Tricyclic derivative inhibitors, methods for manufacturing the same, and applications

Abstract

The invention relates to tricyclic derivative inhibitors, methods for manufacturing the same, and applications. In particular, the invention relates to tricyclic derivative compounds, methods for manufacturing the same, pharmaceutical compositions comprising said compounds, and uses thereof in cancer treatment.

Description

Technology Field

[0001] The present invention belongs to the field of drug synthesis and, specifically, relates to a tricyclic derivative inhibitor and a method for manufacturing the same and its applications. Background Technology

[0002] Protein arginine methyltransferases (PRMTs) are classified into three main categories—Type I, Type II, and Type III—based on catalytic activity and product type. Type I includes PRMT1 / 2 / 3 / 4 / 6 / 8, which primarily 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 includes only PRMT7, which is responsible for catalyzing the formation of monomethylarginine (MMA) from substrates. PRMT5, which uses S-adenosyl-L-methionine (SAM) as a methyl donor, transfers methyl groups onto substrates such as DNA, RNA, and histones. By causing symmetric dimethylation of arginine residues on the substrates to produce SDMA, it regulates several key cellular processes, including transcription, translation, and DNA repair, thereby maintaining cellular homeostasis. At the same time, it is involved in regulating the growth and survival pathways of tumor cells and can promote tumorigenesis and progression. Increased expression of PRMT5 has also been proven to correlate with poor prognosis in various cancers, making it a very promising epigenetic target.

[0003] Methylthioadenosine phosphorylase (MTAP) catalyzes the production of methionine from methylthioadenosine (MTA), which is essential for maintaining normal cell function. Deletion mutations in the MTAP gene cause MTA to accumulate within cells; as MTA competes with SAM, a substrate of PRMT5, PRMT5 activity is reduced, and large amounts of PRMT5-MTA complexes are generated. Deletion of the MTAP gene increases tumor dependence on PRMT5, and inhibiting PRMT5 in tumors lacking MTAP can induce a "synthetic lethality" effect. PARP inhibitors based on this "synthetic lethality" theory have achieved great success in the field of precision therapy in oncology. The MTAP gene is adjacent to CDKN2A, the most common tumor suppressor gene in human cancers, and is frequently co-deleted with CDKN2A. This co-deletion accounts for 10% to 15% of all cancers and occurs mainly in non-small cell lung cancer (12% to 20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), so the market outlook is enormous.

[0004] There are currently no PRMT5 inhibitors on the market, and all early PRMT5 inhibitors were non-selective substrate SAM competitive inhibitors, exhibiting severe hematotoxic side effects and a narrow safety margin in clinical trials. Clinical progress for first-generation PRMT5 inhibitors, such as GSK-3326595, JNJ-64619178, and PF-06939999, was poor. Next-generation PRMT5 inhibitors targeting the PRMT5-MTA complex are effective only in tumors where MTAP is deleted and MTA is enriched, exhibit relatively high selectivity for the wild-type MTAP, and mechanistically reduce hematotoxicity; furthermore, as verified in preclinical studies, they are expected to have a significantly improved safety margin.

[0005] This patent relates to a novel PRMT5-MTA selective inhibitor that exhibits activity only against MTAP-deficient cells and has weak inhibition against MTAP wild-type cells, thereby avoiding side effects such as hematotoxicity caused by inhibition of MTAP wild-type cells by non-selective PRMT5 inhibitors in clinical practice. As a novel PRMT5-MTA inhibitor, this highly selective PRMT5-MTA inhibitor can be used to treat diseases such as various tumors and cancers.

[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]

[0008] M1 is -N- or -CR a Selected from;

[0009] M2 is -N- or -CR b Selected from;

[0010] M3 is selected from N or C;

[0011] Ring A is C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl; preferably C 3-6 It is a cycloalkyl, 3-6-membered heterocyclyl, phenyl, or 5-6-membered heteroaryl;

[0012] Ring B is C 3-14 Cycloalkyl, 3-14-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl; preferably C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is an aryl or a 5-12-membered heteroaryl; more preferably C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-10Fused cycloalkyl, 6-10 fused heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl;

[0013] L1 is binding, -(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 Selected from arylene or 5-12-membered heteroarylene, and C 3-12 Cycloalkylene, 3-12-membered heterocyclylene, C 6-12 Arlylenes and 5-12-membered heteroarylenes are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; preferably -CR aa R bb -, -C(O)-, -S(O) m1 - or NR cc And;

[0014] L2 is binding, -(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 Selected from -; preferably -CR aa R bb -, -C(O)-, -S(O) m1 - or NR cc is;

[0015] R1 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 prion heterocyclil, -(CRcc R dd ) n1 -C 6-12 Aril, -(CR cc R dd ) n1 -5-12 prion 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hhSubstituted with one or more of the following substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8-won heterocyclil, -(CR cc R dd ) n1 -C 6-10 Aril, -(CR cc R dd ) n1 -5-10 won heteroaryl, -OR e , -NR e R f , -C(O)R e , -C(O)NR e R f or -P(O)R e R f and, the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

[0016] R2 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

[0017] R3 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12-membered heterocyclyl, -Y1-C 6-12 Aryl, -Y1-5-12-won 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 Rh Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f Substituted with one or more of the following substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl, 5-10 synonymous heteroaryl and =CR e R f Substituted with one or more of the substituents;

[0018] Or any two R3s are connected to atoms adjacent to them, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Forms aryl and 5-12-membered heteroaryls, and optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is further substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; preferably C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Forms aryl and 5-10-membered heteroaryls, and optionally deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is additionally substituted with one or more substituents selected from aryls and 5-10-membered heteroaryls;

[0019] R a , R b , R c , R e and R f Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the following substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents of aryl and 5-10-membered heteroaryl;

[0020] or R a is R b Connected to C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12Forms aryl and 5-12-membered heteroaryls, and optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is additionally substituted with one or more substituents selected from aryls and 5-12-membered heteroaryls;

[0021] Y1 is bonded, -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 Selected from alkynylene, and the above C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylene is optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl;

[0022] R g , R h , R i and R j Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

[0023] R aa , R bb , R cc and R dd Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

[0024] R eeand R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

[0025] R gg and R hh Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

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

[0027] y is selected from 0, 1, 2, 3, 4, 5, or 6;

[0028] m1 is selected from 0, 1, or 2;

[0029] m2 is selected from 0, 1, or 2;

[0030] n1 is selected from 0, 1, 2, 3, or 4;

[0031] n2 is selected from 0, 1, 2, 3, or 4.

[0032] In one preferred embodiment of the present invention, regarding the compound, its stereoisomer, or its pharmaceutically acceptable salt,

[0033] The above Is or It is characterized by being selected from.

[0034] In one preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further represented by the general formula (II), and

[0035]

[0036] R 1-2 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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)Ree R ff , -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents;

[0037] R 1-3 Silver, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents;

[0038] Or, R 1-2 is R 1-3 Connected to form a 3-10-membered heterocyclyl, and the 3-10-membered heterocyclyl is optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents;

[0039] R ee and R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl;

[0040] R gg and R hh Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl;

[0041] n2 is selected from 0, 1, 2, 3, or 4;

[0042] n3 is selected from 0, 1, 2, 3, or 4;

[0043] Ring A, Ring B, M1, M2, M3, L2, R2, R3, R c The definitions of , x and y are characterized as being as defined in any one of the embodiments described above.

[0044] The present invention further 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 as follows.

[0045]

[0046] X1 is selected from O or CH2;

[0047] X2 is selected from C or N;

[0048] X3 is selected from C or N;

[0049] X4 is selected from CH or N;

[0050] X5 is selected from CH or N;

[0051] X6 is CR 4a , NR 4a or selected from N; preferably CR 4a or N and;

[0052] X7 is CR 4b , NR 4b or selected from N; preferably CR 4b or N;

[0053] Or, R 4a is R 4b Connected to form ring A;

[0054] Ring A is C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl, optionally 0, 1, 2, 3, 4, 5, or 6 R 2c It is replaced with;

[0055] Ring F is C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl;

[0056] R 2c is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C3-12 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl;

[0057] R 3e and R 3gEach independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl, 5-10 prion 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 Selected from, and the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR a3 R a4 Substituted with one or more of the substituents;

[0058] Or, 2 Rs 3e C is connected 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Forming an aryl or 5-10-membered heteroaryl, and the above C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls selectively accept hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, -SF5, =N-OR a5 , =CR a5 CR a6 , -S(O)R a5 (=NR a6 ) and -N=S(O)R a5 R a6 It may be additionally replaced with one or more of the following;

[0059] R 3f is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, -(CR b1 R b2 ) n6 -C 3-8 Cycloalkyl, -(CR b1 R b2 ) n6 -3-8-won heterocyclil, -(CR b1 R b2 ) n6 -C 6-10 Aril, -(CR b1 R b2 ) n6 -5-10 prion 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 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls selectively accept deuterium, halogen, amino, hydroxyl, cyano, nitro, and C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR b3 CR b4 Substituted with one or more of the following substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl, 5-10 prion 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 This or;

[0060] Or, 2 Rs 3f C is connected 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Forming an aryl or 5-10-membered heteroaryl, and the above C3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls selectively accept hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0061] R 4a is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0062] R 4b is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl, 5-14 prismatic 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)2NRc1 R c2 , -NR c3 S(O)2R c1 , -S(O)R c1 (=NR c3 ) or -N=S(O)R c1 R c2 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0063] R a1 , R a2 , R a3 , R a4 , R a5 and R a6 Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0064] R b1 , R b2 , R b3 and R b4Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0065] R c1 , R c2 and R c3 Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0066] a is selected from 0, 1, 2, 3, or 4;

[0067] b is selected from 0, 1, 2, 3, or 4;

[0068] c is selected from 0, 1, 2, 3, or 4;

[0069] n6 is selected from 0, 1, 2, 3, or 4;

[0070] M1, M2, R1, R c , R ee , R ff The definitions of and n2 are as described in any one of the embodiments above.

[0071] In one preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further represented by the general formula (IV) or (IV-1), and

[0072]

[0073] R 1-2 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents;

[0074] R 1-3 Silver, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents;

[0075] Or, R 1-2 is R 1-3 Connected to form a 3-10-membered heterocyclyl, and the 3-10-membered heterocyclyl is optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents;

[0076] 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 characterized as being as defined in any one of the embodiments described above.

[0077] In one preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further represented by the general formula (V) or (V-1), and

[0078]

[0079] 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 The definitions of , x, a, b and c are characterized as being as defined in any one of the embodiments described above.

[0080] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, ring A is selected from 3-12-membered heterocyclyl or 5-12-membered heteroaryl; preferably 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl; more preferably or and; more preferably or It is characterized by being.

[0081] In one preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further represented by the general formula (V-2), and

[0082]

[0083] Ring A' is selected from 3-8-membered heterocyclil or 5-10-membered heteroaryl; preferably, it is 5-membered heterocyclil, 6-membered heterocyclil, 5-membered heteroaryl or 6-membered heteroaryl;

[0084] R 2dis hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl, 5-14 prion 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be additionally substituted with one or more of aryls and 5-10-membered heteroaryls;

[0085] R ee and R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl;

[0086] n2 is selected from 0, 1, or 2;

[0087] d is selected from 0, 1, 2, 3, or 4;

[0088] 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 characterized as being as defined in any one of the embodiments described above.

[0089] In one preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further characterized by being represented by the general formula (VI).

[0090]

[0091] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, ring B is selected from 3-6-membered heterocyclyl conjugated phenyl or 3-6-membered heterocyclyl conjugated 5-6-membered heteroaryl; preferably or It is characterized by being.

[0092] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, ring B is selected from 6-14-membered tricyclic heterocyclils; preferably, it is a 6-14-membered tricyclic spiroheterocyclil or a 6-14-membered tricyclic fused heterocyclil; more preferably or It is characterized by being.

[0093] In one preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt is further represented by the general formula (VI-A) or (VI-B), and

[0094]

[0095] M4 is N or R 3a Selected from;

[0096] X2 and X3 are selected from C or N;

[0097] R 3a , R 3c and R 3d Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl, 5-12-membered heteroaryl and -SF5, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f Substituted with one or more of the substituents;

[0098] R 3b is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl, 5-12-membered heteroaryl and -SF5, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f Substituted with one or more of the substituents;

[0099] n5 is characterized by being selected from 0, 1, or 2.

[0100] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, R2 or R 2c Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl or -C(O)NR ee R ff Selected from, and the amino, C 1-3Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Cycloalkyl groups are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Substituted with one or more cycloalkyl substituents;

[0101] R ee and R ff are independently hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano 1-3 Selected from alkyls;

[0102] Preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuteride methyl, difluoromethyl, trifluoromethyl, or It is characterized by being.

[0103] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, R a is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3It is selected from alkyl; preferably characterized as being hydrogen, deuterium, fluorine, chlorine, methyl, deuteride methyl, difluoromethyl, or trifluoromethyl.

[0104] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, R b is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, --(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 Selected from, and the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8-membered heterocyclyls are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl and =CR gg R hh It is substituted with one or more of the following substituents; preferably hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, -(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 and, the above amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8-membered heterocyclyls are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Substituted with one or more substituents selected from cycloalkyl or 3-8-membered heterocyclyl;

[0105] R ee and R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Selected from cycloalkyl or 3-8-membered heterocyclyl, and said amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8Cycloalkyl and 3-8-membered heterocyclyls are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryl and 5-10-membered heteroaryl;

[0106] n2 is selected from 0, 1, or 2;

[0107] Preferably hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuteride methyl, deuteride ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuteride methoxy, difluoromethoxy, trifluoromethoxy, or It is characterized by being.

[0108] In one preferred embodiment of the present invention, in the compound, its stereoisomer, or its pharmaceutically acceptable salt, R3 and R 3f Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C6-10 Selected from aryl, 5-10-membered heteroaryl or -SF5, and said amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl;

[0109] R 3e and R 3g Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10Selected from aryl or 5-10-membered heteroaryl, and said amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is characterized by being substituted with one or more substituents among aryl and 5-12-membered heteroaryl.

[0110] The present invention further provides a compound represented by the general formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the structure of which is as follows, and

[0111]

[0112] Preferably, the above general formula (VII) is further represented by formula (VII-1), and

[0113]

[0114] n4 is selected from 0 or 1;

[0115] X2, X3, R 1-2 , R 1-3 , R 3e, R 3f , R 3g , a, b, c and n4 are as defined in any one of the embodiments described above.

[0116] The present invention further provides a method for preparing a compound represented by general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and

[0117]

[0118] A compound represented by general formula (III-I) and a compound represented by general formula (III-II) are reacted under conditions in the presence of a condensing agent and a base to obtain a compound represented by general formula (III-III), and additionally, a protecting group is removed to obtain a compound represented by general formula (III);

[0119] Preferably, the above method is a method for preparing a compound represented by general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0120]

[0121] A compound represented by general formula (IV-I) and a compound represented by general formula (IV-II) are reacted under conditions in the presence of a condensing agent and a base to obtain a compound represented by general formula (IV-III), and additionally, a protecting group is removed to obtain a compound represented by general formula (IV);

[0122] More preferably, the method is a method for preparing a compound represented by the general formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0123]

[0124] A compound represented by general formula (VI) and a compound represented by general formula (V-II) are reacted under conditions in the presence of a condensing agent and a base to obtain a compound represented by general formula (V-III), and additionally, a protecting group is removed to obtain a compound represented by general formula (V);

[0125] Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, tosyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butoxycarbonyl, benzyl, or p-methoxyphenyl; preferably, benzyl, p-methoxybenzyl, or tert-butoxycarbonyl;

[0126] Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, tosyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butoxycarbonyl, benzyl, or p-methoxyphenyl; preferably, hydrogen, benzyl, p-methoxybenzyl, or tert-butoxycarbonyl;

[0127] 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 characterized as being as defined in any one of the embodiments described above.

[0128] In one preferred embodiment of the present invention, in the manufacturing method, the condensing agent is selected from thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, ethyl chloroformate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(benzotriazole-1-yl)-tetramethyluronium hexafluorophosphate, or tetramethylchloroformamidinium hexafluorophosphate; Preferably phosphorus oxychloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(benzotriazole-1-yl)-tetramethyluronium hexafluorophosphate, or tetramethylchloroformamidinium hexafluorophosphate.

[0129] The base is selected from potassium carbonate, methylamine, triethylamine, diisopropylamine, pyridine, imidazole, N-methylimidazole, or N-methylmorpholine.

[0130] The present invention further relates to a pharmaceutical composition, said pharmaceutical composition comprising a compound according to any one embodiment in a therapeutically effective amount, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0131] The present invention further relates to a compound according to any one embodiment, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or the application of said pharmaceutical composition in the manufacture of a PRMT5 inhibitor drug.

[0132] The present invention further relates to the application of a compound according to any one embodiment, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a drug for treating cancer; preferably, the cancer is a cancer in which the MTAP gene is deleted.

[0133] The present invention further relates to a method for preparing a compound according to any one embodiment, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of cancer; preferably, the cancer is a cancer in which the MTAP gene is deleted.

[0134] 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 cholangiocarcinoma; the lung cancer is selected from non-small cell lung cancer, pulmonary squamous cell carcinoma or lung adenocarcinoma; and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0135] The present invention also relates to a method for the treatment, prevention, and / or treatment of cancer, wherein the method comprises the step of administering to a patient a therapeutically effective amount of a compound according to any one embodiment, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0136] The present invention also relates to a method for treating cancer in mammals, said method comprising the step of administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0137] In some embodiments of the present invention, in the pharmaceutical composition, the weight percentage of the compound, its stereoisomer, or its pharmaceutically acceptable salt, based on free alkali, is 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, and 50%.

[0138] In some embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations, or injectables, preferably further comprises a filler, optionally further comprises a disintegrant, or further comprises one or more of a lubricant or a lubricant.

[0139] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0140] In some embodiments of the present invention, in the pharmaceutical composition, the unit dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt, based on free alkali, is 1 to 1000 mg, preferably 1 to 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.

[0141] In some embodiments of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt may be administered by any convenient method, for example, orally, parenterally, orally, sublingually, nasally, rectally, intrathecally, or transdermally, and the pharmaceutical composition is adjusted accordingly.

[0142] In some embodiments of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt may be prepared into a liquid or solid formulation such as a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0143] In some embodiments, the present method relates to the treatment of conditions such as, for example, 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 cholangiocarcinoma.

[0144] 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.

[0145] Detailed description of the invention

[0146] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art, and specifically, terms used in the specification and claims have the following meanings.

[0147] The term "alkyl" means a straight-chain or branched-chain saturated aliphatic hydrocarbon group, and said alkyl may optionally be substituted with one or more substituents. In certain embodiments, the alkyl is 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 A straight-chain saturated hydrocarbon group having ) carbon atoms, or 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 It refers to a branched-chain saturated hydrocarbon group having ) carbon atoms. The straight-chain C used here 1-6 Alkyl and branched chain C 3-6 Alkyl groups are also called "lower alkyls." 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. In one embodiment, the C 1-6 The alkyl group contains 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Non-limiting embodiments 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, Includes 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. In one embodiment, the alkyl is an optionally substituted alkyl described in other parts of the text.

[0148] The term "alkylene" means that one hydrogen atom of the alkyl group is additionally substituted, wherein the definition of "alkyl" is as set forth above. Non-limiting embodiments 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 as described in other parts of the text.

[0149] The term "alkenyl" means a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group, comprising at least one carbon-carbon double bond, the carbon-carbon double bond may be located at any position within the alkenyl, and the alkenyl may optionally be substituted with one or more substituents. In certain embodiments, the alkenyl is 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 A straight-chain unsaturated hydrocarbon group having ) carbon atoms, or 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 It refers to a branched-chain unsaturated hydrocarbon group having ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched-chain alkenyls. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched-chain unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6The alkenyl comprises 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, or 6). Non-limiting embodiments of the alkenyl are or Includes. Those skilled in the art will understand that the term "alkenyl" may include a group having "cis" and "trans" arrangements, or alternatively, a group having "E" and "Z" arrangements. In one embodiment, the alkenyl is an optionally substituted alkenyl described in other parts of the text.

[0150] The term "alkenylene" means that one hydrogen atom of the alkenyl is additionally substituted, where the definition of "alkenyl" is as described above. In one embodiment, the alkenylene is an optionally substituted alkyl as described in other parts of the text.

[0151] The term "alkynyl" means a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group, comprising at least one carbon-carbon triple bond, the carbon-carbon triple bond may be located at any position within the alkynyl, and the alkynyl may optionally be substituted with one or more substituents. In certain embodiments, the alkynyl is 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 A straight-chain unsaturated hydrocarbon group having ) carbon atoms, or 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 3-6It is a branched-chain unsaturated hydrocarbon group having ) carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched-chain alkynoyls. For example, C 2-6 Alkynyl means a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched-chain unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl comprises 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, or 6). Non-limiting embodiments of the alkynyl are or Includes. In one embodiment, the alkynyl is an optionally substituted alkynyl described in other parts of the text.

[0152] The term "alkynylene" means that one hydrogen atom of alkynyl is additionally substituted, where the definition of "alkynyl" is as described above. In one embodiment, the alkynylene is an optionally substituted alkyl as described in other parts of the text.

[0153] The term "cycloalkyl" means a saturated or partially unsaturated aliphatic hydrocarbon single-ring or polycyclic (two or more) cyclic group, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring is 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 It comprises ) carbon atoms; in one embodiment, the cycloalkyl ring is 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10It comprises ) carbon atoms; it may include one or more double bonds but does not have a fully conjugated π-electron system. Non-limiting embodiments of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, or cyclooctyl, etc.; in one embodiment, the polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and cross-linked cycloalkyl. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described in other parts of the text or a cycloalkyl optionally fused to a heterocyclyl, aryl, or heteroaryl, and non-limiting embodiments include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0154] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group sharing one carbon atom (called a spiro atom) between the monocyclic rings, which may contain one or more double bonds but none of the rings have a fully conjugated π-electron system. In certain embodiments, spirocycloalkyl is 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It contains )(e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of spiro atoms shared between rings, it is classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, and in one embodiment, it is monospirocycloalkyl or bispirocycloalkyl. In one embodiment, it is quaternary / quaternary, ternary / five-memberary, quaternary / five-memberary, quaternary / six-memberary, six-memberary / five-memberary, or six-memberary monospirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl as described in other parts of the text. Non-limiting embodiments of spirocycloalkyl are

[0155] Includes

[0156] The term "fused cycloalkyl" refers to a total-carbon polycyclic group in which each ring of the system shares a pair of carbon atoms adjacent to another ring of the system, wherein one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. In certain embodiments, the fused cycloalkyl is 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It contains )(e.g., 7, 8, 9, 10) carbon atoms. Depending on the number constituting the ring, it can be divided into dicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyls, and in one embodiment, it is dicyclic or tricyclic, and additionally in one embodiment, it is a ternary / five-membered, tetracyclic / five-membered, five-memberary / five-membered, or five-memberary / six-membered bicycloalkyl. In one embodiment, the fused cycloalkyl is a fused cycloalkyl optionally substituted as described elsewhere in the text, or a fused cycloalkyl optionally fused with a heterocyclyl, aryl, or heteroaryl. Non-limiting embodiments of the fused cycloalkyl are or Includes

[0157] The term “crosslinked cycloalkyl” means a total carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may include one or more double bonds but none of the rings have a fully conjugated π-electron system. In certain embodiments, the crosslinked cycloalkyl is 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10It contains (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic cross-linked cycloalkyls, preferably bicyclic or tricyclic. In one embodiment, the cross-linked cycloalkyl is an optionally substituted cross-linked cycloalkyl as described in other parts of the text. Non-limiting embodiments of the cross-linked cycloalkyl are

[0158] Includes

[0159] The term "cycloalkylene" means a divalent cycloalkyl formed by additionally substituting one hydrogen atom of a cycloalkyl, wherein the cycloalkylene is optionally substituted or unsubstituted, and the definition of cycloalkyl is as described above.

