example 342

[0628] 4-Amino-N'-methyl-N-(2-(trifluoromethyl)-6,7-dihydro-4H-pyrano[3,4-d]thiazol-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide

[0629] Step 1: Disperse 2-amino-4H-pyrano[3,4-d]thiazol-7(6H)-one 342a (4.00 g, 23.53 mmol), diiodomethane (26.80 g, 100.00 mmol), and tert-butyl nitrite (2.58 g, 25.00 mmol) in 40 mL of tetrahydrofuran and stir at 65°C for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to afford 342b (3.41 g) in a 51.4% yield. MS m / z (ESI): 282 [M+1] +

[0630] Step 2: Compound 342b (3.41 g, 12.14 mmol), methyl fluorosulfonyldifluoroacetate (4.61 g, 24.00 mmol), and cuprous iodide (4.56 g, 24.00 mmol) were dispersed in 30 mL of N,N-dimethylformamide and stirred at 100°C for 4 hours. The reaction mixture was decanted to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford compound 342c (1.81 g) in a 66.9% yield. MS m / z (ESI): 224 [M+1] +

[0631] Step 3: Disperse 342c (1.40 g, 6.28 mmol), tert-butyl 1-methylhydrazine-1-carboxylate (1.75 g, 12.00 mmol), and sodium cyanoborohydride (756 mg, 12.00 mmol) in 20 mL of trifluoroethanol and stir for 16 hours. The reaction mixture was decanted to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 342d (1.21 g) in a 54.6% yield. MS m / z (ESI): 354 [M+1] +

[0632] Step 4: Compound 342d (650 mg, 1.84 mmol) and 4-((3,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid 342e (762 mg, 2.00 mmol) were dispersed in 10 mL of dichloromethane and 2 mL of pyridine. Phosphorus oxychloride (918 mg, 6.00 mmol) was added at 0°C and stirred for 2 hours. The reaction mixture was decanted to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford compound 342f (180 mg) in a 13.7% yield. MS m / z (ESI): 717 [M+1]. +

[0633] Referring to the synthesis method of step 8 of Example 8, Example 342 (21 mg) was obtained from 342f (60 mg, 0.08 mmol) in a yield of 53.7%. MS m / z (ESI): 467 [M+1] +

[0634] 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.96(s,1H),7.07(s,2H),5.66(s,1H ),5.40(s,2H),5.06(t,2H),4.81(dd,2H),4.40–4.03(m,2H),2.33(s,3H).

[0635] Example 351

[0636] 4-Amino-7-fluoro-N'-(trideuteriomethyl)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid hydrazide

[0637] Step 1: tert-Butyl 1-(methyl-d3)-2-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)hydrazinecarboxylate 351a (150 mg, 385.22 μmol) and 4-[(2,4-dimethoxyphenyl)methylamino]-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid (184.16 mg, 462.27 μmol) were dissolved in dichloroethane (5 mL). Pyridine (304.71 mg, 3.85 mmol, 310.33 μL) was added, and phosphorus oxychloride (177.20 mg, 1.16 mmol) was slowly added dropwise under ice bath and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with dichloromethane (10 mL x 3). The mixture was 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 351b (94.5 mg) in a 31.8% yield. MS m / z (ESI): 770 [M+1] +

[0638] Step 2: 351b (94.5 mg, 122.77 μmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 80°C for 1 hour. LCMS indicated the reaction was complete, and the reaction solution was dried to afford the crude product, which was purified by preparative liquid chromatography to afford Example 351 (30.2 mg) in a 47.3% yield. MS m / z (ESI): 520 [M+1] +

[0639] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.10(s,1H),7.64(s,1H),7.21(d,2H),6.53(s,2H),5.35(s,2H),5.03(s,5H),4.23(s,2H).

[0640] Example 354

[0641] 4-amino-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl-7-d)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide

[0642] Step 1: Dissolve 5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraen-10-one 354a (100 mg, 390.35 μmol) and tert-butyl N-amino-N-(trideuteriomethyl)carbamate (87.36 mg, 585.52 μmol) in methanol (1 mL). Add acetic acid (23.44 mg, 390.35 μmol) and stir at room temperature overnight. Then add NaBD3CN (29.44 mg, 468.42 μmol) and stir at 60°C for 48 h. During this period, NaBD3CN can be added as needed. After the reaction, the reaction solution was dried by rotary evaporation, extracted with EA, washed with saturated brine, and the organic phases were combined and dried over a column to obtain 354b (110 mg) with a yield of 72.4%. MS m / z(ESI):391[M+1] +

[0643] Step 2: 354b (127 mg, 325.31 μmol) and 4-[(2,4-dimethoxyphenyl)methylamino]-1,3-dihydrofurfuro[3,4-c][1,7]naphthyridine-8-carboxylic acid (223.32 mg, 585.56 μmol) were dissolved in DCE (1 mL). Pyridine (257.32 mg, 3.25 mmol, 262.07 μL) and POCl3 (149.64 mg, 975.94 μmol, 89.34 μL) were added and stirred at room temperature for 1 h. The reaction was quenched with water, extracted with DCM, and dried over a column to afford 354c (186 mg) in a 75.9% yield. MS m / z (ESI): 754 [M+1]. +

[0644] Step 3: 354c (180 mg, 238.80 μmol) was dissolved in TFA (5 mL) and stirred at 80°C for 1 h. LCMS indicated the reaction was complete. The reaction solution was then dried to give the crude product, which was purified by preparative liquid chromatography to afford Example 354 (41.4 mg) in a 34.4% yield. MS m / z (ESI): 504 [M+1] +

[0645] 1 H NMR (400MHz, DMSO-d6) δ8.98(d,1H),8.48(dd,1H),8.11(dd,4H),7.18(dd,1H),5.45(d,2H),5.10(s,2H),4.93(s,2H),4.23(d,2H).

[0646] Example 354 Preparation of Chiral Isomers

[0647] Example 354 (40 mg, 0.079 mmol) was separated by Chiral-HPLC (Condition 3) to give 354-P1: (R)-4-amino-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl-7-d)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine -8-carboxylic acid hydrazide (18.5 mg), yield: 46.3%; 354-P2: (S)-4-amino-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl-7-d)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide (18.8 mg), yield: 47.0%.

[0648] 354-P1(t R :4.968min): 1 H NMR (400MHz, DMSO-d6) δ8.98(d,1H),8.48(dd,1H),8.11(dd,4H),7.18(dd,1H),5.45(d,2H),5.10(s,2H),4.93(s,2H),4.23(d,2H).

[0649] 354-P2(t R :4.198min): 1H NMR (400MHz, DMSO-d6) δ8.98(d,1H),8.48(dd,1H),8.11(dd,4H),7.18(dd,1H),5.45(d,2H),5.10(s,2H),4.93(s,2H),4.23(d,2H).

[0650] Example 357

[0651] 4-amino-7-methyl-N'-methyl-d3-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid hydrazide

[0652] Step 1: To a single-necked flask were added methyl 4-amino-5-bromo-2-methylbenzoate 357a (11 g, 45.07 mmol), palladium acetate (505.89 mg, 2.25 mmol), n-butyldiphenylphosphine (1.09 g, 4.51 mmol), potassium acetate (8.85 g, 90.13 mmol), B2pin2 (22.89 g, 90.13 mmol), and 1'4-Dioxane (100 mL). The atmosphere was replaced with nitrogen and the reaction was continued at 100°C for 4 h. The reaction was quenched by cooling and the system was concentrated to dryness. The resulting residue was purified by normal phase column chromatography using eluent System A to afford 357b (6.37 g) in a 61.6% yield. MS m / z (ESI): 230 [M+1]. +

[0653] Step 2: To a single-necked flask were added 357b (2.29 g, 10.00 mmol), methyl 4-trifluoromethanesulfonyloxy-2,5-dihydrofuran-3-carboxylate (2.76 g, 10.00 mmol), Pd(dppf)Cl2 (731.68 mg, 999.97 μmol), Na2CO3 (2.12 g, 20.00 mmol), 1'4-Dioxane (20 mL), and water (4 mL). The atmosphere was replaced with N2 and the reaction was carried out at 100°C for 16 h. The reaction was quenched by cooling, concentrated, extracted with EA, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated to dryness. The resulting residue was purified by normal phase column chromatography using eluent System D to afford 357c (2.02 g, 7.25 mmol) in a 72.3% yield. MS m / z (ESI): 280 [M+1]. +

[0654] Referring to the synthesis method of steps 6 to 9 of Example 12, 357f (105 mg) was obtained from 357c (2.02 g, 7.25 mmol) in a yield of 2.8%. MS m / z (ESI): 516 [M+1] +

[0655] Step 6: To a single-necked flask were added 357f (590 mg, 750.44 μmol), methylboronic acid (135 mg, 2.25 mmol), cataCXiumA-Pd-G3 (55 mg, 75 μmol), Cs2CO3 (489 mg, 1.50 mmol), water (3 mL), and 1'4-dioxane (15 mL). The atmosphere was replaced with N2 and the reaction was carried out at 100°C for 12 h. The reaction was quenched by cooling and the system was concentrated to dryness to yield 357 g (350 mg, 457.04 μmol) in a 60.9% yield. MS m / z (ESI): 766 [M+1]. +

[0656] Referring to the synthesis method of step 10 of Example 12, 357 g (350 mg, 457 μmol) was used to obtain Example 357 (105 mg) with a yield of 44.5%. MS m / z (ESI): 516 [M+1] +

[0657] 1 H NMR(400MHz,DMSO-d6)δ8.48(m,1H),8.18(m,2H),7.38(m,2H),6.64(s,1H),6 .50(s,1H),5.51(s,1H),5.32(s,3H),4.96(m,5H),4.26(m,1H),2.38(s,2H).

