Polycyclic derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a polycyclic derivative inhibitor as well as a preparation method and application thereof. In particular, the present invention relates to a polycyclic derivative compound, a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof in cancer treatment.

Description

Technical Field

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

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

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

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

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

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

[0007]

[0008] L1 is selected from a bond, -(CR a R b ) n1 -、-(CR a R b ) n1 O(CR a R b ) n2 -、-(CR a R b ) n1 S(CR a R b ) n2 -、-(CR a R b ) n1 NR c (CR a R b ) n2 -、-(CR a R b ) n1 C(O)(CR a R b ) n2 -、-(CR aR b ) n1 S(O) m2 (CR a R b ) n2 -、-(CR a R b ) n1 C(O)NR c (CR a R b ) n2 -、-(CR a R b ) n1 NR c C(O)(CR a R b ) n2 -、-(CR a R b ) n1 -C 3-12 Cycloalkyl-(CR a R b ) n2 -、-(CR a R b ) n1 -3-12 membered heterocyclic group-(CR a R b ) n2 -、-(CR a R b ) n1 -C 6-12 Aryl-(CR a R b ) n2 -or-(CR a R b ) n1 -5-12 membered heteroaryl-(CR a R b ) n2 -, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n3-substituted or unsubstituted C 3-12 Cycloalkyl, -(CH2) n3 -substituted or unsubstituted 3-12 membered heterocyclic group, -(CH2) n3 -substituted or unsubstituted C 6-12 Aryl and -(CH2) n3 -substituted or unsubstituted 5-12 membered heteroaryl, substituted by one or more substituents; preferably a bond, -(CR a R b ) n1 -、-(CR a R b ) n1 O(CR a R b ) n2 -、-(CR a R b ) n1 S(CR a R b ) n2 -、-(CR a R b ) n1 NR c (CR a R b ) n2 -、-(CR a R b ) n1 C(O)(CR a R b ) n2 -、-(CR a R b ) n1 S(O) m2 (CR a R b ) n2 -、-(CR a R b ) n1 C(O)NR c (CR a R b ) n2 -、-(CR a R b ) n1 NR c C(O)(CR a R b ) n2 -、-(CR a R b ) n1 -C 3-8 Cycloalkyl-(CR a Rb ) n2 -、-(CR a R b ) n1 -3-8 membered heterocyclic group-(CR a R b ) n2 -、-(CR a R b ) n1 -C 6-10 Aryl-(CR a R b ) n2 -or-(CR a R b ) n1 -5-10 membered heteroaryl-(CR a R b ) n2 -, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n3 -substituted or unsubstituted C 3-8 Cycloalkyl, -(CH2) n3 -substituted or unsubstituted 3-8 membered heterocyclic group, -(CH2) n3 -substituted or unsubstituted C 6-10 Aryl and -(CH2) n3 -substituted by one or more substituents in a substituted or unsubstituted 5-10 membered heteroaryl;

[0009] R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0010] R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 S(O) m3 R d 、-(CH2) n4 N=S(O) m3 R d R e 、-(CH2) n4 N=S(O) m3 R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0011] or R 1d and R 1e The atoms adjacent to it, R 1c and R 1d The atoms adjacent to it, R 1b and R 1c The adjacent atoms or R 1a and R 1b Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0012] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0013] R a , R b , R c , R d and R e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0014] or R d and R e Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0015] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0016] m1 is selected from 0, 1 or 2;

[0017] m2 is selected from 0, 1 or 2;

[0018] n1 is selected from 0, 1, 2, 3 or 4;

[0019] n2 is selected from 0, 1, 2, 3 or 4;

[0020] n3 is selected from 0, 1, 2, 3 or 4;

[0021] n4 is selected from 0, 1, 2, 3 or 4;

[0022] m3 is selected from 0, 1 or 2; and

[0023] x is selected from 0, 1, 2, 3 or 4.

[0024] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that L1 is selected from -(CR a R b )NR c -、-NR c (CR a R b )-、-C(O)NR c -、-NR c C(O)-, 5-10 membered heteroaryl, -(CR a R b )-5-10 membered heteroaryl or 5-10 membered heteroaryl-(CR a R b )-, the 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl;

[0025] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that the compound is further represented by general formula (II):

[0026]

[0027] Ring A is selected from

[0028] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n5 -C 3-12 Cycloalkyl, -(CH2) n5 -3-12 membered heterocyclic group, -(CH2) n5 -C 6-12 Aryl, -(CH2) n5 -5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n5 -C 3-8 Cycloalkyl, -(CH2) n5 -3-8 membered heterocyclic group, -(CH2) n5 -C 6-10 Aryl or -(CH2) n5 -5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0029] n5 is selected from 0, 1, 2, 3 or 4;

[0030] R 1a , R 1b , R 1c , R 1d , R 1e , R2 and x are as described in any embodiment.

[0031] Another object of the present invention is to provide a compound represented by general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0032]

[0033] Ring B is selected from C 3-12 Saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0034] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0035] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0036] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n6 -C 3-12 Cycloalkyl, -(CH2) n6 -3-12 membered heterocyclic group, -(CH2) n6 -C 6-12 Aryl, -(CH2) n6 -5-12 membered heteroaryl, -(CH2) n6 OR f 、-(CH2) n6 NR f R g 、-(CH2)n4 C(O)R d 、-(CH2) n6 S(O) m4 R f 、-(CH2) n6 N=S(O) m4 R f 、-(CH2) n6 C(O)NR f R g or -(CH2) n6 P(O)R f R g , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n6 -C 3-8 Cycloalkyl, -(CH2) n6 -3-8 membered heterocyclic group, -(CH2)n6 -C 6-10 Aryl, -(CH2) n6 -5-10 membered heteroaryl, -(CH2) n6 OR f 、-(CH2) n6 NR f R g 、-(CH2) n6 C(O)R f 、-(CH2) n6 C(O)NR f R g or -(CH2) n6 P(O)R f R g , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0037] Or two R5 on the same carbon atom form =O, =NR h , =CR h R i , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents in aryl and 5-12 membered heteroaryl; preferably forming =O, =NR h , =CR h R i , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0038] R d , R e , R f , R g , R h and R i Each independently selected from

[0039] Hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0040] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0041] n4 is selected from 0, 1, 2, 3 or 4;

[0042] n6 is selected from 0, 1, 2, 3 or 4;

[0043] m4 is selected from 0, 1 or 2;

[0044] x is selected from 0, 1, 2, 3 or 4;

[0045] q is selected from 0, 1, 2, 3 or 4; and

[0046] z is selected from 0, 1, 2, 3, 4 or 5.

[0047] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from benzoC 3-8 Cycloalkyl, benzo 3-8 membered heterocyclic group or benzo 5-8 membered heteroaryl group; preferably

[0048] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from C 7-10 Saturated or unsaturated bridged cycloalkyl, C 3-8 Cycloalkyl 3-8 membered heterocyclic group, C 3-8 Cycloalkylphenyl or C 3-8 Cycloalkyl and 5-8 membered heteroaryl; preferably

[0049] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from a 7-10 membered saturated or unsaturated bridged heterocyclic group, a 3-8 membered heterocyclic group and C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 3-8 membered heterocyclyl, 3-8 membered heterocyclyl and phenyl, or 3-8 membered heterocyclyl and 5-8 membered heteroaryl; preferably

[0050] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from 5-10 membered heteroaryl, 5-10 membered heteroaryl and 3-10 membered cycloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, 5-10 membered heteroaryl and phenyl or 5-10 membered heteroaryl and 5-10 membered heteroaryl; preferably 5 membered heteroaryl or 6 membered heteroaryl; more preferably

[0051] Another object of the present invention is to provide a compound represented by general formula (IV) or (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0052]

[0053] Ring C is selected from 6-14 membered spiro heterocyclic groups; preferably

[0054] Ring D is selected from C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0055] Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-8 Cycloalkylphenyl, C 3-8 Cycloalkyl 5-8 membered heteroaryl, 3-8 membered heterocyclyl phenyl or 3-8 membered heterocyclyl 5-8 membered heteroaryl;

[0056] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0057] R6, R7 or R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0058] R d , R e , R j and R k are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0059] n4 is selected from 0, 1, 2, 3 or 4;

[0060] x is selected from 0, 1, 2, 3 or 4;

[0061] p is selected from 0, 1, 2, 3 or 4;

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

[0063] s is selected from 0, 1, 2, 3 or 4.

[0064] Another object of the present invention is to provide a compound represented by general formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0065]

[0066] R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0067] R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 S(O) m3 R d 、-(CH2) n4 N=S(O) m3 R d R e 、-(CH2) n4 N=S(O) m3 R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0068] or R 1d and R 1e The atoms adjacent to it, R 1c and R 1d The atoms adjacent to it, R 1b and R 1c The adjacent atoms or R 1a and R 1b Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0069] R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n7 C 3-12 Cycloalkyl, -(CH2) n7 3-12 membered heterocyclic group, -(CH2) n7 C 6-12 Aryl, -(CH2) n7 5-12 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n7 C 3-8 Cycloalkyl, -(CH2) n7 3-8 membered heterocyclic group, -(CH2) n7 C 6-10 Aryl, -(CH2) n7 5-10 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0070] R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0071] R 3b and R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2)n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0072] R d , R e , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0073] or R d and R e Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents;

[0074] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0075] n4 is selected from 0, 1, 2, 3 or 4;

[0076] n7 is selected from 0, 1, 2, 3 or 4; and

[0077] n8 is selected from 0, 1, 2, 3 or 4;

[0078] m3 is selected from 0, 1 or 2.

[0079] Another object of the present invention is to provide a compound represented by the general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0080]

[0081] R 1a , R 1b , R 1cand R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0082] R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 S(O) m3 R d 、-(CH2) n4 N=S(O) m3 R d R e 、-(CH2) n4 N=S(O) m3 R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0083] or R 1d and R 1e The atoms adjacent to it, R 1c and R 1d The atoms adjacent to it, R 1b and R 1c The adjacent atoms or R 1a and R 1b Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0084] R 2a and R 1e The atoms adjacent to it, R 2a and R 1d The adjacent atoms or R 2a and R 1c Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0085] R 2b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n7 C 3-12 Cycloalkyl, -(CH2) n7 3-12 membered heterocyclic group, -(CH2) n7 C 6-12 Aryl, -(CH2) n7 5-12 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n7 C 3-8 Cycloalkyl, -(CH2) n7 3-8 membered heterocyclic group, -(CH2) n7 C 6-10 Aryl, -(CH2) n7 5-10 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0086] R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0087] R 3b and R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0088] or R 2b and R 3b Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0089] R d , R e , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aaSum = R aa R bb Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0090] or R d and R e Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents;

[0091] or R p and R q Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = Raa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents;

[0092] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0093] n4 is selected from 0, 1, 2, 3 or 4;

[0094] n7 is selected from 0, 1, 2, 3 or 4; and

[0095] n8 is selected from 0, 1, 2, 3 or 4;

[0096] m3 is selected from 0, 1 or 2.

[0097] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by general formula (VIII):

[0098]

[0099] Ring F is selected from 5-12 membered heterocyclyl or 5-12 membered heteroaryl; preferably 5-6 membered monocyclic heterocyclyl, 5-10 membered spiro heterocyclyl, 7-10 membered fused heterocyclyl or 7-10 membered bridged heterocyclyl;

[0100] R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2)n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0101] R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n7 C 3-12 Cycloalkyl, -(CH2) n7 3-12 membered heterocyclic group, -(CH2) n7 C 6-12 Aryl, -(CH2) n7 5-12 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n7 C 3-8 Cycloalkyl, -(CH2) n7 3-8 membered heterocyclic group, -(CH2) n7 C 6-10 Aryl, -(CH2) n7 5-10 membered heteroaryl, -(CH2) n7 OR m 、-(CH2)n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents selected from aryl and 5-10 membered heteroaryl; more preferably methyl or cyclopropyl;

[0102] R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8-C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, one or more substituents; more preferably -CH2NH2, -CH2NHCH3, -CH2NHCH2CH3, -CH2OH, -C(O)NH2,

[0103] R 3b and R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0104] R9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -COOR aa , =NOR aa or =R aa R bb , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa or =R aa R bb , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0105] R d , R e , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0106] or R p and R q Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents;

[0107] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0108] n4 is selected from 0, 1, 2, 3 or 4;

[0109] n7 is selected from 0, 1, 2, 3 or 4; and

[0110] n8 is selected from 0, 1, 2, 3 or 4;

[0111] m3 is selected from 0, 1 or 2.

[0112] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0113] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of PRMT5 inhibitor drugs.

[0114] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer, wherein the cancer is selected from MTAP-related cancers.

[0115] The present invention further relates to a method for preparing a method for treating cancer using a compound, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as shown in any embodiment, wherein the cancer is selected from MTAP-related cancers.

[0116] In some embodiments, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0117] The present invention also relates to a method for preventing and / or treating cancer, which comprises administering to a patient a therapeutically effective dose of a compound shown in any embodiment, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0118] The present invention also relates to a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0119] In certain embodiments of the present invention, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition, calculated as free base, is 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50%.

[0120] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0121] In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0122] In certain embodiments of the present invention, the pharmaceutical composition, calculated as a free base, has a unit dose of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0123] In certain embodiments of the invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, may be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0124] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules or lozenges.

[0125] In some embodiments, the method relates to the treatment of conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, or bile duct cancer.

[0126] 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.

[0127] Detailed description of the invention

[0128] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

[0129] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6 The alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-ethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, and the like. In one embodiment, the alkyl group is an optionally substituted alkyl group described elsewhere herein.

[0130] The term "alkylene" refers to a further substitution of a hydrogen atom of an alkyl group, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-) or butylene (-(CH2)4-). In one embodiment, the alkylene group is an optionally substituted alkyl group described elsewhere herein.