[0160] The term “heterocyclil” means 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 said nitrogen, phosphorus, or sulfur atoms may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the ring carbon atoms may optionally be substituted with oxygen but do not include the ring portion of -OO- or -OS-, and the remaining ring atoms are carbon, which may include one or more double bonds but do not have a fully conjugated π-electron system. In certain embodiments, the heterocyclil comprises 3 to 20, 3 to 14, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; In one embodiment, the heterocyclyl comprises 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 comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, 8). Non-limiting embodiments of the monocyclic heterocyclyl include tetrahydropyrrolyl, azetidinyl, oxetanil, oxanil, tetrahydrofuranil, tetrahydropyranil, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranil, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, pyrerazinyl, morpholinyl, thiomomorpholinyl, homopyrerazinyl, and pyranil, etc. Polycyclic heterocyclils include spiroheterocyclils, fused heterocyclils, and cross-linked heterocyclils. In one embodiment, the heterocyclil is a heterocyclil that is optionally substituted as described in other parts of the text, or additionally conjugated to another cycloalkyl, heterocyclil, aryl, and heteroaryl through any two or more atoms on the ring.

[0161] The term “spiroheterocyclil” means a polycyclic heterocyclil group sharing one atom (referred to as a spiro atom) between 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 none of the rings have a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclil comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; and depending on the number of spiro atoms shared between rings, the spiroheterocyclil is divided into monospiroheterocyclil, bispiroheterocyclil, or polyspiroheterocyclil; Preferably monospiroheterocyclil and bispiroheterocyclil; in one embodiment, the spiroheterocyclil is a tetra / tetra, tetra / five, tetra / six, five / five, or five / six monospiroheterocyclil; in one embodiment, the spiroheterocyclil is an optionally substituted spiroheterocyclil as described in other parts of the text; and non-limiting embodiments of the spiroheterocyclil are

[0162] or Includes

[0163] The term “fused heterocyclil” refers to a polycyclic heterocyclil group in which each ring of the system shares a pair of atoms adjacent to another ring of the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully 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 certain embodiments, the fused heterocyclil comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 ring atoms (e.g., 7, 8, 9, 10); depending on the number constituting the rings, it may be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclil; preferably, it is bicyclic or tricyclic; and in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclil; In one embodiment, the fused heterocyclyl is a fused heterocyclyl that may be optionally substituted or fused to a cycloalkyl, heterocyclyl, aryl, or heteroaryl as described in other parts of the text; non-limiting embodiments of the fused heterocyclyl are

[0164] or Includes

[0165] The term “crosslinked heterocyclil” refers to a polycyclic heterocyclil group in which any two rings share two non-directly connected atoms, which may include one or more double bonds, but none of the rings have a fully 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 certain embodiments, the crosslinked heterocyclil comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, comprises 7 to 10 ring atoms (e.g., 7, 8, 9, 10); may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked heterocyclils depending on the number constituting the rings; preferably, it is bicyclic, tricyclic, or tetracyclic; and in one embodiment, it is bicyclic or tricyclic; In one embodiment, the cross-linked heterocyclil is an optionally substituted cross-linked heterocyclil described in other parts of the text; non-limiting embodiments of the cross-linked heterocyclil are

[0166] or Includes

[0167] The term "tricyclic heterocyclyl" means a heterocyclyl having three rings forming a ring system, wherein the three rings may be a conjugated ring system, a spiro ring system, or a cross-linked ring system, and in one embodiment, the tricyclic heterocyclyl has at least one of the three rings in the system being heterocyclyl, and the other two rings may be cycloalkyl, heterocyclyl, aryl, or heteroaryl, the definitions of cycloalkyl, heterocyclyl, aryl, or heteroaryl are as described above, and a non-limiting embodiment thereof is preferably the following tricyclic heterocyclyl:

[0168] or Includes the back.

[0169] The term "heterocyclile" refers to a divalent heterocyclile formed by additionally substituting one hydrogen atom of a heterocyclile, wherein the heterocyclile is optionally substituted or unsubstituted, and the definition of a heterocyclile is as described above.

[0170] The term “aryl” means comprising a whole-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having at least one conjugated π-electron system, which may optionally be substituted with one or more substituents. In certain embodiments, the aryl comprises 6 to 20, 6 to 14, 6 to 12, or 6 to 10 ring atoms; in one embodiment, the aryl may further mean a dicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring and the other ring may be a saturated, partially unsaturated carbon ring or a ring comprising one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl is selected from benzo 5-10-membered heteroaryl, benzo 3-10-membered cycloalkyl, or benzo 3-10-membered heterocyclyl. In one embodiment, the aryl is selected from benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl, or benzo 3-6-membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl comprising 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting embodiments include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl), and Includes

[0171] The term "arylene" refers to a divalent aryl formed by additionally substituting one hydrogen atom of an aryl, wherein the arylene is optionally substituted or unsubstituted, and the definition of an aryl is as described above.

[0172] The term “heteroaryl” means an optionally substituted monocyclic, polycyclic, or ring system comprising at least one aromatic ring, wherein the aromatic ring independently has one or more heteroatoms selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; and in certain embodiments, the heteroaryl may additionally mean a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms selected from O, S, and N independently, and the other ring may be a saturated, partially unsaturated carbon ring or a ring comprising one or more heteroatoms selected from O, S, and N independently. In one embodiment, the heteroaryl is selected from a heteroaryl conjugated 6-10-membered aryl, a heteroaryl conjugated 3-10-membered cycloalkyl, or a heteroaryl conjugated 3-10-membered heterocyclil; additionally, in one embodiment, the heteroaryl is selected from a 5-membered or 6-membered heteroaryl conjugated 6-10-membered aryl, a 5-membered or 6-membered heteroaryl conjugated 3-6-membered cycloalkyl, or a 5-membered or 6-membered heteroaryl conjugated 3-6-membered heterocyclil, wherein the heterocyclil is a heterocyclil comprising 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms.The non-limiting embodiment is furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothienyl, phenylthio, benzothienyl, benzothriazolyl, imidazopyridyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthiridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, Purinyl, Pyridopyridinyl, Pyrrolopyridinyl, Quinolyl, Quinoxalinyl, Quinazolinil, Thiadiazolopyrimidinyl, Thienopyridinyl, Acridinyl, Benzindolyl, Carbazolyl, Bibenzofuranil, Phenanthrolinil, Phenanthridinil, Phenopyrazinil, Phenazinil, Phenothiazinil, Phenoxazinil, Xanthenil. and Includes

[0173] The term "heteroarylene" refers to a divalent heteroaryl formed by additionally substituting one hydrogen atom of a cycloalkyl group, wherein the heteroarylene is optionally substituted or unsubstituted, and the definition of a heteroaryl is as described above.

[0174] The term “heteroalkyl” means a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, which consists of a given number of carbon atoms and one or more heteroatoms selected from O, N, Si, and S (one to three in one embodiment), wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position of the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position of the heteroalkyl group (e.g., internal or terminal position) including a position connected to the alkyl group and the rest of the molecule. Non-limiting embodiments include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl is an optionally substituted heteroalkyl described in other parts of the text.

[0175] The term “alkoxy” means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definitions of alkyl or cycloalkyl are as set forth above. Non-limiting embodiments of the alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy as described in other parts of the text.

[0176] The term "alkylacyl" means -C(O)-alkyl, where the definition of alkyl is as described above.

[0177] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein the definition of an alkyl is as described above. Non-limiting embodiments of the haloalkyl include trifluoromethyl, -CH2CF3, or Includes

[0178] The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, and the definition of alkoxy is as described above.

[0179] The term "hydroxyalkyl" means an alkyl group substituted with hydroxyl, and the definition of alkyl is as described above.

[0180] The term "alkylthio" means -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein the definitions of alkyl or cycloalkyl are as set forth above. Non-limiting embodiments of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described in other parts of the text.

[0181] The term "haloalkylthio" means an alkylthio substituted with one or more halogens, and the definition of alkylthio is as described above.

[0182] The term "alkenyl carbonyl" means -C(O)-(alkenyl), wherein the definition of alkenyl is as set forth above. Non-limiting embodiments of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described in other parts of the text.

[0183] The term "aminocarbonyl" means NH2-C(O)-.

[0184] The term "alkylaminocarbonyl" means that one or both of the two hydrogens on aminocarbonyl (NH2-C(O)-) are substituted with alkyl, where the definition of alkyl is as described above.

[0185] The term "alkylamino" means that one or both of the two hydrogens on the amino are substituted with alkyl, where the definition of alkyl is as described above.

[0186] The term "carbonyl" means -C(O)-, -(CO)-, or -C(=O)- group. All labels may be used interchangeably in the specification.

[0187] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0188] The term "oxo" or "side-chain oxygen" means =O.

[0189] The term "C(X)" or "C(=X)" is It refers to a group. When X is O, the group represents a carbonyl; when X is S, the group represents a mercapto; and when X is NR, the group It represents; and when X is CRR, the above device It represents.

[0190] The term "hydrogen" refers to a proton ( 1 H), deuterium ( 2 H), tritium ( 3 It includes H) and / or mixtures thereof. In certain embodiments, one or more positions occupied by hydrogen in the compound may be enriched to deuterium and / or tritium. Such isotope enrichment analogs may be prepared from suitable isotope-labeled starting materials obtained from commercial sources or through the steps of known literature.

[0191] The above 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, and in one embodiment, the substituent is selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide group, oxymido, phosphate group, oxo group, thio group, carboxyl, carboxylate group, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0192] Different terms 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 represent the same meaning, that is, X can be any one or more of A, B, and C.

[0193] "Optional" or "optional" means that the event or environment described below may occur but is not required to occur, and that the description includes cases where the event or environment occurs or is not. For example, "heterocyclyl group optionally substituted by an alkyl" means that an alkyl may be present but is not required to be present, and that the description includes cases where the heterocyclyl is substituted with an alkyl and cases where the heterocyclyl is not substituted with an alkyl.

[0194] Linking substituents are described in each part of the present invention. Where a linker is clearly required for the structure, the Markush variable listed for the group should be understood as a linker. For example, if the structure requires a linker and the Markush group definition for the variable lists "alkyl" or "aryl," the "alkyl" or "aryl" should be understood as representing the linked alkylene group or arylene group, respectively.

[0195] "Substituted" means that, in one embodiment, any one or more hydrogen atoms on a specific atom are substituted with a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable. If the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are substituted. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise defined, the type and number of substituents may be arbitrary on a chemically feasible basis. Of course, substituents are placed only in possible chemical positions, and a person skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) without excessive effort. For example, an amino or hydroxyl having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefin) bond. Substituents may be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo group, thio group, deuterium alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0196] "Substituted or unsubstituted" means that it may or may not be substituted. If it may be substituted, the substituents are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -SF5, -C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from 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';

[0197] R and R' are each independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, - -C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is selected from aryls or 5-12-membered heteroaryls.

[0198] Unless otherwise specified, the indefinite articles “one” and “one thing” and the definite article “above” in this specification and claims include plural and singular forms.

[0199] "Pharmaceutical composition" refers to a mixture comprising one or more compounds according to the text or physiologically / pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism and to facilitate the absorption of the active ingredient to exert biological activity.

[0200] "Pharmaceuticalally acceptable salt" refers to a salt of the compound of the present invention, and such salt has appropriate biological activity, possessing safety and efficacy when administered into the body of a mammal.

[0201] "Stereoisomers" include compounds of the present invention that are pure in all enantiomers / diastereoisomers / stereoisomers and concentrated in enantiomers / diastereoisomers / stereoisomers.

[0202] "Stereoisomerically pure" means a composition that contains stereoisomers of a specific compound and is essentially free of other stereoisomers of said compound. For example, a stereoisomerically pure composition of a compound having one chiral center is one that is essentially free of the relative enantiomer of said compound. A stereoisomerically pure composition of a compound having two chiral centers is one that is essentially free of other diastereomers of said compound. A typical stereoisomerically pure compound comprises one stereoisomer of the compound with a mass content of about 80% or more and another stereoisomer of the compound with a mass content of about 20% or less, one stereoisomer of the compound with a mass content of about 90% or more and another stereoisomer of the compound with a mass content of about 10% or less, one stereoisomer of the compound with a mass content of about 95% or more and another stereoisomer of the compound with a mass content of about 5% or less, one stereoisomer of the compound with a mass content of about 97% or more and another stereoisomer of the compound with a mass content of about 3% or less, or one stereoisomer of the compound with a mass content of about 99% or more and another stereoisomer of the compound with a mass content of about 1% or less.

[0203] "Steoisomerically concentrated" means a composition of stereoisomers containing a specific compound with a mass content of about 55% or more, about 60% or more, about 70% or more, or about 80% or more.

[0204] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically concentrated" refers to a stereoisomerically concentrated composition of a compound having a single chiral center.

[0205] “Optical activity” and “enantiomer activity” refer to a molecular combination having an excess of enantiomers or diastereomers of about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and less than about 5% of the second preferred enantiomer or diastereomer based on the total weight of the racemic mixture.

[0206] When describing optically active compounds, the prefixes R and S are used to indicate the absolute arrangement of the molecule relative to the chiral center. (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction of the plane of polarization rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, meaning it rotates the plane of polarization to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, meaning it rotates the plane of polarization to the right or clockwise. However, the sign (+) and (-) of the optical rotation is independent of the absolute arrangements R and S of the molecule. Specific details for implementing the invention

[0207] The present invention will be further described below with reference to examples, but these examples do not limit the scope of the invention.

[0208] Examples

[0209] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 It is provided in units of (ppm). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO- d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard substance is tetramethylsilane (TMS).

[0210] MS measurements are performed using a FINNIGAN LCQAd(ESI) mass spectrometer (Manufacturer: Thermo, Model: Finnigan LCQ advantage MAX).

[0211] HPLC measurements were performed using the Agilent 1200DAD high-pressure liquid chromatography (Sunfire C 18 150 x 4.6 mm chromatography column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 A 150 x 4.6 mm chromatography column is used.

[0212] Average kinase inhibition rate and IC5 50 Values ​​are measured using a NovoStar microplate reader (BMG, Germany).

[0213] For thin-layer chromatography, the silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, the specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications of the silica gel plates used for thin-layer chromatography separation and purification products are 0.4 mm to 0.5 mm.

[0214] Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

[0215] The known starting materials of the present invention may be synthesized by adopting known methods in the art or according to known methods in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0216] Unless otherwise specified in the examples, all reactions may be carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction flask is connected to one argon or nitrogen balloon with a volume of about 1 L. A hydrogen atmosphere means that the reaction flask is connected to one hydrogen balloon with a volume of about 1 L.

[0217] The pressurized hydrogenation reaction uses a Parr 3916EKX type hydrogenation unit and a Clear Blue QL-500 type hydrogen generator or an HC2-SS type hydrogenation unit.

[0218] The hydrogenation reaction is generally performed under vacuum, filled with hydrogen, and repeated three times.

[0219] Microwave reactions use a CEM Discover-S 908860 type microwave reactor.

[0220] Unless otherwise specified in the examples, a solution refers to an aqueous solution.

[0221] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20℃ to 30℃.

[0222] Monitoring of the reaction flow in the example is performed using thin-layer chromatography (TLC), and the system of developing agents used in the reaction comprises A: a dichloromethane and methanol system, B: an n-hexane and ethyl acetate system, C: a petroleum ether and ethyl acetate system, and D: acetone, and the volume ratio of the solvents is adjusted according to the polarity of the compounds.

[0223] The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for compound purification include A: n-hexane and ethyl acetate system and B: n-hexane and tetrahydrofuran system, and the volume ratio of the solvent can be adjusted according to the polarity of the compound or by adding a small amount of alkaline or acidic reagent such as triethylamine and acetic acid.

[0224] In an embodiment of the present invention, the HPLC separation conditions for chiral preparatives are as follows, and t R It indicates the time of stay.

[0225] Condition 1:

[0226] Chiral preparative conditions

[0227]

[0228] Chiral analysis conditions:

[0229]

[0230] Condition 2:

[0231] Chiral preparative conditions

[0232]

[0233] Chiral analysis conditions

[0234]

[0235] Condition 3:

[0236] Chiral preparative conditions

[0237]

[0238] Chiral analysis conditions

[0239]

[0240] The compound according to an embodiment of the present invention was prepared by referring to the preparation steps of the following example.

[0241] Example 1

[0242] (4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0243]

[0244] Step 1: 2-Methyl-1H-Imidazole 1a (5 g, 60.89 mmol) was dissolved in DMSO (50 mL), DBU (13.91 g, 91.35 mmol, 14 mL) and methyl 3-fluoro-4-nitrobenzoate (13.34 g, 66.99 mmol) were slowly added, and the reaction was stirred at 25°C for 2 hours; water (200 mL) was added to the reaction mixture and extracted with ethyl acetate (200 mL x 3); the organic phases were combined, washed with saturated saline (200 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system C. 1b (9 g) was obtained, and the yield is 56.6%. MS m / z (ESI): 262 [M+1] +

[0245] Phase 2: 1b (2 g, 7.66 mmol) is dissolved in methanol (20 mL), Pd / C (816 mg, 766 μmol, 10% purity) is added, and after three hydrogen substitutions, the reaction is stirred at 50°C for 12 hours under hydrogen protection; the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, the filter cake is stirred for 15 minutes in a mixed solvent of methanol:EA = 1:10 (10 mL), filtered, and the filter cake is dried under reduced pressure, 1c(1.45 g) was obtained, and the yield is 81.9%. MS m / z (ESI): 232 [M+1] +

[0246] Phase 3: 1c (1 g, 4.32 mmol) is dissolved in DCM (15 mL), DMAP (265 mg, 2.16 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (1.06 g, 6.49 mmol, 926 μL) are added, and the reaction is stirred at 80°C for 16 hours; the reaction mixture is concentrated under reduced pressure, dichloromethane (10 mL) and tert-butylmethyl ether (10 mL) are added to the concentrated residue and stirred for 15 minutes, filtered, the filter cake is collected, and dried under reduced pressure, 1g (750 mg) was obtained, and the yield is 45.8%. MS m / z (ESI): 380 [M+1] +

[0247] Phase 4: 1g (600 mg, 1.52 mmol) is dissolved in pyridine (2 mL), phosphorus oxychloride (280 mg, 1.83 mmol, 171 μL) is added, and the reaction is stirred at 120°C for 16 hours; the reaction solution is concentrated under reduced pressure, water (50 mL) is added to the concentrated residue, and it is extracted with ethyl acetate (50 mL x 3); the organic phases are combined, washed with saturated saline (50 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography using eluent system C. 1d (250 mg) was obtained, and the yield is 43.7%. MS m / z (ESI): 377 [M+1] +

[0248] Step 5: 1d(250 mg, 664 μmol) is dissolved in water (2 mL) / methanol (2 mL) / tetrahydrofuran (6 mL), lithium hydroxide (32 mg, 1.33 mmol) is added, and the reaction is stirred at 80°C for 3 hours; the pH of the system is adjusted to 5 using 0.5 M hydrochloric acid, filtered, the filter cake is stirred with ethanol (5 mL) for 0.5 hours, filtered, and the filter cake is dried under reduced pressure, 1h (110 mg) was obtained, and the yield is 45.7%. MS m / z (ESI): 363 [M+1] +

[0249] Step 6: 1h (50 mg, 138 μmol) and N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano-[3,4-b]pyridine-5-amine (39 mg, 166 μmol, obtained by synthesizing according to the known method "Patent WO 2021163344") are dissolved in DMF (2 mL), N-methylimidazole (46 mg, 552 μmol, 44 μL) and TCFH (58 mg, 207 μmol) are added, and the reaction is continuously stirred at 25°C for 1.5 hours; the reaction mixture is concentrated under reduced pressure, water (15 mL) is added to the concentrated residue, and the mixture is extracted with ethyl acetate (20 mL x 3); The organic phases are combined, washed with saturated saline (20 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue is separated by preparative high-performance liquid chromatography, 1i (55 mg) was obtained, and the yield is 68.9%. MS m / z (ESI): 576 [M+1] +

[0250] Step 7: 1i (45 mg, 78 μmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was stirred continuously at 90°C for 16 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by preparative high-performance liquid chromatography, Example 1(20 mg) was obtained, and the yield is 56.2%. MS m / z (ESI): 458 [M+1] +

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 8.23-8.11 (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).

[0252] Example 1 Preparation of Chiral Isomers

[0253]

[0254] Preparation of Step 1 Chiral Isomers

[0255] Example 1 (20 mg, 0.044 mmol) was separated by Chiral-HPLC, and respectively 1-P1 : ( R )-(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (9.5 mg) was obtained with a yield of 47.5%; 1-P2 : ( S )-(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (9.8 mg) was obtained, and the yield was 49.0%.

[0256] The preparation of the following examples is Example 1 Referred to.

[0257]

[0258]

[0259] Example 8

[0260] 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]quinoxalin-8-carboxamide

[0261]

[0262] Step 1: 6-Bromo-2-chloro-3-methylquinoxalin8a (1.5 g, 5.82 mmol) and cesium carbonate (2.85 g, 8.47 mmol) were dispersed in 15 mL of dimethylformamide, 4-methoxybenzylamine (799 mg, 5.82 mmol) was added, and the reaction was carried out at 100°C for 2 hours while stirring. The reaction mixture was poured into 50 mL of ethyl acetate, washed with a saturated sodium chloride solution (50 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A, 8b (1.5 g) was obtained, and the yield is 71.9%. MS m / z (ESI): 358 [M+1] +

[0263] Phase 2: 8b (1.5 g, 4.19 mmol) was dissolved in 10 mL of dioxane and 1 mL of water, selenium dioxide (929 mg, 8.37 mmol) was added, and the reaction was carried out at 85°C for 2 hours while stirring. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL x 2). After extraction, the organic phase was taken, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 8c (1.43 g) was obtained, and the yield is 91.7%. MS m / z (ESI): 372 [M+1] +

[0264] Phase 3: 8c (1.43 g, 3.84 mmol) and 4-methylbenzenesulfonohydrazide (1.07 g, 5.76 mmol) were dissolved in 10 mL of methanol, and the reaction was carried out at 60°C for 3 hours while stirring. Water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50 mL x 2). After extraction, the organic phase was taken, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 8d(1.43 g) was obtained, and the yield is 96.2%. MS m / z (ESI):386 [M+1] +

[0265] Phase 4: 8d (1.43 g, 3.70 mmol) and sodium ethoxide (1.01 g, 14.80 mmol) were dissolved in 10 mL of dioxane and 10 mL of cyclohexane, and the reaction was carried out at 60°C for 3 hours while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 8e (560 mg) was obtained, and the yield is 41.2%. MS m / z (ESI): 384 [M+1] +

[0266] Step 5: 8e (250 mg, 0.65 mmol), triethylamine (131 mg, 1.30 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (48 mg, 0.07 mmol) were dissolved in 10 mL of ethanol, and the reaction was carried out under a carbon monoxide environment at 80°C for 72 hours while stirring. Water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50 mL x 2). After extraction, the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A, 8f (91 mg) was obtained, and the yield is 37.1%. MS m / z (ESI): 363 [M+1] +

[0267] Example 1 Referring to the synthesis method of steps 5 through 7 of, 8f from (91 mg) Example 8 (6 mg) was obtained, and the yield is 5.6%. MS m / z (ESI): 444 [M+1] +

[0268] 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.44 (d, 1H), 8.17 (d, 1H), 7.86 (d, 3H), 7.75 (s, 1H), 7.55 (d, 1H), 5.84 (s, 1H), 5.02-4.71 (m, 2H), 4.18 (d, 2H), 2.76 (d, 3H).

