Pyrimidine-containing polybasic ring derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a pyrimidine-containing polybasic ring derivative inhibitor as well as a preparation method and application thereof. In particular, the invention relates to a pyrimidine-containing multi-element fused ring compound or a stereoisomer thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound or the stereoisomer thereof in preparation of drugs for treating cancers and other related diseases.

Description

Pyrimidine-containing polycyclic derivative inhibitors, preparation method and application thereof Technical Field

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

[0002] Rat sarcoma (RAS) proteins are encoded by the proto-oncogenes HRAS, NRAS, and KRAS. They are divided into four proteins: HRAS, NRAS, KRAS4A, and KRAS4B. RAS is a GTP (guanosine triphosphate)-binding protein. Located on the inner surface of the cell membrane, RAS is upstream of receptor tyrosine kinases (RTKs). Upon activation, RAS regulates downstream signaling pathways such as PI3K and RAF, thereby controlling cell growth, survival, migration, and differentiation.

[0003] RAS exists in two main states within the body: an inactive state bound to GDP (guanosine diphosphate) and an activated state bound to GTP. Its activity is regulated by two proteins: the guanine nucleotide exchange factor (GEF), which releases GDP from the RAS protein, allowing GTP to bind and activate RAS; and the GTPase activating protein (GAP), which activates the GTPase activity of the RAS protein, hydrolyzing the bound GTP to GDP, thereby inactivating RAS. Under normal circumstances, the RAS protein is in an inactive state. However, mutations alter its conformation, leaving RAS in a persistently activated state and continuously activating downstream signaling pathways, leading to the development of various cancers.

[0004] RAS was the first oncogene identified and is also the most frequently mutated oncogene, accounting for an average of 25% of human cancers. The most common oncogenic mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are prevalent in a range of cancers, including pancreatic cancer (95%), colorectal cancer (52%), and lung cancer (31%). The most common KRAS mutation is a point mutation, occurring at G12 and G13 within the p-loop (aa 10-17), and Q61 within the Switch II region (aa59-76). G12 mutations are the most common (83%). Epidemiological studies in Europe and the United States have shown that KRAS G12D is the most common pathogenic mutation in pancreatic cancer, colorectal cancer, endometrial cancer, and lung cancer, with incidences of 36%, 12%, 6%, and 4%, respectively.

[0005] Despite the significant clinical need, no drug directly targeting KRAS has yet been marketed. Currently, chemotherapy is the only treatment option for patients with KRAS mutations. The development of KRAS inhibitors is hampered by two main factors: the smooth structure of the RAS protein makes it difficult for small molecules to bind to the protein surface; and RAS GTPases have a picomolar (pM) affinity for GTP, coupled with high endogenous GTP levels, making it difficult for small molecule drugs to block their binding. Currently, no KRAS G12D inhibitors have entered clinical trials.

[0006] There are currently no specific targeted drugs for KRAS G12D, leaving a significant clinical need. KRAS G12D inhibitors with greater selectivity, improved activity, and enhanced safety have the potential to treat a variety of cancers and hold broad market promise.

[0007] Summary of the Invention

[0008] 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:

[0009] X1 is selected from N or CR 3b ;

[0010] X2 is selected from N-OR 6a or CR 6b R 6c ;

[0011] X3 is selected from O, S or NR n1 ; Preferably selected from O or S;

[0012] L1 is selected from a bond, O, S or NR n2 ; Preferably selected from O or S; More preferably selected from O;

[0013] L2 is selected from C1-C4 alkylene, wherein the C1-C4 alkylene is optionally replaced by 1 or 2 R a Substituted; preferably C1-C4 alkylene or C1-C4 deuterated alkylene, the C1-C4 alkylene and C1-C4 deuterated alkylene optionally by 1-4 R a replace;

[0014] Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0015] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-14 Aryl or 5-14 membered heteroaryl; preferably selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably 5-8 membered saturated or unsaturated heterocyclic group, 7-10 membered fused heterocyclic group or 6-10 membered bridged heterocyclic group;