[0131] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group, and the alkenyl group can be optionally substituted with one or more substituents. In a specific embodiment, the alkenyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 The alkenyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0132] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, and the alkynyl group can be optionally substituted with one or more substituents. In a specific embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0133] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a specific embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls and bridged cycloalkyls in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0134] The term "spirocycloalkyl" refers to an aliphatic polycyclic group in which the single rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. In a specific embodiment, the spirocycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spirocycloalkyl, double spirocycloalkyl or multi-spirocycloalkyl, and in one embodiment is single spirocycloalkyl and double spirocycloalkyl. In one embodiment, it is 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

[0135]

[0136] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. In a specific embodiment, the fused cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, further in one embodiment, a bicyclic or tricyclic, further in one embodiment, a 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. In one embodiment, the condensed cycloalkyl is an optionally substituted condensed cycloalkyl described elsewhere herein or a condensed cycloalkyl optionally fused with a heterocyclic, aryl or heteroaryl group, further in one embodiment, a bicyclic or tricyclic, further in one embodiment, C 3-8 Cycloalkyl 3-8 membered heterocyclic group, C 3-8 Cycloalkylphenyl or C 3-8 Cycloalkyl and 5-8 membered heteroaryl, further in one embodiment is C 3-6 Cycloalkyl 3-6 membered heterocyclic group, C 3-6 Cycloalkylphenyl or C 3-6 Cycloalkyl and 5-6 membered heteroaryl. Non-limiting examples of fused cycloalkyl include:

[0137]

[0138] The term "bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π-electron system. In a specific embodiment, the bridged cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl is an optionally substituted bridged cycloalkyl described elsewhere herein. Non-limiting examples of bridged cycloalkyl include:

[0139]

[0140] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atom may be optionally substituted by oxygen, but does not include the ring part of -OO-, -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds, but does not have a completely conjugated π electron system. In a specific embodiment, the heterocyclyl contains 3 to 20, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10 or 7 to 11 ring atoms; in one embodiment, the heterocyclyl contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridge heterocyclic radical.In one embodiment, the heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0141] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of spiro atoms shared between the rings, the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl; preferably a monospiroheterocyclyl and a bispiroheterocyclyl; in one embodiment, the spiroheterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:

[0142]

[0143] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclic group is a group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is an optionally substituted fused heterocyclic group described elsewhere herein, or may be fused with a cycloalkyl, heterocyclic group, aryl or heteroaryl group, preferably a bicyclic or tricyclic group, and in one embodiment, a 3-8-membered heterocyclic group and C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 3-8 membered heterocyclyl, 3-8 membered heterocyclyl and phenyl, or 3-8 membered heterocyclyl and 5-8 membered heteroaryl, further in one embodiment, 3-6 membered heterocyclyl and C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 3-6 membered heterocyclyl, 3-6 membered heterocyclyl and phenyl, or 3-6 membered heterocyclyl and 5-6 membered heteroaryl; non-limiting examples of fused heterocyclyl include:

[0144]

[0145] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group; preferably a bicyclic, tricyclic or tetracyclic group; in one embodiment, it is a bicyclic or tricyclic group; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0146]

[0147] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted by one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo 5-8 membered heteroaryl, benzo 3-8 membered cycloalkyl, or benzo 3-8 membered heterocyclyl. In one embodiment, the aryl group is selected from benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl, or benzo 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

[0148] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

[0149] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system containing at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In specific embodiments, the heteroaryl group contains 5 to 20, 5 to 14 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in specific embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl or heteroaryl and 3-10 membered heterocyclyl; further in one embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0150] The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

[0151] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples thereof include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0152] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

[0153] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0154] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH2CF3,

[0155] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0156] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0157] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.

[0158] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein alkylthio is as defined above.

[0159] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

[0160] The term "aminocarbonyl" refers to NH2-C(O)-.

[0161] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the two hydrogen atoms are replaced by alkyl groups, wherein the alkyl group has the same definition as above.

[0162] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0163] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0164] The term " aa R bb "refer to Substituent.

[0165] The term "hydroxy" refers to an -OH group.

[0166] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0167] The term "oxo" or "oxo" refers to =0.

[0168] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared from suitable isotopically labeled starting materials obtained from commercial sources or prepared by known literature procedures.

[0169] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

[0170] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0171] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0172] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0173] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment. In one embodiment. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical realization. It goes without saying that the substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0174] In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

[0175] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0176] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0177] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0178] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0179] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

[0180] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0181] "Optically active" and "enantiomerically active" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound contains about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate. In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of the optical rotation have nothing to do with the absolute configuration R and S of the molecule. DETAILED DESCRIPTION

[0182] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0183] Example

[0184] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0185] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0186] HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0187] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0188] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0189] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0190] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

[0191] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0192] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0193] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0194] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0195] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0196] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0197] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0198] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0199] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

[0200] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system, C: acetonitrile and water system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0201] Example The separation of chiral isomers was performed using an OZ column, and the HPLC chiral analysis conditions were as follows:

[0202]

[0203]

[0204] Example 1

[0205] 2-(4-(4-(Aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-4H-1,2,4-triazol-3-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0206]

[0207] first step

[0208] 3-Chloro-6-cyano-5-cyclopropyloxy-2-fluorobenzamide

[0209] 4-Chloro-6-cyclopropyloxy-3-fluoro-2-iodobenzonitrile 1a (2 g, 5.93 mmol, synthesized by the known method "Patent WO2022192745"), methoxyamine hydrochloride (0.60 g, 7.12 mmol), sodium iodide (178 mg, 1.19 mmol) and triethylenediamine (1.33 g, 11.85 mmol) were dissolved in 35 mL of acetonitrile, nitrogen was replaced three times, palladium dichloride (105 mg, 0.59 mmol) was added, carbon monoxide was replaced three times, and the system was heated to 90 ° C in carbon monoxide (5 atm) for 8 hours. Cool to room temperature, concentrate, add water, extract with ethyl acetate (80 mL×3), combine the organic phases, wash with saturated sodium chloride solution (50 mL×1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title product 3-chloro-6-cyano-5-cyclopropyloxy-2-fluorobenzamide 1b (0.90 g), yield: 59.6%. MS m / z (ESI): 255 [M+1]

[0210] Step 2

[0211] 4-Chloro-6-cyclopropyloxy-3-fluoro-2-(4H-1,2,4-triazol-3-yl)benzonitrile

[0212] 3-Chloro-6-cyano-5-cyclopropyloxy-2-fluorobenzamide 1b (0.5 g, 1.96 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (2.34 g, 19.64 mmol), nitrogen was replaced three times, and the system was heated to 120 ° C for 2 hours. Cool to room temperature, concentrate, the residue was dissolved in acetic acid (10 mL), hydrazine hydrate (139 mg, 2.36 mmol) was added dropwise, and the system was heated to 90 ° C for 2 hours. Concentrate, add ether to the residue, and stir the system at 0 ° C for 30 minutes. Filter, wash the filter residue with a small amount of ether, and spin dry with a pump to obtain the title product 4-chloro-6-cyclopropyloxy-3-fluoro-2-(4H-1,2,4-triazol-3-yl) benzonitrile 1c (0.30 g), yield: 54.8%.

[0213] MS m / z(ESI):280[M+1]

[0214] Step 3

[0215] tert-Butyl (7-(3-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0216] 4-Chloro-6-cyclopropyloxy-3-fluoro-2-(4H-1,2,4-triazol-3-yl)benzonitrile 1c (0.20 g, 0.72 mmol), (7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester 1d (0.28 g, 0.79 mmol, synthesized by the known method "Patent WO2022192745") and cesium carbonate (935 mg, 2.87 mmol) were dissolved in 10 mL of toluene, nitrogen was replaced three times, bis(dibenzylideneacetone)palladium (41 mg, 0.072 mmol) was added, and the system was heated to 80 ° C for 16 hours. The mixture was cooled to room temperature, concentrated, and water was added. The mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title product (tert-butyl (7-(3-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 1e (70 mg) in a yield of 17.7%.

[0217] MS m / z(ESI):553[M+1]

[0218] Step 4

[0219] 2-(4-(4-(Aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-4H-1,2,4-triazol-3-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0220] Tert-butyl (7-(3-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 1e (70 mg, 0.13 mmol) was dissolved in 5 mL of 1,4-dioxane, and 5 mL of 4M hydrochloric acid in dioxane was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using eluent system C. The residue was then separated by SFC chiral column to give 2-(4-(4-(aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-4H-1,2,4-triazol-3-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 1 (16 mg), yield: 27.9%.

[0221] MS m / z(ESI):453[M+1]

[0222] The synthesis of the following examples refers to Example 1.

[0223]

[0224]

[0225]

[0226] Example 9

[0227] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0228]

[0229] first step

[0230] 4-Bromo-1-cyclopropyl-1H-pyrazole

[0231] 4-Bromo-1-hydropyrazole 1 (3 g, 20.41 mmol), cyclopropylboronic acid 9b (7.01 g, 81.65 mmol), copper acetate (4.89 g, 24.49 mmol), 2,2'-bipyridine (3.51 g, 22.45 mmol), sodium carbonate (4.76 g, 44.91 mmol) and DME (45 mL) were added to a single-mouth bottle and reacted at 80°C for 24 hours. Ammonia water (25 mL) was added dropwise to the reaction solution, and EA was extracted three times, and the organic phases were combined. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4-bromo-1-cyclopropyl-1H-pyrazole 9c (1.3 g) with a yield of 34%.

[0232] 1 H NMR (400MHz, CDCl3) δ7.44(d,2H),3.57(dq,1H),1.14-1.05(m,2H),1.05-0.94(m,2H).

[0233] Step 2

[0234] 4-Bromo-1-cyclopropyl-5-boronic acid-1H-pyrazole

[0235] 4-Bromo-1-cyclopropyl-1H-pyrazole 9c (2.10 g, 11.23 mmol) was added to a three-necked flask and dissolved in THF (4.85 mL). The mixture was cooled to -65°C, and n-butyl lithium solution (2.5 M, 6.76 mL) was added dropwise. The mixture was reacted at -65°C for 1 hour. Triisopropyl borate (6.33 g, 33.68 mmol) was added dropwise to the reaction solution, and the mixture was heated to 10°C and reacted for 2 hours. Saturated ammonium chloride solution (5 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with EA three times. The organic phases were combined. The residue was purified by silica gel column chromatography with eluent system A to obtain 4-Bromo-1-cyclopropyl-5-boronic acid-1H-pyrazole 9d (1 g) with a yield of 38.6%.

[0236] MS m / z(ESI):231[M+1]

[0237] Step 3

[0238] 4-Chloro-6-cyclopropyloxy-2-(1-cyclopropyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile

[0239] 4-Bromo-1-cyclopropyl-5-boronic acid-1H-pyrazole 9d (0.5 g, 2.17 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-iodobenzonitrile (220 mg, 0.65 mmol), K3PO4 (1.84 g, 4.33 mmol), Pd(dtbpf)Cl2 (140 mg, 0.22 mmol), H2O (2.5 mL) and 1'4-dioxane (10 mL) were added to a single-mouth bottle and reacted at 85°C in a microwave for 45 minutes under nitrogen protection. The system was concentrated to dryness and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4-chloro-6-cyclopropyloxy-2-(1-cyclopropyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile 9e (230 mg) with a yield of 33.0%.

[0240] MS m / z(ESI):318[M+1]

[0241] Step 4

[0242] 2-(4-Bromo-1-cyclopropyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0243] 4-Chloro-6-cyclopropyloxy-2-(1-cyclopropyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile 9e (230 mg, 0.72 mmol) and N-bromosuccinimide (248 mg, 1.40 mmol) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 2-(4-bromo-1-cyclopropyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 9f (161 mg) in a yield of 56.1%.

[0244] MS m / z(ESI):396[M+1]

[0245] Referring to the synthesis method of the fourth to fifth steps of Example 1, 2-(4-bromo-1-cyclopropyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 9f (80 mg, 0.29 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 9 (7 mg) with a yield of 5.0%.

[0246] MS m / z(ESI):491[M+1]

[0247] 1H NMR (400MHz, DMSO) δ12.52(s,1H),8.31(s,1H),8.24(s,1H),8.16(d,1H),8.03(d,1H),7.76(d,1H),7.6 7(dd,1H),4.20(dq,1H),3.88(s,2H),3.57-3.54(m,1H),1.10-1.00(m,2H),0.92(dp,4H),0.82(q,2H).

[0248] Embodiment 17

[0249] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0250]

[0251] first step

[0252] 2-Chloro-1-ethyl-1H-pyrrole-3-carbaldehyde

[0253] 1-Ethyl-1H-pyrrole-3-carboxaldehyde 17a (5 g, 40.65 mmol) was dispersed in 50 mL of acetonitrile, and N-chlorosuccinimide (6.65 g, 50 mmol) was added, and the mixture was stirred at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 2-chloro-1-ethyl-1H-pyrrole-3-carboxaldehyde 17b (5.1 g) in a yield of 79.4%.

[0254] MS m / z(ESI):158[M+1]

[0255] Step 2

[0256] 6-Ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole

[0257] 2-Chloro-1-ethyl-1H-pyrrole-3-carboxaldehyde 17b (5.10 g, 32.48 mmol) was dispersed in 30 mL of ethanol, methylhydrazine (1.84 g, 40 mmol) was added, and the mixture was stirred at 60°C for 12 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 17c (3.10 g) in a yield of 64.0%.

[0258] MS m / z(ESI):150[M+1]

[0259] Step 3

[0260] 5-Chloro-6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole

[0261] 6-Ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 17c (3.10 g, 20.81 mmol) was dissolved in 30 mL of acetonitrile, and N-chlorosuccinimide (3.32 g, 25 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 5-chloro-6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 17d (2.15 g). The yield was 56.4%. MS m / z (ESI): 184 [M+1]

[0262] Step 4

[0263] 5-Chloro-6-ethyl-4-iodo-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole

[0264] 5-Chloro-6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 17d (2 g, 10.87 mmol) was dissolved in 20 mL of acetonitrile, and N-iodosuccinimide (2.70 g, 12 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product 5-chloro-6-ethyl-4-iodo-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 17e (1.7 g) in a yield of 50.3%.

[0265] MS m / z(ESI):310[M+1]

[0266] Referring to the synthesis method of the third step of Example 1, 5-chloro-6-ethyl-4-iodo-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 17e (1 g, 3.23 mmol) and tert-butyl ((7-(6-ethyl-2-methyl-5-chloro-2,6-dihydropyrrolo[2,3-c]pyrazole-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 17g (510 mg) was obtained with a yield of 34.5%.

[0267] MS m / z(ESI):457[M+1]

[0268] Step 6

[0269] tert-Butyl ((7-(6-ethyl-2-methyl-5-(boronic acid pinacol ester)-2,6-dihydropyrrolo[2,3-c]pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0270] Dissolve 17 g (510 mg, 1.12 mmol) of tert-butyl ((7-(6-ethyl-2-methyl-5-chloro-2,6-dihydropyrrolo[2,3-c]pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate in 10 mL of 1,4-dioxane, add pinacol diboron (381 mg, 1.5 mmol), potassium acetate (294 mg, 3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol). Stir the reaction at 100°C for 2 hours under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product, tert-butyl ((7-(6-ethyl-2-methyl-5-(boronic acid pinacol ester)-2,6-dihydropyrrolo[2,3-c]pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 17h (410 mg) in a yield of 66.9%.

[0271] MS m / z(ESI):549[M+1]

[0272] Referring to the synthesis method of the third step to the fourth step of Example 1, the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester 17h (410 mg, 0.75 mmol) and 2-bromo-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 17i (289 mg, 1 mmol) were obtained, with a yield of 13.1%.

[0273] MS m / z(ESI):532[M+1]

[0274] Embodiment 18

[0275] 2-[4-[4-(Aminomethyl)-1-oxo-2H-phthalazin-6-yl]-2-methylpyrazol-3-yl]-4-(o-tolyl)benzonitrile

[0276]

[0277] first step

[0278] 2-Bromo-4-(o-tolyl)benzonitrile

[0279] Compound 2-bromo-4-iodo-benzonitrile 18a (2 g, 6.50 mmol) and o-tolylboronic acid 18b (971 mg, 7.14 mmol) were dissolved in DMF (30 mL) and Pd(dtbpf)Cl was added. 2· CH2Cl2 (527 mg, 0.65 mmol) and K3PO4 (4.14 g, 19.49 mmol) were added, and the system was stirred at 80°C for 16 hr. Water (30 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give 2-bromo-4-(o-tolyl)benzonitrile 18c (876 mg) in a yield of 49.6%. MS m / z (ESI): 272 [M+1]

[0280] Step 2

[0281] 2'-Methyl-3-(1-methyl-1H-pyrazol-5-yl)-[1,1'-biphenyl]-4-carbonitrile

[0282] Compound 2-bromo-4-(o-tolyl)benzonitrile 18c (500 mg, 1.84 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole 18d (573 mg, 2.76 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL), potassium acetate (541 mg, 5.51 mmol) and 1,1'-di-tert-butylphosphinoferrocenepalladium dichloride (119 mg, 0.18 mmol) were added, and the system was stirred at 100°C for 16 hr. The reaction solution was cooled to 25°C and concentrated under reduced pressure. Water (20 mL) was added to the residue, extracted with ethyl acetate (3×30 mL), the organic phases were combined, washed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give 2-(2-methylpyrazol-3-yl)-4-(o-tolyl)benzonitrile 18e (431 mg) in a yield of 85.9%.