[0269] Example 9

[0270] 4-amino- N -(2-(3,3-difluoroazetidine-1-yl)-5,8-dihydro-6 H -Piranno[3,4-b]pyridin-5-il)- N ,1-dimethyl-1 H -Pyrazolo[4,3-c]quinoline-8-carboxamide

[0271]

[0272] Step 1: 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) were dispersed in 150 mL of carbon tetrachloride and reacted at 80°C for 16 hours while stirring. The reaction solution was filtered to remove insoluble substances, and the filtrate was concentrated under reduced pressure. 9b (30.50 g, crude product) was obtained. MS m / z (ESI): 338 [M+1] +

[0273] Phase 2: 9b (30.50 g crude product), diethyl phosphite (14.00 g, 101.45 mmol) and N , N - Diisopropylethylamine (26.00 g, 201.55 mmol) was dispersed in 400 mL of dichloromethane and reacted at 25°C for 2 hours while stirring. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system B, 9c(12.00 g) was obtained, and the yield is 55.9%. MS m / z (ESI): 260 [M+1] +

[0274] Step 3: 200 mL of methyl 2-hydroxyacetate (8.50 g, 94.44 mmol) N , N - It was dispersed in dimethylformamide, sodium hydride (5.70 g, 142.48 mmol, 60% dispersed in mineral oil) was added at 0°C, and the reaction was carried out for 1 hour while stirring. 9c (12.00 g, 46.33 mmol) was added, and the reaction was carried out at 25°C for 16 hours while stirring. The reaction mixture was poured into 2000 mL of water and extracted with ethyl acetate (300 mL x 3); the organic phases were combined, washed with saturated saline (200 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 9d (22.00 g, crude product) was obtained. MS m / z (ESI): 238 [M+1] +

[0275] Phase 4: 9d (22.00 g, crude product) was dispersed in 100 mL of ethanol and 100 mL of concentrated hydrochloric acid, and reacted at 100°C for 2 hours while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 9e (4.00 g) was obtained, and the yield is 52.3%. MS m / z (ESI): 166 [M+1] +

[0276] Step 5: 9e(4.00 g, 24.24 mmol) was dispersed in 30 mL of phosphorus oxychloride and reacted at 90°C for 2 hours while stirring. The mixture was concentrated under reduced pressure, the residue was dispersed in 300 mL of dichloromethane, washed sequentially with a saturated sodium bicarbonate solution (200 mL x 2) and a sodium chloride solution (200 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure 9f (4.30 g) was obtained, and the yield is 96.9%. MS m / z (ESI): 184 [M+1] +

[0277] Step 6: 9f (300 mg, 1.64 mmol), 3,3-difluoroazetidine hydrochloride (260 mg, 2.02 mmol) and N , N - Diisopropylethylamine (800 mg, 6.20 mmol) was dispersed in 5 mL of acetonitrile and reacted at 80°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B, 9g (240 mg) was obtained, and the yield is 61.0%. MS m / z (ESI): 241 [M+1] +

[0278] Step 7: 9g (240 mg, 1.00 mmol) and methylamine (310 mg, 3.00 mmol, 30% methanol solution) were dispersed in 3 mL of trifluoroethanol and reacted at 25°C for 16 hours while stirring. Sodium borocyanide (130 mg, 2.06 mmol) was added and reacted at 25°C for 1 hour while stirring. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 9h (150 mg) was obtained, and the yield is 58.8%. MS m / z (ESI): 256 [M+1] +

[0279] Example 1 Referring to the synthesis method of Step 7, 9h From (50 mg, 0.20 mmol) Example 9 (9 mg) was obtained, and the yield is 9.3%. MS m / z (ESI): 480 [M+1] +

[0280] Example 10

[0281] 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

[0282]

[0283] Step 1: Methyl 2-hydroxy-4-nitrobenzoate 10a Sodium chlorodifluoroacetate (1.1 g, 5.58 mmol), sodium chlorodifluoroacetate (1.02 g, 6.70 mmol), and sodium carbonate (768 mg, 7.25 mmol) were dispersed in 15 mL of dimethylformamide, and the reaction was carried out under nitrogen protection at 100°C for 16 hours with stirring. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A, 10b (330 mg) was obtained, and the yield is 23.9%. MS m / z (ESI): 248 [M+1] +

[0284] Phase 2: 10b (330 mg, 1.34 mmol) was dissolved in 8 mL of methanol, palladium carbon (284 mg, 5% purity, 0.13 mmol) was added, and the reaction was carried out under a hydrogen environment at room temperature for 2 hours while stirring. The palladium carbon was filtered out of the reaction solution using diatomite, and the reaction solution was concentrated under reduced pressure, 10c(250 mg) was obtained, and the yield is 86.2%. MS m / z (ESI): 218[M+1] +

[0285] Phase 3: 10c (250 mg, 1.15 mmol) and N-bromosuccinimide (204 mg, 1.15 mmol) were dissolved in 6 mL of dichloromethane and reacted at room temperature for 30 minutes while stirring. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 10d (160 mg) was obtained, and the yield is 47.0%. MS m / z (ESI): 296[M+1] +

[0286] Phase 4: 10d (160 mg, 0.54 mmol), [1,1-Bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.05 mmol), potassium acetate (106 mg, 1.08 mmol), and bis(pinacoleto)diborone (292 mg, 1.15 mmol) were dissolved in 5 mL of dioxane, and the reaction was carried out at 90°C for 16 hours while stirring. The reaction mixture was filtered, the filtrate was poured into 100 mL of water, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 10e (71 mg) was obtained, and the yield is 38.3%. MS m / z (ESI): 344[M+1] +

[0287] Step 5: 10e5-bromo-1-methylpyrazole-4-carbonitrile (71 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol), and sodium carbonate (44 mg, 0.41 mmol) were dissolved in 5 mL of dioxane and 1 mL of water, and the reaction was carried out at 90°C for 16 hours while stirring. The reaction mixture was filtered, the filtrate was poured into 100 mL of water, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with a saturated sodium chloride solution (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 10f (37 mg) was obtained, and the yield is 55.5%. MS m / z (ESI): 323[M+1] +

[0288] Example 1 Referring to the synthesis method of steps 5 to 6 of, 10f From (37 mg, 0.11 mmol) Example 10 (7.1 mg) was obtained, and the yield is 11.8%. MS m / z (ESI): 523 [M+1] +

[0289] Example 11 The manufacture of Example 10 Referred to.

[0290]

[0291] Example 12

[0292] 4-amino-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxalin-8-carboxamide

[0293]

[0294] Step 1: Methyl 4-amino-3-nitrobenzoate 12a(5 g, 25.49 mmol) is dissolved in dichloromethane (50 mL), 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) are added sequentially, and the reaction is stirred at 25°C for 2 hours; water (100 mL) is added to the reaction solution and extracted with dichloromethane (100 mL x 3); the organic phase is combined, washed with saturated saline (100 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue is purified using eluent system C, 12b (6.5 g) was obtained, and the yield is 86.0%.

[0295] Phase 2: 12b (5 g, 16.88 mmol) is dissolved in methanol (60 mL), Pd / C (2.05 g, 1.69 mmol, 10% purity) is added, and the reaction is stirred at 50°C for 16 hours; a layer of diatomaceous earth is spread evenly in a suction filtration funnel, the reaction solution is filtered, the filtrate is collected, and concentrated under reduced pressure, 12c (4 g) was obtained, and the yield is 89.0%. MS m / z (ESI): 267 [M+1] +

[0296] Phase 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, and the reaction was stirred at 100°C in a microwave for 10 minutes, and after the reaction was completed, it was used directly in the next step.

[0297] 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 toluenesulfonylmethyl isocyanide 12f (417.95 mg, 2.14 mmol) and potassium carbonate (493.11 mg, 3.57 mmol) are added, and the reaction is stirred in a microwave at 80°C for 10 minutes; water (60 mL) is added to the reaction solution and extracted with ethyl acetate (60 mL x 3); the organic phase is combined, washed with saturated saline (60 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 12g (700 mg) was obtained and used directly in the next step.

[0298] Step 5: 12g (600 mg, 1.54 mmol) is dissolved in 1,2-dichloroethane (6 mL) / trifluoroacetic acid (0.6 mL), and the reaction is stirred in a microwave at 80°C for 10 minutes; the reaction solution is concentrated under reduced pressure, the concentrated residue is stirred in dichloromethane (10 mL) for 15 minutes, filtered, and the filter cake is dried under reduced pressure, 12h (200 mg) was obtained, and the yield is 53.4%. MS m / z (ESI): 244 [M+1] +

[0299] Step 6: 12h (200 mg, 822 μmol) is dissolved in phosphorus oxychloride (3 mL), and the reaction is stirred at 180°C for 8 hours; the reaction solution is concentrated under reduced pressure, water (15 mL) is added to the concentrated residue, and the organic phase is separated; the aqueous layer is extracted with ethyl acetate (15 mL x 3); the organic phases are combined, washed with saturated saline (15 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 12i (100 mg) was obtained and used directly in the next step. MS m / z (ESI): 262 [M+1] +

[0300] Step 7:12i (100 mg, 383 μmol) is dissolved in N,N-dimethylformamide (2 mL), 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) are added sequentially, and the reaction is stirred at 120°C for 2 hours; water (20 mL) is added to the reaction solution and the organic phase is separated; the aqueous layer is extracted with ethyl acetate (20 mL x 3); the organic phases are combined, washed with saturated saline (20 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 12j (200 mg) was obtained and used directly in the next step. MS m / z (ESI): 363 [M+1] +

[0301] Step 8: 12j (100 mg, 276 μmol) is dissolved in water (1 mL) / methanol (1 mL) / tetrahydrofuran (3 mL), lithium hydroxide (25.45 mg, 1.06 mmol) is added, and the reaction is stirred at 80°C for 3 hours; the pH is adjusted to 5 with 0.5 M hydrochloric acid, filtered, the filter cake is rinsed with water (5 mL), and the filter cake is dried under reduced pressure, 12k (60 mg) was obtained, and the yield is 62.4%. MS m / z (ESI): 349 [M+1] +

[0302] Step 9: 12k (50 mg, 144 μmol) and N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridine-5-amine 12l (40 mg, 172 μmol) was dissolved in N,N-dimethylformamide, N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added, and the reaction was stirred continuously at 25°C for 16 hours; the reaction solution was separated and purified by direct preparative Pre-HPLC, 12m(18 mg) was obtained, and the yield is 22.3%. MS m / z (ESI): 563 [M+1] +

[0303] Step 10: 12m (18 mg, 32 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred continuously at 90°C for 3 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by preparative Pre-HPLC (acid method), Example 12 (6 mg) was obtained, and the yield is 42.4%. MS m / z (ESI): 443[M+1] +

[0304] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (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).

[0305] Example 13

[0306] 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

[0307]

[0308] Step 1: Methyl 2-methyl-thiophene-3-carboxylate 13a (8.00 g, 51.22 mmol) is dissolved in carbon tetrachloride (100 mL), NBS (10.03 g, 56.34 mmol) and AIBN (841 mg, 5.12 mmol) are added, and the reaction is stirred continuously at 80°C for 16 hours; water (100 mL) is added to the reaction solution and extracted with dichloromethane (200 mL x 3); the organic phase is combined, washed with saturated saline (200 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue is purified using eluent system C, 13b(8.60 g) was obtained, and the yield is 71.4%. MS m / z (ESI): 235 [M+1] + .

[0309] Step 2: Sodium hydride (510 mg, 12.76 mmol, 60% purity) was added to a 3 mL DMF solution of methyl 2-hydroxyacetate (766 mg, 8.51 mmol) at 0°C, and after stirring for 20 minutes at 0°C, 13b (1.00 g, 4.25 mmol) was added to the reaction solution and stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with water and saline solution, concentrated the organic phase, and the residue was purified using eluent system C, 13c (430 mg) was obtained, and the yield is 47.6%. MS m / z (ESI): 213 [M+1] + .

[0310] Phase 3: 13c (3.10 g, 14.61 mmol) was dissolved in dioxane (15 mL) and concentrated hydrochloric acid (15 mL, 12 M). The reaction mixture was heated to 100°C and stirred for 2 hours. The reaction mixture was concentrated, extracted with dichloromethane (80 mL x 3), the organic phases were combined, washed with saturated saline (80 mL x 2), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was purified using eluent system C, 13d (1.80 g) was obtained, and the yield is 79.9%. MS m / z (ESI): 155 [M+1] + .

[0311] Phase 4: 13d(800 mg, 5.19 mmol) and NIS (1.20 g, 6.75 mmol) were dissolved in acetonitrile (20 mL) and acetic acid (5 mL). The reaction mixture was stirred at 30°C for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saline solution, and the organic phase was concentrated. The concentrated residue was purified using eluent system C, 13e (680 mg) was obtained, and the yield is 54.6%. MS m / z (ESI): 281 [M+1] + .

[0312] Step 5: 13e (850 mg, 3.03 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (2.33 g, 12.14 mmol), and copper(I) iodide (1.73 g, 9.10 mmol) were dispersed in DMF (10 mL), protected by nitrogen displacement, and stirred at 90°C for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove solid material, washed the organic phase with water and saline solution, and concentrated. The concentrated residue was purified using eluent system C, 13f (520 mg) was obtained, and the yield is 77.1%.

[0313] 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 mixture was stirred at room temperature for 3 hours, sodium borohydride (16 mg, 0.49 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saline solution, and the organic phase was concentrated. The concentrated residue was purified using eluent system C, 13g (58 mg) was obtained, and the yield is 46.9%. MS m / z (ESI): 238 [M+1] + .

[0314] Step 7: 13g (20 mg, 0.08 mmol) and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (39 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), N-methylpyrazol (20 mg, 0.24 mmol) and TCFH (45 mg, 0.16 mmol) were added, and the reaction was stirred continuously at 25°C for 16 hours; the reaction solution was separated and purified by direct preparative Pre-HPLC, Example 13 (16 mg) was obtained, and the yield is 42.0%. MS m / z (ESI): 462 [M+1] +

[0315] 1 H NMR (400 MHz, CD3OD) δ 8.54 (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).

[0316] Example 14

[0317] 4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]]pyridin-5-yl]imidazo-[1,5-a]quinoxalin-8-carboxamide

[0318]

[0319] Step 1: 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) were dissolved in methanol (15 mL), titanium tetraisopropoxide (1.96 g, 6.91 mmol, 2 mL) was added, and the reaction was stirred at 25°C for 16 hours, sodium borohydride acetate (732.02 mg, 3.45 mmol) was added, and the mixture was stirred at 25°C for 30 minutes; an aqueous solution of saturated sodium bicarbonate (8 mL) was added to the reaction mixture, filtered, the filtrate was collected, concentrated under reduced pressure, and the concentrated residue was separated by pre-TLC. 14b (52 mg) was obtained, and the yield is 8.3%. MS m / z (ESI): 273 [M+1] +

[0320] Step 2: Methyl 4-amino-3-nitrobenzoate 14c (5 g, 25.49 mmol) is dissolved in dichloromethane (50 mL), 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) are added sequentially, and the reaction is stirred at 25°C for 2 hours; water (100 mL) is added to the reaction solution and extracted with dichloromethane (100 mL x 3); the organic phase is combined, washed with saturated saline (100 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue is purified using eluent system C, 14d (6.5 g) was obtained, and the yield is 86.0%.

[0321] Phase 3: 14d(5 g, 16.88 mmol) is dissolved in methanol (60 mL), Pd / C (2.05 g, 1.69 mmol, 10% wt) is added, and the reaction is stirred at 50°C for 16 hours; a layer of diatomaceous earth is spread evenly in a suction filtration funnel, the reaction solution is filtered, the filtrate is collected, and concentrated under reduced pressure, 14e (4 g) was obtained, and the yield is 89.0%. MS m / z (ESI): 267 [M+1] +

[0322] Phase 4: 14e (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), ethyl 2-oxoacetate (575.05 mg, 5.63 mmol, 559 μL) was added, and the reaction was stirred at 100°C in a microwave for 10 minutes, and after the reaction was completed, it was used directly in the next step.

[0323] Step 5: Methyl 4-(tert-butoxycarbonylamino)-3-[(E)-(2-methoxy-2-oxo-ethylidene)amino]benzoate 14f (500 mg, 1.49 mmol) is dissolved in N,N-dimethylformamide (7 mL), 1-methyl-1-toluenesulfonylmethyl isocyanide (373.30 mg, 1.78 mmol) and potassium carbonate (410.92 mg, 2.97 mmol) are added, and the reaction is stirred in a microwave at 80°C for 10 minutes; water (60 mL) is added to the reaction solution and extracted with ethyl acetate (60 mL x 3); the organic phase is combined, washed with saturated saline (60 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 14g I obtained it and used it directly in the next step.

[0324] Step 6: 14g(600 mg, 1.49 mmol) is dissolved in 1,2-dichloroethane (6 mL) / trifluoroacetic acid (0.6 mL), and the reaction is stirred in a microwave at 80°C for 10 minutes; the reaction solution is concentrated under reduced pressure, the concentrated residue is stirred in dichloromethane (10 mL) for 15 minutes, filtered, and the filter cake is dried under reduced pressure, 14h (200 mg) was obtained, and the yield is 52.3%. MS m / z (ESI): 258 [M+1] +

[0325] Step 7: 14h (200 mg, 778 μmol) is dissolved in phosphorus oxychloride (3 mL), and the reaction is stirred at 180°C for 8 hours; the reaction solution is concentrated under reduced pressure, water (15 mL) is added to the concentrated residue, and the organic phase is separated; the aqueous layer is extracted with ethyl acetate (15 mL x 3); the organic phases are combined, washed with saturated saline (15 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 14i (100 mg) was obtained and used directly in the next step. MS m / z (ESI): 276 [M+1] +

[0326] Step 8: 14i (100 mg, 363 μmol) is dissolved in N,N-dimethylformamide (2 mL), 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) are added sequentially, and the reaction is stirred at 120°C for 2 hours; water (20 mL) is added to the reaction solution and the organic phase is separated; the aqueous layer is extracted with ethyl acetate (20 mL x 3); the organic phases are combined, washed with saturated saline (20 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 14j (200 mg) was obtained and used directly in the next step. MS m / z (ESI): 377 [M+1] +

[0327] Step 9: 14j (100 mg, 266 μmol) is dissolved in water (1 mL) / methanol (1 mL) / tetrahydrofuran (3 mL), lithium hydroxide (25.45 mg, 1.06 mmol) is added, and the reaction is stirred at 80°C for 3 hours; the pH is adjusted to 5 with 0.5 M hydrochloric acid, filtered, the filter cake is rinsed with water (5 mL), and the filter cake is dried under reduced pressure, 14k (60 mg) was obtained, and the yield is 62.3%. MS m / z (ESI): 363 [M+1] +

[0328] Step 10: 14k (50 mg, 138 μmol) and 14b (45.08 mg, 166 μmol) was dissolved in N,N-dimethylformamide, N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added, and the reaction was continuously stirred at 25°C for 16 hours; the reaction solution was separated and purified by direct preparative Pre-HPLC, 14l (18 mg) was obtained, and the yield is 21.2%. MS m / z (ESI): 617 [M+1] +

[0329] Step 11: 14l (18 mg, 29 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred continuously at 90°C for 3 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by preparative Pre-HPLC (acid method), Example 14 (6 mg) was obtained, and the yield is 41.4%. MS m / z (ESI): 497 [M+1] +

[0330] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.25 (d, 2H), 7.81 (d, 1H), 7.41 (s, 2H), 6.88 (s, 2H), 5.32 (t, 1H), 4.94 - 4.63 (m, 2H), 4.28 (s, 2H), 2.63 (s, 3H), 2.00 (q, 1H), 1.26 - 1.21 (m, 2H), 1.09 - 0.73 (m, 2H), 0.32 (d, 2H).

[0331] The preparation of the following examples is Example 1 Referred to.

[0332]

[0333]

[0334]

[0335] Example 28

[0336] 4-amino-7-(methoxymethyl)-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxalin-8-carboxamide

[0337]

[0338] Step 1: Methyl 4-fluoro-2-methyl-5-nitrobenzoate 28a (20 g, 93.83 mmol) was dissolved in 1'4-dioxane, water ammonia (2 M, 93.8 mL) was added, and the reaction was stirred at 25°C for 16 hours; the reaction solution was concentrated under reduced pressure to obtain a crude product; the crude product was stirred with dichloromethane (100 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure, 28b (22 g, crude product) was obtained. MS m / z (ESI): 211 [M+1] +

[0339] Phase 2: 28b(22 g, 104.67 mmol) was dissolved in DMF (150 mL), 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 hours; water (200 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL x 3); the organic phases were combined, washed with saturated saline (200 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was purified using eluent system C, 28c (18 g) was obtained, and the yield is 55.4%.

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.42 (s, 1H), 7.80 (s, 1H), 3.85 (s, 3H), 2.58 (s, 3H), 1.48 (s, 9H).

[0341] Phase 3: 28c(10 g, 32.23 mmol) is dissolved in carbon tetrachloride (100 mL), NBS (17.21 g, 96.68 mmol) and BPO (1.12 g, 3.22 mmol, 70% purity) are added, and the reaction is stirred continuously at 80°C for 16 hours; water (100 mL) is added to the reaction solution and extracted with dichloromethane (200 mL x 3); the organic phase is combined, washed with saturated saline (200 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; The residue is added to tetrahydrofuran (120 mL), diethyl phosphite (7.03 g, 51.27 mmol, 6.6 mL) and DIEA (6.63 g, 51.27 mmol, 9.0 mL) are added and stirred at 25°C for 1 hour; water (100 mL) is added and extracted with ethyl acetate (120 mL x 3); the organic phases are combined, washed with saturated saline (120 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue is purified using eluent system C, 28d (9 g) was obtained, and the yield is 90.2%.

[0342] 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.44 (s, 1H), 8.03 (s, 1H), 5.05 (s, 2H), 3.89 (s, 3H), 1.47 (s, 9H).

[0343] Phase 4: 28d (4.8 g, 12.33 mmol) was dissolved in DMF (50 mL), sodium methoxide (5 M, 9.9 mL, 30% purity) / DMF (20 mL) was added dropwise, and the reaction was stirred at 25°C for 2 hours; water (150 mL) was added to the reaction mixture and extracted with ethyl acetate (150 mL x 3); the organic phases were combined, washed with saturated saline (150 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was purified using eluent system C.28e (1.3 g) was obtained, and the yield is 31.0%.

[0344] Example 14 Referring to the synthesis method of steps 3 through 11 of, 28e from (500 mg) Example 28 (5.5 mg) was obtained, and the yield is 1%. MS m / z (ESI): 487 [M+1] +

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (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).

[0346] The preparation of the following examples is Example 13 Referred to.

[0347]

[0348] Example 32

[0349] 4-amino-7-fluoro-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxalin-8-carboxamide

[0350]

[0351] Step 1: Methyl 2,4-difluoro-5-nitrobenzoate 32a (12 g, 55.27 mmol) is dissolved in tetrahydrofuran (50 mL), ammonia (2 M, 10.4 mL) is added in an ice bath, and the reaction is stirred at 0°C for 0.5 hours, then tetrahydrofuran (50 mL) is added, and the reaction is stirred at 25°C for 16 hours; the reaction solution is concentrated under reduced pressure, water (100 mL) is added to the concentrated residue and stirred for 15 minutes, filtered, and the filter cake is dried under reduced pressure, 32b(12 g, crude product) was obtained. MS m / z (ESI): 214 [M+1] +

[0352] Example 12 Referring to the synthesis method of steps 1 through 10 of, 32b From (500 mg, 2.33 mmol) Example 32 (10 mg) was obtained, and the yield is 0.9%. MS m / z (ESI): 461 [M+1] +

[0353] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (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).

[0354] Example 33

[0355] 4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxalin-8-carboxamide

[0356]

[0357] Step 1: Methyl 4-fluoro-2-methyl-5-nitrobenzoate 33a (10 g, 46.92 mmol) was dissolved in 1'4-dioxane, water ammonia (2 M, 46.9 mL) was added, and the reaction was stirred at 25°C for 16 hours; the reaction solution was concentrated under reduced pressure to obtain a crude product; the crude product was stirred with dichloromethane (50 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure, 33b (11 g, crude product) was obtained. MS m / z (ESI): 211 [M+1] +

[0358] Example 12 Referring to the synthesis method of steps 1 through 10 of, 33b From (500 mg, 1.78 mmol) Example 33(9.8 mg) was obtained, and the yield is 1.2%. MS m / z (ESI): 458 [M+1] +

[0359] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (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).