[0658] Example 357 Preparation of Chiral Isomers

[0659] Example 357 (105 mg, 0.027 mmol) was subjected to chiral preparative HPLC separation (condition 1) to give rel-(S)-4-amino-7-methyl-N'-methyl-d3-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide Hydrazine 357-P1 (45 mg) in 42.9% yield and rel-(R)-4-amino-7-methyl-N'-methyl-d3-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid hydrazide 357-P2 (46 mg) in 43.8% yield.

[0660] 357-P1(t R :17.930min): 1 H NMR(400MHz,DMSO-d6)δ8.48(m,1H),8.18(m,2H),7.38(m,2H),6.64(s,1H),6 .50(s,1H),5.51(s,1H),5.32(s,3H),4.96(m,5H),4.26(m,1H),2.38(s,2H).

[0661] 357-P1(t R :21.680min): 1 H NMR(400MHz,DMSO-d6)δ8.48(m,1H),8.18(m,2H),7.38(m,2H),6.64(s,1H),6 .50(s,1H),5.51(s,1H),5.32(s,3H),4.96(m,5H),4.26(m,1H),2.38(s,2H).

[0662] Example 362

[0663] 4-Amino-3-methyl-N'-(trideuteriomethyl)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]naphthyridine-8-carboxylic acid hydrazide

[0664] Step 1: 3-Trifluoromethyl-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7(10H)-one 362a (200 mg, 780.70 μmol) and tert-butyl N-amino-N-(trideuteriomethyl)carbamate (128.13 mg, 858.77 μmol) were dissolved in methanol (2 mL). Acetic acid (46.88 mg, 780.70 μmol) and sodium cyanoborohydride (147.18 mg, 2.34 mmol) were added with stirring at room temperature. The reaction was stirred at 60°C for 3 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using petroleum ether / ethyl acetate (1:1) as eluent to obtain 362b (180 mg, 462.27 μmol). Yield: 59.2%. MS m / z (ESI): 390 [M+1]. +

[0665] Step 2: 362b (118.17 mg, 303.48 μmol) and 4-(tert-butoxycarbonylamino)-3-methyl-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid (87.34 mg, 252.90 μmol) were dissolved in 1,2-dichloroethane (2.2 mL). Pyridine (200.05 mg, 2.53 mmol, 203.73 μL) and phosphorus oxychloride (116.33 mg, 758.71 μmol) were added with stirring at 0°C. The reaction was stirred at room temperature for 1 h. LCMS monitored the reaction completion. After completion, water and saturated ammonium chloride solution were added to the system. The mixture was extracted three times with DCM (10 mL x 3) and washed with saturated sodium chloride. The organic phase was collected after standing, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (V:V=1:1) to afford 362c (120 mg, 167.43 μmol) in a 66.2% yield. MS m / z (ESI): 817 [M+1] +

[0666] Step 3: Dissolve 362c (120 mg, 146.91 μmol) in dichloromethane (1.5 mL). Add trifluoroacetic acid (16.75 mg, 146.91 μmol, 0.3 mL) with stirring at room temperature. Stir the mixture for 1 h. Remove the solvent under reduced pressure, and separate by HPLC to afford Example 362 (52.2 mg, 101.07 μmol) in a 68.8% yield. MS m / z (ESI): 517 [M+1]. +

[0667] 357-P1(t R :32.973min): 1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.40(d,1H),8.09(s,1H),7.95(s,1H),7.21-7.1 4(m,1H),6.78(s,2H),5.63-5.29(m,4H),4.99(s,2H),4.29-4.15(m,2H),1.47(d,3H).

[0668] 357-P2(t R :18.127min): 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.40(d,1H),8.09(s,1H),7.95(s,1H),7.21-7.1 4(m,1H),6.78(s,2H),5.63-5.29(m,4H),4.99(s,2H),4.29-4.15(m,2H),1.47(d,3H).

[0669] 357-P3(t R :22.473min): 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.40(d,1H),8.09(s,1H),7.95(s,1H),7.21-7.1 4(m,1H),6.78(s,2H),5.63-5.29(m,4H),4.99(s,2H),4.29-4.15(m,2H),1.47(d,3H).

[0670] 357-P4(t R :47.857min): 1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.40(d,1H),8.09(s,1H),7.95(s,1H),7.21-7.1 4(m,1H),6.78(s,2H),5.63-5.29(m,4H),4.99(s,2H),4.29-4.15(m,2H),1.47(d,3H).

[0671] Example 362 Preparation of Chiral Isomers

[0672] Example 362 (30 mg, 0.079 mmol) was separated by Chiral-HPLC to give 362-P1: (R)-4-amino-3-methyl-N'-(trideuteriomethyl)-N-((S)-3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuran 362-P2: (R)-4-amino-3-methyl-N'-(trideuteriomethyl)-N-((R)-3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]naphthyridine-8-carboxylic acid hydrazide (7 mg), yield: 23.3%; 362-P2: (R)-4-amino-3-methyl-N'-(trideuteriomethyl)-N-((R)-3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]naphthyridine-8 -formyl hydrazide (7 mg), yield: 23.3%; 362-P3: (S)-4-amino-3-methyl-N'-(trideuteriomethyl)-N-((S)-3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]naphthyridine-8-carboxylic acid hydrazide (6.7 mg) , yield: 22.3%; 362-P4: (S)-4-amino-3-methyl-N'-(trideuteriomethyl)-N-((R)-3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]naphthyridine-8-carboxylic acid hydrazide (6.3 mg), yield: 21.0%.

[0673] 1 H NMR(400MHz,DMSO-d6)δ8.86(d,1H),8.47(dd,1H),8.16(d,J=11.4Hz,1H),7.95(d,1H), 7.24-6.99(m,3H),5.53-5.26(m,4H),5.06-4.90(m,2H),4.28-4.07(m,2H),1.42(d,3H).

[0674] Example 371

[0675] 4-amino-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide

[0676] Step 1: Methyl 4-oxotetrahydrofuran-3-carboxylate 371a (27.98 g, 194.17 mmol) was dissolved in 280 mL of dichloromethane. N,N-diisopropylethylamine (27.60 g, 213.59 mmol) and trifluoromethanesulfonic anhydride (54.78 g, 194.17 mmol) were added sequentially under ice-cooling. The reaction was stirred at room temperature for approximately 16 hours. 300 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (300 mL x 2). The organic phase was 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 B to afford 371b (36 g) in a 67.0% yield. MS m / z (ESI): 277 [M+1]. +

[0677] Step 2: Methyl 5-amino-4-bromopicolinate 371c (36 g, 155.81 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (59.35 g, 233.72 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.80 g, 31.16 mmol), and potassium acetate (45.87 g, 467.44 mmol) were placed in a reaction flask. Toluene (360 mL) was added and the mixture was stirred at 90°C under nitrogen for 16 h. The reaction mixture was cooled, filtered, and the solid was washed with water to afford 371d (38.2 g) in an 88.2% yield. MS m / z (ESI): 197 [M+1]. +

[0678] Step 3: 371d (54 g, 194.17 mmol) was dissolved in dioxane (500 mL), and H2O (50 mL) was added. Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate 371b (53.63 g, 194.17 mmol), Pd(dppf)Cl2 (7.10 g, 9.71 mmol), and sodium carbonate (61.74 g, 582.50 mmol) were added, and the mixture was stirred at 90°C under nitrogen for 1 hour. The reaction mixture was cooled to room temperature, and the filtered solid was slurried with EA and then with water. The solid was dried to afford 371e (46.2 g) in a 96.6% yield. MS m / z (ESI): 247 [M+1] +

[0679] Step 4: Dissolve 371e (70 g, 284.30 mmol) in DMSO (700 mL), add 2,4-dimethoxybenzylamine (57.04 g, 341.16 mmol) and DBU (64.92 g, 426.45 mmol, 63.65 mL), and add BOP (188.61 g, 426.45 mmol) in portions under an ice bath. Warm to room temperature and stir for 2 hours. The reaction solution was slowly added dropwise to water (1 L). A large amount of solid precipitated and was filtered. The resulting solid was slurried with methanol to obtain 371f (77.6 g) in a 69.0% yield. MS m / z (ESI): 396 [M+1] +