[0283] MS m / z(ESI):274[M+1]

[0284] Step 3

[0285] 2-(4-iodo-2-methylpyrazol-3-yl)-4-(o-tolyl)benzonitrile

[0286] Compound 2-(2-methylpyrazol-3-yl)-4-(o-tolyl)benzonitrile 18e (330 mg, 1.21 mmol) was dissolved in acetic acid (7 mL), N-iodosuccinimide (543 mg, 2.41 mmol) was added, and the system was stirred at 80°C for 2 hours. The reaction solution was cooled to 25°C, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain 2-(4-iodo-2-methylpyrazol-3-yl)-4-(o-tolyl)benzonitrile 18f (400 mg) with a yield of 82.8%.

[0287] MS m / z(ESI):400[M+1]

[0288] Step 4

[0289] tert-Butyl N-[[7-[5-[2-cyano-5-(o-tolyl)phenyl]-1-methyl-pyrazol-4-yl]-4-oxo-3H-phthalazin-1-yl]methyl]carbamate

[0290] The compound 2-(4-iodo-2-methylpyrazol-3-yl)-4-(o-tolyl)benzonitrile 18f (100 mg, 0.25 mmol) and [4-[(tert-butoxycarbonylamino)methyl]-1-oxo-2H-phthalic acid-6-yl]boronic acid 18g (synthesized by reference "J. Med. Chem. 2022, 65, 1749-1766", 96 mg, 0.30 mmol) were dissolved in 1,4-dioxane (5 mL), and cesium fluoride (228 mg, 1.50 mmol), potassium phosphate (160 mg, 0.75 mmol), and cataCXium-A-Pd-G3 (36 mg, 0.05 mmol) were added, and the system was stirred and reacted at 85 ° C. under microwave conditions for 1 hr. The reaction solution was cooled to 25°C and concentrated under reduced pressure. Water (20 mL) was added to the concentrated residue, and the mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give tert-butyl N-[[7-[5-[2-cyano-5-(o-tolyl)phenyl]-1-methyl-pyrazol-4-yl]-4-oxo-3H-phthalazin-1-yl]methyl]carbamate 18h (117 mg), yield: 85.3%.

[0291] MS m / z(ESI):548[M+1]

[0292] Step 5

[0293] 2-[4-[4-(Aminomethyl)-1-oxo-2H-phthalazin-6-yl]-2-methylpyrazol-3-yl]-4-(o-tolyl)benzonitrile

[0294] Compound N-[[7-[5-[2-cyano-5-(o-tolyl)phenyl]-1-methyl-pyrazol-4-yl]-4-oxo-3H-phthalazin-1-yl]methyl]carbamic acid tert-butyl ester 18h (175.1 mg, 320.33 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (37 mg, 0.32 mmol) was added, and the system was stirred at 25°C for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using eluent system D to give 2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]-2-methylpyrazol-3-yl]-4-(o-tolyl)benzonitrile 18 (30 mg), yield: 21.0%.

[0295] MS m / z(ESI):447[M+1]

[0296] 1H NMR(400MHz,DMSO)δ12.86(s,1H),8.29(s,2H),8.13(dd,3H),7.79-7.71(m, 3H),7.49(dd,1H),7.37-7.30(m,4H),4.26(d,2H),3.80(s,3H),2.20(s,3H).

[0297] Synthesis of the following examples Reference Example 18

[0298]

[0299]

[0300]

[0301]

[0302] Embodiment 40

[0303] 1'-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-7-cyclopropyloxyspiro[indoline-3,3'-pyrrole]-2-one

[0304]

[0305] first step

[0306] tert-Butyl 3-((2,6-dibromophenyl)carbamoyl)pyrrole-1-carboxylate

[0307] 1-(tert-Butyloxycarbonyl)pyrrole-3-carboxylic acid 40a (3 g, 13.95 mmol) and 2,6-dibromoaniline 40b (3.48 g, 14 mmol) were dispersed in 30 mL of dichloromethane, triethylamine (2.02 g, 20 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (7.60 g, 20 mmol) were added, and the mixture was stirred at 40°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product tert-butyl 3-((2,6-dibromophenyl)carbamoyl)pyrrole-1-carboxylate 40c (4.48 g) in a yield of 72.1%. MS m / z (ESI): 447 [M+1]

[0308] Step 2

[0309] tert-Butyl 7-bromo-2-oxospiro[indoline-3,3'-pyrrole]-1'-carboxylate

[0310] Tert-butyl 3-((2,6-dibromophenyl)carbamoyl)pyrrole-1-carboxylate 40c (2 g, 4.48 mmol) was dispersed in 30 mL of 1,4-dioxane, and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (174 mg, 0.22 mmol) and sodium tert-butoxide (576 mg, 6 mmol) were added. The mixture was stirred at 100°C for 2 hours under nitrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product, tert-butyl 7-bromo-2-oxospiro[indoline-3,3'-pyrrole]-1'-carboxylate 40d (573 mg), with a yield of 35.1%.

[0311] MS m / z(ESI):367[M+1]

[0312] Step 3

[0313] tert-Butyl 7-cyclopropyloxy-2-oxospiro[indoline-3,3'-pyrrole]-1'-carboxylate

[0314] Disperse tert-butyl 7-bromo-2-oxospiro[indoline-3,3'-pyrrole]-1'-carboxylate 40d (573 mg, 1.57 mmol) and cyclopropanol (116 mg, 2 mmol) in 20 mL of tetrahydrofuran, add tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol) and sodium tert-butoxide (384 mg, 4 mmol). Stir and react at 70°C for 16 hours under nitrogen atmosphere. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title product tert-butyl 7-cyclopropyloxy-2-oxospiro[indoline-3,3'-pyrrole]-1'-carboxylate 40e (222 mg, yellow solid), yield: 41.1%.

[0315] MS m / z(ESI):345[M+1]

[0316] Step 4

[0317] 7-Cyclopropyloxyspiro[indoline-3,3'-pyrrole]-2-one

[0318] Referring to the synthesis method of the eighth step of Example 3, the title product 7-cyclopropoxyspiro[indoline-3,3'-pyrrole]-1'-carboxylic acid tert-butyl ester 40e (222 mg, 0.65 mmol) was obtained, with a yield of 100%, 7-cyclopropoxyspiro[indoline-3,3'-pyrrole]-2-one 40f (158 mg).

[0319] MS m / z(ESI):245[M+1]

[0320] Step 5: Tert-butyl ((7-(7-cyclopropyloxy-2-oxospiro[indoline-3,3'-pyrrole]-1'-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0321] 7-Cyclopropyloxyspiro[indoline-3,3'-pyrrole]-2-one 40f (158 mg, 0.64 mmol) and tert-butyl ((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 1d (353 mg, 1 mmol, synthesized by the known method "Patent WO2021050915 A1") were dispersed in 5 mL of tetrahydrofuran, and tetrakis(triphenylphosphine)palladium (34 mg, 0.03 mmol) and sodium tert-butoxide (192 mg, 2 mmol) were added. The reaction was stirred at 70 ° C for 16 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give 40 g (58 mg) of the title product, tert-butyl ((7-(7-cyclopropyloxy-2-oxospiro[indoline-3,3'-pyrrole]-1'-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate, in a yield of 17.8%.

[0322] MS m / z(ESI):518[M+1]

[0323] Referring to the synthesis method of the fourth step of Example 1, 40 g (58 mg, 0.11 mmol) of tert-butyl ((7-(7-cyclopropyloxy-2-oxospiro[indoline-3,3'-pyrrole]-1'-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate was used to obtain the title product 1'-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-7-cyclopropyloxyspiro[indoline-3,3'-pyrrole]-2-one 40 (25 mg), with a yield of 53.4%.

[0324] MS m / z(ESI):418[M+1]

[0325] Synthesis of the following examples Reference Example 40

[0326]

[0327]

[0328] Embodiment 47

[0329] 2-(4-(4-(2-aminocyclopropyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyl-3-fluorobenzonitrile

[0330]

[0331] first step

[0332] tert-Butyl (2-hydroxymethyl)cyclopropylcarbamate

[0333] 2-(tert-Butyloxycarbonyl)aminocyclopropane-1-carboxylic acid methyl ester 47a (2.28 g, 9.70 mmol) was dispersed in 25 mL of ether, cooled to 0°C, and lithium aluminum tetrahydride (0.55 g, 14.55 mmol) was added. The mixture was naturally heated to room temperature and stirred for 1 hour. 5 mL of saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product tert-butyl (2-hydroxymethyl)cyclopropylcarbamate 47b (1.38 g) in a yield of 76.0%.

[0334] MS m / z(ESI):188[M+1]

[0335] Step 2

[0336] tert-Butyl (2-Formylcyclopropyl)carbamate

[0337] Tert-butyl (2-hydroxymethyl)cyclopropylcarbamate 47b (1.38 g, 7.37 mmol) was dispersed in 25 mL of chloroform, and manganese dioxide (1.28 g, 14.74 mmol) was added, and the mixture was stirred at 60°C for 12 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title product, tert-butyl (2-formylcyclopropyl)carbamate 47c (1.08 g), with a yield of 79.2%.

[0338] MS m / z(ESI):186[M+1]

[0339] Step 3

[0340] 4-Bromo-2-(hydroxy(2-((tert-butyloxycarbonyl)amino)cyclopropyl)methyl)benzoic acid

[0341] 2,4-Dibromobenzoic acid 47d (1.63 g, 5.84 mmol) was dissolved in 25 mL of dry tetrahydrofuran, cooled to -78°C, 2M n-butyl lithium tetrahydrofuran solution (8.8 mL, 17.6 mmol) was added, and the mixture was stirred at -78°C for 0.5 hours. Then tert-butyl (2-formylcyclopropyl)carbamate (1.08 g, 5.84 mmol) was added, and the mixture was stirred at -78°C for 0.5 hours, and then the mixture was naturally heated to room temperature and stirred for 12 hours. 5 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 4-bromo-2-(hydroxy(2-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)benzoic acid 47e (1.04 g) in a yield of 46.1%.

[0342] MS m / z(ESI):386[M+1]

[0343] Step 4

[0344] 4-Bromo-2-(2-((tert-butyloxycarbonyl)amino)cyclopropane-1-carbonyl)benzoic acid

[0345] 4-Bromo-2-(hydroxy(2-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)benzoic acid 47e (1.04 g, 2.69 mmol) was dissolved in 20 mL of dichloromethane, and Dess-Martin periodinane (2.28 g, 5.38 mmol) was added, and the mixture was stirred at 20°C for 12 hours. 5 mL of saturated sodium sulfite solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 4-bromo-2-(2-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)benzoic acid 47f (0.58 g) in a yield of 56.5%.

[0346] MS m / z(ESI):384[M+1]

[0347] Step 5

[0348] tert-Butyl (2-(7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate

[0349] 4-Bromo-2-(2-((tert-butyloxycarbonyl)amino)cyclopropane-1-carbonyl)benzoic acid 47f (0.58 g, 1.52 mmol) was dissolved in 20 mL of ethanol, 80% hydrazine hydrate (313 μL, 7.60 mmol) was added, and the mixture was stirred at 78°C for 12 hours. After cooling, the reaction solution was filtered and dried to obtain the title product (tert-butyl 2-(7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate 47 g (0.42 g), with a yield of 72.0%.

[0350] MS m / z(ESI):380[M+1]

[0351] Step 6

[0352] tert-Butyl (2-(4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate

[0353] 47 g (0.42 g, 1.09 mmol) of tert-butyl (2-(7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate, bipyralidin (416 mg, 1.64 mmol), {[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride} dichloromethane complex (89 mg, 0.11 mmol), and potassium acetate (321 mg, 3.27 mmol) were dissolved in 20 mL of dioxane, replaced with nitrogen atmosphere, and stirred at 100°C for 2 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product, tert-butyl (2-(4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate 47h (258 mg), yield: 55.3%.

[0354] MS m / z(ESI):428[M+1]

[0355] Step 7

[0356] tert-Butyl (2-(7-(5-(3-chloro-6-cyano-5-cyclopropyl-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate

[0357] Tert-butyl (2-(4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate 47h (258 mg, 0.60 mmol), 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyl-3-fluorobenzonitrile 47i (667 mg, 1.80 mmol, synthesized by the known method "Patent WO22022192745"), SPhos-Pd-G2 (86.4 mg, 0.12 mmol) and cesium carbonate (586 mg, 1.80 mmol) were dissolved in a mixed solvent of 5 mL of dioxane and 1 mL of water, replaced with a nitrogen atmosphere, and stirred at 90°C for 3 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to give the title product, tert-butyl (2-(7-(5-(3-chloro-6-cyano-5-cyclopropyl-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate 47j (177 mg) in a yield of 50.0%.

[0358] MS m / z(ESI):591[M+1]

[0359] Step 8

[0360] 2-(4-(4-(2-aminocyclopropyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyl-3-fluorobenzonitrile

[0361] Tert-butyl (2-(7-(5-(3-chloro-6-cyano-5-cyclopropyl-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)cyclopropyl)carbamate 47j (177 mg, 0.30 mmol) was dissolved in 10 mL of acetonitrile and cerium ammonium nitrate (159 mg, 0.60 mmol) was added. 5 mL of saturated sodium sulfite solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 2-(4-(4-(2-aminocyclopropyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyl-3-fluorobenzonitrile 47 (41 mg, white solid) in a yield of 28.0%.

[0362] MS m / z(ESI):491[M+1]

[0363] Embodiment 55

[0364] 2-(4-(4-aminomethyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(tetrahydro-2H-pyran-2-yl)benzonitrile

[0365]

[0366] first step

[0367] 4-Chloro-2-(3,4-dihydro-2H-pyran-2-yl)-5-fluorobenzonitrile

[0368] 2-Bromo-4-chloro-5-fluorobenzonitrile 55a (2.33 g, 10.00 mmol, synthesized by the known method "Patent US2017291892"), palladium acetate (166 mg, 1.00 mmol), and triethylamine (2.02 g, 20.00 mmol) were dissolved in 50 mL of N,N-dimethylformamide, and heated and stirred at 140°C for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4-chloro-2-(3,4-dihydro-2H-pyran-2-yl)-5-fluorobenzonitrile 55b (2.12 g), with a yield of 89.2%.

[0369] MS m / z(ESI):238[M+1]

[0370] Step 2

[0371] 4-Chloro-2-(tetrahydro-2H-pyran-2-yl)-5-fluorobenzonitrile

[0372] 4-Chloro-2-(3,4-dihydro-2H-pyran-2-yl)-5-fluorobenzonitrile 55b (2.12 g, 8.92 mmol) and 10% palladium on carbon (212 mg) were dispersed in 50 mL of methanol, replaced with a hydrogen atmosphere, and stirred at room temperature for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-5-fluorobenzonitrile 55c (2.09 g) in a yield of 97.8%.