[0360] Example 34

[0361] 4-amino- N,7 -dimethyl- N -(8-methyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano [3,4-b] Pyridin-5-il)imidazo [1,5-a] Quinoxalin-8-Carboxamide

[0362]

[0363] Step 1: Methyl 2-chloro-6-methoxy-pyridine-3-carboxylate 34a (9 g, 44.64 mmol), potassium vinylfluoroborate (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); after pumping and replacing with nitrogen three times, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (3.27 g, 4.46 mmol) was added, and the reaction system was stirred at 90°C for 15 hours. The reaction was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (500 mL x 3); the organic phases were combined, washed with saturated saline (200 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent system B. 34b(6 g) was obtained, and the yield is 69.6%. MS m / z (ESI): 194 [M+1] +

[0364] Phase 2: 34b (6 g, 31.06 mmol) was dissolved in methanol (100 mL), and after pumping and replacing with nitrogen three times, palladium carbon (377 mg, 0.31 mmol, 10% purity) was added, and the reaction system was stirred at 25°C for 2 hours under hydrogen balloon conditions. The reaction was filtered and concentrated, 34c (5.90 g, crude product) was obtained. MS m / z (ESI): 196 [M+1] +

[0365] Phase 3: 34c (5.9 g, 30.22 mmol), azobisisobutyronitrile (496 mg, 3.02 mmol) and N- Bromosuccinimide (8.61 g, 48.36 mmol) was dissolved in carbon tetrachloride (60 mL), pumped and replaced with nitrogen three times, and the system was heated to 90°C to carry out the reaction. The reaction was cooled to room temperature, concentrated, water was added, extracted with ethyl acetate (100 mL x 3), washed with saline solution (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 34d (7.50 g) was obtained, and the yield is 90.5%. MS m / z (ESI): 275 [M+1] +

[0366] Example 9 Referring to the synthesis method of the third and fourth steps of, 34d From (7.80 g, 28.46 mmol) 34f (2.60 g) was obtained, and the yield is 51.0%. MS m / z (ESI): 180 [M+1] +

[0367] Step 6: 34f(0.5 g, 2.79 mmol) was dissolved in dichloromethane (40 mL), pumped and replaced with nitrogen three times, cooled to 0°C, and triethylamine (339 mg, 3.35 mmol, 0.47 mL) and trifluoromethanesulfonic acid anhydride (866 mg, 3.07 mmol) were added, and the system was reacted at 25°C for 2 hours. Then, sodium iodide (2.09 g, 13.95 mmol) and concentrated hydrochloric acid (12 M, 0.28 mL) were added to the system, and the system was reacted at 20°C for 15 hours. The solution was filtered and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 34g (0.35 g) was obtained, and the yield is 43.4%. MS m / z (ESI): 290 [M+1] +

[0368] Step 7: 34g (0.32 g, 1.11 mmol) and copper(I) iodide (527 mg, 2.77 mmol) were dissolved in N,N-dimethylformamide (5 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (532 mg, 2.77 mmol) was added, and after three pump replacements with nitrogen, the mixture was heated to 100°C and reacted for 2 hours. The reaction was cooled to room temperature, concentrated, water was added, extracted with ethyl acetate (5 mL x 3), washed with saline solution (3 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 34h (0.14 g) was obtained, and the yield is 54.7%. MS m / z (ESI): 232 [M+1] +

[0369] Step 8: 34hSodium cyanobofluoride (0.14 g, 0.61 mmol) and methylamine alcohol solution (314 mg, 3.03 mmol, 30% wt) were dissolved in trifluoroethanol (10 mL), and after three pump replacements with nitrogen, the reaction was carried out at 25°C for 2 hours. Sodium cyanobofluoride (76 mg, 1.21 mmol) was added to the system, and after the addition was complete, the system was carried out 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 1 hour. Extraction was performed using dichloromethane / methanol = 10 / 1 (50 mL × 3), washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A. 34i (80 mg) was obtained, and the yield is 53.6%. MS m / z (ESI): 247 [M+1] +

[0370] Example 12 Referring to the synthesis method of steps 9 to 10 of 4-[(3,5-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxalin-8-carboxylic acid 34j (160 mg, 0.41 mol) and 34i 4-amino- from (100 mg, 0.41 mmol) N,7 -dimethyl- N -(8-methyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 34A (23 mg) was obtained, 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]pyridine-5-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 34B (10 mg) was obtained, and the yield is 9.5%. MS m / z (ESI): 471 [M+1] + .

[0371] 34A: 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (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).

[0372] 34B: 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (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).

[0373] The preparation of the following examples is Example 12 Referred to

[0374]

[0375]

[0376] Example 37

[0377] 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

[0378]

[0379] Step 1: Methyl 2-chloro-3-methyl-pyridine-4-carboxylate 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 is yellow. First, H2O was added to quench the mixture, then 50 mL of water and 300 mL of ethyl acetate were added to the mixed solution, the organic phase was washed three times with 30 mL of saturated saline solution each time, the organic phase was dried, and spin-dried. The obtained residue was purified by silica gel column chromatography using eluent system A, 37b (1.9 g) was obtained, and the yield is 42.2%. MS m / z (ESI): 167 [M+1] +

[0380] Phase 2: 37b (1.4 g, 8.42 mmol), 2-bromo-1,1-dimethoxy-ethane (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, and the reaction solution was yellow. 10 mL of saturated ammonium chloride was added and quenched, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2), and the layers were separated to obtain the organic phase. After drying with anhydrous sodium sulfate and filtering, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A, 37c (0.64 g) was obtained, and the yield is 39.8%. MS m / z (ESI): 191 [M+1] +

[0381] Phase 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, and the reaction solution was yellow. The mixture was cooled, concentrated, quenched with the addition of 10 mL of water, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A, 37d (0.06 g) was obtained, and the yield is 70.8%. MS m / z (ESI):269 [M+1] +

[0382] Phase 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, and the reaction mixture was yellow. The reaction was carried out at 90°C for 16 hours with stirring. After cooling, filtering, and spin-drying, 37e (25 mg) was obtained, and the yield is 65.1%. MS m / z (ESI): 349 [M+1] +

[0383] Step 5: 37e (380 mg, 1.09 mmol), methyl hydroxyacetate (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. 10 mL of water was added and quenched, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 37f(180 mg) was obtained, and the yield is 46.3%. MS m / z (ESI): 357 [M+1] +

[0384] 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, and the reaction solution was yellow. The crude product was prepared using eluent system A and C 18 As a residue obtained by purification by column chromatography 37g (35 mg) was obtained, and the yield is 76.9%. MS m / z (ESI): 325 [M+1] +

[0385] Step 7: 37g (26 mg, 0.08 mmol), hydrochloric acid (2 mL), and ethanol (2 mL) were reacted at 80°C for 16 hours, and the reaction solution was yellow. After cooling, concentrating, and spin-drying, the crude product was eluted using eluent system A and C 18 As a residue obtained by purification by column chromatography 37h (8 mg) was obtained, and the yield is 37.5%. MS m / z (ESI): 267 [M+1] +

[0386] 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, and the reaction mixture was yellow. After cooling, concentrating, and spin-drying, the crude product was eluted using eluent system A and C 18 As a residue obtained by purification by column chromatography 37i (15 mg) was obtained, and the yield is 48.3%. MS m / z (ESI): 282 [M+1] +

[0387] Step 9: 37iN,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (24 mg, 0.086 mmol), N,N,N'-tetramethylchloroformamidinium 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, and the reaction solution was yellow. 10 mL of water was added and quenched, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL x 2), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A, Example 37 (16.8 mg) was obtained, and the yield is 38.6%. MS m / z (ESI): 506 [M+1] +

[0388] 1 HNMR (400 MHz, DMSO-d6) δ 8.35 (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).

[0389] Example 37 Preparation of Chiral Isomers

[0390]

[0391] Example 37 (16 mg, 0.032 mmol) was separated by Chiral-HPLC (Condition 1), and respectively 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) was obtained, with a yield of 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) was obtained, and the yield was 47.5%.

[0392] 37-P1 (t R : 6.687 min) : 1 HNMR (400 MHz, DMSO-d6) δ 8.35 (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).

[0393] 37-P2 (t R : 9.125 min) : 1 HNMR (400 MHz, DMSO-d6) δ 8.35 (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).

[0394] The preparation of the following examples is Example 37 Referred to.

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402] or, Example 39 , 48, 62, 68 The manufacturing of adopted the following method.

[0403] Example 39

[0404] 4-amino- N ,7-dimethyl- N -(2-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridin-7-yl)imidazo[1,5-a]quinoxalin-8-carboxamide

[0405]

[0406] Step 1: Methyl 2-amino-3-methylisonicotinate 39a 3-bromo-1,1,1-trifluoroacetone (3.43 g, 18.07 mmol) and 3-bromo-1,1,1-trifluoroacetone (3.43 g, 18.07 mmol) were dispersed in 50 mL of acetonitrile and reacted at 80°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 39b (2.71 g) was obtained, and the yield is 57.9%. MS m / z (ESI): 259 [M+1] +

[0407] Example 34 Referring to the synthesis method of steps 3 through 8 of, 39b From (1.45 g, 5.62 mmol) 39g (100 mg) was obtained, and the yield is 5.1%. MS m / z (ESI): 350 [M+1] +

[0408] Step 7: 39g (100 mg, 0.29 mmol) and palladium carbon (100 mg, 5% wt) were dispersed in 10 mL of methanol and reacted under a hydrogen atmosphere for 1 hour while stirring. The reaction solution was filtered to remove insoluble substances, and the filtrate was concentrated under reduced pressure. 39h (70 mg) was obtained, and the yield is 90.1%. MS m / z (ESI): 272 [M+1]

[0409] Example 12 Referring to the synthesis method of steps 9 to 10 of, 39h From (20 mg, 0.07 mmol) Example 39 (5 mg) was obtained, and the yield is 14.4%. MS m / z (ESI): 496 [M+1] +

[0410] 1 H NMR (400 MHz, 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).

[0411] Example 39 Preparation of Chiral Isomers

[0412]

[0413] Example 39 (21 mg, 0.042 mmol) was separated by Chiral-HPLC (condition 2), and respectively 39-P1 : ( S )-4-amino- N ,7-dimethyl- N -(2-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridin-7-yl)imidazo[1,5-a]quinoxalin-8-carboxamide (10.1 mg) was obtained, with a yield of 48.1%; 39-P2 : ( R )- 4-amino- N ,7-dimethyl- N -(2-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c]pyridin-7-yl)imidazo[1,5-a]quinoxalin-8-carboxamide (10.2 mg) was obtained, and the yield was 48.2%.

[0414] 39-P1 (t R : 1.562 min) : 1 H NMR (400 MHz, 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).

[0415] 39-P2 (t R : 1.943 min) : 1 H NMR (400 MHz, 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).

[0416] Example 48

[0417] 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]quinoxalin-8-carboxamide

[0418]

[0419] Step 1: 2-chloro-7,8-dihydro-6H-quinoline-5-one 48a(1.7 g, 9.36 mmol, obtained by synthesizing according to the known method "Patent WO 2021163344"), 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 is yellow. After the reaction was completed, the reaction solution was filtered, a hydrogen chloride solution in methanol was added to the filtrate, and the reaction was carried out at 20°C for 3 hours. The reaction solution is yellow. After adding a NaHCO3 solution and quenching, the solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent system A, 48b (1.1 g) was obtained, and the yield is 71.2%. MS m / z (ESI): 165 [M+1] +

[0420] Phase 2: 48b (400 mg, 2.44 mmol), 3-bromo-1,1,1-trifluoropropan-2-one (465 mg, 2.44 mmol), and acetonitrile (6 mL) were reacted at 80°C for 3 hours, and the reaction solution was yellow. After adding NaHCO3 solution and quenching, 10 mL of water was added and quenched, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A, 48c (30 mg) was obtained, and the yield is 4.8%. MS m / z (ESI): 257 [M+1] +

[0421] Phase 3: 48c(70 mg, 0.273 mmol), methylamine (8.5 mg, 0.273 mmol), sodium borohydrogen cyanohydride (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, and the reaction solution was yellow. After adding NaHCO3 solution and quenching, 2 mL of water was added and quenched, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, 48d (28 mg) was obtained, and the yield is 37.7%. MS m / z (ESI): 272 [M+1] +

[0422] Phase 4: 48d (17 mg, 0.062 mmol), 4-amino-7-methyl-imidazo[1,5-a]quinoxalin-8-carboxylic acid 48e (15 mg, 0.062 mmol, Example 28 (Refer to steps 1 through 11 of), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (26 mg, 0.093 mmol), N-methylimidazole (15 mg, 0.186 mmol), and N,N-dimethylformamide (2 mL) are reacted at 20°C for 2 hours, and the reaction solution is yellow. After adding H2O and quenching, 10 mL of water is added and quenched, extraction with ethyl acetate (40 mL x 3), the organic phase is combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL x 2), dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography using eluent system A, Example 417 (10 mg) was obtained, and the yield is 32.5%. MS m / z (ESI): 496 [M+1] +

[0423] 1HNMR (400 MHz, DMSO-d6) δ 9.15 (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).

[0424] Example 62

[0425] 4-amino- N ,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridin-7-il)imidazo[1,5- a ]Quinoxaline-8-Carboxamide

[0426]

[0427] Step 1: Methyl 2-amino-3-methylisonicotinate 62a Bromoacetaldehyde dimethyl acetal (5 g, 30.12 mmol) and bromoacetaldehyde dimethyl acetal (10.12 g, 60.24 mmol) were dispersed in 50 mL of ethanol and 10 mL of hydrochloric acid (2 M / L) and reacted at 80°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 62b (3.2 g) was obtained, and the yield is 55.9%. MS m / z (ESI): 191 [M+1] +

[0428] Phase 2: 62b (3.2 g, 16.84 mmol) was dispersed in 50 mL of acetonitrile, and N- Iodosuccinimide (4.5 g, 20 mmol) was added. The reaction was carried out for 1 hour while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 62c (2.80 g) was obtained, and the yield is 52.6%. MS m / z (ESI): 317 [M+1] +

[0429] Phase 3: 62c (2.80 g, 8.86 mmol), copper(I) iodide (8.42 g, 44.30 mmol), and potassium fluoride (1.54 g, 26.58 mmol) in 30 mL N , N It was dispersed in dimethylformamide, and (trifluoromethyl)trimethylsilane (3.77 g, 26.58 mmol) was added. The reaction was carried out at 90°C for 16 hours while stirring. 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, 62d (830 mg) was obtained, and the yield is 36.3%. MS m / z (ESI): 259 [M+1] +

[0430] Example 34 Stages 3 through 8 of and Example 12 Referring to the synthesis method of steps 9 to 10 of, 62d From (400 mg, 1.55 mmol) Example 62 (19 mg) was obtained, and the yield is 2.5%. MS m / z (ESI): 496 [M+1] +

[0431] 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.87 (s, 2H), 8.31 (dd, 4H), 7.50 (s, 1H), 7.16 (s, 1H), 5.93 - 4.56 (m, 3H), 4.27 (s, 2H), 2.79 (d, 3H), 2.42 (s, 3H).

[0432] Example 62 Preparation of Chiral Isomers

[0433]

[0434] Example 62 (19 mg, 0.042 mmol) was separated by Chiral-HPLC (condition 2), and respectively 62-P1 : ( S )-4-amino- N ,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridin-7-yl)imidazo[1,5-a]quinoxalin-8-carboxamide (9.1 mg) was obtained, with a yield of 47.8%; 62-P2 : ( R )- 4-amino- N ,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridin-7-yl)imidazo[1,5-a]quinoxalin-8-carboxamide (8.8 mg) was obtained, and the yield was 46.3%.

[0435] 62-P1 (t R : 1.982 min) : 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.87 (s, 2H), 8.31 (dd, 4H), 7.50 (s, 1H), 7.16 (s, 1H), 5.93 - 4.56 (m, 3H), 4.27 (s, 2H), 2.79 (d, 3H), 2.42 (s, 3H).

[0436] 62-P2 (t R : 1.436 min) : 1H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.87 (s, 2H), 8.31 (dd, 4H), 7.50 (s, 1H), 7.16 (s, 1H), 5.93 - 4.56 (m, 3H), 4.27 (s, 2H), 2.79 (d, 3H), 2.42 (s, 3H).

[0437] Example 68

[0438] 4-amino- N,1- dimethyl- N -(3-(trifluoromethyl)-7,10-dihydro-8H-pyrano [4,3-h] Quinoline-7-yl)-1H-pyrazolo [4,3-c] Quinoline-8-Carboxamide

[0439]

[0440] Step 1: 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) were dissolved in water (30 mL) and concentrated sulfuric acid (40 mL), and the reaction system was stirred at 150°C for 1 hour. The reaction was cooled to room temperature, the pH was adjusted to 3 using a 12 M aqueous sodium hydroxide solution, extracted with ethyl acetate (500 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. 68b (15 g, crude product) was obtained. MS m / z (ESI): 188 [M+1] +

[0441] Phase 2: 68b(0.7 g, 3.74 mmol) was dissolved in methanol (10 mL), thionyl chloride (1.33 g, 11.22 mmol, 0.81 mL) was added, and the reaction system was stirred at 70°C for 15 hours. After cooling to room temperature, water was added and quenched; the mixture was extracted with ethyl acetate (80 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 68c (350 mg) was obtained, and the yield is 46.5%. MS m / z (ESI): 202 [M+1] +

[0442] Phase 3: 68c (2.9 g, 14.41 mmol), N- Iodosuccinimide (3.89 g, 17.29 mmol) was dissolved in acetic acid (10 mL), and after pumping and replacing with nitrogen three times, the reaction system was stirred at 100°C for 18 hours. The reaction solution was concentrated, water was added and quenched, extracted with ethyl acetate (100 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 68d (3.0 g) was obtained, and the yield is 63.6%. MS m / z (ESI): 328 [M+1] +

[0443] Phase 4: 68d(2.9 g, 8.87 mmol) and copper(I) iodide (4.22 g, 22.16 mmol) were dissolved in N,N-dimethylformamide (20 mL), methyl fluorosulfonyl difluoroacetate (4.26 g, 22.16 mmol, 2.82 mL) was added, and after three pump replacements with nitrogen, the mixture was heated to 100°C and reacted for 2 hours. The reaction was cooled to room temperature, filtered, concentrated, spin-dried, water was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 68e (2.1 g) was obtained, and the yield is 88.0%. MS m / z (ESI): 270 [M+1] +

[0444] Example 9 Referring to the synthesis method of steps 1 through 4 of, 68e From (2.5 g, 9.29 mmol) 68j (520 mg) was obtained, and the yield is 21.0%. MS m / z (ESI): 268 [M+1] +

[0445] Example 9 Referring to the synthesis method of Step 7, 68j From (520 mg, 1.95 mmol) 68k (320 mg) was obtained, and the yield is 58.3%. MS m / z (ESI): 283 [M+1] +

[0446] Example 1 Referring to the synthesis method of Step 7, 68k From (58 mg, 0.20 mmol) Example 68 (44 mg) was obtained, and the yield is 42.1%. MS m / z (ESI): 507 [M+1] +

[0447] 1H NMR (400 MHz, DMSO-d6) δ 13.21 (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).

[0448] Example 79

[0449] 4-amino-N-(7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxalin-8-carboxamide

[0450]

[0451] Example 12 Referring to steps 9 and 10 of 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-8-carboxylic acid 79a (90 mg, Example 28 (Refer to steps 1 through 11 of) and 3-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine 79b (40 mg, Example 37 (refer to steps 1 through 8 of) 79d (47 mg) was obtained, and the yield is 40.5%.

[0452] Phase 3: 79d (15 mg, 0.029 mmol), Pd / C (3 mg, 20% by weight), and methanol (2 mL) were reacted at 20°C under an H2 atmosphere for 4 hours. The reaction solution is 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, Example 79 (2.1 mg) was obtained, and the yield is 16%. MS m / z (ESI): 428 [M+1] +

[0453] 1HNMR (400 MHz, DMSO-d6) δ 9.12 (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).

[0454] Example 80

[0455] 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

[0456]

[0457] Example 79 Referring to steps 1 and 3 of 2-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine 80a (20 mg, Example 48 (Refer to Steps 1 and 3 of) and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 80b From (20 mg, obtained by synthesizing using the known method "Patent WO 2022169948") Example 80 (2.2 mg) was obtained, and the yield is 5.6%. MS m / z (ESI): 428 [M+1] +

[0458] 1 HNMR (400 MHz, DMSO-d6) δ 8.50 (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).

[0459] Example 81

[0460] 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

[0461]

[0462] N-methyl-4-(trifluoromethyl)-12-oxa-2,5-diazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7-tetraene-10-amine 81a (11 mg, 0.041 mmol, Example 48 (refer to the synthesis of steps 1 to 3 of), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 81b N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (10 mg, 0.066 mmol, obtained by synthesis according to the known method "Patent WO 2022169948"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (2 mg, 0.066 mmol), and N-methylimidazole (10 mg, 0.124 mmol) were dissolved in 2 mL of N,N-dimethylformamide and reacted at 20°C for 2 hours while stirring. 10 mL of water was added and quenched, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A, Example 81 (2 mg) was obtained, and the yield is 9.8%. MS m / z (ESI): 496 [M+1] +

[0463] 1HNMR (400 MHz, DMSO-d6) δ 8.41 (d, 2H), 8.21 (d, 1H), 7.73 - 7.60 (m, 2H), 7.50 (s, 1H), 7.13 (s, 1H), 5.08 (s, 1H), 4.83 (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).

[0464] Example 82

[0465] 4-amino- N -(2-chloro-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ] Pirano[3,4- c ]Pyridin-7-day)- N ,7-dimethylimidazo[1,5- a ]Quinoxaline-8-Carboxamide

[0466]

[0467] Step 1: Methyl 2-amino-3-methylisonicotinate 82a (5 g, 30.12 mmol) and ethyl bromoacetate (5.03 g, 30.12 mmol) were dispersed in 50 mL of tetrahydrofuran and reacted at 25°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, 20 mL of phosphorus oxychloride was added, and the reaction was carried out at 90°C for 1 hour while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 82b (3.31 g) was obtained, and the yield is 49.1%. MS m / z (ESI): 225 [M+1] +

[0468] Example 62 The second to third stage of, Example 34 Stages 3 through 8 of and Example 12Referring to the synthesis method of steps 9 to 10 of, 82b From (1.21 g, 5.40 mmol) Example 82 (20 mg) was obtained, and the yield is 0.7%. MS m / z (ESI): 530 [M+1] +

[0469] Example 83

[0470] 4-amino- N ,1-dimethyl- N -(3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]Pyridin-7-day)-1 H -pyrazolo[4,3- c ]quinoline-8-carboxamide

[0471]

[0472] Example 1 Referring to the synthesis method of Step 7, N -methyl-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-amine 83a From (30 mg, 0.11 mmol) Example 83 (10 mg) was obtained, and the yield is 18.4%. MS m / z (ESI): 496 [M+1] +

[0473] 1 H NMR (400 MHz, 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).

[0474] Example 84

[0475] 4-amino- N ,1-dimethyl- N -(2-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]Pyridin-7-day)-1 H -pyrazolo[4,3- c ]Quinoline-8-Carboxamide

[0476]

[0477] Example 1 Referring to the synthesis method of Step 7, N -methyl-2-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-amine 84a From (40 mg, 0.11 mmol) Example 84 (10 mg) was obtained, and the yield is 18.4%. MS m / z (ESI): 496 [M+1] +

[0478] 1 H NMR (400 MHz, 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).

[0479] The preparation of the following examples is Example 37 Referred to.

[0480]

[0481]

[0482]

[0483] The manufacture of the examples in the table below is Example 62 Referred to

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494] The preparation of the following examples is Example 82 Referred to

[0495]

[0496] Example 192 , 193 , 194 The manufacture of Example 33 Refer to; Example 195 , 196 The manufacture of Example 14 Referred to

[0497]

[0498] or, Examples 144, 146 It was manufactured by adopting the following method.

[0499] Example 144

[0500] 4-amino-N-[3-(difluoromethylene)cyclobutyl]-7-methyl-N-[5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-10-yl]imidazo[1,5-a]quinoxalin-8-carboxamide

[0501]

[0502] Step 1: 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) were dissolved in dichloromethane (4 mL) and cooled to 0°C, and methanesulfonic acid anhydride (404.80 mg, 2.32 mmol) was added. The mixture was stirred continuously at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was purified by column chromatography, the eluent was petroleum ether / ethyl acetate (1:1), and the mixture was separated 144b (100 mg, 297.37 μmol) was obtained, and the yield is 38.4%. MS m / z (ESI): 337 [M+1] +

[0503] Phase 2: 144b 3-(difluoromethylene)cyclobutylamine (100 mg, 297.37 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 reacted at 60°C for 16 hours while stirring, cooled to room temperature, removed the solvent under reduced pressure, purified the residue by column chromatography, the eluent was petroleum ether / ethyl acetate (1:2), and separated 144c (50 mg, 139.16 μmol) was obtained, and the yield is 46.7%. MS m / z (ESI): 360 [M+1] +

[0504] Phase 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 was carried out with stirring for 3 hours at 0°C. The reaction mixture was spin-dried. N-[3-(difluoromethylene)cyclobutyl]-5-(trifluoromethyl)-12-oxa-3,6-diazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-10-amine (55 mg, 153.08 μmol) was dissolved in DCM (1.5 mL), and acid chloride and triethylamine (31 mg, 306.16 μmol) were added at 0°C. The reaction was carried out with stirring for 16 hours at room temperature. The solvent is removed by reducing pressure, the residue is purified by column chromatography, the eluent is petroleum ether / ethyl acetate (10:1), and separated 144d (25 mg, 35.63 μmol) was obtained, and the yield is 22.2%. MS m / z (ESI): 734 [M+1] +

[0505] Phase 4: 144d Trifluoroacetic acid (200 μL) was added to (20 mg, 28.50 μmol) and reacted at 90°C for 2 hours while stirring. After cooling to room temperature and removing the solvent under reduced pressure, the residue was purified by HPLC and separated. Example 144 (4.2 mg, 7.20 μmol) was obtained, and the yield is 25.2%. MS m / z (ESI): 584 [M+1] +

[0506] 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.41 (d, 1H), 8.11 (s, 2H), 7.90 (d, 1H), 7.37 (s, 1H), 7.25-7.03 (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).