[0680] Step 5: 371f (82.2 g, 207.89 mmol) was dissolved in a mixture of MeOH (25 mL), THF (25 mL), and H₂O (25 mL). Lithium hydroxide monohydrate (43.62 g, 1.04 mol) was added and the mixture was stirred at room temperature for 3 h. The organic phase was concentrated under reduced pressure and then slightly acidified by adding 2N HCl. A large amount of solid precipitated and was filtered to yield 371 g (73.6 g) in a 92.8% yield. MS m / z (ESI): 382 [M+1] +

[0681] Step 6: 2-Chloro-4-iodo-3-methylpyridine 371h (150 g, 591.79 mmol), palladium acetate (13.29 g, 59.18 mmol), 1,1'-bis(diphenylphosphino)ferrocene (32.75 g, 59.18 mmol), and sodium bicarbonate (149.14 g, 1.78 mol) were placed in a reactor. MeOH (500 mL) and DMF (500 mL) were added. The mixture was stirred under a CO atmosphere at 0.4 MPa and 80°C for 16 hours. The reaction mixture was added to water and extracted with EA. The organic phase was separated, dried, concentrated, and then purified by column chromatography to afford 371i (137 g) in a 62.4% yield. MS m / z (ESI): 186 [M+1]. +

[0682] Step 7: Dissolve 371i (73.04 g, 403.00 mmol) in 1,4-Dioxane (1700 mL), add Pd2(dba)3 (33.55 g, 36.64 mmol), Xantphos (42.40 g, 73.27 mmol), benzophenone imine (146 g, 806 mmol), and cesium carbonate (179.05 g, 549.55 mmol). Heat to 100°C under nitrogen and stir for 16 hours. The reaction mixture was cooled, filtered through celite, and the filtrate was concentrated. 400 mL of HCl (4 M in dioxane) and 200 mL of MeOH were added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was directly concentrated under reduced pressure, then adjusted to pH 8 with aqueous NaHCO3 solution. Extraction was performed with ethyl acetate, and the organic phase was separated, dried, concentrated, and separated by column chromatography to afford 371j (60 g) in a 49.3% yield. MS m / z(ESI):167[M+1] +

[0683] Step 8: Dissolve 371j (59 g, 284.03 mmol) in EtOH (590 mL), add 2-chloroacetaldehyde (83.61 g, 426.05 mmol) and NaHCO₃ (35.79 g, 426.05 mmol), and stir at 70°C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to afford 371k (34 g) in a 62.9% yield. MS m / z (ESI): 191 [M+1] +

[0684] Step 9: Dissolve 371k (34 g, 178.76 mmol) in acetonitrile (500 mL), add NIS (42.23 g, 187.70 mmol), and stir at room temperature for 1 hour. The reaction mixture was filtered to obtain solid 371l (56 g), with a yield of 99.1%. MS m / z (ESI): 317 [M+1] +

[0685] Step 10: Dissolve 371l (53 g, 167.67 mmol) and methyl 2,2-difluoro-2-fluorosulfonylacetate (96.64 g, 503.01 mmol) in DMF (600 mL) and add CuI (95.80 g, 503.01 mmol). Heat the reaction mixture to 100°C and stir for 16 h. Cool the reaction mixture, dilute it with EtOAc (200 mL), filter it, and extract the filtrate with water. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to afford 371m (17 g) in a 99.1% yield. MS m / z (ESI): 259 [M+1] +

[0686] Step 11: Dissolve 371m (17 g, 65.84 mmol) in carbon tetrachloride (200 mL), add NBS (14.06 g, 79.01 mmol) and azobisisobutyronitrile (2.16 g, 13.17 mmol). Stir the reaction at 80°C under a nitrogen atmosphere for 2 h. Cool the reaction mixture to room temperature and filter. The filter cake is washed with a small amount of dichloromethane. The filtrate is concentrated under reduced pressure and separated by column chromatography to afford 371n (22 g) in a 99.1% yield. MS m / z (ESI): 337 [M+1] +

[0687] Step 12: Dissolve methyl 2-hydroxyacetate (16.03 g, 177.99 mmol) in DMF (100 mL) and cool to 0°C. Add NaH (7.12 g, 177.99 mmol, 60% purity) in portions. Stir the reaction mixture at 0°C for 15 min. Then, add a solution of 371n (20 g, 59.33 mmol) in DMF (80 mL). Warm the mixture to room temperature and stir for 2 h. Pour the reaction mixture into saturated ammonium chloride solution and extract with ethyl acetate. Separate the organic phase, wash it once with saturated brine, dry it over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 371o. MS m / z (ESI): 315 [M+1]. +

[0688] Step 13: Dissolve 371o (14 g, 44.56 mmol) in EtOH (150 mL) and add HCl (12 M, 75 mL). Stir and react at 80°C for 2 h. The reaction mixture was concentrated under reduced pressure to remove ethanol. The pH was adjusted to 6 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 371p (6.2 g) in a yield of 54.3%. MS m / z (ESI): 257 [M+1] +

[0689] Step 14: Dissolve 371p (100 mg, 390.35 μmol) and tert-butyl N-amino-N-(trideuteriomethyl)carbamate (87.36 mg, 585.52 μmol) in methanol (1 mL). Add acetic acid (23.44 mg, 390.35 μmol) and stir at room temperature overnight. Then add NaBH3CN (29.44 mg, 468.42 μmol) and stir at 60°C for 48 h. After completion of the reaction, concentrate the reaction solution and extract with ethyl acetate. The organic phase is washed with saturated brine, separated, dried, concentrated, and separated by column chromatography to afford 371q (110 mg) in a yield of 72.4%. MS m / z (ESI): 390 [M+1]. +

[0690] Step 15: Dissolve 371q (100 mg, 256.81 μmol) and 371g (146.92 mg, 385.22 μmol) in DCE (896.56 μL), add pyridine (203.14 mg, 2.57 mmol, 206.88 μL), and slowly add POCl3 (118.13 mg, 770.44 μmol) dropwise in an ice bath. Stir at room temperature for 1 h. After completion of the reaction, quench with water and extract with DCM. The organic phase is separated, dried, concentrated, and then purified by column chromatography to afford 371r (190 mg) in a 98.3% yield. MS m / z (ESI): 721 [M+1]. +

[0691] Step 16: Dissolve 371r (190 mg, 252.41 μmol) in TFA (5 mL) and stir at 80°C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative liquid chromatography to afford Example 371 (30 mg) in a 57.1% yield. MS m / z (ESI): 503 [M+1] +

[0692] 1 H NMR (400MHz, DMSO-d6) δ8.97(d,1H),8.48(dd,1H),8.11(dd,3.72H),7.17(dd,1H),5.46(t,3H),5.13-4.91(m,4H),4.28-4.22(m,2H).

[0693] Example 371 Preparation of Chiral Isomers

[0694] Example 371 (19 mg, 0.079 mmol) was separated by Chiral-HPLC (Condition 3) to give 371-P1: (R)-4-amino-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine Pyridine-8-carboxylic acid hydrazide (6 mg), yield: 31.5%; 371-P2: (S)-4-amino-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carboxylic acid hydrazide (11.4 mg), yield: 57.9%.

[0695] 371-P1(t R :4.564min): 1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.48(dd,1H),8.15(d,1H),7.97(dd,1H),7.15(t,3H),5.63- 5.45(m,1H),5.43(s,2H),5.29(s,1H),5.06(s,2H),5.01(q,1H),4.93(s,1H),4.35-4.06(m,2H).

[0696] 371-P2(t R :4.277min): 1 H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.48(dd,1H),8.15(d,1H),7.97(dd,1H),7.15(t,3H),5.63- 5.45(m,1H),5.43(s,2H),5.29(s,1H),5.06(s,2H),5.01(q,1H),4.93(s,1H),4.35-4.06(m,2H).

[0697] Example 372

[0698] rel-(R)-4-amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide

[0699] Step 1: 3-(Pentafluorosulfanyl)phenol 372a (3 g, 13.63 mmol) was dissolved in toluene (30 mL). The atmosphere was purged with nitrogen three times and cooled to 0°C. Sodium hydroxide (981 mg, 24.53 mmol, 60% purity) was added and the reaction system was incubated at 0°C for 1 hour. Iodine (3.46 g, 13.63 mmol) was then added and the reaction was continued at 25°C for 15 hours. The reaction was quenched by addition of saturated aqueous sodium sulfite solution, extracted with ethyl acetate (80 mL x 3), 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 372b (4.60 g) in a 97.6% yield.