[0373] MS m / z(ESI):240[M+1]

[0374] Step 3

[0375] 2-Bromo-4-chloro-3-fluoro-6-(tetrahydro-2H-pyran-2-yl)benzonitrile

[0376] 4-Chloro-2-(tetrahydro-2H-pyran-2-yl)-5-fluorobenzonitrile 55c (2.09 g, 8.72 mmol), N-bromosuccinimide (3.10 g, 17.44 mmol), palladium acetate (144 mg, 0.87 mmol) and p-toluenesulfonic acid (751 mg, 4.36 mmol) were dispersed in 50 mL of 1,2-dichloroethane and heated at 75°C with stirring for 12 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (20 mL×1), washed with saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product, 2-bromo-4-chloro-3-fluoro-6-(tetrahydro-2H-pyran-2-yl)benzonitrile 55d (1.21 g). Yield: 43.6%.

[0377] MS m / z(ESI):319[M+1]

[0378] Step 4

[0379] 4-Chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(tetrahydro-2H-pyran-2-yl)benzonitrile

[0380] 2-Bromo-4-chloro-3-fluoro-6-(tetrahydro-2H-pyran-2-yl)benzonitrile 55d (1.21 g, 3.80 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 55e (3.65 g, 11.40 mmol), sodium carbonate (1.61 g, 15.20 mmol), and Pd(dtbpf)Cl2 (245 mg, 0.38 mmol) were dispersed in a mixed solvent of 25 mL of dioxane and 5 mL of water, and the reaction was heated and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to give the title product 4-chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(tetrahydro-2H-pyran-2-yl)benzonitrile 55f (551 mg) in a yield of 45.2%.

[0381] MS m / z(ESI):320[M+1]

[0382] Step 5

[0383] 4-Chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(tetrahydro-2H-pyran-2-yl)benzonitrile

[0384] 4-Chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(tetrahydro-2H-pyran-2-yl)benzonitrile 55f (551 mg, 1.72 mmol) was dissolved in 20 mL of acetonitrile, N-iodosuccinimide (2.32 g, 10.32 mmol) was added, and the mixture was heated and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(tetrahydro-2H-pyran-2-yl)benzonitrile 55 g (481 mg) in a yield of 62.8%.

[0385] MS m / z(ESI):446[M+1]

[0386] Step 6: Tert-butyl ((7-(5-(3-chloro-6-cyano-2-fluoro-5-(tetrahydro-2H-pyran-2-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrazine-1-yl)methyl)carbamate

[0387] 55 g (481 mg, 1.08 mmol) of 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(tetrahydro-2H-pyran-2-yl)benzonitrile, sodium carbonate (286 mg, 2.70 mmol), and Pd(dppf)Cl2 (80 mg, 0.11 mmol) were dissolved in a mixed solvent of 5 mL of 1,4-dioxane and 1 mL of water, and heated at 80°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product, tert-butyl ((7-(5-(3-chloro-6-cyano-2-fluoro-5-(tetrahydro-2H-pyran-2-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrazin-1-yl)methyl)carbamate 55h (260 mg) in a yield of 40.6%.

[0388] MS m / z(ESI):593[M+1]

[0389] Step 7

[0390] 2-(4-(4-aminomethyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(tetrahydro-2H-pyran-2-yl)benzonitrile

[0391] Tert-butyl ((7-(5-(3-chloro-6-cyano-2-fluoro-5-(tetrahydro-2H-pyran-2-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrazin-1-yl)methyl)carbamate 55h (260 mg, 0.44 mmol) was dissolved in 5 mL of 1,4-dioxane, and 5 mL of 4M hydrochloric acid in dioxane was added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 2-(4-(4-aminomethyl-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(tetrahydro-2H-pyran-2-yl)benzonitrile 55 (152 mg) in a yield of 70.1%.

[0392] MS m / z(ESI):493[M+1]

[0393] The synthesis of the following examples refers to Example 55.

[0394]

[0395]

[0396]

[0397]

[0398] Embodiment 63

[0399] 2-(4-(4-(aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-((dimethyl(carbonyl)-λ 6 -sulfanediyl)amino)-3-fluorobenzonitrile

[0400]

[0401] first step

[0402] 2-Bromo-5-chloro-4-fluorophenol

[0403] 3-Chloro-4-fluorophenol 63a (10 g, 68.24 mmol) was dissolved in 50 ml of chloroform, and then bromine water (10.90 g, 68.24 mmol) was added and stirred at 20°C for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain 2-bromo-5-chloro-4-fluorophenol 63b (12 g) with a yield of 78.0%.

[0404] MS m / z(ESI):225[M+1]

[0405] Step 2

[0406] 1-Bromo-4-chloro-5-fluoro-2-methoxybenzene

[0407] 2-Bromo-5-chloro-4-fluorophenol 63b (12 g, 53.23 mmol) and cesium carbonate (17 g, 52.18 mmol) were dissolved in 100 mL of N,N-dimethylformamide, and then iodomethane (7.70 g, 54.25 mmol) was added and stirred at 20°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give 1-bromo-4-chloro-5-fluoro-2-methoxybenzene 63c (10 g) in a yield of 78.4%.

[0408] MS m / z(ESI):239[M+1]

[0409] Step 3

[0410] 4-Chloro-5-fluoro-2-methoxybenzonitrile

[0411] 1-Bromo-4-chloro-5-fluoro-2-methoxybenzene 63c (10 g, 41.76 mmol), zinc cyanide (2.5 g, 21.29 mmol), tetrakistriphenylphosphine palladium (4.8 g, 4.15 mmol) were dissolved in 100 mL of N,N-dimethylformamide and stirred at 100°C for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-5-fluoro-2-methoxybenzonitrile 63d (5 g) in a yield of 64.5%.

[0412] MS m / z(ESI):186[M+1]

[0413] Step 4

[0414] 4-Chloro-3-fluoro-2-iodo-6-methoxybenzonitrile

[0415] 4-Chloro-5-fluoro-2-methoxybenzonitrile 63d (5 g, 26.94 mmol) was dissolved in 50 mL of tetrahydrofuran solvent and then condensed to -60°C. A tetrahydrofuran solution of LDA (13.5 ml, 27 mmol, 2 M) was added at -60°C and reacted at this temperature for 2 hours, iodine was added, and then stirred at 20°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 4-chloro-3-fluoro-2-iodo-6-methoxybenzonitrile 63e (5.5 g) in a yield of 65.5%.

[0416] MS m / z(ESI):312[M+1]

[0417] Step 5

[0418] 4-Chloro-3-fluoro-6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile

[0419] 4-Chloro-3-fluoro-2-iodo-6-methoxybenzonitrile 63e (5.50 g, 17.66 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.74 g, 18.0 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (1.1 g, 1.70 mmol) and potassium carbonate (9.76 g, 70.62 mmol) were dissolved in a mixed solvent of 50 mL of dioxane and 10 mL of water and stirred at 80°C for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to give 4-chloro-3-fluoro-6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile 63f (1.5 g) in a yield of 32.0%.

[0420] MS m / z(ESI):266[M+1]

[0421] Step 6

[0422] 4-Chloro-3-fluoro-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile

[0423] 4-Chloro-3-fluoro-6-methoxy-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile 63f (1.5 g, 5.64 mmol) was dissolved in 50 ml of boron tribromide in dichloromethane (1 M) and stirred at 50°C for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain 4-chloro-3-fluoro-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile 63g (900 mg) in a yield of 63.3%.

[0424] MS m / z(ESI):252[M+1]

[0425] Step 7

[0426] 5-Chloro-2-cyano-4-fluoro-3-(1-methyl-1H-pyrazol-5-yl)phenyl trifluoromethanesulfonic acid

[0427] 4-Chloro-3-fluoro-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile 63g (900mg, 3.58mmol), triethylamine (44mg, 0.12mmol), trifluoromethanesulfonic anhydride (7.3mg, 4.3mmol) were dissolved in 10mL dichloromethane solvent and stirred at 20°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 5-chloro-2-cyano-4-fluoro-3-(1-methyl-1H-pyrazol-5-yl)phenyltrifluoromethanesulfonic acid 63h (1g) with a yield of 72.9%.

[0428] MS m / z(ESI):384[M+1]

[0429] Step 8

[0430] 4-Chloro-6-((dimethyl(carbonyl)-16-sulfaneylidene)amino)-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile

[0431] 5-Chloro-2-cyano-4-fluoro-3-(1-methyl-1H-pyrazol-5-yl)phenyltrifluoromethanesulfonic acid 63h (300 mg, 0.78 mmol), dimethylsulfinyl imide (146 mg, 1.567 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (90 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (72 mg, 0.079 mmol) and cesium carbonate (510 mg, 1.56 mmol) were dissolved in 10 mL of dioxane solvent and stirred at 100 °C for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent System A to give 4-chloro-6-((dimethyl(carbonyl)-16-sulfaneylidene)amino)-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile 63i (150 mg) in a yield of 58.7%.

[0432] MS m / z(ESI):327[M+1]

[0433] Step 9

[0434] 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-((dimethyl(carbonyl)-λ 6 -sulfanediyl)amino)-3-fluorobenzonitrile

[0435] 4-Chloro-6-((dimethyl(carbonyl)-16-sulfanylidene)amino)-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile 63i (150 mg, 0.46 mmol) and N-bromosuccinimide (90 mg, 0.51 mmol) were dissolved in 10 mL of acetonitrile and stirred at 20°C for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-((dimethyl(carbonyl)-λ 6 -sulfanediyl)amino)-3-fluorobenzonitrile 63j (90 mg), yield: 48.3%.

[0436] MS m / z(ESI):405[M+1]

[0437] Step 10

[0438] ((7-(5-(3-chloro-6-cyano-5-((dimethyl(carbonyl)-λ 6 tert-Butyl (-sulfanediyl)amino)-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0439] 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-((dimethyl(carbonyl)-λ 6 -sulfane ylidene)amino)-3-fluorobenzonitrile 63j (90 mg, 0.22 mmol), ((4-carbonyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (120 mg, 0.30 mmol, synthesized by the known method "Patent WO22022192745"), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (15 mg, 0.023 mmol) and sodium carbonate (95 mg, 0.90 mmol) were dissolved in a mixed solvent of 5 mL of dioxane and 1 mL of water, and the reaction was stirred at 80°C for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain ((7-(5-(3-chloro-6-cyano-5-((dimethyl(carbonyl)-λ 6 (4-(2 ...

[0440] MS m / z(ESI):601[M+1]

[0441] Step 11

[0442] 2-(4-(4-(aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-((dimethyl(carbonyl)-λ 6 -sulfanediyl)amino)-3-fluorobenzonitrile

[0443] ((7-(5-(3-chloro-6-cyano-5-((dimethyl(carbonyl)-λ 6 tert-butyl)-1-(4-(4-(aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate 63k (45 mg, 0.075 mmol) and 0.2 mL of trifluoroacetic acid were dissolved in 5 mL of dichloromethane and stirred at 20°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain 2-(4-(4-(aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-((dimethyl(carbonyl)-λ 6 -sulfanediyl)amino)-3-fluorobenzonitrile (9 mg), yield: 24.0%.

[0444] MS m / z(ESI):500[M+1]

[0445] 1 H NMR (400MHz, MeOD) δ8.43(s,1H),8.29(d,1H),8.08(s,1H),7.72(s,1H),7.68-7.58(m,1H),4.17(s,2H),3.83(s,3H),1.32(d,6H).

[0446] Embodiment 64

[0447] 2-(4-(4-(Aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(pyrrolidin-1-yl)benzonitrile

[0448]

[0449] first step

[0450] 4-Chloro-5-fluoro-2-(pyrrolidin-1-yl)benzonitrile

[0451] 4-Chloro-2,5-difluorobenzonitrile 64a (5 g, 28.81 mmol) and pyrrolidine (2.2 g, 30.93 mmol) were dissolved in 50 mL of acetonitrile and stirred at 80°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-5-fluoro-2-(pyrrolidin-1-yl)benzonitrile 64b (4.6 g) in a yield of 71.0%.

[0452] MS m / z(ESI):225[M+1]

[0453] With reference to the fourth to fifth steps and the ninth to eleventh steps of Example 63, 4-chloro-5-fluoro-2-(pyrrolidin-1-yl)benzonitrile 64b (4.6 g, 20.48 mmol) was used to obtain 2-(4-(4-(aminomethyl)-1-carbonyl-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(pyrrolidin-1-yl)benzonitrile 64 (15 mg). Yield: 0.2%.

[0454] MS m / z(ESI):478[M+1]

[0455] 1 H NMR (400MHz, MeOD) δ8.48(d,1H),8.17(s,1H),8.08(d,1H),7.61(d,1H),7.12(d,1H),4.26(s,2H),3.83(s,3H),3.69(s,4H),2.13-1.89(m,4H).

[0456] Embodiment 73

[0457] 4-(Aminomethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one

[0458]

[0459] Referring to the synthesis method of the first to fifth steps of Example 20, 5-bromobenzo[c][1,2,5]oxadiazole 73a (250 mg, 1.26 mmol) was used to obtain the title product 4-(aminomethyl)-6-(5-(benzo[c][1,2,5]oxadiazole-4-yl)-1-methyl-1H-pyrazol-4-yl)phthalazine-1(2H)-one 73 (23 mg) with a yield of 4.8%.

[0460] MS m / z(ESI):373[M+1]

[0461] 1H NMR (400MHz, DMSO) δ12.48(s,1H),8.32(dd,1H),8.28(s,1H),8.10(d,1H),7.91-7.79(m,3H),7.69(dd,1H),3.86(s,3H),3.77(s,2H).

[0462] Embodiment 76

[0463] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-(1H-pyrazol-1-yl)benzonitrile

[0464]

[0465] first step

[0466] 2-Bromo-4-(1H-pyrazol-1-yl)benzonitrile

[0467] 2-Bromo-4-iodobenzonitrile 76a (1.85 g, 6 mmol), 1H-pyrazole (247 mg, 1.26 mmol), (1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (416 mg, 2.40 mmol) and cuprous iodide (228 mg, 1.20 mmol) were dispersed in 20 mL DMF and stirred at 120°C for 16 h. After cooling to room temperature, the system was concentrated to dryness and the residue was purified by silica gel column chromatography with eluent system A to give the title product 2-bromo-4-(1H-pyrazol-1-yl)benzonitrile 76b (420 mg) in a yield of 28.2%.

[0468] MS m / z(ESI):249[M+1]

[0469] Step 2

[0470] 2-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-4-(1H-pyrazol-1-yl)benzonitrile

[0471] 4-Bromo-1-methyl-pyrazole (314.11 mg, 1.95 mmol), 2-bromo-4-(1H-pyrazol-1-yl)benzonitrile 76b (550 mg, 2.22 mmol), tricyclohexylphosphine fluoroborate (163 mg, 443.41 μmol) and palladium acetate (50 mg, 0.22 mmol) were dispersed in 20 mL DMF and reacted at 140°C for 2 h. After cooling to room temperature, the system was concentrated to dryness and the residue was purified by silica gel column chromatography with eluent system A to give the title product 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(1H-pyrazol-1-yl)benzonitrile 76c (53 mg) in a yield of 7.3%.