[0507] Example 146

[0508] 4-amino-N-(3-((dimethyl(oxo)-l6-sulfanilidene)amino)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxalin-8-carboxamide

[0509]

[0510] Step 1: 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) were dissolved in dichloromethane and reacted at room temperature for 1 hour while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 146a (240 mg) was obtained, and the yield is 80.5%. MS m / z (ESI): 382 [M+1] +

[0511] Phase 2: 146aImino-dimethyl-oxo-sulfane (100 mg, 0.26 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 reacted under nitrogen protection at 80°C for 2 hours with stirring. Ethyl acetate (50 mL) was added to the reaction mixture for extraction, washed with saturated saline (50 mL x 2), the organic phase was taken after extraction, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 146b (57 mg) was obtained, and the yield is 55.1%. MS m / z (ESI): 395 [M+1] +

[0512] Phase 3: 146b (57 mg, 0.13 mmol) was dissolved in 5 mL of hydrogen chloride in 2 M dioxane and reacted at room temperature for 2 hours while stirring. The reaction solution was concentrated under reduced pressure, 146c (33 mg) was obtained, and the yield is 85.7%. MS m / z (ESI): 295 [M+1] +

[0513] Example 37 Referring to Step 9 of, 146c From (33 mg, 0.11 mmol) Example 146 (4.2 mg) was obtained, and the yield is 7.4%. MS m / z (ESI): 519 [M+1] +

[0514] 1H NMR (400 MHz, DMSO-d6) δ 9.08 (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).

[0515] Example 197

[0516] 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]quinoxalin-8-carboxamide

[0517]

[0518]

[0519] Step 1: THF (70 mL) was added to a 3-neck flask, purged with nitrogen three times, and cooled to 0°C; dibromodifluoromethane (20.72 g, 98.74 mmol, 9.02 mL) was rapidly added and stirred in an ice bath for 10 minutes; HMPT (16.12 g, 98.74 mmol, 18 mL) was slowly added dropwise, and it was confirmed that a white solid was formed; after the addition was complete, 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, 0.3 mL of HMPT was additionally added, and the temperature was transferred to 75°C and stirred for 5 hours; water (100 mL) was added to the reaction mixture and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (100 mL x 3); the organic phases were combined, washed with saturated saline (100 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was purified using purification system C,197b (2 g) was obtained, and the yield is 43.1%.

[0520] Phase 2: 197b (1.5 g, 7.35 mmol) is dissolved in DCM (15 mL) and TFA (10 mL), and the reaction is stirred at 25°C for 1 hour; the reaction solution is then concentrated directly under reduced pressure, 197c (1 g, crude product) was obtained.

[0521] Phase 3: 197c (1 g, crude product), 2-hydroxyisoindole-1,3-dione (1.21 g, 7.43 mmol) was dissolved in DCM (10 mL), DMAP (82.49 mg, 675.19 μmol) was added, N,N-diisopropylcarbodiimide (937.29 mg, 7.43 mmol, 1.2 mL) was added dropwise, and after purging with nitrogen three times, the reaction was stirred at 25°C for 16 hours under nitrogen protection; water (20 mL) was added to the reaction mixture and extracted with dichloromethane (20 mL x 3); the organic phases were combined, washed with saturated saline (20 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was separated and purified using purification system C, 197d (1.92 g) was obtained, and the yield is 96.9%. MS m / z (ESI): 294 [M+1] +

[0522] Phase 4: 197d(1.92 g, 6.55 mmol) and 2,2-bis-1,3,2-benzodioxabolol (1.95 g, 8.18 mmol) were dissolved in DMA (120 mL), and after purging with nitrogen three times, stirred for 15 hours in a blue light reactor (18 w, 456 nm) under nitrogen protection; then pinacol (3.10 g, 26.19 mmol) and TEA (4.18 g, 41.32 mmol, 5.8 mL) were added sequentially, and after purging with nitrogen three times, the reaction was stirred for 1 hour at 25°C under nitrogen protection; water (200 mL) was added to the reaction mixture and extracted with ethyl acetate (200 mL x 3); The organic phases are combined, washed with saturated saline (200 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue is separated and purified using purification system C, 197e (540 mg) was obtained, and the yield is 35.9%.

[0523] Example 32 Referring to the synthesis method of steps 1 to 10 of methyl 2-bromo-4-fluoro-5-nitrobenzoate 197f From (2 g, 3.60 mmol) 197o (600 mg) was obtained, and the yield is 0.1%. MS m / z (ESI): 671 [M+1] +

[0524] Step 14: 197o (100 mg, 149 μmol), 197e(137.05 mg, 596 μmol) was dissolved in DMF (5 mL), Ni(dtbppy)Cl2 (29.64 mg, 75 μmol), [Ir(dtbppy)[dF(CF3)ppy]2]PF6 (7.52 mg, 8 μmol), and morpholine (19.46 mg, 224 μmol) were added sequentially, and after purging with nitrogen three times, the reaction was stirred at 25°C for 16 hours under nitrogen protection; water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL x 3); the organic phases were combined, washed with saturated saline (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 197p (100 mg, crude product) was obtained. MS m / z (ESI): 695 [M+1] +

[0525] Step 15: 197p (100 mg, crude product) is dissolved in TFA (1 mL), and the reaction is stirred at 90°C for 3 hours; the reaction solution is concentrated under reduced pressure, and the concentrated residue is separated and purified by Pre-HPLC, Example 197 (7.5 mg) was obtained. MS m / z (ESI): 545 [M+1] +

[0526] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (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).

[0527] Example 198

[0528] 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]quinoxalin-8-carboxamide

[0529]

[0530] Example 28 Referring to the synthesis method of the first and second steps of tert-butyl 4-oxopiperidine-1-carboxylate 198a From (5 g, 25.09 mmol) 198c (1.5 g) was obtained, and the yield is 44.9%.

[0531] Example 32 Referring to the synthesis method of steps 1 to 10 of methyl 4-fluoro-2-methyl-5-nitrobenzoate 198e From (2 g, 9.38 mmol) 198n (600 mg) was obtained, and the yield is 12%. MS m / z (ESI): 617 [M+1] +

[0532] Step 12: 198n (120 mg, 195 μmol), 198c (51.75 mg, 389 μmol) was dissolved in DMF (3 mL), Xphos-Pd-G2 (15.27 mg, 20 μmol) and t-BuoNa (112.05 mg, 1.17 mmol) were added sequentially, and after purging with nitrogen three times, the reaction was stirred in a microwave at 110°C for 3 hours under nitrogen protection; water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL x 3); the organic phases were combined, washed with saturated saline (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, 198o (100 mg, crude product) was obtained. MS m / z (ESI): 670 [M+1] +

[0533] Step 13: 198o (100 mg, 150 μmol) was dissolved in TFA (3 mL), and after purging with nitrogen three times, the reaction was stirred at 90°C for 3 hours under nitrogen protection; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by Pre-HPLC, Example 198(18 mg) was obtained. MS m / z (ESI): 520 [M+1] +

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (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).

[0535] Example 199

[0536] 4-amino-N-methoxy-7-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxalin-8-carboxamide

[0537]

[0538] Step 1: 2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one (500 mg, 2.30 mmol, obtained by synthesis according to the known method "Patent WO 2022169948") was dissolved in methanol, and sodium borohydride (435 mg, 11.51 mmol) was added in several installments in an ice bath while reacting at 0°C for 1 hour with stirring. Saturated ammonium chloride solution (30 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 2). After extraction, the organic phase was taken, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B, 199b (470 mg) was obtained, and the yield is 93.1%. MS m / z (ESI): 220 [M+1] +

[0539] Phase 2: 199b(470 mg, 2.14 mmol) and triethylamine (651 mg, 6.43 mmol) were dissolved in 10 mL of dichloromethane, and methanesulfonic acid anhydride (560 mg, 3.22 mmol) was added and reacted at room temperature for 1 hour while stirring. Saturated ammonium chloride solution (30 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 2). After extraction, the organic phase was taken, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 199c (430 mg) was obtained, and the yield is 66.8%. MS m / z (ESI): 298 [M+1] +

[0540] Phase 3: 199c (220 mg, 0.74 mmol) was dissolved in 10 mL of acetonitrile, potassium carbonate (511 mg, 3.7 mmol) was added, and the reaction was carried out at 80°C in a sealed tube for 16 hours while stirring. The reaction mixture was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A, 199d (139 mg) was obtained, and the yield is 75.7%. MS m / z (ESI): 249 [M+1] +

[0541] Phase 4: 199d (139 mg, 0.56 mmol) and 4-((3,4-dimethylbenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-8-carboxylic acid 199e(241 mg, 0.62 mmol) was dissolved in 5 mL of dichloromethane, phosphorus oxychloride (257 mg, 1.68 mmol) and pyridine (265 mg, 3.36 mmol) were added sequentially, and the reaction was carried out at room temperature for 2 hours while stirring. 2 M hydrochloric acid (30 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 2). After extraction, the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B, 199f (67 mg) was obtained, and the yield is 19.2%. MS m / z (ESI): 623 [M+1] +

[0542] Example 1 Referring to Step 7 of, 199f From (67 mg, 0.11 mmol) Example 199 (20.2 mg) was obtained, and the yield is 38.9%. MS m / z (ESI): 473 [M+1] +

[0543] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.13 (d, 1H), 7.90 (d, 1H), 7.38 (s, 1H), 5.70 (s, 1H), 4.90 (d, 1H), 4.78 (d, 1H), 4.37 - 4.15 (m, 2H), 3.43(s, 3H), 2.38 (s, 3H).

[0544] Example 200

[0545] 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]pyridin-8-carboxamide

[0546]

[0547] Step 1: Methyl 3-bromo-4-hydroxybenzoate 200aA reaction mixture of N,N-dimethylformamide (50 mL) containing 3-bromo-4-chloro-5-nitropyridine (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) was stirred at 35°C for 16 hours. The reaction mixture was filtered to remove the solid and concentrated. The organic phase was concentrated, and the residue was purified by silica gel column chromatography. 200b (7.60 g) was obtained, and the yield is 81.3%. MS m / z (ESI): 433 [M+1] +

[0548] Phase 2: 200b A reaction mixture of (5.00 g, 11.55 mmol) and iron powder (6.48 g, 115.51 mmol) in methanol (100 mL) and saturated ammonium chloride aqueous solution (50 mL) was stirred at 50°C for 16 hours. After the reaction was complete, the reaction mixture was filtered to remove the solid. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. 200c (3.92 g) was obtained, and the yield is 84.2%. MS m / z (ESI): 403 [M+1] +

[0549] Phase 3: 200c A reaction mixture of 1,4-dioxane (3 mL) and water (0.3 mL) containing bis(pinacoleto)diborone (20 mg, 0.050 mmol), potassium phosphate (15.82 mg, 0.075 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.64 mg, 0.005 mmol) was purged with nitrogen, sealed in a microwave tube, and stirred at 90°C for 16 hours. The reaction mixture was filtered to remove the solid and concentrated. The organic phase was concentrated, and the residue was purified by silica gel column chromatography. 200d (8 mg) was obtained, and the yield is 66.4%. MS m / z (ESI): 243 [M+1] +

[0550] Phase 4: 200d A reaction solution of (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 solution was concentrated. The organic phase was concentrated, and the residue was purified by reverse-phase column chromatography. 200e (22 mg) was obtained, and the yield is 46.7%. MS m / z (ESI): 229 [M+1] +

[0551] Step 5: 200e A reaction solution of N,N-dimethylformamide (2 mL) containing N-methyl-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine (15 mg, 0.066 mmol), N-methylimidazole (16 mg, 0.197 mmol), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (28 mg, 0.099 mmol) was stirred at room temperature for 3 hours. The reaction solution was concentrated. The organic phase was concentrated, and the residue was purified by prep-HPLC column chromatography. Example 200 (5 mg) was obtained, and the yield is 15.8%. MS m / z (ESI): 482 [M+1] +

[0552] 1 ¹H NMR (400 MHz, CD3OD) δ 8.83 (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).

[0553] Example 201

[0554] 4-amino-7-fluoro-N-methoxy-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxalin-8-carboxamide

[0555]

[0556] Example 199 The fourth stage of and Example 1 Referring to step 7 of 4-((3,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxalin-8-carboxylic acid 201a From (88 mg, 0.24 mmol) Example 201 (20 mg) was obtained, and the yield is 17.4%. MS m / z (ESI): 477 [M+1] +

[0557] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (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).

[0558] Example 202

[0559] 4-amino- N -(2-(cyclohexylidenefluoromethyl)-5,8-dihydro-6H-pyrano[ 3,4-b ]pyridine-5-yl)-7-fluoro- N -methylimidazo[ 1,5-a ]Quinoxaline-8-Carboxamide

[0560]

[0561] 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). After pumping and replacing the solution with nitrogen three times, diethyl zinc (3.02 g, 24.45 mmol, 24.5 mL, 1 M) was added dropwise to the system at 25°C. After the addition was complete, the system was reacted at 25°C for 1 hour. The completion of the reaction was monitored by TLC, and 50 mL of methanol was added for quenching, concentration, and filtration. The residue was purified by silica gel column chromatography using eluent system B. 202b (1.20 g) was obtained, and the yield is 30.5%.

[0562] 1 H NMR (400 MHz, CDCl3) δ 2.27 (td, 2H), 2.15-2.10 (m, 2H), 1.59-1.49 (m, 6H).

[0563] Phase 2: 202b (2 g, 10.36 mmol), bis(pinacoleto)diborone (5.26 g, 20.72 mmol), and potassium acetate (3.05 g, 31.08 mmol) were dissolved in 1'4-dioxane (20 mL). After pumping and replacing with nitrogen three times, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (758 mg, 1.04 mmol) was added to the system, and the reaction system was reacted at 90°C for 5 hours. After cooling to room temperature, adding water and quenching, extracting with ethyl acetate (80 mL x 3), washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating. The residue was purified by silica gel column chromatography using eluent system B. 202c (0.55 g) was obtained, and the yield is 22.1%.

[0564] 1H NMR (400 MHz, CDCl3) δ 2.39 (d, 2H), 2.31 (d, 2H), 1.56 (d, 6H), 1.30 (s, 12H).

[0565] 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). After three pump replacements with nitrogen, tetrakis(triphenylphosphine)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, extracted with ethyl acetate (50 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 202e (130 mg) was obtained, and the yield is 91.2%. MS m / z (ESI): 377 [M+1] +

[0566] Phase 4: 202e (130 mg, 0.35 mmol) was dissolved in 1'4-dioxane (4 mL), and after pumping and replacing with nitrogen three times, hydrochloric acid / 1'4-dioxane (4 M, 4 mL) was added to the system, and the reaction system was reacted at 25°C for 1 hour. After concentration, 202f (0.10 g, crude product) was obtained. MS m / z (ESI): 277 [M+1] +

[0567] Step 5: 4-amino-7-fluoro-imidazo[1,5-a]quinoxalin-8-carboxylic acid 202g(40 mg, 0.16 mmol), 202f (54 mg, 0.19 mmol), and N,N,N',N'-tetramethylchloroformamidinium 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 after pumping and replacing with nitrogen three times, the reaction system was stirred at 25°C for 1 hour. Water was added and quenched, extracted with ethyl acetate (50 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A, Example 202 (36 mg) was obtained, and the yield is 43.9%. MS m / z (ESI): 505 [M+1] +

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (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).

[0569] The preparation of the following examples is Example 34 Referred to

[0570]

[0571] The preparation of the following examples is Example 146 Referred to.

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578] The preparation of the following examples is Example 201 Referred to.

[0579]

[0580]

[0581] Example 204

[0582] 4-amino- N -(2-(4-(difluoromethylene)piperidine-1-yl)-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-yl)-7-fluoro-N-methylimidazo[1,5- a ]Quinoxaline-8-Carboxamide

[0583]

[0584] Step 1: Methyl 2-amino-3-methylisonicotinate 204a (15 g, 90.36 mmol) and ethyl bromoacetate (15.09 g, 90.36 mmol) were dispersed in 70 mL of tetrahydrofuran and reacted at 25°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, the residue was dispersed in 800 mL of acetonitrile, phosphorus oxybromide (64.16 g, 225.90 mmol) was added, and the reaction was reacted at 90°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A, 204b (5.41 g) was obtained, and the yield is 22.3%. MS m / z (ESI): 269 [M+1] +

[0585] Example 62 Referring to the synthesis method of steps 2 through 8 of, 204bFrom (5.41 g, 20.19 mmol) 204h (490 mg) was obtained, and the yield is 6.9%. MS m / z (ESI): 350 [M+1] +

[0586] Step 8: 204h (490 mg, 1.40 mmol) and triethylamine (202 mg, 2.00 mmol) were dispersed in 10 mL of dichloromethane, and di-tert-butyl dicarbonate (436 mg, 2.00 mmol) was added. The reaction was carried out at 25°C for 1 hour while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 204i (610 mg) was obtained, and the yield is 96.8%. MS m / z (ESI): 450 [M+1] +

[0587] Example 198 Referring to the synthesis method of Step 12 of, 204i From (100 mg, 0.22 mmol) 204k (62 mg) was obtained, and the yield is 55.5%. MS m / z (ESI): 503 [M+1] +

[0588] Step 10: 204k (62 mg, 0.12 mmol) was dispersed in 2 mL of trifluoroacetic acid. The reaction was carried out at 25°C for 1 hour while stirring. The reaction solution was concentrated under reduced pressure, 204l (49 mg) was obtained, and the yield is 98.7%. MS m / z (ESI): 403 [M+1] +

[0589] Example 12 Referring to the synthesis method of steps 9 and 10 of, 204l From (49 mg, 0.12 mmol) Example 204 (18 mg) was obtained, and the yield is 23.4%. MS m / z (ESI): 631 [M+1] +

[0590] Example 205

[0591] 4-amino- N -(2-((dimethyl(oxo)-l6-sulfanilidene)amino)-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-yl)-7-fluoro- N -methylimidazo[1,5- a ]Quinoxaline-8-Carboxamide

[0592]

[0593] Example 198 The 12th stage of, Example 204 The 10th stage of, Example 12 Referring to the synthesis method of steps 9 and 10 of tert-butyl (2-bromo-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-yl)(methyl)carbamate 205a From (100 mg, 0.22 mmol) Example 205 (18 mg) was obtained, and the yield is 13.7%. MS m / z (ESI): 591 [M+1] +

[0594] or, Examples 206, 234 The manufacturing of adopted the following method.

[0595] Example 206

[0596] 4-amino- N -(4-(difluoromethylene)-3,4,7,10-tetrahydro-2 H ,8 H -Piranho[4,3- h ]chroman-7-yl)-7-fluoro- N -methylimidazo[1,5- a ]Quinoline-8-Carboxamide

[0597]

[0598] Step 1: 206a(8.00 g, 32.79 mmol), triethylamine (5.05 g, 50.00 mmol), and bromomethylmethyl ether (6.25 g, 50.00 mmol) were dispersed in 100 mL of dichloromethane and reacted at 25°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, and the resulting residue was purified by silica gel column chromatography using eluent system A, 206b (9.00 g) was obtained, and the yield is 95.3%. MS m / z (ESI): 289 [M+1] +

[0599] sequentially Example 9 Referring to steps 1 through 4 and step 7 of the method, 206b From (9.00 g, 31.25 mmol) 206f (4.50 g) was obtained, and the yield is 56.0%. MS m / z (ESI):258 [M+1] +

[0600] Step 6: 206f (1.00 g, 3.89 mmol) and di-tert-butyl dicarbonate (1.09 g, 5.00 mmol) were dispersed in 10 mL of dichloromethane and reacted at 25°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, and the obtained residue was purified by silica gel column chromatography using eluent system A. 206g (1.51 g crude product) was obtained. MS m / z (ESI): 358 [M+1] +

[0601] Step 7: 206g(1.51 g crude product), tributyl(1-ethoxyvinyl)tin (1.44 g, 4.00 mmol), and bis(triphenylphosphine)palladium dichloride (280 mg, 0.40 mmol) were dispersed in 20 mL of 1,4-dioxane and reacted at 100°C for 16 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, and the resulting residue was purified by silica gel column chromatography using eluent system A. 206h (1.21 g crude product) was obtained. MS m / z (ESI): 322 [M+1] +

[0602] Step 8: 206h (1.21 g crude product) and N , N -Dimethylformamide dimethyl acetal (952 mg, 8.00 mmol) was dispersed in 10 mL of toluene and reacted at 80°C for 2 hours while stirring. 5 mL of concentrated hydrochloric acid was added and reacted at 50°C for 1 hour while stirring. The reaction solution was concentrated under reduced pressure until dry. 206i (2.21 g crude product) was obtained. MS m / z (ESI): 232 [M+1] +

[0603] Step 9: 206i (2.21 g crude product) and di-tert-butyl dicarbonate (3.27 g, 15.00 mmol) were dispersed in 20 mL of dichloromethane and reacted at 25°C for 2 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, and the resulting residue was purified by silica gel column chromatography using eluent system A. 206j (270 mg) was obtained, and the yield is 21.0%. MS m / z (ESI): 332 [M+1] +

[0604] Step 10: 206j(270 mg, 0.82 mmol), dichlorotris(triphenylphosphine)ruthenium (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, and reacted at 110°C for 16 hours while stirring. The reaction mixture was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure until dry, and the obtained residue was purified by silica gel column chromatography using eluent system A. 206k (160 mg) was obtained, and the yield is 58.6%. MS m / z (ESI): 334 [M+1] +

[0605] Step 11: 206k (160 mg, 0.48 mmol) and difluoromethyl(2-pyridyl)sulfone (139 mg, 0.72 mmol) in 10 mL N , N It was dispersed in dimethylformamide. Potassium tert-butoxide (108 mg, 0.96 mmol) was added, and the reaction was carried out at -40°C for 1 hour while stirring. The reaction solution was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure until dry, and the obtained residue was purified by silica gel column chromatography using eluent system A. 206l (80 mg) was obtained, and the yield is 45.4%. MS m / z (ESI): 368 [M+1] +

[0606] Step 12: 206l (80 mg, 0.22 mmol) was dispersed in 2 mL of trifluoroacetic acid and 2 mL of dichloromethane. The reaction was carried out at 25°C for 1 hour while stirring. The reaction solution was concentrated under reduced pressure until dry. 206m (100 mg crude product) was obtained. MS m / z (ESI): 268 [M+1] +

[0607] Example 12Referring to the synthesis method of steps 9 to 10 of, 206m From (100 mg crude product) Example 206 (36 mg) was obtained, and the yield is 33.1%. MS m / z (ESI): 496 [M+1] +

[0608] 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (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).