[0700] Step 2: Dissolve 372b (4.6 g, 13.29 mmol), potassium ethylene trifluoroborate (3.56 g, 26.59 mmol), and potassium carbonate (5.51 g, 39.88 mmol) in water (10 mL) and 1'4-dioxane (50 mL). The atmosphere was purged with nitrogen three times. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (981 mg, 1.33 mmol) was added, and the reaction system was incubated at 80°C for 3 hours. The reaction was quenched by adding water, extracted with ethyl acetate (80 mL x 3), 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 372c (3 g) in a 91.7% yield.

[0701] Step 3: 372c (1.3 g, 5.28 mmol), tetrabutylammonium iodide (390 mg, 1.06 mmol), and benzoic acid (709 mg, 5.81 mmol) were dissolved in 1,2-dichloroethane (15 mL). t-Butyl peroxide (1.43 g, 15.84 mmol, 1.53 mL) was added, and the reaction system was heated to 60°C in an air bath for 6 hours. The reaction was quenched with saturated sodium sulfite, extracted with ethyl acetate (50 mL x 3), 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 372d (0.6 g) in a 46.5% yield.

[0702] 1 H NMR (400MHz, CDCl3) δ8.07–8.00(m,2H),7.67–7.56(m,2H),7.44(t,2H),7.40–7.30(m,2H),6.51(dd,1H),4.83(dd,1H),4.75(dd,1H).

[0703] Step 4: Compound 372d (2.7 g, 7.37 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Sodium hydroxide (590 mg, 14.74 mmol) was added and the reaction mixture was allowed to react at 25°C for 2 h. The reaction mixture was quenched by addition of water and extracted with ethyl acetate (80 mL x 3). The mixture was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford (6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-ol 372e (1.80 g) in 93.1% yield.

[0704] 1H NMR (400MHz, CDCl3) δ7.49(d,1H),7.37(dd,1H),7.28(d,1H),5.42(dd,1H),4.65(dd,J 1H),4.53(dd,1H).

[0705] Step 5: Dissolve 372e (1.8 g, 6.87 mmol), tert-butyl (1,3-dioxoindole-2-yl)carbamate (2.16 g, 8.24 mmol), and triphenylphosphine (2.70 g, 10.30 mmol) in tetrahydrofuran (20 mL). The mixture was purged with nitrogen three times and cooled to 0°C. Diisopropyl azodicarboxylate (2.08 g, 10.30 mmol, 2.03 mL) was added. The mixture was concentrated and the residue was purified by silica gel column chromatography using eluent System B to afford 372f (1.7 g) in a 48.9% yield.

[0706] 1 H NMR (400MHz, CDCl3) δ7.91–7.73(m,4H),7.63(dd,1H),7.33–7.27(m,1H),7.12(dd,1H),6.17(dd,1H),5.04–4.97(m,1H),4.79(td,1H),1.39(d,9H).

[0707] Step 6: Dissolve 372f (1.7 g, 3.36 mmol) in dichloromethane (20 mL), replace nitrogen three times, and add 85% hydrazine hydrate (336.08 mg, 6.71 mmol, 0.35 mL). The reaction system was stirred at 25 ° C for 15 hours. The reaction was filtered and concentrated. The residue was dissolved in 5 mL of dichloromethane / petroleum ether (v / v = 1:3), filtered, and concentrated. This was repeated twice to give 372g (1.20 g, crude product). MS m / z (ESI): 377 [M+1] +

[0708] Step 7: Dissolve 372g (1.2g, 3.19mmol) and pyridine (504mg, 6.38mmol, 0.51mL) in dichloromethane (15mL). The atmosphere was purged with nitrogen three times. Benzyl chloroformate (816mg, 4.78mmol, 0.67mL) was added dropwise at 0°C. The reaction was stirred at 25°C for 2 hours. The reaction was quenched with water, extracted with ethyl acetate (80mL x 3), washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 372h (1.3g) in an 80.0% yield.

[0709] Step 8: 372h (1.3 g, 2.55 mmol) was dissolved in tetrahydrofuran (20 mL), purged with nitrogen three times, and cooled to 0°C. NaH (204 mg, 5.09 mmol, 60% purity) was added, and the reaction system was stirred at 0°C for 15 minutes. Iodomethane (542 mg, 3.82 mmol, 0.24 mL) was added, and the reaction system was stirred at 25°C for 2 hours. The reaction was quenched with water, extracted with ethyl acetate (80 mL × 3), 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 372i (0.9 g) in a 67.4% yield.

[0710] Step 9: 372i (0.9 g, 1.72 mmol) was dissolved in ethyl acetate (5 mL), and ethyl acetate hydrochloride (5 mL) was added. The reaction system was stirred at 25°C for 1 hour and concentrated to give 372j (0.7 g, crude product).

[0711] Step 10: 372k (108 mg, 0.28 mmol) and benzyl 1-methyl-2-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)hydrazine-1-carboxylate 372j (0.15 g, 0.35 mmol) were dissolved in dichloromethane (10 mL). The atmosphere was purged with nitrogen three times. Phosphine oxychloride (271 mg, 1.77 mmol, 0.16 mL) and pyridine (140 mg, 1.77 mmol, 0.14 mL) were added, and the reaction system was stirred at 25°C for 15 hours. The reaction was quenched with water, extracted with ethyl acetate (50 mL × 3), 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 A to afford 372l (80 mg) in a 28.7% yield. MS m / z (ESI): 788 [M+1]. +

[0712] Step 11: Dissolve 372l (60 mg, 76 μmol) in tetrahydrofuran (5 mL), add palladium on carbon (9 mg, 76 μmol), evacuate the hydrogen atmosphere three times, and stir the reaction system under a hydrogen balloon at 25°C for 1 hour. Filter and concentrate to obtain 372m (50 mg, crude product). MS m / z (ESI): 654 [M+1] +

[0713] Step 12: Dissolve 372m (50 mg, 76 μmol) in trifluoroacetic acid (2 mL). The nitrogen atmosphere was purged three times, and the reaction system was stirred at 80°C for 15 minutes. The mixture was concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford Example 372 (35 mg) in a 90.9% yield. MS m / z (ESI): 504 [M+1] +

[0714] 1 H NMR(400MHz,DMSO-d6)δ8.81(d,1H),8.10–7.65(m,2H),7.53–7.25(m,2H),7.07(s,2H) ),6.29–5.92(m,2H),5.33(s,2H),4.98(s,2H),4.81–4.49(m,2H),2.27–1.89(m,3H).

[0715] Example 372 Preparation of Chiral Isomers

[0716] Example 372 (35 mg, 0.07 mmol) was separated by chiral preparative HPLC (Condition 2) to give rel-(R)-4-amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide 372-P1 (14 mg), yield: 40.6% and rel-(R)-4-amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide 372-P2 (13 mg), yield: 36.0%.

[0717] 372-P1(t R :1.169min): 1 H NMR(400MHz,DMSO-d6)δ8.87(d,1H),7.87(d,2H),7.50–7.31(m,2H),7.15(s,2H) ),6.38–5.96(m,2H),5.40(s,2H),5.05(t,2H),4.85–4.52(m,2H),2.14(d,3H).

[0718] 372-P2(t R :1.856min): 1 H NMR(400MHz,DMSO-d6)δ8.87(d,1H),7.87(d,2H),7.50–7.33(m,2H),7.14(s,2H) ),6.37–5.98(m,2H),5.40(s,2H),5.05(s,2H),4.87–4.55(m,2H),2.14(d,3H).

[0719] Example 374

[0720] 4-Amino-N'-methyl-N-(2-pentafluorosulfanyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-hydrazide

[0721] Step 1: 5-Bromo-6-methyl-2(1H)-pyridone 374a (35 g, 186 mmol) and Lawesson's reagent (37.6 g, 93 mmol) were dissolved in toluene (350 mL). The reaction system was incubated at 110°C for 16 hours. The mixture was concentrated and filtered to afford 374b (30 g) in a 78.7% yield. MS m / z (ESI): 205 [M+1] +

[0722] Step 2: 374b (60 g, 294 mmol), ferric chloride (23.9 g, 147 mmol), and sodium iodide (22 g, 147 mmol) were dissolved in acetonitrile (600 mL). The reaction system was allowed to react open-air at 20°C for 16 hours. Saturated sodium thiosulfate was added to quench the mixture. After filtration, 800 mL of water and 2000 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 200 mL of saturated brine, then dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent System A to afford 374c (42 g) in a 48.3% yield. MS m / z (ESI): 591 [M+1]. +

[0723] Step 3: Dissolve 374c (18 g, 44.3 mmol), tetraethylammonium chloride (14.7 g, 88.6 mmol), and silver difluoride (129 g, 886 mmol) in dichloromethane (200 mL). In a sealed tube, react at 20°C for 16 hours. Filter and concentrate. The residue is purified by reverse-phase column chromatography using eluent System A to afford 374d (21.4 g) in 80.8% yield. MS m / z (ESI): 299 [M+1]. +