[0472] MS m / z(ESI):328[M+1]

[0473] Step 3: Tert-butyl ((7-(5-(2-cyano-5-(1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)yl)carbamate

[0474] 2-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-4-(1H-pyrazol-1-yl)benzonitrile 76c (33 mg, 0.10 mmol), tert-butyl N-[[4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-phthalazin-1-yl]methyl]carbamate (44 mg, 0.11 mmol), potassium phosphate (64 mg, 0.30 mmol) and cataCXium-A-Pd-G3 (10 mg, 0.01 mmol) were dispersed in a mixed solvent of 1 mL of water and 5 mL of dioxane and reacted at 80°C for 1 h. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography using eluent System A to give the title product, tert-butyl ((7-(5-(2-cyano-5-(1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)yl)carbamate 76d (20 mg) in a yield of 38.3%.

[0475] MS m / z(ESI):524[M+1]

[0476] Referring to the synthesis method of the fourth step of Example 1, the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-(1H-pyrazol-1-yl)benzonitrile 76 (2.6 mg) was obtained by using tert-butyl ((7-(5-(2-cyano-5-(1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl))carbamate 76d (63 mg, 0.12 mmol) with a yield of 5.1%.

[0477] MS m / z(ESI):423[M+1]

[0478] 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.78(d,1H),8.33-8.23(m,3H),8.19(d,1H),8.11 (d,1H),7.89(d,1H),7.74(d,1H),7.68(dd,1H),6.66(t,1H),3.79(s,3H),3.69(s,2H).

[0479] Embodiment 77

[0480] 3-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-5-cyclopropyl-2'-methyl-[1,1'-biphenyl]-4-carbonitrile

[0481]

[0482]

[0483] first step

[0484] 4-Bromo-2-chloro-6-cyclopropyloxybenzonitrile

[0485] Cyclopropyl alcohol (139 mg, 2.40 mmol) was dissolved in 20 mL of tetrahydrofuran, sodium cyanide (96 mg, 4 mmol) was added at 0°C, and the reaction was stirred at 0°C for 1 h. Then 4-bromo-2-chloro-6-fluorobenzonitrile 77a (469 mg, 2 mmol) was added, and the reaction was stirred at 60°C for 12 h. After cooling to room temperature, methanol (5 mL) and 0.5 M dilute hydrochloric acid (5 mL) were added in sequence to quench, the system was concentrated to dryness, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4-bromo-2-chloro-6-cyclopropyloxybenzonitrile 77b (330 mg), with a yield of 70.4%.

[0486] MS m / z(ESI):272[M+1]

[0487] Referring to the synthesis method of the first to fifth steps of Example 18, 4-bromo-2-chloro-6-cyclopropyloxybenzonitrile 77b (282 mg, 1.03 mmol) was used to obtain the title product 3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-5-cyclopropyl-2'-methyl-[1,1'-biphenyl]-4-carbonitrile 77 (12 mg) with a yield of 2.3%.

[0488] MS m / z(ESI):503[M+1]

[0489] 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.34(t,2H),8.26(s,1H),8.13(d,1H),7.78(d,1H),7.63(d,1H),7.49(dd, 1H),7.43-7.29(m,4H),7.26(d,1H),4.33(s,2H),4.25-4.15(m,1H),3.79(s,3H),2.24(s,3H),0.97-0.77(m,4H).

[0490] Embodiment 86

[0491] 3-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(4-azaspiro[2.4]heptane-4-yl)benzonitrile

[0492]

[0493] Referring to the synthesis method from the second step to the third step of Example 18, 2-bromo-4-chloro-3,6-difluorobenzonitrile 86a (1.56 g, 6.18 mmol, synthesized by the known method "Patent WO22022192745") was used to obtain the product 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (300 mg) with a yield of 12.8%.

[0494] MS m / z(ESI):380[M+1]

[0495] Step 3

[0496] 4-Chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(4-azaspiro[2.4]heptane-4-yl)benzonitrile

[0497] 4-Azaspiro[2.4]heptane hydrochloride (147 mg, 1.10 mmol), 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (190 mg, 0.50 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (224 μL, 1.50 mmol) were dissolved in 5 mL of acetonitrile and stirred at 80° C. for 16 h. After cooling to room temperature, the system was concentrated to dryness and the residue was purified by silica gel column chromatography with eluent system A to give the title product 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(4-azaspiro[2.4]heptane-4-yl)benzonitrile 86d (60 mg) in a yield of 26.2%.

[0498] MS m / z(ESI):457[M+1]

[0499] Referring to the synthesis method of the fourth to fifth steps of Example 18, 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(4-azaspiro[2.4]heptane-4-yl)benzonitrile 86d (60 mg, 0.13 mmol) was used to obtain the title product 3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(4-azaspiro[2.4]heptane-4-yl)benzonitrile 86 (9.5 mg) in a yield of 14.4%.

[0500] MS m / z(ESI):504[M+1]

[0501] 1 H NMR(400MHz,DMSO-d6)δ12.40(broad s,1H),8.27(d,J=2.7Hz,1H),8.8.18(d,1H),8.11(d,1H),7.74(d,1H),7.43(d,1H),4.29(qd, 1H),3.78(d,3H),3.75-3.69(m,2H),3.56-3.44(m,1H),2.08-1.79(m,4H),0.99-0.69(m,4H).

[0502] Embodiment 88

[0503] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3-(difluoromethylene)pyrrolidin-1-yl)-3-fluorobenzonitrile

[0504]

[0505] Referring to the synthesis method of the third to fifth steps of Example 86, 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (190 mg, 0.50 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3-(difluoromethylene)pyrrolidin-1-yl)-3-fluorobenzonitrile 88 (16 mg) in a yield of 5.9%.

[0506] MS m / z(ESI):526[M+1]

[0507] 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.36(s,2H),8.35(s,1H),8.16(d,1H),7.87(s,1H) ,7.52(d,1H),7.43(d,1H),4.35(d,4H),3.78(s,3H),3.74(t,J=7.6Hz,2H),2.71(s,2H).

[0508] Embodiment 90

[0509] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-(difluoropyrrolidin-1-yl)-3-fluorobenzonitrile

[0510]

[0511] Referring to the synthesis method of the third to fifth steps of Example 86, 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (190 mg, 0.50 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-(difluoropyrrolidin-1-yl)-3-fluorobenzonitrile 90 (14 mg) in a yield of 5.2%.

[0512] MS m / z(ESI):514[M+1]

[0513] 1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.67(s,2H),8.41(s,1H),8.16(d,1H),7.84(d ,1H),7.55(d,1H),7.42(d,1H),4.35(d,4H),3.78(s,3H),3.74(t,2H),2.71(s,2H).

[0514] Embodiment 95

[0515] 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(4-(difluoromethylene)piperidin-1-yl)-3-fluorobenzonitrile

[0516]

[0517] Referring to the synthesis method of the third to fifth steps of Example 86, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(4-(difluoromethylene)piperidin-1-yl)-3-fluorobenzonitrile 95 (3 mg) was obtained by using 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (0.30 g, 0.79 mmol) and 4-(difluoromethylene)piperidine (105 mg, 0.79 mmol, synthesized in reference "J. Org. Chem. 2022, 87, 16676-16690"), with a yield of 0.6%.

[0518] MS m / z(ESI):540[M+1]

[0519] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.23(s,1H),8.09(d,1H),7.75-7.51(m,4H),3.75(d,5H),3.11(dq,4H),2.22(s,4H).

[0520] Embodiment 98

[0521] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(4,4,4-trifluorobutoxy)benzonitrile

[0522]

[0523] first step

[0524] 4-Chloro-5-fluoro-2-(4,4,4-trifluorobutoxy)benzonitrile

[0525] Sodium hydride (645.36 mg, 16.13 mmol, 60% purity) was dispersed in tetrahydrofuran (10 mL), 4,4,4-trifluorobutane-1-ol (1.77 g, 13.83 mmol) was slowly added, and stirred at 25 ° C for 30 minutes. A solution of 4-chloro-2,5-difluorobenzonitrile 98a (2 g, 11.52 mmol) in tetrahydrofuran (20 mL) was slowly added, and the reaction was stirred at 60 ° C for 12 hours. The reaction solution was quenched by adding water (50 mL), extracted with ethyl acetate (3×100 mL), and the organic phases were combined, washed with saturated brine (3×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give 4-chloro-5-fluoro-2-(4,4,4-trifluorobutoxy)benzonitrile 98b (2.4 g) in a yield of 74.0%.

[0526] MS m / z(ESI):282[M+1]

[0527] Step 2

[0528] 4-Chloro-3-fluoro-2-iodo-6-(4,4,4-trifluorobutoxy)benzonitrile

[0529] The compound 4-chloro-5-fluoro-2-(4,4,4-trifluorobutoxy)benzonitrile 98b (1 g, 3.55 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction system was cooled to -78 ° C, lithium diisopropylamide solution (2 M, 2.66 mL) was added, nitrogen was replaced three times, and stirred at -78 ° C for 30 minutes; iodine (1.08 g, 4.26 mmol) in tetrahydrofuran (10 mL) was added dropwise at -78 ° C, and then the temperature was naturally raised to room temperature and stirred for 16 hours. The reaction solution was quenched by adding water (50 mL), extracted with ethyl acetate (3×80 mL), and the organic phases were combined, washed with saturated brine (3×80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent (petroleum ether:tetrahydrofuran=10:1) to give 4-chloro-3-fluoro-2-iodo-6-(4,4,4-trifluorobutoxy)benzonitrile 98c (1.4 g) in a yield of 96.8%.

[0530] MS m / z(ESI):408[M+1]

[0531] Step 3

[0532] 4-Chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(4,4,4-trifluorobutoxy)benzonitrile

[0533] Compound 4-chloro-3-fluoro-2-iodo-6-(4,4,4-trifluorobutoxy)benzonitrile 98c (400 mg, 0.98 mmol) and 1-methyl-5-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (245 mg, 1.18 mmol) were dissolved in 1'4-dioxane (15 mL) and water (3 mL), and sodium carbonate (312 mg, 2.94 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (63 mg, 0.01 mol, 184 μL) were added, and the reaction was stirred at 100°C under microwave for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (20 mL) was added to the obtained residue for washing. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The organic phases were combined, washed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was concentrated by silica gel column chromatography using eluent System A to give 4-chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(4,4,4-trifluorobutoxy)benzonitrile 98d (312 mg) in a yield of 70.3%.

[0534] MS m / z(ESI):362[M+1]

[0535] Step 4

[0536] 4-Chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(4,4,4-trifluorobutoxy)benzonitrile

[0537] Compound 4-chloro-3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-6-(4,4,4-trifluorobutoxy)benzonitrile 98d (300 mg, 0.83 mmol) was dissolved in acetic acid (10 mL), N-iodosuccinimide (373 mg, 1.66 mmol) was added, and the system was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(4,4,4-trifluorobutoxy)benzonitrile 98e (274 mg) in a yield of 67.8%.

[0538] MS m / z(ESI):488[M+1]

[0539] Step 5

[0540] tert-Butyl ((7-(5-(3-chloro-6-cyano-2-fluoro-5-(4,4,4-trifluorobutoxy)))phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0541] Compound 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(4,4,4-trifluorobutoxy)benzonitrile 98e and [4-[(tert-butoxycarbonylamino)methyl]-1-oxo-2H-phthalazin-6-yl]boronic acid 18f (synthesized by reference to J. Med. Chem. 2022, 65, 1749-1766, 78 mg, 0.25 mmol) were dissolved in 1'4-dioxane (5 mL) and water (1 mL), and cesium fluoride (81 mg, 1.23 mmol), potassium phosphate (130 mg, 0.62 mmol) and cataCXium-A-Pd-G3 (30 mg, 0 .04mmol), the reaction was stirred at 80°C in a microwave for 1hr; water (10mL) was added to the concentrated residue, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (2×15mL); the organic phases were combined, washed with saturated brine (2×15mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by thin layer chromatography on a silica gel preparation plate to give tert-butyl ((7-(5-(3-chloro-6-cyano-2-fluoro-5-(4,4,4-trifluorobutoxy)))phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 98f (59mg), yield: 45.3%.

[0542] MS m / z(ESI):635[M+1]

[0543] Step 6

[0544] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(4,4,4-trifluorobutoxy)benzonitrile

[0545] Compound tert-butyl ((7-(5-(3-chloro-6-cyano-2-fluoro-5-(4,4,4-trifluorobutoxy)))phenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 98f (59 mg, 92.91 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) and stirred at 25° C. for 0.5 h. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent System C to give 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(4,4,4-trifluorobutoxy)benzonitrile 98 (26 mg) in a yield of 52.3%.

[0546] MS m / z(ESI):535[M+1]

[0547] 1 H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.24-8.14(m,2H),7.83(d,1H),7.76(d,1H),7.6 8(dd,1H),4.33(t,2H),3.83(d,2H),3.79(s,3H),2.49-2.30(m,4H),2.07-1.96(m,2H).

[0548] Embodiment 99

[0549] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-(tert-butoxy)-4-chloro-3-fluorobenzonitrile

[0550]

[0551] Referring to the first step and the third step to the seventh step of Example 55, 4-chloro-2,5-difluorobenzonitrile (600 mg, 3.47 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-(tert-butoxy)-4-chloro-3-fluorobenzonitrile 99 (2.5 mg) with a yield of 0.15%.

[0552] MS m / z(ESI):481[M+1]

[0553] 1H NMR (400MHz, DMSO) δ12.55(s,1H),8.30(d,2H),8.14(d,1H),7.90-7.76(m,2H),7.58(dd,1H),3.94(s,2H),3.80(s,3H),1.39(s,9H).

[0554] Embodiment 102

[0555] 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3-(difluoromethylene)cyclobutyloxy)-m-fluorobenzonitrile

[0556]

[0557] first step

[0558] ((3-(Difluoromethylene)cyclobutyloxy)methyl)benzene

[0559] Tetrahydrofuran (70 mL) was added to a three-necked flask, replaced with nitrogen three times, and cooled to 0°C. Dibromo(difluoro)methane (10.36 g, 49.37 mmol, 4.51 mL) was quickly added, and stirred in an ice bath for 10 minutes. Tri(dimethylamino)phosphine (8.06 g, 49.37 mmol, 8.97 mL) was slowly added dropwise, and stirring was continued at 0°C for 1 hour. A solution of 3-benzyloxycyclobutanone 102a (2 g, 11.35 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, the temperature was raised to 25°C and stirred for 1 hour, Zn (2.97 g, 45.40 mmol) was added, and 0.15 mL of HMPT was added, and the mixture was transferred to 75°C and stirred for 5 hours. Water (100 mL) was added to the reaction solution, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (2×100 mL); the organic phases were combined, washed with saturated brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to give ((3-(difluoromethylene)cyclobutyloxy)methyl)benzene 102b (580 mg) in a yield of 24.3%.

[0560] 1 H NMR (400MHz, DMSO-d6) δ7.40-7.25(m,5H),4.40(s,2H),4.18(tt,1H),2.92(ddq,2H),2.67-2.55(m,2H).

[0561] Step 2

[0562] 3-(Difluoromethylene)cyclobutane-1-ol

[0563] Compound ((3-(difluoromethylene)cyclobutoxy)methyl)benzene 102b (100 mg, 0.48 mmol) was dissolved in dichloromethane (5 mL), the reaction system was cooled to -78°C, boron tribromide (238 mg, 0.95 mmol, 92 μL) was slowly added dropwise, the reaction was stirred at -78°C for 0.5 hour, saturated sodium bicarbonate aqueous solution was added dropwise to the reaction solution at -78°C to quench, water (10 mL) was added, and extraction was performed with dichloromethane (3×20 mL); the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 3-(difluoromethylene)cyclobutane-1-ol 102c (90 mg), which was directly used in the next step without separation and purification.