[0609] Example 234

[0610] 4-amino-N-(2-(3-(difluoromethylene)azetidine-1-carbonyl)-3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxalin-8-carboxamide

[0611]

[0612] 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 the mixture was stirred uniformly 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, and after purging with nitrogen three times, the reaction system was stirred at 77°C for 16 hours. The reaction mixture was cooled to room temperature, filtered by suction through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B. 234b (14 g, 52.93 mmol) was obtained, and the yield is 98.2%. MS m / z (ESI): 265 [M+1] +

[0613] Step 2: Methyl glycolate (10.01 g, 111.15 mmol) was weighed and added to the reaction flask, ultra-dry tetrahydrofuran (150 mL) was added, and after homogeneous mixing, the mixture was cooled to 0°C. Sodium hydride (6.35 g, 158.79 mmol, 60% purity) was added in several installments, and after the addition was complete, the mixture was transferred to room temperature and reacted for 1 hour. The reaction mixture was cooled to 0°C, and 234b (14 g, 52.93 mmol) was weighed and dissolved in ultra-dried tetrahydrofuran (30 mL), slowly added dropwise to the reaction system, reacted for 30 minutes while maintaining 0°C, and the reaction system was stirred at room temperature for 16 hours. Glacial acetic acid (4 mL) and water (100 mL) were added and quenched, extracted with ethyl acetate (100 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 234c (9.45 g, 38.89 mmol) was obtained, and the yield is 73.5%. MS m / z (ESI): 243 [M+1] +

[0614] Phase 3: 234c (12 g, 49.66 mmol) was weighed and dissolved in 1,4-dioxane (50 mL) and concentrated hydrochloric acid (50 mL) until the solution became clear, and the reaction system was stirred at 100°C for 2 hours. The reaction solution was concentrated to remove 1,4-dioxane, water (100 mL) was added to the residue, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 234d(5.08 g, 27.67 mmol) was obtained, and the yield is 55.7%. MS m / z (ESI): 184 [M+1] +

[0615] Phase 4: 234d (8.6 g, 46.84 mmol) was weighed and dissolved in trifluoroethanol (60 mL) until the solution became clear; methylamine methanol solution (23.28 g, 187.37 mmol) was added, and the reaction system was reacted at room temperature for 16 hours; sodium borohydride (3.54 g, 93.69 mmol) was added in several installments in an ice bath, and the reaction system was reacted at room temperature for 2 hours. An aqueous ammonium chloride solution (5 mL) was added, the mixture was quenched and concentrated, water (50 mL) was added to the residue, and the residue was extracted with dichloromethane (50 mL x 3); the organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A. 234e (4.04 g, 20.34 mmol) was obtained, and the yield is 43.4%. MS m / z (ESI): 199 [M+1] +

[0616] 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, benzyl chloroformate (5.20 g, 30.51 mmol) was added dropwise in an ice bath, and the reaction system was reacted at room temperature for 1 hour. The reaction solution was concentrated directly, and the residue was purified by silica gel column chromatography using eluent system A. 234f (5.6 g, 16.83 mmol) was obtained, and the yield is 82.7%. MS m / z (ESI): 334 [M+1] +

[0617] Step 6: 234f5.6 g (16.83 mmol) was weighed and dissolved in 1,4-dioxane (120 mL); tris(dibenzylideneacetone)dipalladium (1.54 g, 1.68 mmol), 4,5-bis(diphenylphosphino)-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) were added; after purging with nitrogen three times, the reaction system was reacted at 100°C for 16 hours. The reaction mixture was cooled to room temperature, suction filtered with diatomaceous earth, the solid was washed with 1,4-dioxane, and the filtrate was concentrated and used directly in the next step. MS m / z (ESI): 478 [M+1] +

[0618] Step 7: Methanol (40 mL) and hydrochloric acid (25 mL, 4 M in 1,4-dioxane) were added directly to the crude product of the previous step, and the reaction system was reacted at room temperature for 6 hours. The reaction solution was concentrated, adjusted to a weakly alkaline state by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane (20% methanol), washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A. 234h (4.12 g, 13.15 mmol) was obtained, and the yield is 78.1%. MS m / z (ESI): 314 [M+1] +

[0619] Step 8: 234h (4 g, 12.77 mmol) was taken and dissolved in ethanol (40 mL), ethyl 3-bromo-2-oxopropanoate (3.73 g, 19.15 mmol) and sodium bicarbonate (2.14 g, 25.53 mmol) were added, and the reaction system was reacted at 70°C for 18 hours. The reaction solution was concentrated directly, and the residue was purified by silica gel column chromatography using eluent system B. 234i(3.88 g, 9.48 mmol) was obtained, and the yield is 74.2%. MS m / z (ESI): 410 [M+1] +

[0620] Step 9: 234i 3.88 g (9.48 mmol) was taken and dissolved in acetonitrile (40 mL), N-iodosuccinimide (2.56 g, 11.37 mmol) was added, and the reaction system was reacted at room temperature for 1 hour. The reaction solution was concentrated directly, and the residue was purified by silica gel column chromatography using eluent system B. 234j (3.94 g, 7.36 mmol) was obtained, and the yield is 77.7%. MS m / z (ESI): 536 [M+1] +

[0621] Step 10: 234j 3.84 g (7.17 mmol) was taken and dissolved in N,N-dimethylformamide (40 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.13 g, 21.52 mmol) and copper(I) iodide (4.10 g, 21.52 mmol) were added, and the reaction system was reacted at 100°C for 2 hours. Water was added to the reaction mixture to quench it, and it was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 234k (1.42 g, 2.97 mmol) was obtained, and the yield is 41.5%. MS m / z (ESI): 478 [M+1] +

[0622] Step 11: 234k(1.42 g, 2.97 mmol) was taken and dissolved in tetrahydrofuran (20 mL) and water (20 mL), lithium hydroxide (213.70 mg, 8.92 mmol) was added, and the reaction system was reacted at room temperature for 2 hours. The reaction mixture was vacuum distilled to remove tetrahydrofuran, and the residue was acidified by adding 3N hydrochloric acid. The aqueous phase was extracted with dichloromethane (with the addition of 10% methanol), and the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. 234l (1.15 g, 2.56 mmol) was obtained, and the yield is 86.0%. MS m / z (ESI): 450 [M+1] +

[0623] Step 12: 234l 500 mg (1.11 mmol) was taken and dissolved in acetonitrile (5 mL), 3-oxozetidine (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-azabenzotriazole-1-yl)uronium hexafluorophosphate (629.65 mg, 1.67 mmol) were added, and the reaction system was reacted at room temperature for 2 hours. Water was added to the reaction mixture to quench it, and it was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 234m (213 mg, 423.93 μmol) was obtained, and the yield is 38.1%. MS m / z (ESI): 503 [M+1] +

[0624] Step 13: 234m(200 mg, 398.06 μmol) was taken and dissolved in 1,4-dioxane (10 mL), 2,2-difluoro-2-(triphenylphosphinyl)acetate (283.66 mg, 796.11 μmol) was added, and after purging with nitrogen three times, the reaction system was reacted at 80°C for 1 hour. Water was added to the reaction mixture to quench it, and it was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 234n (106 mg, 197.60 μmol) was obtained, and the yield is 49.6%. MS m / z (ESI): 537 [M+1] +

[0625] Step 14: 234n After taking (100 mg, 186.41 μmol), trifluoroacetic acid (5 mL) was added, and the reaction system was reacted at 80°C for 2 hours. The reaction solution was concentrated directly, the alkalinity was adjusted by adding an aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (with the addition of 10% methanol), and the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 234o (55 mg, 136.71 μmol) was obtained, and the yield is 73.3%. MS m / z (ESI): 403 [M+1] +

[0626] Step 15: 234o4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxalin-8-carboxylic acid (65.02 mg, 164.05 μmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-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, and the reaction system was reacted at room temperature for 2 hours. Water was added to the reaction solution and quenched, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B. 234p (62 mg, 79.42 μmol) was obtained, and the yield is 58.1%. MS m / z (ESI): 781 [M+1] +

[0627] Step 16: 234p After taking (62 mg, 79.42 μmol), trifluoroacetic acid (5 mL) was added, and the reaction system was reacted at 90°C for 2 hours. The reaction solution was concentrated directly, the alkalinity was adjusted by adding an aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (with the addition of 10% methanol), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was collected. Example 234 (39 mg, 61.86 μmol) was obtained, and the yield is 77.9%. MS m / z (ESI): 631 [M+1] +

[0628] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (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).

[0629] Example 237

[0630] 4-amino- N -(2-(4-(difluoromethylene)azetidine-1-yl)-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-yl)-7-fluoro-N-methylimidazo[1,5- a ]Quinoxaline-8-Carboxamide

[0631]

[0632] Example 198 The 12th stage of, Example 204 The 10th stage of, Example 12 Referring to the synthesis method of steps 9 and 10 of tert-butyl (2-bromo-3-(trifluoromethyl)-7,10-dihydro-8 H -Imidajo[1,2- a ]Piranho[3,4- c ]pyridine-7-yl)(methyl)carbamate 237a From (100 mg, 0.22 mmol) Example 237 (8 mg) was obtained, and the yield is 6.0%. MS m / z (ESI): 603 [M+1] +

[0633] 1H NMR (400 MHz, DMSO-d6) δ9.07 (s, 1H), 8.29 (s, 2H), 7.94 (s, 1H), 7.40 (s, 2H), 7.24 (d, 1H), 6.96 (s, 1H), 5.77 (s, 1H), 5.13 - 4.64 (m, 6H), 4.19 (s, 2H), 2.76 (t, 3H).

[0634] Example 240

[0635] 4-amino-N-(3-(cyclohexylidenefluoromethyl)-7,10-dihydro-8H-imidazo[ 1,2-a ]Piranha[ 3,4-c ]pyridine-7-yl)-7-fluoro-N-methylimidazo[ 1,5-a ]Quinoxaline-8-Carboxamide

[0636]

[0637] Example 202 Referring to the synthesis method of steps 3 to 5 of 2-(cyclohexylidenefluoromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan 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 From (300 mg, 0.78 mmol) Example 240 (30 mg) was obtained, and the yield is 27.8%. MS m / z (ESI): 544 [M+1] +

[0638] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (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).

[0639] Example 276

[0640] 4-amino-N',N',7-trimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-yl)imidazo[1,5-a]quinoxalin-8-carbohydrazide

[0641]

[0642] Step 1: 4-((3,5-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-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 after pumping and replacing with nitrogen three times, the reaction system was stirred at 25°C for 1 hour. Water was added and quenched, extracted with ethyl acetate (50 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 276b (0.51 g) was obtained, and the yield is 92.1%. MS m / z (ESI): 435 [M+1] +

[0643] Phase 2: 276b (0.40 g, 0.92 mmol), [2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridine-5-yl]methanesulfonate 276cCesium carbonate (410 mg, 1.38 mmol) and cesium carbonate (900 mg, 2.76 mmol) were dissolved in N,N-dimethylformamide (10 mL), and after pumping and replacing with nitrogen three times, 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 x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 276d (30 mg) was obtained, and the yield is 5.1%. MS m / z (ESI): 636 [M+1] +

[0644] Phase 3: 276d (24 mg, 38 μmol) was dissolved in TFA (3 mL), and after pumping and replacing with nitrogen three times, the reaction system was stirred at 90°C for 3 hours. It was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using eluent system A. Example 276 (5 mg) was obtained, and the yield is 27.3%. MS m / z (ESI): 486 [M+1] +

[0645] 1 H NMR (400 MHz, CD3OD) δ 8.99 (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)

[0646] Example 277

[0647] 4-amino-N'-ethyl-7-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-yl)imidazo[1,5-a]quinoxalin-8--carbohydrazide

[0648]

[0649] Example 276 Referring to the synthesis method of steps 1 to 3 of 4-((3,5-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-8-carboxylic acid 277a From (200 mg, 0.51 mmol) Example 277 (35 mg) was obtained, and the yield is 14.1%. MS m / z (ESI): 486 [M+1] +

[0650] 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (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).

[0651] Example 278

[0652] 4-amino-N',7-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-yl)imidazo[1,5-a]quinoxalin-8-carbohydrazide

[0653]

[0654] Example 276 Referring to the synthesis method of steps 1 to 3 of 4-((3,5-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-8-carboxylic acid 278a From (200 mg, 0.51 mmol) Example 278 (26 mg) was obtained, and the yield is 10.9%. MS m / z (ESI): 472 [M+1] +

[0655] 1H NMR (400 MHz, DMSO-d6) δ 9.17 (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).

[0656] Example 278 Preparation of Chiral Isomers

[0657]

[0658] Example 278 (26 mg, 0.055 mmol) was separated by Chiral-HPLC (Condition 1), and respectively 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]quinoxalin-8-carbohydrazide (12.6 mg) was obtained, with a yield of 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]quinoxalin-8-carbohydrazide (13.0 mg) was obtained, and the yield was 50.0%.

[0659] 278-P1 (t R : 5.897 min) : 1H NMR (400 MHz, DMSO-d6) δ 9.17 (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).

[0660] 278-P2 (t R : 5.240 min) : 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (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).

[0661] Example 279

[0662] 4-amino-7-fluoro-N'-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxalin-8-carbohydrazide

[0663]

[0664] Example 278 Referring to the synthesis method of steps 1 to 3 of the compound methyl 2,4-difluoro-5-nitrobenzoate 279e From (500 mg, 2.35 mmol) Example 279 (11 mg) was obtained, and the yield is 0.2%. MS m / z (ESI): 476 [M+1] +

[0665] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.79 (dd, 1H), 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).

[0666] Example 280

[0667] 4-amino-7-fluoro-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-yl)imidazo[1,5-a]quinoxalin-8-carbohydrazide

[0668]

[0669] Step 1: 2-aminoisoindole-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, and the reaction was carried out at room temperature for 1 hour while stirring. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 280b (162 mg) was obtained, and the yield is 39.6%. MS m / z (ESI): 541 [M+1] +

[0670] Phase 2: 280b2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-yl methanesulfonate (133 mg, 0.45 mmol) was dissolved in 10 mL of acetonitrile and microwaved at 100°C for 16 hours. The reaction mixture was filtered, the filtrate was taken, 100 mL of ethyl acetate was added, and the mixture was washed with saturated saline (100 mL x 2). The organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, 280c (66 mg) was obtained, and the yield is 29.7%. MS m / z (ESI): 742 [M+1] +

[0671] Phase 3: 280c (66 mg, 0.09 mmol) was dissolved in 2 mL of tetrahydrofuran and 2 mL of ethanol, hydrazine hydrate (16 mg, 0.27 mmol, 85% purity) was added, and the reaction was carried out in a sealed tube 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, 280d (16 mg) was obtained, and the yield is 29.4%. MS m / z (ESI): 612 [M+1] +

[0672] Phase 4: 280d (16 mg, 0.02 mmol) was dissolved in 2 mL of dichloromethane and 1 mL of water, and 2,3-dichloro-5,6-dicyanobenzoquinone (10.91 mg, 0.05 mmol, 60% purity) was added and reacted at room temperature for 1 hour while stirring. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by HPLC (BASE), Example 280(2 mg) was obtained, and the yield is 16.1%. MS m / z (ESI): 462 [M+1] +

[0673] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.32 (d, 1H), 7.97 (d, 1H), 7.91 (d, 2H), 7.55 (s, 2H), 7.16 (d, 1H), 5.88 (d, 1H), 4.85 - 4.79 (m, 2H), 4.62 (s, 2H), 4.20 (d, 2H).

[0674] Example 281

[0675] 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]quinoxalin-8-carbohydrazide

[0676]

[0677] Example 276 Referring to steps 1 and 2 of tert-butyl 2-(4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-8-carbonyl)-1-methylhydrazine-1-carboxylate 281b From (200 mg, 0.38 mmol) and 3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-yl methanesulfonate (260 mg, 0.76 mmol) 281c (60 mg) was obtained, and the yield is 20%. MS m / z (ESI): 761 [M+1] +

[0678] Phase 3: 281c (20 mg, 0.026 mmol) was dissolved in 2 mL of trifluoroacetic acid and reacted at 90°C for 1 hour while stirring. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, Example 281 (6.7 mg) was obtained, and the yield is 49%. MS m / z (ESI): 511 [M+1] +

[0679] 1 HNMR (400 MHz, DMSO-d6) δ 9.08 (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).

[0680] Example 282

[0681] 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]quinoxalin-8-carbohydrazide

[0682]

[0683] Example 279 Referring to steps 1 and 2 of tert-butyl 2-(4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxalin-8-carbonyl)-1-methylhydrazine-1-carboxylate 282b From (200 mg, 0.38 mmol) and 3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-yl methanesulfonate (260 mg, 0.76 mmol) 282c (200 mg) was obtained, and the yield is 68%. MS m / z (ESI): 765 [M+1] +

[0684] Phase 3: 282c (50 mg, 0.065 mmol) was dissolved in 2 mL of trifluoroacetic acid and reacted at 90°C for 1 hour while stirring. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A, Example 282 (15.3 mg) was obtained, and the yield is 45%. MS m / z (ESI): 515 [M+1] +

[0685] 1 HNMR (400 MHz, DMSO-d6) δ 9.16 (d, 1H), 8.48 (dd, 1H), 8.27 (d, J = 6.5 Hz, 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).

[0686] Example 283

[0687] 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-methyl-imidazo[1,5-a]quinoxalin-8-carboxamide

[0688]

[0689] 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-tetraene-10yl]imidazo[1,5-a]quinoxalin-8-carboxamide 283a (50 mg, 101 μmol, Example 62 ) is dissolved in 1'4-dioxane (3 mL), Lawesson's Reagent (122.45 mg, 303 μmol) is added, and after purging with nitrogen three times, the reaction is stirred at 120°C for 16 hours under nitrogen protection; the reaction solution is concentrated under reduced pressure, and the concentrated residue is separated and purified by Pre-HPLC, Example 283 (14 mg) was obtained, and the yield is 27.1%. MS m / z (ESI): 512 [M+1] +

[0690] 1H NMR (400 MHz, DMSO-d6) δ 9.18 - 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).

[0691] Example 284

[0692] 4-amino-6-fluoro-N',7-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridine-5-yl)imidazo[1,5-a]quinoxalin-8-carbohydrazide

[0693]

[0694] 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-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (6.07 g, 17.13 mmol) was added, and the reaction was carried out at 50°C for 3 hours while stirring. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system C, 284b (1.03 g) was obtained, and the yield is 31.6%. MS m / z (ESI): 229 [M+1] +

[0695] sequentially Example 12 Referring to steps 1 through 9 of the method, Example 280 The second stage of and Example 12 Referring to step 10 of the method, 284b From (1.03 g, 4.51 mmol) Example 284 (29 mg) was obtained, and the yield is 1.3%. MS m / z (ESI): 490 [M+1] +

[0696] The preparation of the following examples is Example 284 Referred to

[0697]

[0698] or, Examples 285, 286 The manufacturing of adopted the following method.

[0699] Example 285

[0700] 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]diazanaphthalene-8-carbohydrazide

[0701]

[0702] 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) was dissolved in 10 mL of methanol and 10 mL of tetrahydrofuran, acetic acid (305 mg, 5.07 mmol) and sodium borocyanide (1.59 g, 25.37 mmol) were added, and the reaction was carried out at 20°C for 48 hours while stirring. 100 mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phase was dried with anhydrous sodium sulfate, the system was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B. 285b (1.6 g) was obtained, and the yield is 81.6%. MS m / z (ESI): 387 [M+1] +

[0703] Phase 2: 285b(400 mg, 1.04 mmol), 4-(2,4-dimethoxybenzylamino)-1,3-dihydrofuro[3,4-c][1,7]naftiridine-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 reacted at 20°C for 2 hours while stirring. After concentrating the reaction mixture, 50 mL of ethyl acetate was added, and the pyridine was removed by washing with 2 M hydrochloric acid. The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B. 285c (220 mg) was obtained, and the yield is 28.3%. MS m / z (ESI): 750 [M+1] +

[0704] Example 14 Referring to step 11 of the synthesis method, 285c From (220 mg, 0.29 mmol) Example 285 (90 mg) was obtained, and the yield is 61.7%. MS m / z (ESI):499 [M+1] +

[0705] Example 285 Preparation of Chiral Isomers

[0706]

[0707] Example 285 (90 mg, 0.18 mmol) was separated by chiral preparative HPLC (condition 2) and (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]diazanaphthalene-8-carbohydrazide 285-P1(38 mg) was obtained, with a yield of 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]diazanaphthalene-8-carbohydrazide 285-P2 (42 mg) was obtained, and the yield is 46.7%.

[0708] 285-P1 (t R : 0.765 min): 1 H NMR (400 MHz, 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).

[0709] 285-P2 (t R : 0.974 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (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).

[0710] Example 286

[0711] 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]naphthiridine-8-carbohydrazide

[0712]

[0713] Step 1: 2-trifluoromethyl-6H-pyrano[3,4-b]pyridine-5(8 H)-on 286a (640 mg, 2.95 mmol), tert-butyl N -amino- N methylcarbamate (430.86 mg, 2.95 mmol) was dissolved in 5 mL of 1,1,1-trifluoroethanol and reacted at 20°C for 3 hours while stirring. The system was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent system A, 286b (1 g) was obtained, and the yield is 98.3%. MS m / z (ESI): 346 [M+1] +

[0714] Phase 2: 286b (900 mg, 2.61 mmol) was dissolved in 20 mL of methanol, the atmosphere was changed to hydrogen, and the reaction was carried out at 20°C for 3 hours while stirring. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 286c (900 mg) was obtained, and the yield is 99.4%. MS m / z (ESI): 348 [M+1] +

[0715] Phase 3: 286c (227 mg, 0.59 mmol), 4-(2,4-dimethoxybenzylamino)-1,3-dihydrofuro[3,4-c][1,7]naftiridine-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 reacted at 20°C for 6 hours while stirring. 1 mL of triethylamine was added to quench the reaction, and the system was concentrated until dry. Then, 20 mL of ethyl acetate was added to dissolve the components sufficiently, the 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. 286d (150 mg) was obtained, and the yield is 42.6%. MS m / z (ESI): 711 [M+1] +

[0716] Phase 4: 286d (150 mg) was dissolved in TFA (20 mL) and reacted at 90°C for 1 hour. The reaction was quenched by cooling, the system was concentrated until dry, and the resulting residue was purified by reverse-phase chromatography using eluent system D, Example 286 (92 mg) was obtained, and the yield is 94.7%. MS m / z (ESI): 461 [M+1] +

[0717] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.85 (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).

[0718] Example 286 Preparation of Chiral Isomers

[0719]

[0720] Example 286 (50 mg, 0.108 mmol) was separated by Chiral-HPLC (condition 2), and respectively 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]naphthiridine-8-carbohydrazide (23.8 mg) was obtained, with a yield of 47.6%; 286-P2 : ( R )- 4-amino- N24.0 mg of '-methyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthiridine-8-carbohydrazide was obtained, and the yield was 48.0%.

[0721] 286-P1 (t R : 2.521 min) : 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.85 (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).

[0722] 286-P2 (t R : 2.818 min) : 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.85 (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).

[0723] The preparation of the following examples is Example 277 Referred to.

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733] The preparation of the following examples is Example 281 Referred to.

[0734]

[0735]

[0736]

[0737] The preparation of the following examples is Example 276 Referred to.

[0738]

[0739]

[0740]

[0741] Alternatively, the following method was used for the preparation of the following examples.

[0742] Example 298

[0743] 4-amino-N'-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-1,3-dihydrofuro[3,4-c][1,7]diazanaphthalene-8-carbohydrazide

[0744]

[0745] Example 277 Referring to the synthesis method of steps 1 to 4 of 7-(trifluoromethyl)isochroman-4-one 298a From (100 mg, 0.46 mmol) Example 298 (12.2 mg) was obtained, and the yield is 5.7%. MS m / z (ESI): 460 [M+1] +

[0746] 1HNMR (400 MHz, DMSO-d6) δ 8.85 (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, 4.7 Hz, 3H).

[0747] Example 301

[0748] 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-carbohydrazide

[0749]

[0750] Example 276 Referring to the synthesis method of steps 1 to 3 of 4-amino-1-methylpyrazolo[4,3-c]quinoline-8-carboxylic acid 301d From (500 mg, 2.05 mmol) Example 301 (42 mg) was obtained, and the yield is 4.3%. MS m / z (ESI): 472 [M+1] +

[0751] 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.48 (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).

[0752] Example 301 Separate by Chiral-HPLC 301-P1 and 301-P2 I obtained.

[0753]

[0754] Example 306

[0755] 4-amino-7-fluoro- N '-methyl- N -(2-trifluoromethyl-5,8-dihydro-6 H -Pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide

[0756]

[0757] Example 286 Referring to the synthesis method of steps 3 to 4 of tert-butyl 1-methyl-2-(2-trifluoromethyl-6 H -Piran[3,4-b]pyridin-5-yl)hydrazino-1-carboxylate 286c From (208 mg, 0.60 mmol) Example 306 (6 mg) was obtained, and the yield is 2.1%. MS m / z (ESI): 478 [M+1] +

[0758] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.06 (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).

[0759] Example 307

[0760] 4-amino-7-methyl- N '-methyl- N -(2-trifluoromethyl-5,8-dihydro-6 H -Pyrano[3,4-b]pyridin-5-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide

[0761]

[0762] Example 286 Referring to the synthesis method of steps 3 to 4 of tert-butyl 1-methyl-2-(2-trifluoromethyl-6 H -Piran[3,4-b]pyridin-5-yl)hydrazino-1-carboxylate286c From (35 mg, 0.10 mmol) Example 307 (4 mg) was obtained, and the yield is 8.4%. MS m / z (ESI): 474 [M+1] +

[0763] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.15 (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).