[0724] Step 4: 374d (10.5 g, 35.2 mmol), N-bromosuccinimide (6.27 g, 35.2 mmol), and azobisisobutyronitrile (1.15 g, 7 mmol) were dissolved in carbon tetrachloride (200 mL). The reaction system was reacted at 80°C for 16 hours. The mixture was concentrated, filtered, and quenched with ammonium chloride. 50 mL of water and 500 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 20 mL of saturated brine, then dried and spin-dried. The residue was purified by reverse phase column chromatography using eluent System A to afford 374e (4.7 g) in a 35.3% yield. MS m / z (ESI): 378 [M+1].+

[0725] Step 5: 374e (4.27 g, 11.3 mmol) and potassium carbonate (4.69 g, 40 mmol) were dissolved in dioxane (40 mL) and water (40 mL). The reaction system was reacted at 100°C for 16 hours. The mixture was concentrated. The residue was purified by reverse phase column chromatography using eluent System A to afford 374f (1.8 g) in a 50.6% yield. MS m / z (ESI): 315 [M+1] +

[0726] Step 6: Dissolve 374f (15 g, 47.7 mmol), tetrabutylammonium hydrogen sulfate (3.24 g, 9.5 mmol), and potassium hydroxide (5.35 g, 95.5 mmol) in allyl bromide (30 mL) and react at 20°C in a solvent-free environment for 16 hours. Water was added to quench the mixture, followed by the addition of 100 mL of water and 500 mL of ethyl acetate. The organic phase was washed three times with 50 mL of saturated brine, then dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent System A to afford 374f (13.5 g) in a 79.7% yield. MS m / z (ESI): 355 [M+1]. +

[0727] Step 7: 374g (22g, 62.1mmol), tris(o-methylphenyl)phosphine (11.3g, 37.2mmol), palladium acetate (2.78g, 12.4mmol), and cesium carbonate (24.2g, 74.5mmol) were dissolved in N,N-dimethylformamide (440mL). The reaction system was reacted at 90°C for 2 hours. Water was added to quench the mixture, and then 200mL of water and 1000mL of ethyl acetate were added to the mixture. The organic phase was washed three times with saturated brine (100mL each time), then dried and spin-dried. The residue was purified by reverse phase column chromatography using eluent system A to obtain 374h (11.1g) in a yield of 65.2%. MS m / z (ESI): 274[M+1]. +

[0728] Step 8: 374h (4 g, 14.6 mmol), N-methylmorpholine oxide (5.15 g, 43.9 mmol), and potassium osmate dihydrate (228 mg, 0.73 mmol) were dissolved in acetone (40 mL) and water (8 mL). The reaction system was reacted at 20°C for 16 hours. Water was added to quench the mixture, and after filtration, 50 mL of water and 300 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with saturated brine (20 mL each time), then dried and spin-dried. The residue was purified by reverse phase column chromatography using eluent System A to give 374i (3.5 g) in a yield of 77.8%. MS m / z (ESI): 308 [M+1]. +

[0729] Step 9: Dissolve 374i (3.5 g, 11.3 mmol) and sodium periodate (7.36 g, 34.1 mmol) in tetrahydrofuran (40 mL) and water (4 mL). The reaction system was incubated at 20°C for 4 hours. Filter and concentrate. The residue was purified by reverse phase column chromatography using eluent System A to afford 374j (2.86 g) in a 91.7% yield. MS m / z (ESI): 276 [M+1] +

[0730] Step 10: 374j (260 mg, 0.945 mmol), N-methyl-Boc hydrazine (276 mg, 1.89 mmol), and acetic acid (57 mg, 0.945 mmol) were dissolved in methanol (6 mL). The reaction system was reacted at 20°C for 16 hours. Water was added to quench the reaction. 10 mL of water and 100 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 10 mL of saturated brine, then dried and spin-dried. The residue was purified by reverse phase column chromatography using eluent System A to afford 374k (310 mg) in an 81.2% yield. MS m / z (ESI): 404 [M+1]. +

[0731] Step 11: 374k (310 mg, 0.77 mmol) and sodium borohydride (87 mg, 2.3 mmol) were dissolved in ethanol (6 mL). The reaction system was reacted at 20°C for 16 hours. Ammonium chloride was added to quench the reaction. Then, 10 mL of water and 100 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with saturated brine (10 mL each time), then dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent System A to afford 374l (220 mg) in a yield of 70.4%. MS m / z (ESI): 406 [M+1]. +

[0732] Step 12: 374l (45 mg, 0.11 mmol), 4-((2,4-dimethoxyphenyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthypyridine-8-carboxylic acid 374m (50 mg, 0.13 mmol), pyridine (70 mg, 0.88 mmol), and phosphorus oxychloride (100 mg, 0.66 mmol) were dissolved in N,N-dimethylacetamide (3 mL). The reaction system was reacted at 20°C for 16 hours. Ammonium chloride was added to quench the reaction. Then, 10 mL of water and 100 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 10 mL of saturated brine, dried, and spin-dried. The residue was purified by reverse phase column chromatography using eluent system A to afford 374n (29 mg) in a 34.3% yield. MS m / z (ESI): 769 [M+1]. +

[0733] Step 13: Dissolve 374n (29 mg, 0.034 mmol) in trifluoroacetic acid (4 mL). The atmosphere was purged with nitrogen three times and the reaction system was incubated at 90°C for 0.5 h. The residue was concentrated and purified by silica gel column chromatography using eluent System A to afford Example 374 (11.2 mg) in a 63.5% yield. MS m / z (ESI): 519 [M+1]. +

[0734] 1 HNMR(400MHz,DMSO-d6)δ8.85(s,1H),8.11(m,1H),7.99–7.90(m,2H),7.15(s,2H),5.64(m,1H),5.42–5.37(m ,2H),5.05(m,2H),4.88–4.79(m,1H),4.78–4.65(m,1H),4.25(m,1H),4.09(m,1H),2.47(s,2H),2.19(s,1H).

[0735] Example 375

[0736] 4-amino-N',1-dimethyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carbohydrazide

[0737] Referring to the synthesis method of steps 10 to 12 of Example 372, Example 375 (5 mg) was obtained from 4-(3,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxylic acid 375a (100 mg, 0.25 mmol) and benzyl 1-methyl-2-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)hydrazine-1-carboxylate 375b (108 mg, 0.25 mmol). The yield was 3.9%. MS m / z (ESI): 516 [M+1]. +

[0738] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.45(s,1H),8.30(s,1H),7.76(s,1H),7.50(s,2H),7 .40(dd,1H),7.30(s,1H),6.21(d,2H),5.31(s,1H),4.73(d,1H),4.40(s,3H),2.12(d,3H).

[0739] Example 375 Preparation of Chiral Isomers

[0740] Example 375 (130 mg, 0.25 mmol) was separated by chiral preparative HPLC (Condition 2) to give rel-(R)-4-amino-N',1-dimethyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carbohydrazide 375-P1 (33 mg), yield: 25.4% and rel-(R)-4-amino-N',1-dimethyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carbohydrazide 375-P2 (32 mg), yield: 24.6%.

[0741] 375-P1(t R :0.656min): 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.52(s,1H),8.37(s,1H),7.83(s,1H),7.57(s,2H), 7.49–7.44(m,1H),7.32(d,1H),6.29(d,2H),4.92–4.60(m,2H),4.47(s,3H),2.20(d,3H).

[0742] 375-P2(t R:0.911min): 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.52(s,1H),8.37(s,1H),7.83(s,1H),7.57(s,2H ),7.46(d,1H),7.37(s,1H),6.29(d,2H),4.94–4.61(m,2H),4.47(s,3H),2.33(s,3H).

[0743] Example 385

[0744] 4-Amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carbohydrazide

[0745] Referring to the synthesis method of steps 10 to 12 of Example 372, Example 385 (15 mg) was obtained from 4-(3,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid 385a (150 mg, 0.40 mmol) and benzyl 1-methyl-2-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)hydrazine-1-carboxylate 385b (166 mg, 0.40 mmol). The yield was 7.5%. MS m / z (ESI): 502 [M+1]. +

[0746] 1 H NMR(400MHz,DMSO-d6)δ9.28(d,1H),8.59(d,2H),7.93(s,1H),7.73(s,2H),7.54–7 .22(m,2H),6.08(d,2H),5.35(s,1H),4.78(d,1H),4.67–4.51(m,1H),2.13(dd,3H).

[0747] Example 385 Preparation of Chiral Isomers

[0748] Example 385 (110 mg, 0.22 mmol) was separated by chiral preparative HPLC (Condition 2) to give rel-(R)-4-amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carbohydrazide 385-P1 (43 mg), yield: 39.1% and rel-(R)-4-amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carbohydrazide 385-P2 (42 mg), yield: 38.2%.