[0564] MS m / z(ESI):121[M+1]

[0565] Referring to the synthesis method of the third to fifth steps of Example 86, the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3-(difluoromethylene)cyclobutoxy)-m-fluorobenzonitrile 102 (10 mg) was obtained from the crude product 3-(difluoromethylene)cyclobutane-1-ol 102c (90 mg, 0.75 mmol). The yield was 2.5%.

[0566] MS m / z(ESI):527[M+1]

[0567] 1 H NMR (400MHz, DMSO) δ12.50(s,1H),8.30(d,3H),8.15(d,1H),7.77(s,1H),7.72-7.62(m,2H),5.12(p,1H),3.87(s,2H),3.78(s,3H),2.87(dp,4H).

[0568] 19 F NMR(377MHz,DMSO)δ-94.91,-122.15.

[0569] Embodiment 103

[0570] 2-4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(1,1-dioxidoisothiazolin-2-yl)-3-fluorobenzonitrile

[0571]

[0572] first step

[0573] 4-Chloro-6-(1,1-dioxidoisothiazolin-2-yl)-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile

[0574] 4-Chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (0.20 g, 0.53 mmol) and potassium carbonate (218 mg, 1.58 mmol) were dissolved in acetonitrile (10 mL), 1,2-thiazolidine 1,1-dioxide (96 mg, 0.79 mmol) was added, nitrogen was replaced three times, and the system was heated to 80 ° C for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in water and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with eluent System A to give 4-chloro-6-(1,1-dioxidoisothiazoline-2-yl)-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 103a (80 mg) in a yield of 31.6%.

[0575] MS m / z(ESI):481[M+1]

[0576] Step 2 (7-(5-(3-chloro-6-cyano-5-(1,1-dioxidoisothiazolin-2-yl)-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester

[0577] [4-[(tert-Butyloxycarbonylamino)methyl]-1-oxo-2H-phthalazin-6-yl]boronic acid 18f (46 mg, 0.15 mmol, synthesized by reference to "J. Med. Chem. 2022, 65, 1749-1766"), 4-chloro-6-(1,1-dioxidoisothiazolin-2-yl)-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (70 mg, 0.1 5mmol), potassium phosphate (93mg, 0.44mmol) and cesium fluoride (58mg, 0.87mmol) were dissolved in water (1mL) and 1'4-dioxane (5mL), nitrogen was replaced three times, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (11mg, 15μmol) was added, and the system was heated to 80°C in a microwave reactor for 1 hour. The mixture was cooled to room temperature, dissolved in water, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system A to give tert-butyl 7-(5-(3-chloro-6-cyano-5-(1,1-dioxidoisothiazoline-2-yl)-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 103b (16 mg), yield: 17.5%.

[0578] MS m / z(ESI):628[M+1]

[0579] Step 3

[0580] 2-4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(1,1-dioxidoisothiazolin-2-yl)-3-fluorobenzonitrile

[0581] Tert-butyl 7-(5-(3-chloro-6-cyano-5-(1,1-dioxidoisothiazolin-2-yl)-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 103b (16 mg, 25 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the system was reacted at 25 °C for 1 hour. After concentration, the residue was purified by silica gel column chromatography with eluent System C to give 2-4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalic acid-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(1,1-dioxidoisothiazolin-2-yl)-3-fluorobenzonitrile 103 (2 mg) in a yield of 14.9%.

[0582] MS m / z(ESI):528[M+1]

[0583] 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.28-8.18(m,2H),8.08(d,1H),7.71-7.60(m ,2H),6.50(s,1H),4.34(t,1H),3.80(t,2H),3.73(d,4H),3.45(s,2H),2.39(d,2H).

[0584] Embodiment 112

[0585] 2-[4-[4-(Aminomethyl)-1-oxo-2H-phthalazin-6-yl]]-methyl epichlorohydrin-pyrazol-3-yl]-4-chloro-3-fluoro-6-(2-hydroxy-methyl epichlorohydrin-propoxy)benzonitrile

[0586]

[0587] first step

[0588] 2-Methylpropane-1,2-diol

[0589] 2-Hydroxy-2-methylpropionic acid ethyl ester 112a (500 mg, 3.78 mmol) was dissolved in THF (5 mL), the reaction system was cooled to 0°C, and LiAlH4 (1 M in THF, 7.57 mL) was slowly added dropwise; the reaction was stirred at 0°C for 1 hr; the reaction was quenched with 2M aqueous sodium hydroxide solution, and attention was paid to slow dropwise addition. After quenching was completed, the reaction was directly filtered and the filtrate was concentrated under reduced pressure to obtain 2-methylpropane-1,2-diol 112b (330 mg) with a yield of 96.8%.

[0590] MS m / z(ESI):91[M+1]

[0591] Step 2

[0592] 4-Chloro-3-fluoro-6-(2-hydroxy-2-methyl-propoxy)-2-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile

[0593] The compound cesium carbonate (343 mg, 1.05 mmol) was suspended in THF (5 mL), and 2-methylpropane-1,2-diol (95 mg, 1.05 mmol) and 4-chloro-3,6-difluoro-2-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile 1i (100 mg, 263 μmol, synthesized in Reference Example 1) were added dropwise. The reaction was stirred at 25°C for 12 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was separated and purified by Pre-TLC (developing solvent PE:EA=10:1) to obtain 4-chloro-3-fluoro-6-(2-hydroxy-2-methyl-propoxy)-2-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile 112c (88 mg) with a yield of 74.4%.

[0594] MS m / z(ESI):450[M+1]

[0595] Referring to the synthesis method of the fifth to sixth steps of Example 9, 4-chloro-3-fluoro-6-(2-hydroxy-2-methyl-propoxy)-2-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile 112c (60 mg, 134 μmol) was used to obtain the title product 2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]]-methylepichlorohydrin-pyrazol-3-yl]-4-chloro-3-fluoro-6-(2-hydroxy-methylepichlorohydrin-propoxy)benzonitrile 112 (7 mg) in a yield of 10.5%.

[0596] MS m / z(ESI):498[M+1]

[0597] 1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.29(s,1H),8.15(d,1H),7.90(d,1H),7.78(d,1H), 7.72-7.65(m,1H),4.79(s,2H),4.05-3.97(m,2H),3.82(s,2H),3.79(s,3H),1.20(d,6H).

[0598] Embodiment 120

[0599] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3-(fluoromethylene)pyrrolidin-1-yl)-3-fluorobenzonitrile

[0600]

[0601] Referring to the synthesis method of the third to fifth steps of Example 86, 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (47 mg, 0.13 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3-(fluoromethylene)pyrrolidin-1-yl)-3-fluorobenzonitrile 120 (3 mg) in a yield of 4.7%.

[0602] MS m / z(ESI):508[M+1]

[0603] 1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.27(s,1H),8.16(d,1H),7.81(d,1H),7.72(dd,1H) ,7.39(d,1H),7.01(s,1H),4.42-4.25(m,2H),3.79(s,3H),3.75-3.59(m,4H),2.63(t,2H).

[0604] Embodiment 123

[0605] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-(difluoropyrrolidin-1-yl)-3-fluorobenzonitrile

[0606]

[0607] Referring to the synthesis method of the third to fifth steps of Example 86, 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (190 mg, 0.50 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-(difluoropyrrolidin-1-yl)-3-fluorobenzonitrile 123 (6 mg) in a yield of 2.4%.

[0608] MS m / z(ESI):500[M+1]

[0609] 1H NMR(400MHz,DMSO-d6)δ12.70(broad s,1H),8.34(s,2H),8.16(d,1H),7.87(s,1H),7.58(d,1H),7.31(d,1H),4.66(hept,4H),4.16(s,2H),3.78(s,3H).

[0610] Embodiment 131

[0611] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1H-pyrazol-1-yl)benzonitrile

[0612]

[0613] Referring to the synthesis method of the third to fifth steps of Example 86, 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (95 mg, 0.25 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1H-pyrazol-1-yl)benzonitrile 131 (16 mg) in a yield of 13.5%.

[0614] MS m / z(ESI):475[M+1]

[0615] 1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.50(d,1H),8.49(d,1H),8.37(s,1H),8.35(t,2H) ,8.15(d,1H),7.90(dd,2H),7.56(dd,1H),6.69(dd,1H),4.46-4.39(m,2H),3.85(s,3H).

[0616] Embodiment 132

[0617] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(5-azaspiro[2.4]heptane-5-yl)benzonitrile

[0618]

[0619] Referring to the synthesis method of the third to fifth steps of Example 86, 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile 86c (95 mg, 0.25 mmol) was used to obtain the title product 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(5-azaspiro[2.4]heptane-5-yl)benzonitrile 132 (15 mg) in a yield of 11.9%.

[0620] MS m / z(ESI):504[M+1]

[0621] 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.45(s,2H),8.36(s,1H),8.17(d,1H),7.90(d,1H),7.52(dd,1H) ,7.24(d,1H),4.40(dd,2H),3.91-3.63(m,2H),3.78(s,3H),3.49(s,2H),1.89(ddt,2H),0.63(dd,4H).

[0622] The syntheses of the following examples refer to Example 136.

[0623]

[0624]

[0625]

[0626]

[0627] Example 150 can also be synthesized by referring to the following method:

[0628] Embodiment 150

[0629] 1-(Aminomethyl)-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile

[0630]

[0631] first step

[0632] Methyl 2-(Benzyloxy)-4-chlorobenzoate

[0633] Methyl 4-chloro-2-hydroxy-benzoate 150a (15 g, 80.39 mmol) and potassium carbonate (22.22 g, 160.78 mmol) were dissolved in N,N-dimethylformamide (100 mL), nitrogen was replaced three times, benzyl bromide (16.50 g, 96.47 mmol, 11.5 mL) was added, and the system was reacted at 90 ° C for 4 hours. The reaction was cooled to room temperature, filtered, and concentrated. It was extracted with ethyl acetate (150 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to obtain methyl 2-(benzyloxy)-4-chlorobenzoate 150b (21 g), with a yield of 94.4%.

[0634] MS m / z(ESI):277[M+1]

[0635] Step 2

[0636] 2-(Benzyloxy)-4-chlorobenzoic acid

[0637] Dissolve methyl 2-(benzyloxy)-4-chlorobenzoate 150b (21 g, 75.89 mmol) in water (20 mL) and ethylene glycol dimethyl ether (100 mL), cool to 0°C, add lithium hydroxide (4.54 g, 189.73 mmol), and react at 25°C for 1 hour. Filter and wash the residue with a small amount of ethyl acetate. Spin dry to obtain 2-(benzyloxy)-4-chlorobenzoic acid 150c (18.0 g, crude product), which is directly used in the next step.

[0638] MS m / z(ESI):263[M+1]

[0639] Step 3

[0640] 2-(Benzyloxy)-4-chlorobenzoyl chloride

[0641] 2-(Benzyloxy)-4-chlorobenzoic acid 150c (16 g, 60.91 mmol) was dissolved in dichloromethane (100 mL), nitrogen was replaced three times, cooled to 0°C, oxalyl chloride (2M, 36.55 mL) and N,N-dimethylformamide (445 mg, 6.09 mmol, 0.45 mL) were added, the system was reacted at 0°C for 0.5 hours and then heated to 25°C for 1 hour. Concentration gave 2-(benzyloxy)-4-chlorobenzoyl chloride 150d (17 g, crude product), which was directly used in the next step.

[0642] Step 4

[0643] 2-(Benzyloxy)-4-chloro-N,N-diisopropylbenzamide

[0644] Diisopropylamine (13.46 g, 133.03 mmol, 18.64 mL) was dissolved in 2-methyltetrahydrofuran (150 mL), nitrogen was replaced three times, and the mixture was cooled to 0°C. 2-(Benzyloxy)-4-chlorobenzoyl 150d (17 g, 60.47 mmol) was dissolved in 2-methyltetrahydrofuran (50 mL) and added dropwise to the system. After the addition was complete, the system was reacted at 25°C for 1 hour. 1M sodium hydroxide (50 mL) was added to the reaction mixture, stirred until layers were separated, extracted with ethyl acetate (100 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to obtain 2-(Benzyloxy)-4-chloro-N,N-diisopropylbenzamide 150e (18 g) with a yield of 86.7%.

[0645] MS m / z(ESI):346[M+1]

[0646] Step 5

[0647] 2-(Benzyloxy)-4-chloro-6-(2-chloroacetyl)-N,N-diisopropylbenzamide

[0648] 2-(Benzyloxy)-4-chloro-N,N-diisopropylbenzamide 150e (10 g, 28.91 mmol) was dissolved in 2-methyltetrahydrofuran (200 mL), nitrogen was replaced three times, and the mixture was cooled to below -60°C. n-Butyl lithium (2.5 M, 23.1 mL) was added dropwise to the system, and the internal temperature was kept below -50°C. After the addition, the system was reacted at -50°C for 30 minutes. ZnCl2 (8.28 g, 60.7 mmol) was added dropwise to the system, and the internal temperature was kept below -50°C. After the addition, the system was reacted at -30°C for 10 minutes. CuCl.2LiCl (0.1 M, 2.9 mL) and chloroacetyl chloride (8.16 g, 72.28 mmol, 5.8 mL) were added dropwise to the system, and the internal temperature was below -10°C during the addition. After the addition, the system was heated to 0°C and reacted for 20 minutes. Water (20 mL) and 30% ammonia (15 ml) were added to the system. During the addition, the system was kept below 10°C. After the addition, the mixture was stirred at room temperature for 30 minutes. The layers were separated, and the organic phase was neutralized by adding 1M HCl. The organic phase was separated and dried by spin drying. The residue was purified by silica gel column chromatography using eluent system B to give 2-(benzyloxy)-4-chloro-6-(2-chloroacetyl)-N,N-diisopropylbenzamide 150f (8.60 g) in a yield of 70.43%.

[0649] MS m / z(ESI):423[M+1]

[0650] Step 6

[0651] (1r, 3R, 5S, 7r)-1-(2-(3-(Benzyloxy)-5-chloro-2-(diisopropylcarbamoyl)phenyl)-2-oxoethyl)-1,3,5-triazaadamantan-1-iodide

[0652] 2-(Benzyloxy)-4-chloro-6-(2-chloroacetyl)-N,N-diisopropylbenzamide 150f (8.9 g, 21.07 mmol) and urotropine (3.25 g, 23.18 mmol) were dissolved in acetone (42 mL), and nitrogen was replaced three times. The system was cooled to 0°C, and sodium iodide (4.74 g, 31.61 mmol) was dissolved in acetone (28 mL) and added dropwise to the system. After the addition was completed, the system was heated to 25°C and reacted for 30 minutes. A large amount of solid precipitated in the system, which was filtered, and the filter cake was washed with acetone. The filter cake was spin-dried to obtain 150 g (11 g) of (1r, 3R, 5S, 7r)-1-(2-(3-(benzyloxy)-5-chloro-2-(diisopropylcarbamoyl)phenyl)-2-oxoethyl)-1,3,5-triazaadamantane-1-iodide, yield: 79.8%. MS m / z (ESI): 526 [M]

[0653] Step 7

[0654] 2-(Benzyloxy)-4-chloro-6-glycyl-N,N-diisopropylbenzamide hydrochloride

[0655] Dissolve 150 g (9.1 g, 13.91 mmol) of (1r, 3R, 5S, 7r)-1-(2-(3-(benzyloxy)-5-chloro-2-(diisopropylcarbamoyl)phenyl)-2-oxoethyl)-1,3,5-triazaadamantane-1-iodide in water (30 mL), cool the system to 0°C, add concentrated hydrochloric acid (9.3 mL), and after the addition, heat the system to 40°C and react for 16 hours. Cool to room temperature, and the reaction solution is directly used in the next step.