[0764] Example 324

[0765] 4-amino-N-[5-deuterio-2-(trifluoromethyl)-6,8-dihydropyrano[3,4-b]pyridine-5-yl]-1-methyl-N'-(trideuteriomethyl)pyrazolo[4,3-c]quinoline-8-carbohydrazide

[0766]

[0767] Example 276 Referring to the synthesis method of steps 1 to 3 of 4-amino-1-methylpyrazolo[4,3-c]quinoline-8-carboxylic acid 324d From (200 mg, 826 μmol) Example 324 (20 mg) was obtained, and the yield is 5.0%. MS m / z (ESI): 476 [M+1] +

[0768] 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.63 (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).

[0769] Example 342

[0770] 4-amino- N '-methyl- N -(2-(trifluoromethyl)-6,7-dihydro-4 H -Piranho[3,4- d ]thiazol-7-yl)-1,3-dihydrofuro[3,4- c ][1,7]Naftiridine-8-Carbohydrazide

[0771]

[0772] Step 1: 2-amino-4H-pyrano[3,4-d]thiazole-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) were dispersed in 40 mL of tetrahydrofuran and reacted at 65°C for 4 hours while stirring. The reaction solution was concentrated under reduced pressure until dry, and the resulting residue was purified by silica gel column chromatography using eluent system A, 342b (3.41 g) was obtained, and the yield is 51.4%. MS m / z (ESI): 282 [M+1] +

[0773] Phase 2: 342b 30 mL of methyl fluorosulfonyl difluoroacetate (3.41 g, 12.14 mmol), methyl fluorosulfonyl difluoroacetate (4.61 g, 24.00 mmol), and copper(I) iodide (4.56 g, 24.00 mmol). N , N - It was dispersed in dimethylformamide and reacted at 100°C for 4 hours while stirring. The reaction solution was filtered to remove insoluble substances, and the filtrate was concentrated under reduced pressure until dry. The obtained residue was purified by silica gel column chromatography using eluent system A. 342c (1.81 g) was obtained, and the yield is 66.9%. MS m / z (ESI): 224 [M+1] +

[0774] Phase 3: 342c1.40 g, 6.28 mmol, tert-butyl 1-methylhydrazine-1-carboxylate (1.75 g, 12.00 mmol), and sodium borohydrogen cyanohydride (756 mg, 12.00 mmol) were dispersed in 20 mL of trifluoroethanol and reacted for 16 hours while stirring. The reaction mixture was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure until dry, and the resulting residue was purified by silica gel column chromatography using eluent system A. 342d (1.21 g) was obtained, and the yield is 54.6%. MS m / z (ESI): 354 [M+1] +

[0775] Phase 4: 342d (650 mg, 1.84 mmol) and 4-((3,4-dimethoxybenzyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthiridine-8-carboxylic acid 342e (762 mg, 2.00 mmol) was dispersed in 10 mL of dichloromethane and 2 mL of pyridine. Phosphorus oxychloride (918 mg, 6.00 mmol) was added at 0°C, and the reaction was carried out with stirring for 2 hours at 0°C. The reaction mixture was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure until dry, and the obtained residue was purified by silica gel column chromatography using eluent system A. 342f (180 mg) was obtained, and the yield is 13.7%. MS m / z (ESI): 717 [M+1] +

[0776] Example 8 Referring to the synthesis method of Step 8, 342f From (60 mg, 0.08 mmol) Example 342 (21 mg) was obtained, and the yield is 53.7%. MS m / z (ESI): 467 [M+1] +

[0777] 1H NMR (400 MHz, 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).

[0778] Example 351

[0779] 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-carbohydrazide

[0780]

[0781] 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)hydrazine carboxylate 351a 4-[(2,4-dimethoxyphenyl)methylamino]-7-fluoro-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid (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, phosphorus oxychloride (177.20 mg, 1.16 mmol) was slowly added dropwise in an ice bath, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added and the mixture was quenched. It was then extracted with dichloromethane (10 mL x 3), washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A. 351b (94.5 mg) was obtained, and the yield is 31.8%. MS m / z (ESI): 770 [M+1] +

[0782] Phase 2: 351b(94.5 mg, 122.77 μmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 80°C for 1 hour. When the reaction was indicated as complete by LCMS, the reaction mixture was spin-dried to obtain the crude product, and the crude product was purified by preparative liquid chromatography. Example 351 (30.2 mg) was obtained, and the yield is 47.3%. MS m / z (ESI): 520 [M+1] +

[0783] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (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).

[0784] Example 354

[0785] 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]naphthiridine-8-carbohydrazide

[0786]

[0787] Step 1: 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) were dissolved in methanol (1 mL), acetic acid (23.44 mg, 390.35 μmol) was added, and the mixture was stirred overnight at room temperature. Then, NaBD3CN (29.44 mg, 468.42 μmol) was added, and the mixture was stirred at 60°C for 48 hours, during which time additional NaBD3CN may be added as appropriate. After the reaction was complete, the reaction mixture was spin-dried, extracted with EA, washed with saturated saline, the organic phases were combined, and then dried and column chromatographed 354b(110 mg) was obtained, and the yield is 72.4%. MS m / z (ESI): 391 [M+1] +

[0788] Phase 2: 354b 4-[(2,4-dimethoxyphenyl)methylamino]-1,3-hydrofurfuro[3,4-c][1,7]naftiridine-8-carboxylic acid (127 mg, 325.31 μmol) and 4-[(2,4-dimethoxyphenyl)methylamino]-1,3-hydrofurfuro[3,4-c][1,7]naftiridine-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 the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added to quench the mixture, it was extracted with DCM, and through column chromatography 354c (186 mg) was obtained, and the yield is 75.9%. MS m / z (ESI): 754 [M+1] +

[0789] Phase 3: 354c (180 mg, 238.80 μmol) was dissolved in TFA (5 mL) and stirred at 80°C for 1 hour. When the reaction was indicated as complete by LCMS, the reaction mixture was spin-dried to obtain a crude product, and the crude product was purified by preparative liquid chromatography. Example 354 (41.4 mg) was obtained, and the yield is 34.4%. MS m / z (ESI): 504 [M+1] +

[0790] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (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).

[0791] Example 354 Preparation of Chiral Isomers

[0792]

[0793] Examples 354 (40 mg, 0.079 mmol) was separated by Chiral-HPLC (condition 3), and respectively 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]naftyridin-8-carbohydrazide (18.5 mg) was obtained, with a yield of 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]naftiridine-8-carbohydrazide (18.8 mg) was obtained, and the yield was 47.0%.

[0794] 354-P1 (t R : 4.968 min) : 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (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).

[0795] 354-P2 (t R : 4.198 min) : 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (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).

[0796] Example 357

[0797] 4-amino-7-methyl-N'-methyl-d 3 -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

[0798]

[0799] Step 1: Methyl 4-amino-5-bromo-2-methylbenzoate in a 1-neck flask 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) were added sequentially, the atmosphere was switched to N2, and the reaction was carried out at 100°C for 4 hours. The reaction was cooled and quenched, the system was concentrated until dry, and the obtained residue was purified by normal-phase column chromatography using eluent system A. 357b (6.37 g) was obtained, and the yield is 61.6%. MS m / z (ESI): 230 [M+1] +

[0800] Step 2: In a 1-neck flask 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) were added sequentially, the atmosphere was changed to N2, and the reaction was carried out at 100°C for 16 hours. The reaction was cooled, quenched, concentrated, extracted with EA, washed with saturated NaCl solution, dried with anhydrous Na2SO4, filtered, and the filtrate concentrated until dry. The obtained residue was purified by normal-phase column chromatography using eluent system D. 357c (2.02 g, 7.25 mmol) was obtained, and the yield is 72.3%. MS m / z (ESI): 280 [M+1] +

[0801] sequentially Example 12Referring to the synthesis method of steps 6 through 9 of, 357c From (2.02 g, 7.25 mmol) 357f (105 mg) was obtained, and the yield is 2.8%. MS m / z (ESI): 516 [M+1] +

[0802] Step 6: In a 1-neck flask 357f (590 mg, 750.44 μmol), methylboronic acid (135 mg, 2.25 mmol), cataCXium A-Pd-G3 (55 mg, 75 μmol), Cs2CO3 (489 mg, 1.50 mmol), water (3 mL), and 1'4-dioxane (15 mL) were added sequentially, the atmosphere was changed to N2, and the reaction was carried out at 100°C for 12 hours. The reaction was cooled and quenched, and the system was concentrated until dry. 357g (350 mg, 457.04 μmol) was obtained, and the yield is 60.9%. MS m / z (ESI): 766 [M+1] +

[0803] Example 12 Referring to the synthesis method of Step 10, 357g From (350 mg, 457 μmol) Example 357 (105 mg) was obtained, and the yield is 44.5%. MS m / z (ESI): 516 [M+1] +

[0804] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (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).

[0805] Example 357 Preparation of Chiral Isomers

[0806]

[0807] Example 357(105 mg, 0.027 mmol) was separated by chiral preparative HPLC (condition 1) and 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-carbohydrazide 357-P1 (45 mg) was obtained, with a yield of 42.9%, 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-carbohydrazide 357-P2 (46 mg) was obtained, and the yield is 43.8%.

[0808] 357-P1 (t R : 17.930 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (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).

[0809] 357-P1 (t R : 21.680 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (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).

[0810] Example 362

[0811] 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]naphthiridine-8-carbohydrazide

[0812]

[0813] 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), and while stirring at room temperature, acetic acid (46.88 mg, 780.70 μmol) and sodium borohydrocyanide (147.18 mg, 2.34 mmol) were added, and the reaction was carried out at 60°C for 3 hours while stirring. The solvent was removed under reduced pressure, the residue was purified by column chromatography, the eluent was petroleum ether / ethyl acetate (1:1), and separated 362b (180 mg, 462.27 μmol) was obtained. The yield is 59.2%. MS m / z (ESI):390 [M+1] +

[0814] Phase 2: 362b 4-(tert-butoxycarbonylamino)-3-methyl-1,3-dihydrofuro[3,4-C][1,7]naftiridine-8-carboxylic acid (118.17 mg, 303.48 μmol) and 4-(tert-butoxycarbonylamino)-3-methyl-1,3-dihydrofuro[3,4-C][1,7]naftiridine-8-carboxylic acid (87.34 mg, 252.90 μmol) were dissolved in 1,2-dichloroethane (2.2 mL), and pyridine (200.05 mg, 2.53 mmol, 203.73 μL) and phosphorus oxychloride (116.33 mg, 758.71 μmol) were added while stirring at 0°C, and the reaction was carried out at room temperature for 1 hour while stirring. The completion of the reaction was monitored by LCMS. After the reaction was complete, water and a saturated ammonium chloride solution were added to the system, the mixture was extracted three times with DCM (10 mL x 3), washed with saturated sodium chloride, allowed to stand to separate the layers, and the organic phase was collected. The mixture was then dried with 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), 362c(120 mg, 167.43 μmol) was obtained, and the yield is 66.2%. MS m / z (ESI): 817 [M+1] +

[0815] Phase 3: 362c (120 mg, 146.91 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (16.75 mg, 146.91 μmol, 0.3 mL) was added while stirring at room temperature, and the reaction was carried out at room temperature for 1 hour while stirring. The solvent was removed under reduced pressure, and the solution was separated by HPLC. Example 362 (52.2 mg, 101.07 μmol) was obtained, and the yield is 68.8%. MS m / z (ESI): 517 [M+1] +

[0816] 357-P1 (t R : 32.973 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.40 (d, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.21-7.14 (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).

[0817] 357-P2 (t R : 18.127 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.40 (d, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.21-7.14 (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).

[0818] 357-P3 (t R : 22.473 min): 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.40 (d, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.21-7.14 (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).

[0819] 357-P4 (t R : 47.857 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.40 (d, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.21-7.14 (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).

[0820] Example 362 Preparation of Chiral Isomers

[0821]

[0822] Example 362 (30 mg, 0.079 mmol) was separated by Chiral-HPLC, and respectively 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-dihydrofuro[3,4-c]naphthiridine-8-carbohydrazide (7 mg) was obtained, with a yield of 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]naphthiridine-8-carbohydrazide (7 mg) was obtained, with a yield of 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]naphthiridine-8-carbohydrazide (6.7 mg) was obtained, with a yield of 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]naphthiridine-8-carbohydrazide (6.3 mg) was obtained, and the yield was 21.0%.

[0823] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, 1H), 8.47 (dd, 1H), 8.16 (d, J = 11.4 Hz, 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).

[0824] Example 371

[0825] 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]naphthiridine-8-carbohydrazide

[0826]

[0827] Step 1: Methyl 4-oxotetrahydrofuran-3-carboxylate 371a Dissolve (27.98 g, 194.17 mmol) in 280 mL of dichloromethane, and in an ice bath N , N- Diisopropylethylamine (27.60 g, 213.59 mmol) and trifluoromethanesulfonic acid anhydride (54.78 g, 194.17 mmol) were added sequentially. The reaction was stirred at room temperature for approximately 16 hours. 300 mL of water was added to the reaction mixture, and it was extracted with ethyl acetate (300 mL x 2). After extraction, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B, 371b (36 g) was obtained, and the yield is 67.0%. MS m / z (ESI): 277 [M+1] +

[0828] Step 2: Methyl 5-amino-4-bromopyridinecarboxylate 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]palladium(II) dichloride (22.80 g, 31.16 mmol), and potassium acetate (45.87 g, 467.44 mmol) were taken and placed in a reaction flask; toluene (360 mL) was added, and the reaction was carried out under a nitrogen atmosphere at 90°C for 16 hours while stirring. The reaction mixture was cooled, and the solid obtained by suction filtration was washed again with water, 371d (38.2 g) was obtained, and the yield is 88.2%. MS m / z (ESI): 197 [M+1] +

[0829] Phase 3: 371d (54 g, 194.17 mmol) was dissolved in dioxane (500 mL), H2O (50 mL) was added, and 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 reaction was carried out under a nitrogen atmosphere at 90°C for 1 hour while stirring. The reaction mixture was cooled to room temperature, and the solid obtained by filtration was first slurried with EA, then slurried with water, and the solid was dried. 371e (46.2 g) was obtained, and the yield is 96.6%. MS m / z (ESI): 247 [M+1] +

[0830] Phase 4: 371e (70 g, 284.30 mmol) was dissolved in DMSO (700 mL), 2,4-dimethoxybenzylamine (57.04 g, 341.16 mmol) and DBU (64.92 g, 426.45 mmol, 63.65 mL) were added, and BOP (188.61 g, 426.45 mmol) was added in several installments in an ice bath. The mixture was heated to room temperature and reacted for 2 hours while stirring. The reaction solution was slowly added dropwise to water (1 L), and after a large amount of solid precipitated, it was filtered. The obtained solid was slurried with methanol, 371f (77.6 g) was obtained, and the yield is 69.0%. MS m / z (ESI): 396 [M+1] +

[0831] Step 5: 371f (82.2 g, 207.89 mmol) was dissolved in a mixed solvent of MeOH (25 mL), THF (25 mL), and H2O (25 mL), lithium hydroxide monohydrate (43.62 g, 1.04 mol) was added, and the reaction was carried out at room temperature for 3 hours while stirring. The reaction mixture was subjected to reduced pressure and the organic phase was concentrated, then 2N HCl was added to adjust the acidity to a weak acid, a large amount of solid precipitated, and the mixture was filtered by suction. 371g (73.6 g) was obtained, and the yield is 92.8%. MS m / z (ESI): 382 [M+1] +

[0832] 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 taken and placed in a reactor; 500 mL of MeOH and 500 mL of DMF were added, and the reaction was carried out under a CO2 atmosphere, at a pressure of 0.4 MPa and a temperature of 80°C for 16 hours while stirring. The reaction mixture was added to water, extracted with EA, the organic phase was separated, dried, and concentrated, and then separated by column chromatography. 371i (137 g) was obtained, and the yield is 62.4%. MS m / z (ESI): 186 [M+1] +

[0833] Step 7: 371i (73.04 g, 403.00 mmol) was dissolved in 1,4-dioxane (1700 mL), and 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) were added. The reaction was carried out under nitrogen protection at 100°C for 16 hours while stirring. The reaction mixture was cooled, filtered by suction through diatomaceous earth, the filtrate was concentrated, 400 mL of HCl (4 M in dioxane) and 200 mL of MeOH were added, and the reaction was carried out at room temperature for 16 hours while stirring. The reaction solution is concentrated directly under reduced pressure, an aqueous NaHCO3 solution is added to adjust the pH to 8, extracted with ethyl acetate, the organic phase is separated, dried and concentrated, and separated by column chromatography. 371j (60 g) was obtained, and the yield is 49.3%. MS m / z (ESI): 167 [M+1] +

[0834] Step 8: 371j(59 g, 284.03 mmol) was dissolved in EtOH (590 mL), 2-chloroacetaldehyde (83.61 g, 426.05 mmol) and NaHCO3 (35.79 g, 426.05 mmol) were added, and the reaction was carried out overnight at 70°C with stirring. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography. 371k (34 g) was obtained, and the yield is 62.9%. MS m / z (ESI): 191 [M+1] +

[0835] Step 9: 371k (34 g, 178.76 mmol) was dissolved in acetonitrile (500 mL), NIS (42.23 g, 187.70 mmol) was added, and the reaction was carried out at room temperature for 1 hour while stirring. The reaction mixture was filtered directly, and the filtered solid 371l (56 g) was obtained, and the yield is 99.1%. MS m / z (ESI): 317 [M+1] +

[0836] Step 10: 371l (53 g, 167.67 mmol) and methyl 2,2-difluoro-2-fluorosulfonylacetate (96.64 g, 503.01 mmol) were dissolved in DMF (600 mL), and CuI (95.80 g, 503.01 mmol) was added. The reaction was heated to 100°C and carried out for 16 hours while stirring. The reaction mixture was cooled, diluted with EtOAc (200 mL), filtered, and extracted by adding water to the filtrate. The organic phase was washed with saturated saline, separated, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography. 371m (17 g) was obtained, and the yield is 99.1%. MS m / z (ESI): 259 [M+1] +

[0837] Step 11: 371m(17 g, 65.84 mmol) was dissolved in carbon tetrachloride (200 mL), and NBS (14.06 g, 79.01 mmol) and azobisisobutyronitrile (2.16 g, 13.17 mmol) were added. The reaction was carried out under a nitrogen atmosphere at 80°C for 2 hours while stirring. After cooling the reaction mixture to room temperature, it was filtered, the filter cake was washed with a small amount of dichloromethane, the filtrate was concentrated under reduced pressure, and then separated by column chromatography. 371n (22 g) was obtained, and the yield is 99.1%. MS m / z (ESI): 337 [M+1] +

[0838] Step 12: Take methyl 2-hydroxyacetate (16.03 g, 177.99 mmol) and dissolve it in DMF (100 mL), cool to 0°C, add NaH (7.12 g, 177.99 mmol, 60% purity) in several installments, and stir the reaction mixture at 0°C for 15 minutes, then, 371n 80 mL of DMF solution (20 g, 59.33 mmol) was added. The reaction was heated to room temperature and stirred for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with ethyl acetate; the organic phase was separated and washed once with saturated saline, then the organic phase was separated, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography. 371o Obtained. MS m / z (ESI): 315 [M+1] +

[0839] Step 13: 371o14 g (44.56 mmol) was taken and dissolved in 150 mL of EtOH, and 75 mL of 12 M HCl was added. The reaction was carried out at 80°C for 2 hours while stirring. The reaction solution was concentrated under reduced pressure to remove ethanol. The pH was adjusted to 6 using saturated sodium bicarbonate, and extraction was performed by adding ethyl acetate. The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography. 371p (6.2 g) was obtained, and the yield is 54.3%. MS m / z (ESI): 257 [M+1] +

[0840] Step 14: 371p (100 mg, 390.35 μmol) and tert-butyl N-amino-N-(trideuteriomethyl)carbonate (87.36 mg, 585.52 μmol) were dissolved in methanol (1 mL), acetic acid (23.44 mg, 390.35 μmol) was added, and the mixture was stirred overnight at room temperature. Then, NaBH3CN (29.44 mg, 468.42 μmol) was added, and the reaction was carried out at 60°C for 48 hours while stirring. After the reaction was complete, the reaction solution was concentrated, extracted with ethyl acetate, the organic phase was washed with saturated saline, the organic phase was separated, dried, and concentrated, and then separated by column chromatography. 371q (110 mg) was obtained, and the yield is 72.4%. MS m / z (ESI): 390 [M+1] +

[0841] Step 15: 371q (100 mg, 256.81 μmol) and 371g(146.92 mg, 385.22 μmol) was dissolved in DCE (896.56 μL), pyridine (203.14 mg, 2.57 mmol, 206.88 μL) was added, and POCl3 (118.13 mg, 770.44 μmol) was slowly added dropwise in an ice bath. The reaction was carried out at room temperature for 1 hour while stirring. After the reaction was complete, water was added to quench the mixture, extracted with DCM, and the organic phase was separated, dried, and concentrated, then separated by column chromatography. 371r (190 mg) was obtained, and the yield is 98.3%. MS m / z (ESI): 721 [M+1] +

[0842] Step 16: 371r (190 mg, 252.41 μmol) was dissolved in TFA (5 mL) and reacted at 80°C for 1 hour while stirring. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by preparative liquid chromatography, Example 371 (30 mg) was obtained, and the yield is 57.1%. MS m / z (ESI): 503 [M+1] +

[0843] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (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).

[0844] Example 371 Preparation of Chiral Isomers

[0845]

[0846] Example 371 (19 mg, 0.079 mmol) was separated by Chiral-HPLC (condition 3), and respectively 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]naphthiridine-8-carbohydrazide (6 mg) was obtained, with a yield of 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]naftiridine-8-carbohydrazide (11.4 mg) was obtained, and the yield was 57.9%.

[0847] 371-P1 (t R : 4.564 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (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).

[0848] 371-P2 (t R : 4.277 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (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).

[0849] Example 372

[0850] rel-(R)-4-amino-N'-methyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1,3-dihydrofuro[3,4-c][1,7]naphthiridine-8-carbohydrazide

[0851]

[0852] Step 1: 3-(pentafluorosulfanyl)phenol 372a (3 g, 13.63 mmol) was dissolved in toluene (30 mL), pumped and replaced with nitrogen three times, cooled to 0°C, sodium hydride (981 mg, 24.53 mmol, 60% purity) was added, and the reaction system was reacted at 0°C for 1 hour, then elemental iodine (3.46 g, 13.63 mmol) was added, and the reaction was carried out at 25°C for 15 hours. An aqueous solution of saturated sodium sulfite was added to the reaction and quenched, extracted with ethyl acetate (80 mL x 3), washed with 30 mL of saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 372b (4.60 g) was obtained, and the yield is 97.6%.

[0853] Phase 2: 372b (4.6 g, 13.29 mmol), potassium vinyltrifluoroborate (3.56 g, 26.59 mmol), and potassium carbonate (5.51 g, 39.88 mmol) were dissolved in water (10 mL) and 1'4-dioxane (50 mL); after three pump replacements with nitrogen, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (981 mg, 1.33 mmol) was added, and the reaction system was reacted at 80°C for 3 hours. The reaction was quenched by adding water, extracted with ethyl acetate (80 mL x 3), washed with 30 mL of saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 372c (3 g) was obtained, and the yield is 91.7%.

[0854] Phase 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), tert-butyl hydroperoxide (1.43 g, 15.84 mmol, 1.53 mL) was added, and the reaction system was heated to 60°C under an air bath and reacted for 6 hours. Saturated sodium sulfite was added to the reaction to quench it, extract with ethyl acetate (50 mL x 3), wash with 30 mL of saturated saline, dry with anhydrous sodium sulfate, filter, and concentrate. The residue was purified by silica gel column chromatography using eluent system B, 372d (0.6 g) was obtained, and the yield is 46.5%.

[0855] 1 H NMR (400 MHz, CDCl3) δ 8.07-8.00 (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).

[0856] Phase 4: 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 system was reacted at 25°C for 2 hours. The reaction was quenched by adding water, extracted with ethyl acetate (80 mL x 3), washed with 30 mL of saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to obtain (6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-ol 372e (1.80 g) was obtained, and the yield is 93.1%.

[0857] 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 1H), 7.37 (dd, 1H), 7.28 (d, 1H), 5.42 (dd, 1H), 4.65 (dd, J 1H), 4.53 (dd, 1H).