[0749] 385-P1(t R :1.101min): 1 H NMR(400MHz,DMSO-d6)δ9.35(d,1H),8.65(d,2H),8.00(s,1H),7.80(s,2H),7.52–7 .32(m,2H),6.22(s,1H),6.10(s,1H),5.42(d,,1H),4.91–4.57(m,2H),2.20(d,3H).

[0750] 385-P2(t R :1.591min): 1 H NMR(400MHz,DMSO-d6)δ9.35(d,1H),8.66(d,2H),8.00(s,1H),7.80(s,2H),7.5 7–7.32(m,2H),6.16(d,2H),5.42(s,1H),4.89–4.57(m,2H),2.36–2.03(m,3H).

[0751] Example 387

[0752] 4-Amino-N'-methyl-N-(2-pentafluorosulfanyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrroline[3,4-e]pyrazoline-8-hydrazide

[0753] Step 1: 374l (50 mg, 0.123 mmol), 4-((2,4-dimethoxyphenyl)amino)imidazole[1,5-a]pyrazolone[3,4-e]pyrazoline-8-carboxylic acid 387a (47 mg, 0.123 mmol), pyridine (78 mg, 0.98 mmol), and phosphorus oxychloride (113 mg, 0.74 mmol) were dissolved in N,N-dimethylacetamide (3 mL). The reaction system was reacted at 20°C for 16 hours. The mixture was quenched by the addition of ammonium chloride. Then, 10 mL of water and 100 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 10 mL of saturated brine, dried, and spin-dried. The residue was purified by reverse phase column chromatography using eluent system A to afford 387b (50 mg) in a 53.0% yield. MS m / z (ESI): 767 [M+1]. +

[0754] Step 2: 387b (50 mg, 0.065 mmol) was dissolved in trifluoroacetic acid (4 mL). The atmosphere was purged with nitrogen three times and the reaction system was incubated at 90°C for 0.5 h. The residue was concentrated and purified by silica gel column chromatography using eluent System A to afford Example 387 (22 mg) in a 65.4% yield. MS m / z (ESI): 517 [M+1] +

[0755] 1 H NMR(400MHz,DMSO-d6)δ9.33(d,1H),8.66-8.54(m,2H),8.11(m,1H),8.01–7.92(m,2H),7.79(m,2H),5.63(t ,1H),5.41(m,1H),4.90–4.80(m,1H),4.79–4.66(m,1H),4.26(m,1H),4.11(m,1H),2.49(s,2H),2.26(m,1H).

[0756] Example 391

[0757] 4-amino-1-methyl-N'-(methyl-d3)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxylic acid hydrazide

[0758] Step 1: Dissolve methyl 5-amino-4-bromopyridine-2-carboxylate 391a (5 g, 17.31 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.32 g, 20.78 mmol), Pd(dppf)Cl2 (2.53 g, 3.46 mmol), and potassium phosphate (11.02 g, 51.94 mmol) in 100 mL of dioxane / water (5:1). The atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C for 2 h. LCMS confirmed the reaction was complete. The reaction mixture was cooled to room temperature, and the organic phase was directly separated and dried to afford the crude product. The crude product was purified by silica gel column chromatography using dichloromethane / methanol (v:v = 10:1) to afford a light brown solid. The brown solid product was purified again by reverse phase column chromatography and lyophilized to give 391b (3.5 g). Yield: 85%. MS m / z (ESI): 233 [M+1] +

[0759] Step 2: 391b (3.5 g, 15.07 mmol) and triphosgene (13.42 g, 45.21 mmol) were dissolved in 50 mL of THF. Triethylamine (6.3 mL, 45.31 mmol) was added dropwise to the reaction mixture at room temperature. The reaction mixture was heated to 80°C and stirred for 16 h. LCMS revealed a distinct product peak. The reaction mixture was cooled to room temperature and filtered. The residue was slurried with cold water and filtered again. The residue was dried to afford 391c (1 g) in a 25.7% yield. MS m / z (ESI): 259 [M+1] +

[0760] Step 3: 391c (1.0 g, 3.87 mmol) was dissolved in 10 ml of dimethyl sulfoxide, and (2,4-dimethoxyphenyl)methylamine (0.647 g, 3.87 mmol), BOP (1.71 g, 3.87 mmol), and DIEA (1.0 g, 7.74 mmol) were added. The reaction was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. 10 ml of water was added to the reaction solution, and the solid was precipitated and filtered to obtain a crude product. The crude product was dissolved in 10 ml of ethyl acetate, slurried, and filtered to obtain 391d (0.75 g) with a yield of 47.5%.

[0761] Step 4: Dissolve 391d (0.75 g, 1.84 mmol) in 5 mL of tetrahydrofuran, add 1 mL of water, and then add lithium hydroxide monohydrate (0.75 g, 17.87 mmol). Stir the mixture at room temperature for 16 h. LCMS confirms the reaction is complete. The reaction mixture is neutralized with 1N HCl and spin-dried to give the crude product. The crude product is purified by preparative liquid chromatography to afford 391e (80 mg) in an 11% yield.

[0762] Step 5: Dissolve 391e (50 mg, 0.127 mmol) in 5 ml of 1,2-dichloroethane, add tert-butyl N-(trideuteriomethyl)-N-[5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraen-10-yl]amino]carbamate (49.5 mg, 0.127 mmol), pyridine (0.1 g, 1.27 mmol), replace the nitrogen atmosphere three times, and slowly add phosphorus oxychloride (58.5 mg, 0.381 mmol) under nitrogen protection. React at room temperature for 16 h. LCMS shows that the reaction is complete. The reaction solution is spin-dried to obtain the crude product of 391f (0.1 g), which is used directly in the next step.

[0763] Step 6: Dissolve 391f (0.1 g, 0.130 mmol) in 5 mL of trifluoroacetic acid, heat to 80°C, and react for 0.5 h. LCMS indicated completion of the reaction. The solvent was removed from the reaction solution by spin drying to afford a crude product. The crude product was purified by preparative liquid chromatography to afford Example 391 (12 mg) in a 17.8% yield. MS m / z (ESI): 515 [M+1] +

[0764] 1 H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.57(s,1H),8.42(s,2H),8.10(s,1H),7.4 9(s,2H),7.23(d,1H),5.64(s,1H),4.99(s,2H),4.49(s,3H),4.35-4.17(m,2H).

[0765] Example 391 Preparation of Chiral Isomers

[0766] Example 391 (14 mg, 0.027 mmol) was subjected to chiral preparative HPLC separation (condition 2) to give rel-(S)-4-amino-1-methyl-N'-(methyl-d3)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxamide Hydrazine 391-P1 (6 mg) in 42.9% yield and rel-(R)-4-amino-1-methyl-N'-(methyl-d3)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c][1,7]naphthyridine-8-carboxylic acid hydrazide 391-P2 (6 mg) in 42.9% yield.

[0767] 391-P1(tR :5.738min): 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.57(s,1H),8.51(s,1H),8.49(d,1H),8.16(d,1H),7.89(br s,2H),7.21(dd,1H),5.56(d,1H),5.36(s,1H),5.03(q,1H),4.93(s,1H),4.49(s,3H),4.35-4.17(m,2H).

[0768] 391-P2(t R :4.953min): 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.57(d,1H),8.44(dd,1H),8.37(d,1H),8.16(d,1H),7.57(s,2H ),7.20(dd,1H),5.56(d,1H),5.36(s,1H),4.99(q,1H),4.94(s,1H),4.47(s,3H),4.35-4.07(m,2H).

[0769] Example 392

[0770] 4-Amino-N'-(trideuteriomethyl)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid hydrazide

[0771] Step 1: tert-Butyl 1-(methyl-d3)-2-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)hydrazinecarboxylate 392a (150 mg, 385.22 μmol) and 4-[(2,4-dimethoxyphenyl)methylamino]-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid (175.84 mg, 462.27 μmol) were dissolved in dichloroethane (5 mL). Pyridine (304.71 mg, 3.85 mmol, 310.33 μL) was added, and phosphorus oxychloride (177.20 mg, 1.16 mmol) was slowly added dropwise under ice bath and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with dichloromethane (10 mL x 3). The mixture was 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 392b (130 mg) in a 44.9% yield. MS m / z (ESI): 752 [M+1]+

[0772] Step 2: 392b (130 mg, 172.93 μmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 80°C for 1 hour. LCMS indicated the reaction was complete, and the reaction solution was dried to afford the crude product, which was purified by preparative liquid chromatography to afford Example 392 (28.1 mg) in a 32.4% yield. MS m / z (ESI): 502 [M+1] +

[0773] 1 H NMR(400MHz,DMSO-d6)δ8.38(d,1H),8.35–8.15(m,1H),8.11(s,1H),7.97(d,1H),7.93(s,1H),7 .77(d,1H),7.21(d,1H),5.47(s,2H),5.39–5.18(m,1H),5.12(s,2H),5.00(d,2H),4.26(s,2H).