[0656] MS m / z(ESI):403[M+1]

[0657] Step 8

[0658] tert-Butyl (2-(3-(Benzyloxy)-5-chloro-2-(diisopropylcarbamoyl)phenyl)-2-oxoethyl)carbamate

[0659] Di-tert-butyl dicarbonate (3.86 g, 17.68 mmol, 4.1 mL) was dissolved in toluene (45 mL), nitrogen was replaced three times, the system was cooled to 0 ° C, ammonia (36 mL) was added to the system, and after the addition was complete, an aqueous solution of 2-(benzyloxy)-4-chloro-6-glycyl-N,N-diisopropylbenzamide hydrochloride (5.7 g, 14.15 mmol) was dripped into the system, and the temperature of the system was kept below 5 ° C during the dripping. After the addition was complete, the system was heated to 25 ° C and reacted for 1 hour. The liquid was separated, the aqueous phase was discarded, and the organic phase was concentrated. The residue was purified by silica gel column chromatography with eluent system B to obtain tert-butyl (2-(3-(benzyloxy)-5-chloro-2-(diisopropylcarbamoyl)phenyl)-2-oxoethyl)carbamate 150i (5.60 g), with a yield of 78.7%.

[0660] MS m / z(ESI):503[M+1]

[0661] Step 9

[0662] tert-Butyl (5-(benzyloxy)-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0663] Tert-butyl (2-(3-(benzyloxy)-5-chloro-2-(diisopropylcarbamoyl)phenyl)-2-oxoethyl)carbamate 150i (5.9 g, 11.73 mmol) was dissolved in toluene (32 mL), heated to 90°C, and AcOH (8 mL) and hydrazine hydrate (2.07 g, 35.19 mmol, 2.01 mL, 85% purity) were added. After the addition, the system was heated to 105°C for 1 hour. The system changed from transparent to precipitate, cooled to room temperature, filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain tert-butyl (5-(benzyloxy)-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 150j (3.1 g), with a yield of 63.5%.

[0664] MS m / z(ESI):416[M+1]

[0665] Step 10

[0666] 4-(Aminomethyl)-6-chloro-8-hydroxyphthalazin-1(2H)-one

[0667] Tert-butyl 5-(benzyloxy)-7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 150j (1 g, 2.40 mmol) was dissolved in acetic acid (5 mL) and concentrated hydrochloric acid (1 mL), and nitrogen was replaced three times. The system was reacted at 80°C for 1 hour. The reaction was cooled to room temperature and concentrated to give 4-(aminomethyl)-6-chloro-8-hydroxyphthalazin-1(2H)-one 150k (0.60 g).

[0668] MS m / z(ESI):226[M+1]

[0669] Step 11

[0670] tert-Butyl (7-chloro-5-hydroxy-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate

[0671] 4-(Aminomethyl)-6-chloro-8-hydroxyphthalazin-1(2H)-one 150k (0.6 g, 2.66 mmol) and sodium bicarbonate (670.17 mg, 7.98 mmol) were dissolved in water (10 mL) and methanol (10 mL), nitrogen was replaced three times, di-tert-butyl dicarbonate (870.54 mg, 3.99 mmol, 0.92 mL) was added, and the system was reacted at 25°C for 16 hours. A large amount of solid precipitated during the reaction, which was concentrated, filtered, washed with a small amount of water and ethyl acetate, and the filter residue was dried to obtain (7-chloro-5-hydroxy-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamic acid tert-butyl ester 150l (0.64 g), with a yield of 73.4%. MS m / z (ESI): 326 [M+1]

[0672] Step 12

[0673] 1-(((tert-Butyloxycarbonyl)amino)methyl)-7-chloro-4-oxo-3,4-dihydrophthalic acid-5-yl trifluoromethanesulfonate

[0674] Dissolve tert-butyl (7-chloro-5-hydroxy-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate 150l (500 mg, 1.53 mmol) in tetrahydrofuran (10 mL), add N,N-diisopropylethylamine (793.50 mg, 6.14 mmol, 1.1 mL) and N,N-phenylditrifluoromethane-sulfonimide (1.37 g, 3.84 mmol), replace nitrogen three times, and stir the reaction system at 75°C for 16 hours. Cool to room temperature, add water to quench, extract with ethyl acetate (50 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by silica gel column chromatography using eluent System B to give 1-(((tert-butyloxycarbonyl)amino)methyl)-7-chloro-4-oxo-3,4-dihydrophthalic acid-5-yl trifluoromethanesulfonate 150m (450 mg). Yield: 64.0%.

[0675] MS m / z(ESI):458[M+1]

[0676] Step 13

[0677] tert-Butyl (7-chloro-5-cyano-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate

[0678] 1-(((tert-Butyloxycarbonyl)amino)methyl)-7-chloro-4-oxo-3,4-dihydrophthalic acid-5-yl trifluoromethanesulfonate 150m (0.17 g, 0.37 mmol) was dissolved in N,N-dimethylformamide (3 mL), nitrogen was replaced three times, zinc hydride (26 mg, 0.22 mmol) and tetrakistriphenylphosphine palladium (64 mg, 56 μmol) were added, and the reaction system was heated to 100°C in a microwave reactor for 1.5 hours. Cool to room temperature, add water to quench, extract with ethyl acetate (50 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by silica gel column chromatography with eluent system B to give tert-butyl (7-chloro-5-cyano-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate 150n (50 mg), yield: 40.2%.

[0679] MS m / z(ESI):335[M+1]

[0680] Step 14

[0681] (4-((tert-Butyloxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalic acid-6-yl)boronic acid

[0682] Tert-butyl (7-chloro-5-cyano-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate 150n (50 mg, 149.36 μmol), biboronic acid pinacol ester (56.89 mg, 224.04 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14 mg, 30 μmol) and potassium acetate (44 mg, 0.45 mmol) were dissolved in 1'4-dioxane (3 mL), nitrogen was replaced three times, tris(dibenzylideneacetone)palladium (14 mg, 15 μmol) was added, and the reaction system was stirred at 100 ° C for 2 hours. The solution was cooled to room temperature, filtered and concentrated to give 4-((tert-butyloxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalic acid-6-yl)boronic acid 150o (0.11 g, crude product).

[0683] MS m / z(ESI):345[M+1]

[0684] Step 15 (5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazole-4-

[0685] tert-Butyl (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0686] 4-((tert-Butyloxycarbonyl)amino)methyl)-8-cyano-1-oxo-1,2-dihydrophthalic acid-6-yl)boric acid 150o (108 mg, 141 μmol, 45% purity), 6-(cyclopropyloxy)-3-fluoro-2-(4-iodo-2-methyl-pyrazol-3-yl)-4-prop-1-ynyl-benzonitrile 150p (35 mg, 83 μmol) and sodium bicarbonate (21 mg, 0.25 mmol) were dissolved in water (2 mL) and 1'4-dioxane (10 mL), and nitrogen was replaced three times. 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7 mg, 8 μmol) was added, and the system was heated to 80°C in a microwave reactor for 1.5 hours. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (30 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A to obtain tert-butyl (7-chloro-5-cyano-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate 150q (30 mg), with a yield of 60.8%.

[0687] MS m / z(ESI):594[M+1]

[0688] Step 16

[0689] 1-(Aminomethyl)-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile

[0690] Tert-butyl (7-chloro-5-cyano-4-oxo-3,4-dihydrophthalazin-1-yl)methylcarbamate 150q (30 mg, 51 μmol) was dissolved in a hydrochloric acid dioxane solution (4M, 4 mL), and the system was reacted at 25°C for 1 hour. After concentration, the residue was purified by silica gel column chromatography using eluent system A to give 1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropoxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile 150 (11 mg), yield: 44.1%.

[0691] MS m / z(ESI):494[M+1]

[0692] 1H NMR(400MHz,DMSO)δ12.80(s,1H),8.42(s,1H),8.29(d,1H),8.21(d,1H),7.89(s,1H), 7.82(d,1H),4.17(td,1H),3.76(d,5H),2.19(s,3H),0.90(dd,2H),0.82–0.73(m,2H).

[0693] Example 150 Preparation of Chiral Isomers

[0694] P1: tert-butyl ((5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0695] P2: tert-butyl ((5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0696]

[0697] First step: preparation of chiral isomers

[0698] The compound ((5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester 1 (130 mg, 0.22 mmol) was separated by Chiral-HPLC to give 150 q-P1: (m)-((5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate )phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (57 mg), yield: 43.8%; 150q-P2: (p)-((5-cyano-7-(5-(2-cyano-3-cyclopropoxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester (51 mg), yield: 39.2%.

[0699] 150q-P1: (m)-tert-butyl ((5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0700] MS m / z(ESI):594[M+1]

[0701] 151q-P2: (p)-tert-butyl ((5-cyano-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0702] MS m / z(ESI):594[M+1]

[0703] Step 2

[0704] 150-P1: (m)-1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile

[0705] 150-P2: (p)-1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile

[0706] 150q-P1: (m)-tert-butyl ((5-cyano-7-(5-(2-cyano-3-cyclopropoxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate (57 mg, 0.096 mmol), and 150q-P2: (p)-tert-butyl ((5-cyano-7-(5-(2-cyano-3-cyclopropoxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl)carbamate (51 mg, 0.086 mmol) were dissolved in 2M methanolic hydrochloric acid solution (10 mL) and stirred at room temperature for 2 h. After the reaction was completed, the solution was concentrated to dryness and the residue was purified by C-18 column chromatography with eluent system C to give the title products 150-P1: (m)-1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropoxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile (21.6 mg) and 150q-P2: (p)-1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropoxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile (20.6 mg) in yields of 45.6% and 48.5%, respectively.

[0707] 150-P1: (m)-1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile

[0708] MS m / z(ESI):494[M+1]

[0709] 1H NMR(400MHz,DMSO)δ12.90(s,1H),8.43(s,1H),8.21(s,1H),7.90(d,1H),7.82(d,1H), 4.18(dt,1H),3.88(s,2H),3.78(s,3H),2.19(s,3H),0.90(dd,2H),0.84–0.73(m,2H).

[0710] 150-P2: (p)-1-(aminomethyl)-7-(5-(2-cyano-3-cyclopropyloxy-6-fluoro-5-(prop-1-yn-1-yl)phenyl)-1-methyl-1H-pyrazol-4-yl)-4-carbonyl-3,4-dihydrophthalazine-5-carbonitrile

[0711] MS m / z(ESI):494[M+1]

[0712] 1H NMR (400MHz, DMSO) δ12.89(s,1H),8.43(s,1H),8.22(d,1H),7.90(d,1H),7.82(d,1H),4. 18(tt,1H),3.85(s,2H),3.78(s,3H),2.19(s,3H),0.94–0.84(m,2H),0.85–0.73(m,2H).

[0713] Embodiment 160

[0714] 2-(4-(4-aminomethyl-8-(3-(difluoromethylene)azetidin-1-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorocyanobenzene

[0715]

[0716] first step

[0717] Di-tert-butyl ((7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)aminodicarboxylate 160a (960 mg, 2.00 mmol, synthesized by the known method "Patent WO2023098439"), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (95 mg, 0.2 mmol) and cesium carbonate (98 mg, 0.3 mmol) were dissolved in 10 mL of dioxane and stirred at 100 ° C for 12 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent System A to give tert-butyl ((7-bromo-5-(3-(difluoromethylene)azetidin-1-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 160b (556 mg) in a yield of 60.8%.

[0718] The synthetic method of the sixth to eighth steps of Reference Example 1 was used to obtain the title product 2-(4-(4-aminomethyl-8-(3-(difluoromethylene)azetidine-1-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid tert-butyl ester 160b (556 mg) in a yield of 9.4% using tert-butyl ((7-bromo-5-(3-(difluoromethylene)azetidine-1-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 160b (556 mg).

[0719] MS m / z(ESI):568[M+1]

[0720] Embodiment 169

[0721] 2-[4-[4-(Aminomethyl)-1-oxo-2H-phthalazin-6-yl]]-2-(2-methoxyethyl)pyrazol-3-yl]-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0722]

[0723] first step

[0724] 2-(5-Bromopyrazol-1-yl)ethanol

[0725] Compound 5-bromo-1H-pyrazole 169a (2 g, 13.61 mmol) and 2-bromoethanol (3.15 g, 25.17 mmol) were dissolved in ethanol (30 mL), and potassium iodide (3.39 g, 20.41 mmol) and potassium hydroxide (1.53 g, 27.23 mmol) were added in sequence. The reaction was stirred at 100 °C for 12 hours, the reaction solution was filtered, the filter cake was rinsed with ethanol (50 mL), the filtrate was concentrated under reduced pressure, water (60 mL) was added to the concentrated residue, and it was extracted with ethyl acetate (60 mL×3), the organic phases were combined, washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain 2-(5-bromopyrazol-1-yl)ethanol 169b (1.3 g), with a yield of 50.0%.

[0726] MS m / z(ESI):191[M+1]

[0727] 1 H NMR (400MHz, DMSO) δ7.54(d,1H),6.41(d,1H),4.91(t,1H),4.16(t,2H),3.72(q,2H).

[0728] Step 2

[0729] 5-Bromo-1-(2-methoxyethyl)pyrazole

[0730] Compound 2-(5-bromopyrazol-1-yl)ethanol 169b (1 g, 5.23 mmol) was dissolved in DMF (20 mL), the reaction system was cooled to 0°C, sodium hydride (419 mg, 10.47 mmol, 60% purity) was added, and the mixture was stirred at 0°C for 20 minutes. Methyl iodide (2.23 g, 15.70 mmol) was added, and the reaction was stirred at 25°C for 2 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to give 5-bromo-1-(2-methoxyethyl)pyrazole 169c (810 mg) in a yield of 75.5%.

[0731] MS m / z(ESI):205[M+1]

[0732] Step 3

[0733] [2-(2-Methoxyethyl)pyrazol-3-yl]boronic acid

[0734] Compound 5-bromo-1-(2-methoxyethyl)pyrazole 169c (500 mg, 2.44 mmol) was dissolved in 1'4-dioxane (10 mL), and diboric acid pinacol ester (929 mg, 3.66 mmol) and potassium acetate (718 mg, 7.32 mmol) were added in sequence. The reaction system was replaced with nitrogen three times, and nitrogen protection was turned on. [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (177 mg, 244 μmol) was quickly added, and the reaction was stirred at 100°C for 2 hours; the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the product [2-(2-methoxyethyl)pyrazol-3-yl]boric acid 169d (320 mg) with a yield of 76.7%.

[0735] MS m / z(ESI):171[M+1]

[0736] Referring to the synthesis method of the third to sixth steps of Example 9, the title product 2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]]-2-(2-methoxyethyl)pyrazol-3-yl]-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (40 mg) was obtained by [2-(2-methoxyethyl)pyrazol-3-yl]boronic acid 169d (320 mg, 1.87 mmol) with a yield of 4.2%.