[0858] Step 5: 372e (1.8 g, 6.87 mmol), tert-butyl (1,3-dioxoisoindole-2-yl)carbamate (2.16 g, 8.24 mmol), and triphenylphosphine (2.70 g, 10.30 mmol) were dissolved in tetrahydrofuran (20 mL), pumped and replaced with nitrogen three times, cooled to 0°C, and diisopropyl azodicarboxylate (2.08 g, 10.30 mmol, 2.03 mL) was added. The solution was concentrated, and the residue was purified by silica gel column chromatography using eluent system B. 372f (1.7 g) was obtained, and the yield is 48.9%.

[0859] 1 H NMR (400 MHz, CDCl3) δ 7.91-7.73 (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).

[0860] Step 6: 372f (1.7 g, 3.36 mmol) was dissolved in dichloromethane (20 mL), and after pumping and replacing with nitrogen three times, 85% hydrazine hydrate (336.08 mg, 6.71 mmol, 0.35 mL) was added. The reaction system was stirred at 25°C for 15 hours. The reaction was filtered, concentrated, and the residue was dissolved by adding 5 mL of dichloromethane / petroleum ether (v / v=1:3), filtered, and concentrated, and this process was repeated twice. 372g (1.20 g, crude product) was obtained. MS m / z (ESI): 377 [M+1] +

[0861] Step 7: 372g (1.2 g, 3.19 mmol) and pyridine (504 mg, 6.38 mmol, 0.51 mL) were dissolved in dichloromethane (15 mL), and after three pump replacements with nitrogen, benzyl chloroformate (816 mg, 4.78 mmol, 0.67 mL) was added dropwise at 0°C, and the reaction system was stirred at 25°C for 2 hours. Water was added to the reaction to quench it, extracted with ethyl acetate (80 mL x 3), washed with 30 mL of saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 372h (1.3 g) was obtained, and the yield is 80.0%.

[0862] Step 8: 372h (1.3 g, 2.55 mmol) was dissolved in tetrahydrofuran (20 mL), pumped and replaced with nitrogen three times, 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. Water was added to the reaction to quench it, extracted with ethyl acetate (80 mL x 3), washed with 30 mL of saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B, 372i (0.9 g) was obtained, and the yield is 67.4%.

[0863] Step 9: 372i (0.9 g, 1.72 mmol) is dissolved in ethyl acetate (5 mL), hydrogen chloride (5 mL) is added to the ethyl acetate, the reaction system is stirred at 25°C for 1 hour, and concentrated. 372j (0.7 g, crude product) was obtained.

[0864] 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) was dissolved in dichloromethane (10 mL), and after pumping and replacing with nitrogen three times, phosphorus 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. Water was added to the reaction to quench it, extracted with ethyl acetate (50 mL x 3), washed with 30 mL of saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A, 372l (80 mg) was obtained, and the yield is 28.7%. MS m / z (ESI): 788 [M+1] +

[0865] Step 11: 372l (60 mg, 76 μmol) was dissolved in tetrahydrofuran (5 mL), palladium carbon (9 mg, 76 μmol) was added, and after three pumping replacements with hydrogen, the reaction system was stirred at 25°C for 1 hour under hydrogen balloon conditions. After filtration and concentration 372m (50 mg, crude product) was obtained. MS m / z (ESI): 654 [M+1] +

[0866] Step 12: 372m (50 mg, 76 μmol) was dissolved in trifluoroacetic acid (2 mL), and after pumping and replacing with nitrogen three times, the reaction system was stirred at 80°C for 15 minutes. The residue was concentrated. The residue was purified by silica gel column chromatography using eluent system A. Example 372 (35 mg) was obtained, and the yield is 90.9%. MS m / z (ESI): 504 [M+1]+

[0867] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (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).

[0868] Example 372 Preparation of Chiral Isomers

[0869]

[0870] Example 372 (35 mg, 0.07 mmol) was separated by chiral preparative HPLC (condition 2) 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]naphthiridine-8-carbohydrazide 372-P1 (14 mg) was obtained, the yield was 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]naftiridine-8-carbohydrazide 372-P2 (13 mg) was obtained, and the yield is 36.0%.

[0871] 372-P1 (t R : 1.169 min): 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (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).

[0872] 372-P2 (t R : 1.856 min): 1H NMR (400 MHz, DMSO-d6) δ 8.87 (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).

[0873] Example 374

[0874] 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]naphthiridine-8-carbohydrazide

[0875]

[0876] Step 1: 5-Bromo-6-methyl-2(1H)-pyridinone 374a (35 g, 186 mmol) and Rawesson reagent (37.6 g, 93 mmol) were dissolved in toluene (350 mL), and the reaction system was reacted at 110°C for 16 hours. It was concentrated. Filtered 374b (30 g) was obtained, and the yield is 78.7%. MS m / z (ESI): 205 [M+1] +

[0877] Phase 2: 374b (60 g, 294 mmol), iron trichloride (23.9 g, 147 mmol), and sodium iodide (22 g, 147 mmol) were dissolved in acetonitrile (600 mL), and the reaction system was reacted openly at 20°C for 16 hours. First, saturated sodium thiosulfate was added and the mixture was quenched and filtered. Then, 800 mL of water and 2000 mL of ethyl acetate were added to the mixed solution, the organic phase was washed three times with 200 mL of saturated saline solution each time, the organic phase was dried, and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A. 374c (42 g) was obtained, and the yield is 48.3%. MS m / z (ESI): 591 [M+1] +

[0878] Phase 3: 374c(18 g, 44.3 mmol), tetraethylammonium chloride (14.7 g, 88.6 mmol), and silver difluoride (129 g, 886 mmol) were dissolved in dichloromethane (200 mL) and reacted in a sealed tube under a closed system at 20°C for 16 hours. The mixture was filtered and concentrated. The residue was purified by reverse-phase column chromatography using eluent system A. 374d (21.4 g) was obtained, and the yield is 80.8%. MS m / z (ESI): 299 [M+1] +

[0879] Phase 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), and the reaction system was reacted at 80°C for 16 hours. After concentration and filtration, ammonium chloride was added and quenched; then, 50 mL of water and 500 mL of ethyl acetate were added to the mixed solution, the organic phase was washed three times with 20 mL of saturated saline solution each time, the organic phase was dried, and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A, 374e (4.7 g) was obtained, and the yield is 35.3%. MS m / z (ESI): 378 [M+1] +

[0880] 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), and 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. 374f (1.8 g) was obtained, and the yield is 50.6%. MS m / z (ESI): 315 [M+1] +

[0881] Step 6: 374f (15 g, 47.7 mmol), tetrabutylammonium hydrogen sulfate (3.24 g, 9.5 mmol), and potassium hydroxide (5.35 g, 95.5 mmol) were dissolved in allyl bromide (30 mL) and reacted for 16 hours at 20°C under a solvent-free system. First, water was added and quenched; then, 100 mL of water and 500 mL of ethyl acetate were added to the mixed solution, and the organic phase was washed three times with 50 mL of saturated saline solution each time, after which the organic phase was dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A. 374g (13.5 g) was obtained, and the yield is 79.7%. MS m / z (ESI): 355 [M+1] +

[0882] Step 7: 374g (22 g, 62.1 mmol), tri(o-tolyl)phosphine (11.3 g, 37.2 mmol), palladium acetate (2.78 g, 12.4 mmol), and cesium carbonate (24.2 g, 74.5 mmol) were dissolved in N,N-dimethylformamide (440 mL), and the reaction system was reacted at 90°C for 2 hours. First, water was added and quenched; then, 200 mL of water and 1000 mL of ethyl acetate were added to the mixed solution; the organic phase was washed three times with 100 mL of saturated saline solution each time, the organic phase was dried, and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A, 374h (11.1 g) was obtained, and the yield is 65.2%. MS m / z (ESI): 274 [M+1] +

[0883] 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), and the reaction system was reacted at 20°C for 16 hours. First, water was added and quenched, then filtered; subsequently, 50 mL of water and 300 mL of ethyl acetate were added to the mixed solution, and the organic phase was washed three times with 20 mL of saturated saline solution each time; then, the organic phase was dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A, 374i (3.5 g) was obtained, and the yield is 77.8%. MS m / z (ESI): 308 [M+1] +

[0884] Step 9: 374i Sodium periodide (3.5 g, 11.3 mmol) and sodium periodontate (7.36 g, 34.1 mmol) were dissolved in tetrahydrofuran (40 mL) and water (4 mL), and the reaction system was reacted at 20°C for 4 hours. The mixture was filtered and concentrated. The residue was purified by reverse-phase column chromatography using eluent system A. 374j (2.86 g) was obtained, and the yield is 91.7%. MS m / z (ESI): 276 [M+1] +

[0885] 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), and the reaction system was reacted at 20°C for 16 hours. First, water was added and quenched; then, 10 mL of water and 100 mL of ethyl acetate were added to the mixed solution, and the organic phase was washed three times with 10 mL of saturated saline solution each time, after which the organic phase was dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A,374k (310 mg) was obtained, and the yield is 81.2%. MS m / z (ESI): 404 [M+1] +

[0886] Step 11: 374k Sodium borohydride (310 mg, 0.77 mmol) and sodium borohydride (87 mg, 2.3 mmol) were dissolved in ethanol (6 mL), and the reaction system was reacted at 20°C for 16 hours. First, ammonium chloride was added and quenched; then, 10 mL of water and 100 mL of ethyl acetate were added to the mixed solution, and the organic phase was washed three times with 10 mL of saturated saline solution each time, after which the organic phase was dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A, 374l (220 mg) was obtained, and the yield is 70.4%. MS m / z (ESI): 406 [M+1] +

[0887] Step 12: 374l (45 mg, 0.11 mmol), 4-((2,4-dimethoxyphenyl)amino)-1,3-dihydrofuro[3,4-c][1,7]naphthiridine-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), and the reaction system was reacted at 20°C for 16 hours. First, ammonium chloride was added and quenched; then, 10 mL of water and 100 mL of ethyl acetate were added to the mixed solution, and the organic phase was washed three times with 10 mL of saturated saline solution each time, after which the organic phase was dried and spin-dried. The residue was purified by reverse-phase column chromatography using eluent system A, 374n (29 mg) was obtained, and the yield is 34.3%. MS m / z (ESI): 769 [M+1] +

[0888] Step 13: 374n(29 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (4 mL), and after pumping and replacing with nitrogen three times, the reaction system was reacted at 90°C for 0.5 hours. The residue was concentrated, and the residue was purified by silica gel column chromatography using eluent system A. Example 374 (11.2 mg) was obtained, and the yield is 63.5%. MS m / z (ESI): 519 [M+1] +

[0889] 1 HNMR (400 MHz, DMSO-d6) δ 8.85 (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).

[0890] Example 375

[0891] 4-amino-N',1-dimethyl-N-(6-(pentafluoro-6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazolo[4,3-c][1,7]naphthiridine-8-carbohydrazide

[0892]

[0893] Example 372 Referring to the synthesis method of steps 10 to 12 of 4-(3,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c][1,7]naphthiridine-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 From (108 mg, 0.25 mmol) Example 375 (5 mg) was obtained, and the yield is 3.9%. MS m / z (ESI): 516 [M+1] +

[0894] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (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).

[0895] Example 375 Preparation of Chiral Isomers

[0896]

[0897] Example 375 (130 mg, 0.25 mmol) was separated by chiral preparative HPLC (condition 2) 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]naphthiridine-8-carbohydrazide 375-P1 (33 mg) was obtained, the yield was 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]naftiridine-8-carbohydrazide 375-P2 (32 mg) was obtained, and the yield is 24.6%.

[0898] 375-P1 (t R : 0.656 min): 1 H NMR (400 MHz, 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).

[0899] 375-P2 (t R : 0.911 min): 1H NMR (400 MHz, DMSO-d6) δ 8.90 (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).

[0900] Example 385

[0901] 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

[0902]

[0903] Example 372 Referring to the synthesis method of steps 10 to 12 of 4-(3,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxyl...

Claims

Claim 1 As a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, M1 is -N- or -CR a Selected from -; M2 is -N- or -CR b Selected from; M3 is selected from N or C; ring A is C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl; preferably C 3-6 It is a cycloalkyl, 3-6-membered heterocyclyl, phenyl, or 5-6-membered heteroaryl; ring B is C 3-14 Cycloalkyl, 3-14-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl; preferably C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is an aryl or a 5-12-membered heteroaryl; more preferably C 3-6 Cycloalkyl, 3-6-membered heterocyclyl, C 6-10 Fused cycloalkyl, 6-10 fused heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl; L1 is bonded, -(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 Selected from arylene or 5-12-membered heteroarylene, and C 3-12 Cycloalkylene, 3-12-membered heterocyclylene, C 6-12 Arlylenes and 5-12-membered heteroarylenes are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; preferably bonded, -(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 -is; more preferably combined, -CR aa R bb -, -C(O)-, -NR cc C(O), -S(O) m1 - or -NR cc Selected from -; more preferably -CR aa R bb -, -C(O)-, -S(O) m1 - or -NR cc - and; L2 is combined, -(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 Selected from -; preferably combined, -CR aa R bb -, -C(O)-, -S(O) m1 - or NR cc Selected from; more preferably -CR aa R bb -, -C(O)-, -S(O) m1 - or NR cc And; R1 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 prion heterocyclil, -(CR cc R dd ) n1 -C 6-12 Aril, -(CR cc R dd ) n1 -5-12 prion 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the following substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8-won heterocyclil, -(CR cc R dd ) n1 -C 6-10 Aril, -(CR cc R dd ) n1 -5-10 won heteroaryl, -OR e , -NR e R f , -C(O)R e , -C(O)NR e R f or -P(O)R e R f and, the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents of aryl and 5-10-membered heteroaryl; or R1 is R a , R b or R c Connected to C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Forms aryl and 5-12-membered heteroaryls, and optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is further substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; preferably C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Forms aryl and 5-10-membered heteroaryls, and optionally deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is further substituted with one or more substituents selected from aryl and 5-10-membered heteroaryls; R2 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is substituted with one or more substituents selected from aryl and 5-10-membered heteroaryls; R3 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12-membered heterocyclyl, -Y1-C 6-12 Aryl, -Y1-5-12-won 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f Substituted with one or more of the following substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12 prismatic 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 and, the above amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f It is substituted with one or more of the following substituents; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl, 5-10 synonymous heteroaryl and =CR e R f Substituted with one or more of the substituents; or any two R3s are connected to atoms adjacent to them, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Forms aryl and 5-12-membered heteroaryls, and optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is further substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; preferably C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Forms aryl and 5-10-membered heteroaryls, and optionally deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is additionally substituted with one or more substituents selected from aryls and 5-10-membered heteroaryls;R a , R b , R c , R e and R f Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the following substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents of aryl and 5-10-membered heteroaryl; or R a is R b Connected to C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Forms aryl and 5-12-membered heteroaryls, and optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Further substituted with one or more substituents of aryl and 5-12-membered heteroaryl; Y1 is bonded, -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 Selected from alkynylene, and the above C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylene is optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; R g , R h , R i and R j Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents of aryl and 5-10-membered heteroaryl; or R g is R h Connected to C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Forms aryl and 5-12-membered heteroaryls, and optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 It is additionally substituted with one or more substituents selected from aryls and 5-12-membered heteroaryls;R aa , R bb , R cc and R dd Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents of aryl and 5-10-membered heteroaryl; R ee and R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with one or more substituents selected from aryls and 5-10-membered heteroaryls;R gg and R hh Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryls; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It is an aryl or 5-10-membered heteroaryl, and the above amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from 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. Claim 2 In paragraph 1, the above silver or A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from. Claim 3 In paragraph 1, the above general formula is additionally represented by general formula (II), and R 1-2 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the following substituents; preferably C 1-3 Alkyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano 1-3 Selected from alkyls, and C 1-3 Alkyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl and cyano groups 1-3 Alkyl groups are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; R 1-3 Silver, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the following substituents; preferably hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano 1-3 Selected from alkyls, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl and cyano groups 1-3 Alkyl groups are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents of aryl and 5-12-membered heteroaryl; or, R 1-2 is R 1-3 Connected to form a 3-10-membered heterocyclyl, and the 3-10-membered heterocyclyl is optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents; R ee and R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; R gg and R hh Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl or 5-12-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from 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 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the definitions of , x, and y are as defined in claim 1. Claim 4 As a compound represented by 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 is CR 4a , NR 4a or selected from N; X7 is CR 4b , NR 4b or selected from N; or, R 4a is R 4b Connected to form ring A; ring A is C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl, optionally 0, 1, 2, 3, 4, 5, or 6 R 2c It is replaced by; ring F is C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl; R 2c is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; R 3e and R 3g Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl, 5-10 prion 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 Selected from, and the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR a3 R a4 Substituted with one or more of the substituents; or, two R 3e C is connected 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Forming an aryl or 5-10-membered heteroaryl, and the above C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls selectively accept hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl, 5-10 prion heteroaryl, -SF5, =N-OR a5 , =CR a5 CR a6 , -S(O)R a5 (=NR a6 ) and -N=S(O)R a5 R a6 It may be additionally replaced with one or more of the following;R 3f is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, -(CR b1 R b2 ) n6 -C 3-8 Cycloalkyl, -(CR b1 R b2 ) n6 -3-8-won heterocyclil, -(CR b1 R b2 ) n6 -C 6-10 Aril, -(CR b1 R b2 ) n6 -5-10 prion 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 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls selectively accept deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR b3 CR b4 Substituted with one or more of the following substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl, 5-10 prion 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; or, 2 R 3f C is connected 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Forming an aryl or 5-10-membered heteroaryl, and the above C 3-10 Cycloalkyl, 3-10-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls selectively accept hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio groups, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be further substituted with one or more of aryls and 5-10-membered heteroaryls;R 4a is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be further substituted with one or more of aryls and 5-10-membered heteroaryls;R 4b is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl, 5-14 prismatic 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be further substituted with one or more of aryls and 5-10-membered heteroaryls;R a1 , R a2 , R a3 , R a4 , R a5 and R a6 Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be further substituted with one or more of aryls and 5-10-membered heteroaryls;R b1 , R b2 , R b3 and R b4 Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be further substituted with one or more of aryls and 5-10-membered heteroaryls;R c1 , R c2 and R c3 Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo group, thio group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Selected from aryl or 5-14-membered heteroaryl, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 Aryl or 5-14-membered heteroaryls optionally consist of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterium alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 It may be further substituted with one or more of aryls and 5-10-membered heteroaryls; 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; n6 is selected from 0, 1, 2, 3, or 4; M1, M2, R1, R c , R ee , R ff The definition of n2 is a compound as described in paragraph 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 5 In paragraph 4, the above general formula is additionally denoted as general formula (IV) or (IV-1), and R 1-2 is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents; R 1-3 Silver, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 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 Selected from, and the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh Substituted with one or more of the substituents; or, R 1-2 is R 1-3 Connected to form a 3-10-membered heterocyclyl, and the 3-10-membered heterocyclyl is optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl, 5-12-membered heteroaryl and =CR gg R hh A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more of the following substituents. Claim 6 In any one of paragraphs 1 to 5, the above general formula is additionally represented by general formula (V) or (V-1), and Ring A, Ring F, X2, X3, R 2c , R 3e , R 3g , R 3f The definitions of , a, b, and c are as stated in Paragraph 4; R 1-2 and R 1-3 The definition of is as stated in Paragraph 3 or 5; M1, M2, M3, R c A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by the definition of x as described in claim 1. Claim 7 In any one of claims 1 to 6, ring A is selected from 3-12-membered heterocyclil or 5-12-membered heteroaryl; preferably 5-membered heterocyclil, 6-membered heterocyclil, 5-membered heteroaryl or 6-membered heteroaryl; more preferably or A compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized by being. Claim 8 In any one of paragraphs 1 through 7, the above general formula is additionally represented by general formula (VI), and A compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized by being. Claim 9 In any one of claims 1 to 8, ring B is selected from 3-6-membered heterocyclyl conjugated phenyl or 3-6-membered heterocyclyl conjugated 5-6-membered heteroaryl; preferably or or; or, ring B is selected from 6-14-membered tricyclic heterocyclils; preferably 6-14-membered tricyclic spiroheterocyclils or 6-14-membered tricyclic fused heterocyclils; more preferably or A compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized by being. Claim 10 In any one of claims 1 to 9, the above general formula is additionally represented as general formula (VI) or (VI-A), and M4 is N or R 3a and; X2 is C or N and; X3 is C or N and; R 3a , R 3c and R 3d Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl, 5-12-membered heteroaryl and -SF5, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f Substituted with one or more of the substituents; R 3b is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Selected from aryl, 5-12-membered heteroaryl and -SF5, and said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Aryl and 5-12-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, substituted, or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted 5-12-membered heteroaryls and =CR e R f A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more of the following substituents; where n5 is selected from 0, 1, or 2. Claim 11 In any one of paragraphs 1 through 10, R2 or R 2c Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl or -C(O)NR ee R ff Selected from, and the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Cycloalkyl groups are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Substituted with one or more substituents from cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuteride methyl, difluoromethyl, trifluoromethyl, or Igo;R c is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Selected from alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuteride methyl, difluoromethyl, or trifluoromethyl; R a is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 Selected from alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuteride methyl, difluoromethyl, or trifluoromethyl; R b is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, --(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 Selected from, and the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8-membered heterocyclyls are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl and =CR gg R hh It is substituted with one or more of the following substituents; preferably hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, -(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 and, the above amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8-membered heterocyclyls are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Substituted with one or more substituents selected from cycloalkyl or 3-8-membered heterocyclyl; R ee and R ff Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Selected from cycloalkyl or 3-8-membered heterocyclyl, and said amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8-membered heterocyclyls are optionally deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, oxo group, thio group, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Substituted with 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, deuteride methyl, deuteride ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuteride methoxy, difluoromethoxy, trifluoromethoxy, or A compound, its stereoisomer, or its pharmaceutically acceptable salt, characterized by being. Claim 12 In any one of paragraphs 1 through 11, R3 and R 3f Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Selected from aryl, 5-10-membered heteroaryl or -SF5, and said amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 Substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl; R 3e and R 3g Each independently consists of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Selected from aryl or 5-10-membered heteroaryl, and said amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkinyl, C 1-3 Deuterium alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 C substituted with hydroxyalkyl or cyano groups 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclyl, C 6-10 Aryl and 5-10-membered heteroaryls optionally include deuterium, halogen, amino, hydroxyl, cyano, nitro, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo group, thio group, C 1-6 Deuterium alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 C substituted with hydroxyalkyl or cyano groups 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-12 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from aryl and 5-12-membered heteroaryl. Claim 13 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that, in any one of claims 1 to 12, the structure of the compound is as follows: or . Claim 14 A compound represented by general formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Preferably, it is a compound represented by the general formula (VII-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and 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 compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof as defined in paragraph 3 or 4. Claim 15 In paragraph 13, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is characterized as follows: or . Claim 16 A method for preparing a compound represented by general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A compound represented by general formula (III-I) and a compound represented by general formula (III-II) are reacted under conditions in the presence of a condensing agent and a base to obtain a compound represented by general formula (III-III), and further a protecting group is removed to obtain a compound represented by 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, wherein A compound represented by general formula (IV-I) and a compound represented by general formula (IV-II) are reacted under conditions in the presence of a condensing agent and a base to obtain a compound represented by general formula (IV-III), and further a protecting group is removed to obtain a compound represented by 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, wherein A compound represented by general formula (VI) and a compound represented by general formula (V-II) are reacted under conditions in the presence of a condensing agent and a base to obtain a compound represented by general formula (V-III), and further removing a protecting group to obtain a compound represented by general formula (V); Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, tosyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, Selected from 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, tosyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; M1, M2, M3, R a , R b and R c is as defined in Paragraph 1; X2, X3, R 1-2 , R 1-3 , R 2c , R 3e , R 3f , R 3g , a, b, c, x and n4 are a manufacturing method as defined in paragraph 3 or 4. Claim 17 A pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Claim 18 Application of a compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 in the manufacture of PRMT5 inhibitor drugs. Claim 19 Application of a compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 in the manufacture of a drug for treating cancer. Claim 20 In claim 19, the above 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 lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, biliary tract cancer, or cholangiocarcinoma; the above lung cancer is selected from non-small cell lung cancer, pulmonary squamous cell carcinoma or lung adenocarcinoma; and the above esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma, characterized in that the application.

Images