[0774] Example 393

[0775] 4-Amino-7-fluoro-3-methyl-N'-(trideuteriomethyl)-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid hydrazide

[0776] Step 1: Methyl 4-amino-7-fluoro-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 393a (300 mg, 1.09 mmol) was dissolved in 10 mL of toluene. 2,4-Dimethoxybenzaldehyde (180 mg, 1.09 mmol) was added, along with a catalytic amount of acetic acid. The mixture was heated to 125°C and stirred for 16 h. The mixture was cooled to room temperature, and sodium cyanoborohydride (136 mg, 2.17 mmol) was slowly added. The reaction mixture was allowed to react at room temperature for 1 h. The reaction mixture was evaporated to dryness, and the residue was purified by column chromatography using eluent A to afford 393b (64 mg) in a 13.8% yield. MS m / z (ESI): 427 [M+1]. +

[0777] Step 2: Dissolve 393b (64 mg, 0.15 mmol) in 5 mL of tetrahydrofuran, add 1 mL of water, and hydrated lithium hydroxide (0.18 g, 0.45 mmol). Stir at room temperature for 16 h. The reaction mixture is adjusted to a neutral pH with 1N HCl solution, and the solvent is removed by spin drying to afford crude product 393c (62 mg), which is used directly in the next step. MS m / z (ESI): 413 [M+1] +

[0778] Step 3: 393c (62 mg, 0.150 mmol) was dissolved in 5 ml of 1,2-dichloroethane, and tert-butyl N-(trideuteriomethyl)-N-[5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraen-10-yl]amino]amino]carboxylate (87.8 mg, 0.225 mmol), tetramethylchlorouronium hexafluorophosphonate (50 mg, 0.180 mmol), and N-methylimidazole (60 mg, 0.750 mmol) were added. The mixture was reacted at room temperature for 1 hour. The solvent was removed by rotary evaporation, and the residue was purified by reverse phase chromatography to give 393d (28 mg) in a yield of 23.8%. MS m / z (ESI): 784 [M+1] +

[0779] Step 4: Dissolve 393d (28 mg, 0.036 mmol) in 5 mL of trifluoroacetic acid, heat to 80°C, and react for 0.5 h. LCMS indicated completion of the reaction. The reaction solution was spin-dried to remove the solvent to afford a crude product. The crude product was purified by preparative liquid chromatography to afford Example 393 (14 mg) in a 73.4% yield. MS m / z (ESI): 534 [M+1] +

[0780] 1 H NMR(400MHz, DMSO-d6)δ9.04(s,0.4H),8.62–7.97(m,3.5H),7.70(t,0.8H),7.55–7. 44(m,0.3H),7.32(d,1H),7.22(s,0.5H),6.79(dd,0.5H),5.85(s,0.5H),5.53–5.30 (m,1.5H),5.25–5.06(m,1H),4.81(m,,1H),4.62(d,1H),4.41(d,0.7H),3.99(d,0.5 H),3.93(s,0.4H),3.86(d,1.5H),3.77(s,0.2H),3.67(d,0.9H),1.47–1.34(m,3H).

[0781] The preparation of the following examples is shown in Table 371:

[0782] Alternatively, the following examples are prepared using the following method:

[0783] Example 394

[0784] 4-amino-7-chloro-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide

[0785] Referring to the second to fourth steps of Example 393, methyl 7-chloro-4-((3,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate 394a (200 mg, 466 μmol) was used to obtain Example 394 (67 mg) in a 26.8% yield. MS m / z (ESI): 536 [M+1]. +

[0786] 1 H NMR(400MHz,DMSO-d6)δ8.50(t,1H),8.21–8.10(m,1H),7.94–7.44(m,3H),7.22(dd ,1H),6.99(s,2H),5.34(t,2H),5.12–4.88(m,4H),4.60(d,1H),4.34–4.08(m,2H).

[0787] Example 395

[0788] 4-amino-1-ethyl-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrrolo[3,4-c]quinoline-8-carbohydrazide

[0789] Referring to the first to sixth steps of Example 391, methyl 4-amino-3-iodobenzoate 395a (2 g, 7.22 mmol) was used to give Example 395 (70 mg) in a 10.8% yield. MS m / z (ESI): 528 [M+1] +

[0790] 1 H NMR(400MHz,DMSO-d6)δ13.41(s,1H),8.95–8.29(m,4H),8.17(s,1H),7.98(d,1H),7.7 9(s,1H),7.28(s,1H),5.36(d,2H),5.16–4.79(m,4H),4.48–4.16(m,2H),1.50(t,3H).

[0791] Example 424

[0792] 4-Amino-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide

[0793] Step 1: A reaction mixture of 3-(trifluoromethyl)-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7(10H)-one 424a (500 mg, 1.95 mmol) and acetic acid (117 mg, 1.95 mmol) in methanol (10 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to afford 424b (600 mg) in a 91.3% yield. MS m / z (ESI): 371 [M+1] +

[0794] Step 2: A reaction mixture of 424b (500 mg, 1.35 mmol) and palladium hydroxide on carbon (500 mg, 20% palladium content, 55% water content) in tetrahydrofuran (20 mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction, the reaction mixture was filtered to remove solids. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to afford 424c (430 mg) in an 85.5% yield. MS m / z (ESI): 373 [M+1] +

[0795] Referring to the synthesis method of steps 5 to 6 of Example 391, Example 424 (20 mg) was obtained from 424c (80 mg, 0.22 mmol) in an 18.7% yield. MS m / z (ESI): 486 [M+1] +

[0796] 1 H NMR(400MHz,CD3OD)δ9.05(d,1H),8.41(m,1H),8.10(m,2H),7.28(m,1H),5.88(s,1H),5.40(m,2H),5.10(m,4H),4.31(m,2H)

[0797] Example 424 Preparation of Chiral Isomers

[0798] Example 424 (260 mg, 0.54 mmol) was separated by chiral preparative HPLC (condition 2) to give: (S)-4-amino-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide 424-P1 (80 mg) in 90.8% yield and (R)-4-amino-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthyridine-8-carbohydrazide 424-P2 (80 mg) in 80.8% yield.

[0799] 424-P1(t R :1.732min): 1 H NMR (400MHz, CD3OD) δ9.05(d,1H),8.41(m,1H),8.10(m,2H),7.28(m,1H),5.88(s,1H),5.40(m,2H),5.10(m,4H),4.31(m,2H).

[0800] 424-P2(t R :2.891min): 1 H NMR (400MHz, CD3OD) δ9.05(d,1H),8.41(m,1H),8.10(m,2H),7.28(m,1H),5.88(s,1H),5.40(m,2H),5.10(m,4H),4.31(m,2H).

[0801] Example 435

[0802] 4-Amino-7-chloro-1-methyl-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide

[0803] Referring to the synthesis method from steps 5 to 6 of Example 391, Example 435 (30 mg) was obtained from 7-chloro-4-((3,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 435a (200 mg, 0.47 mmol) in an 11.7% yield. MS m / z (ESI): 548 [M+1]. +

[0804] 1H NMR (400MHz, CD3OD) δ8.45(m,3H),8.07(d,1H),7.80(s,1H),7.38(d,1H),5.72(s,1H),5.25(d,1H),5.01(d,1H),4.53(m,4H),4.29(m,1H)

[0805] Example 436

[0806] 4-amino-1-methyl-N'-(trideuteriomethyl)-N-(3-(trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid hydrazide

[0807] Referring to the first to third steps of Example 391, methyl 4-amino-3-bromobenzoate 436a (8.00 g, 34.96 mmol) was used to obtain 436d (9.68 g) in a 68.0% yield. MS m / z (ESI): 407 [M+1] +

[0808] Step 4: Disperse 436d (9.68 g, 23.84 mmol) and lithium hydroxide (1.92 g, 80.00 mmol) in 80 mL of methanol and 16 mL of water. Stir and react at 25°C for 16 hours. The reaction solution was adjusted to a neutral pH with hydrochloric acid. A solid precipitated and was filtered to afford 436e (7.62 g) in an 81.5% yield. MS m / z (ESI): 393 [M+1] +

[0809] Referring to the third and fourth steps of Example 393, Example 436 (80 mg) was obtained from 436e (1.6 g, 4.08 mmol) in a yield of 3.8%. MS m / z (ESI): 514 [M+1] +

[0810] 1 H NMR (400MHz, DMSO-d6) δ8.44(dd,3H),8.15(d,1H),7.76(d,3H),7.24(s,1H),5.10(d,3H),4.36(d,5H).

[0811] Example 436 Preparation of Chiral Isomers

[0812] Example 436 (70 mg, 0.14 mmol) was separated by Chiral-HPLC (Condition 2) to give 436-P1: (S)-4-amino-1-methyl-N'-(trideuteriomethyl)-N-(3-(trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline; Quinoline-8-carboxylic acid hydrazide (22 mg), yield: 31.4%; 436-P2: (R)-4-amino-1-methyl-N'-(trideuteriomethyl)-N-(3-(trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid hydrazide (23 mg), yield: 32.9%.