[0737] MS m / z(ESI):509[M+1]

[0738] 1 H NMR (400MHz, DMSO) δ12.22(s,1H),8.24(s,1H),8.18(dd,1H),7.94(d,1H),7.75-7.64(m,2H),4.24–4. 10(m,3H),3.80(d,2H),3.68–3.59(m,2H),3.10(s,3H),1.64(s,2H),0.91(dddd,2H),0.81(dddt,2H).

[0739] Embodiment 170

[0740] 4-(Aminomethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one

[0741]

[0742] first step

[0743] 5-(1-Methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole

[0744] 5-Bromobenzo[c][1,2,5]oxadiazole 170a (250 mg, 1.26 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (288 mg, 1.38 mmol), potassium phosphate (400 mg, 1.88 mmol) and 1,1-bis(diphenylphosphine)diferronichloridopalladium (91 mg, 0.13 mmol) were dispersed in a mixed solvent of 4 mL of dioxane and 2 mL of water, and the reaction was stirred at 100°C for 1.5 h. The reaction solution was poured into 50 ml of water to quench, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 5-(1-methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole 170b (250 mg), yield: 99.4%. MS m / z(ESI):201[M+1]

[0745] Step 2

[0746] 5-(4-Bromo-1-methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole

[0747] 5-(1-methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole 170b (250 mg, 1.25 mmol) and N-bromosuccinimide (248 mg, 1.40 mmol) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system B to give the title product 5-(4-bromo-1-methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole 170c (201 mg) in a yield of 56.9%.

[0748] MS m / z(ESI):279[M+1]

[0749] Step 3

[0750] 5-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole

[0751] 5-(4-Bromo-1-methyl-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole 170c (80 mg, 0.29 mmol), bipyraclostrobin (73 mg, 0.29 mmol), potassium acetate (42 mg, 0.42 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (21 mg, 0.03 mmol) were dissolved in 3 mL of dioxane and stirred at 100°C for 3 h. The reaction solution was poured into 50 ml of water to quench, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product 5-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole 170d (22 mg) in a yield of 23.5%.

[0752] MS m / z(ESI):327.1[M+1]

[0753] Step 4

[0754] 4-(tert-Butylcarbamatemethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one

[0755] 4-(tert-Butylcarbamatemethyl)-6-bromophthalazin-1(2H)-one (16 mg, 0.05 mmol, synthesized by the known method WO2022192745), 5-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-yl)benzo[c][1,2,5]oxadiazole 170d (15 mg, 0.05 mmol), potassium phosphate (15 mg, 0.08 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (3 mg, 0.004 mmol) were dissolved in 1 mL of dioxane and 0.5 mL of water, and the reaction was stirred at 100°C for 3 h. The reaction solution was poured into 20 ml of water to quench, and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title product 4-(tert-butylcarbamatemethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one 170e (18 mg) in a yield of 76.0%.

[0756] MS m / z(ESI):474[M+1]

[0757] Step 5

[0758] 4-(Aminomethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazine-1(2H)-

[0759] ketone

[0760] 4-(tert-Butylcarbamatemethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one 170e (18 mg, 0.04 mmol) was dissolved in 1 mL of dioxane and 0.5 mL of 4M hydrochloric acid in dioxane and stirred at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 4-(aminomethyl)-6-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-1-methyl-1H-pyrazol-4-yl)phthalazin-1(2H)-one 170 (9 mg) in a yield of 63.4%.

[0761] MS m / z(ESI):374[M+1]

[0762] 1H NMR(400MHz,DMSO)δ12.87(s,1H),8.40(s,2H),8.22(s,1H),8.16(d,1H),8. 10(d,1H),7.89(s,1H),7.60(d,2H),7.41(d,1H),4.32(s,2H),3.90(s,3H).

[0763] Biological test evaluation

[0764] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0765] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells

[0766] 1.1 Experimental Purpose: The purpose of this test case is to measure the inhibitory effect of compounds on the proliferation activity of HCT116 wild-type and HCT116 MTAP knockout cells.

[0767] 1.2 Experimental instruments:

[0768] Centrifuge (Eppendorf 5810R); microplate reader (BioTek Synergy H1 or PerkinElmer Envision); pipette (Eppendorf or Rainin).

[0769] 1.3 Experimental reagents:

[0770] HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega with catalog number G7573; McCoy`5A was purchased from Gibco with catalog number 12330031; FBS was purchased from Gibco with catalog number 10091148; PBS was purchased from Gibco with catalog number 10010023; trypsin was purchased from Gibco with catalog number 25200056; and cell culture plates were purchased from Corning with catalog number 3610.

[0771] 1.4 Experimental methods:

[0772] When HCT116 and MTAP Knockout HCT116 cells were cultured to an appropriate cell density using McCoy'5A medium containing 10% FBS, the cells were collected and adjusted to an appropriate cell concentration using complete medium. The cell suspension was plated on a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of different concentrations were prepared using DMSO and culture medium, and a solvent control was set up. The compound solution was added to a 96-well plate at 10 μL per well and placed in a 37°C, 5% CO2 incubator for continued culture for 72 to 240 hours. Then, the CellTiter-Glo solution was added, the plate was shaken to mix evenly, incubated in the dark for 10 to 30 minutes, and read using a Synergy H1 or Envision microplate reader.

[0773] 1.5 Experimental data processing method:

[0774] The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 The values ​​are shown in Table 1.

[0775] Table 1 Inhibitory activity of compounds on HCT116 and MTAP Knockout HCT116 cell proliferation

[0776]

[0777] 1.6 Experimental conclusion:

[0778] The compound of the present invention has obvious proliferation inhibition activity on MTAP-deficient tumor cells and has high selectivity for wild-type cells.

[0779] Test Example 2: Pharmacokinetics in Balb / C mice

[0780] 2.1 Research Purpose:

[0781] Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compound in plasma in mice at a dose of 30 mg / kg after oral administration.

[0782] 2.2 Experimental plan

[0783] 2.2.1 Trial Drugs:

[0784] Compounds of the present invention

[0785] 2.2.2 Experimental animals:

[0786] Balb / C mice (3 mice / example), male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0787] 2.2.3 Administration:

[0788] Three male Balb / C mice were fasted overnight and administered orally at a dose of 30 mg / kg in a dosing volume of 10 mL / kg.

[0789] 2.2.4 Sample collection:

[0790] Before and after administration of the mice, 0.1 mL of blood was collected from the eye sockets at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in EDTA-K2 tubes, centrifuged at 6000 rpm at 4°C for 6 min to separate plasma, and stored at -80°C.

[0791] 2.2.5 Sample processing:

[0792] 1) Add 160uL acetonitrile to 40uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5-20 minutes.

[0793] 2) Take 100uL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0794] 2.2.6 Liquid phase analysis:

[0795] Liquid phase conditions: Shimadzu LC-20AD pump

[0796] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0797] Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0798] Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile

[0799] Flow rate: 0.8mL / min

[0800] Elution time: 0-4.0 minutes, eluent is as follows:

[0801]

[0802] 2.3 Test results

[0803] The main pharmacokinetic parameters were calculated using WinNonlin 8.2, and the results are shown in the following table:

[0804] Table 2: Pharmacokinetic parameters of compounds administered intravenously in mice

[0805]

[0806] Table 3: Pharmacokinetic parameters of the compounds in mice after oral administration

[0807]

[0808] 2.4 Experimental Conclusion

[0809] The compound of the present invention has good mouse blood pharmacokinetic parameters, and the compound shows high oral exposure and high bioavailability.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: L1 is selected from a bond, -(CR a R b ) n1 -, -(CR a R b ) n1 O(CR a R b ) n2 -, -(CR a R b ) n1 S(CR a R b ) n2 -, -(CR a R b ) n1 NR c (CR a R b ) n2 -, -(CR a R b ) n1 C(O)(CR a R b ) n2 -, -(CR a R b ) n1 S(O) m2 (CR a R b ) n2 -, -(CR a R b ) n1 C(O)NR c (CR a R b ) n2 -, -(CR a R b ) n1 NR c C(O)(CR a R b ) n2 -, -(CR a R b ) n1 -C 3-12 cycloalkyl-(CR a R b ) n2 -, -(CR a R b ) n1 -3- to 12-membered heterocyclic group-(CR a R b ) n2 -, -(CR a R b ) n1 -C 6-12 Aryl-(CR a R b ) n2 -or-(CR a R b ) n1 -5-12 membered heteroaryl-(CR a R b ) n2 -, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n3 -substituted or unsubstituted C 3-12 Cycloalkyl, -(CH2) n3 -substituted or unsubstituted 3-12 membered heterocyclic group, -(CH2) n3 -substituted or unsubstituted C 6-12 Aryl and -(CH2) n3 -substituted or unsubstituted 5-12 membered heteroaryl, substituted by one or more substituents; preferably a bond, -(CR a R b ) n1 -、-(CR a R b ) n1 O(CR a R b ) n2 -、-(CR a R b ) n1 S(CR a R b ) n2 -、-(CR a R b ) n1 NR c (CR a R b ) n2 -、-(CR a R b ) n1 C(O)(CR a R b ) n2 -、-(CR a R b ) n1 S(O) m2 (CR a R b ) n2 -、-(CR a R b ) n1 C(O)NR c (CR a R b ) n2 -、-(CR a R b ) n1 NR c C(O)(CR a R b ) n2 -、-(CR a R b ) n1 -C 3-8 Cycloalkyl-(CR a R b ) n2 -、-(CR a R b ) n1 -3-8 membered heterocyclic group-(CR a R b ) n2 -、-(CR a R b ) n1 -C 6-10 Aryl-(CR a R b ) n2 -or-(CR a R b ) n1 -5-10 membered heteroaryl-(CR a R b ) n2 -, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n3 -substituted or unsubstituted C 3-8 Cycloalkyl, -(CH2) n3 -substituted or unsubstituted 3-8 membered heterocyclic group, -(CH2) n3 -substituted or unsubstituted C 6-10 Aryl and -(CH2) n3 -substituted by one or more substituents in a substituted or unsubstituted 5-10 membered heteroaryl; R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 S(O) m3 R d 、-(CH2) n4 N=S(O) m3 R d R e 、-(CH2) n4 N=S(O) m3 R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R 1d and R 1e The atoms adjacent to it, R 1c and R 1d The atoms adjacent to it, R 1b and R 1c The adjacent atoms or R 1a and R 1b Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R a , R b , R c , R d and R e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R d and R e Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; 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; n2 is selected from 0, 1, 2, 3 or 4; n3 is selected from 0, 1, 2, 3 or 4; n4 is selected from 0, 1, 2, 3 or 4; m3 is selected from 0, 1 or 2; and x is selected from 0, 1, 2, 3 or 4.

2. The compound of the general formula according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L1 is selected from -(CR a R b )NR c -、-NR c (CR a R b )-、-C(O)NR c -、-NR c C(O)-, 5-10 membered heteroaryl, -(CR a R b )-5-10 membered heteroaryl or 5-10 membered heteroaryl-(CR a R b )-, the 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl; R a , R b and R c As defined in any preceding claim.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that The compound is further represented by general formula (II): Ring A is selected from R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n5 -C 3-12 Cycloalkyl, -(CH2) n5 -3-12 membered heterocyclic group, -(CH2) n5 -C 6-12 Aryl, -(CH2) n5 -5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n5 -C 3-8 Cycloalkyl, -(CH2) n5 -3-8 membered heterocyclic group, -(CH2) n5 -C 6-10 Aryl or -(CH2) n5 -5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; n5 is selected from 0, 1, 2, 3 or 4; R 1a , R 1b , R 1c , R 1d , R 1e , R2 and x are as described in any of the above claims.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (VI): R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 S(O) m3 R d 、-(CH2) n4 N=S(O) m3 R d R e 、-(CH2) n4 N=S(O) m3 R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R 1d and R 1e The atoms adjacent to it, R 1c and R 1d The atoms adjacent to it, R 1b and R 1c The adjacent atoms or R 1a and R 1b Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n7 C 3-12 Cycloalkyl, -(CH2) n7 3-12 membered heterocyclic group, -(CH2) n7 C 6-12 Aryl, -(CH2) n7 5-12 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n7 C 3-8 Cycloalkyl, -(CH2) n7 3-8 membered heterocyclic group, -(CH2) n7 C 6-10 Aryl, -(CH2) n7 5-10 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 3b and R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R d , R e , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb Preferably, the substituted amine group is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R d and R e Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; or R p and R q Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; n4 is selected from 0, 1, 2, 3 or 4; n7 is selected from 0, 1, 2, 3 or 4; and n8 is selected from 0, 1, 2, 3 or 4; m3 is selected from 0, 1 or 2.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (VIII): Ring F is selected from 5-12 membered heterocyclyl or 5-12 membered heteroaryl; preferably 5-6 membered monocyclic heterocyclyl, 5-10 membered spiro heterocyclyl, 7-10 membered fused heterocyclyl or 7-10 membered bridged heterocyclyl; R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n4 -C 3-8 Cycloalkyl, -(CH2) n4 -3-8 membered heterocyclic group, -(CH2) n4 -C 6-10 Aryl, -(CH2) n4 -5-10 membered heteroaryl, -(CH2) n4 OR d 、-(CH2) n4 NR d R e 、-(CH2) n4 C(O)R d 、-(CH2) n4 C(O)NR d R e or -(CH2) n4 P(O)R d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n7 C 3-12 Cycloalkyl, -(CH2) n7 3-12 membered heterocyclic group, -(CH2) n7 C 6-12 Aryl, -(CH2) n7 5-12 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n7 C 3-8 Cycloalkyl, -(CH2) n7 3-8 membered heterocyclic group, -(CH2) n7 C 6-10 Aryl, -(CH2) n7 5-10 membered heteroaryl, -(CH2) n7 OR m 、-(CH2) n7 NR m R n 、-(CH2) n7 C(O)R m 、-(CH2) n7 C(O)NR m R n or -(CH2) n7 P(O)R m R n , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents selected from aryl and 5-10 membered heteroaryl; more preferably methyl or cyclopropyl; R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, one or more substituents; more preferably -CH2NH2, -CH2NHCH3, -CH2NHCH2CH3, -CH2OH, -C(O)NH2, R 3b and R 3c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n8 -C 3-12 Cycloalkyl, -(CH2) n8 -3-12 membered heterocyclic group, -(CH2) n8 -C 6-12 Aryl, -(CH2) n8 -5-12 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n8 -C 3-8 Cycloalkyl, -(CH2) n8 -3-8 membered heterocyclic group, -(CH2) n8 -C 6-10 Aryl, -(CH2) n8 -5-10 membered heteroaryl, -(CH2) n8 OR p 、-(CH2) n8 NR p R q 、-(CH2) n8 C(O)R p 、-(CH2) n8 C(O)NR p R q or -(CH2) n8 P(O)R p R q , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -COOR aa , =NOR aa or =R aa R bb , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa or =R aa R bb , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R d , R e , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R p and R q Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =NOR aa Sum = R aa R bb is substituted by one or more substituents; R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; n4 is selected from 0, 1, 2, 3 or 4; n7 is selected from 0, 1, 2, 3 or 4; and n8 is selected from 0, 1, 2, 3 or 4; m3 is selected from 0, 1 or 2.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

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

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

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

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

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