[0813] 436-P1(t R :2.850min): 1 H NMR (400MHz, DMSO-d6) δ8.44(dd,3H),8.15(d,1H),7.76(d,3H),7.24(s,1H),5.10(d,3H),4.36(d,5H).

[0814] 436-P2(t R :3.204min): 1 H NMR (400MHz, DMSO-d6) δ8.44(dd,3H),8.15(d,1H),7.76(d,3H),7.24(s,1H),5.10(d,3H),4.36(d,5H).

[0815] Example 440

[0816] 4-amino-3-chloro-1-methyl-N'-(methyl-d3)-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid hydrazide

[0817] From the first step to the second step of the method of Example 391, 4-amino-3-bromobenzyl ester 440a (5 g, 21.82 mmol) was used to obtain 440c (4.1 g) in a yield of 73.1%. MS m / z (ESI): 258 [M+1] +

[0818] Step ...

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 -; M3 is selected from N or C; 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; more preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6- 10 Condensed cycloalkyl, 6-10 membered condensed heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 C(S)-、-(CR aa R bb ) m2 C(NR cc )-、-(CR aa R bb ) m2 NR cc C(O)-、-(CR aa R bb ) m2 S(O) m1 -、-(CR aa R bb ) m2 NR cc -、-(CR aa R bb ) m2 P(O)2-、-(CR aa R bb ) m2 P(O)(OR cc )-、C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; more preferably self-bond, -CR aa R bb -、-C(O)-、-NR cc C(O), -S(O) m1 -or-NR cc -; more preferably -CR aa R bb -、-C(O)-、-S(O) m1 -or-NR cc -; L2 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; preferably self-bond, -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc More preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ; R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-12 Aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e 、-NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-N=S(O)R e R f 、-S(O)R e (=NR f ) or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 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 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12 membered heterocyclic group, -Y1-C 6-12 Aryl, -Y1-5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h 、-C(=NR i )NR g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1- 6Alkyl, 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, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h 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, 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 More preferably, it is substituted by one or more substituents of 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 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 heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6 alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 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 R a With R b Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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; Y1 is selected from a bond, -O-, -S-, -C(O), -NR j -、-C(O)NR j -、-NR j C(O)-、-S(O)2NR j -、-NR j S(O)2-、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -NR j -C 1-6 Alkylene-, -C 1-6 Alkylene-NR j -、C 2- 6 alkenylene or C 2-6 Alkyne, the C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 g , R h , R i and R j are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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, R g With R h Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 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; R gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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; m2 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and n2 is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Said Selected from 3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula is further shown in general formula (II): R 1-2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents; preferably selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl and cyano substituted C 1-3 Alkyl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine 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, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, 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, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl and cyano substituted C 1-3 Alkyl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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, R 1-2 With R 1-3 The 3-10 membered heterocyclic group is linked to form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents; 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 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R gg and R hh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; n2 is selected from 0, 1, 2, 3 or 4; n3 is selected from 0, 1, 2, 3 or 4; Ring A, Ring B, M1, M2, M3, L2, R2, R3, R c , x and y are as defined in claim 1.

4. A compound represented by the general formula (III) or (III-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: X1 is selected from O or CH2; X2 is selected from C or N; X3 is selected from C or N; X4 is selected from CH or N; X5 is selected from CH or N; X6 from CR 4a NR 4a or N; X7 from CR 4b NR 4b or N; Or, R 4a With R 4b Link to form ring A; Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R 2c replaced by; Ring F is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 2c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 3e and R 3g 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, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -OR a1 、-NR a1 R a2 、-C(O)R a1 、-C(O)NR a1 R a2 、-N=S(O)R a1 R a2 、-S(O)R a1 (=NR a2 )、-P(O)R a1 R a2 or =R a1 R a2 , 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 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 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 a3 R a4 is substituted by one or more substituents; Or, two R 3e Link Form C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, =N-OR a5 , =CR a5 CR a6 、-S(O)R a5 (=NR a6 ) and -N=S(O)R a5 R a6 One or more substitutions in; R 3f is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -(CR b1 R b2 ) n6 -C 3-8 Cycloalkyl, -(CR b1 R b2 ) n6 -3-8 membered heterocyclic group, -(CR b1 R b2 ) n6 -C 6-10 Aryl, -(CR b1 R b2 ) n6 -5-10 membered heteroaryl, -SF5, -OR b1 、-NR b1 R b2 、-C(O)R b1 、-C(O)NR b1 R b2 , =N-OR b1 , =CR b1 CR b2 、-S(O)R b1 (=NR b2 ) and -N=S(O)R b1 R b2 , the 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl and 5-10 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 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 b3 CR b4 Preferably, the alkyl group is substituted by one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -OR b1 、-NR b1 R b2 、-C(O)R b1 、-C(O)NR b1 R b2 , =N-OR b1 , =CR b1 CR b2 、-S(O)R b1 (=NR b2 ) and -N=S(O)R b1 R b2 ; Or, two R 3f Link Form C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; R 4a 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; R 4b 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR c1 、-C(O)R c1 、-C(O)OR c1 、-NR c1 R c2 、-P(O)R c1 R c2 、-NR c3 C(O)R c1 、-C(O)NR c1 R c2 、-S(O)2R c1 、-S(O)2NR c1 R c2 、-NR c3 S(O)2R c1 、-S(O)R c1 (=NR c3 ) or -N=S(O)R c1 R c2 , 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; R a1 , R a2 , R a3 , R a4 , R a5 and R a6 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; R b1 , R b2 , R b3 and R b4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; R c1 , R c2 and R c3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1- 6-alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; a is selected from 0, 1, 2, 3 or 4; b is selected from 0, 1, 2, 3 or 4; c is selected from 0, 1, 2, 3 or 4; and n6 is selected from 0, 1, 2, 3 or 4; M1, M2, R1, R c , R ee , R ff and n2 are as defined in claim 1.

5. The compound according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula is further shown in general formula (IV) or (IV-1): R 1-2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents; R 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents; Or, R 1-2 With R 1-3 The 3-10 membered heterocyclic group is linked to form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula is further shown in general formula (V) or (V-1): Ring A, Ring F, X2, X3, R 2c , R 3e , R 3g , R 3f , a, b and c are as defined in claim 4; R 1-2 and R 1-3 as defined in claim 3 or 5; M1, M2, M3, R c and x are as defined in claim 1.

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 8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula is further shown in general formula (VI):

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring B is selected from 3-6 membered heterocyclyl and phenyl or 3-6 membered heterocyclyl and 5-6 membered heteroaryl; preferably Or, Ring B is selected from a 6-14 membered tricyclic heterocyclic group; preferably a 6-14 membered tricyclic spiro heterocyclic group or a 6-14 membered tricyclic fused heterocyclic group; more preferably 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula is further shown in general formula (VI) or (VI-A): M4 is N or R 3a ; X2 is C or N; X3 is C or N; R 3a , 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, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and -SF5, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, 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 is substituted by one or more substituents; R 3b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and -SF5, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1- 6-Hydroxyalkyl, cyano-substituted C 1-6 Alkyl, 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 is substituted by one or more substituents; n5 is selected from 0, 1 or 2.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 or R 2c 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, 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; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl; R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl; R b Selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and =CR gg R hh Preferably, hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 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 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents selected from aryl and 5-10 membered heteroaryl; n2 is selected from 0, 1 or 2; preferably hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, 12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R3 and R 3f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl or -SF5, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 3e and R 3g are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl group and the 5- to 12-membered heteroaryl group may be substituted by one or more substituents.

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

14. A compound represented by general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Preferably, the compound represented by the general formula (VII-1), its stereoisomer or a pharmaceutically acceptable salt thereof: n4 is selected from 0 or 1; X2, X3, R 1-2 , R 1-3 , R 3e , R 3f , R 3g , a, b, c and n4 are as defined in claim 3 or 4.

15. The compound according to claim 13, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

16. A method for preparing a compound represented by general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (III-I) reacts with the compound represented by the general formula (III-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (III-III), and the protecting group is further removed to obtain the compound represented by the general formula (III); Preferably, the method is a method for preparing a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (IV-I) reacts with the compound represented by the general formula (IV-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV); More preferably, the method is a method for preparing a compound represented by general formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (VI) reacts with the compound represented by the general formula (V-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (V-III), 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, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; M1, M2, M3, R a , R b and R c As defined in claim 1; X2, X3, R 1-2 , R 1-3 , R 2c , R 3e , R 3f , R 3g , a, b, c, x and n4 are as defined in claim 3 or 4.

17. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 13, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a PRMT5 inhibitor drug.

19. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a drug for treating cancer.

20. The use according to claim 19, characterized in that The cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.