[0016] R 1a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C(O)(CH2) n3 R b 、-C(O)O(CH2) n3 R b or -C(O)[(CH2NR c C(O))] n4 (CH2) n3 R b , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n3 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) n3 R b 、-C(O)O(CH2) n3 R b or -C(O)[(CH2NR c C(O))] n4 (CH2) n3 R b , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n3 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0017] R 1a Preferably hydrogen or Pg, wherein said Pg is selected from trityl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxyphenyl, -C(O)O(CRaa R bb ) n9 OC(O)(CR dd R ee ) n10 R b 、-C(O)(CR aa R bb ) n9 R b 、-C(O)O(CR aa R bb ) n9 R b or -C(O)[(CR aa R bb NR cc C(O))] n9 (CR dd R ee ) n10 R b ;

[0018] R 1b 、R 1c or R 1d are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0019] or R 1b and R 1c It is linked to adjacent atoms to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, optionally substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -(CH2)n7 -C 1-6 Alkoxy, -(CH2) n7 -C 1-6 Deuterated alkoxy, -(CH2) n7 -C 1-6 Haloalkoxy, -(CH2) n7 -C 2-6 Alkenyl, -(CH2) n7 -C 2-6 Alkynyl, -(CH2) n7 -C 3-12 Cycloalkyl, -(CH2) n7 -3-12 membered heterocyclic group, -(CH2) n7 -C 6-14 Aryl or -(CH2) n7 -substituted by one or more substituents in a 5-14 membered heteroaryl; preferably forming a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; more preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0020] R2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl or haloethyl;

[0021] Or any two R2 substituents are linked to their adjacent atoms to form a C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; more preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl

[0022] R 3a or R 3bare each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0023] R4 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d Re , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2)n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0024] R5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n6 R f 、-O(CH2) n6 C(O)R f 、-O(CH2) n1 C(O)OR f、-OC(O)O(CH2) n6 R f 、-O(CH2) n6 C(O)NR f R g 、-O(CH2) n6 OC(O)NR f R g or -O(CH2) n6 P(=O)R f R g , the amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n6 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n6 R f 、-O(CH2) n6 C(O)Rf 、-O(CH2) n6 C(O)OR f 、-OC(O)O(CH2) n6 R f 、-O(CH2) n6 C(O)NR f R g 、-O(CH2) n6 OC(O)NR f R g or -O(CH2) n6 P(=O)R f R g , the amino, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n6 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0025] Or any two R5 atoms are linked to their adjacent atoms to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0026] R 6a 、R 6b or R 6c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0027] or R 6b and R 6c Linked to its adjacent atoms to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0028] R n1 or R n2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] R a 、R b 、R c 、R d 、R e 、R f or R g are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0030] or two R attached to the same carbon atom a Link Form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0031] R aa 、R bb 、R cc 、R ddor R ee are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0032] x is selected from 0, 1, 2, 3, 4, 5 or 6;

[0033] y is selected from 0, 1, 2, 3, 4, 5 or 6;

[0034] z is selected from 0, 1, 2, 3, 4, 5 or 6;

[0035] n1 is selected from 0, 1 or 2;

[0036] n2 is selected from 0, 1 or 2;

[0037] n3 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0038] n4 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0039] n5 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0040] n6 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0041] n7 is selected from 0, 1 or 2;

[0042] n9 is selected from 0, 1 or 2; and

[0043] n10 is selected from 0, 1 or 2.

[0044] In a preferred embodiment, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R 1b and R 1c Linked with its adjacent atoms to form the following structure Preferably, the following structure is formed More preferably, the following structure is formed

[0045] In a preferred embodiment, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that L2 is selected from Selected from

[0046] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Hydroxyalkyl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; more preferably hydrogen or deuterium;

[0047] R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0048] p is selected from 0, 1, 2, 3 or 4.

[0049] In a preferred embodiment, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring A is selected from phenyl, pyridyl, naphthyl, phenylthienyl, benzopyrazolyl, quinolyl or isoquinolyl.

[0050] In a preferred embodiment, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that the compound is further represented by general formula (II) or (II-A):

[0051] R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2)n5 P(=O)R d R e , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NRd R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0052] R 4a 、R 4c 、R 4d or R 4e are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0053] R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0054] R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; more preferably C 2-4 Alkynyl;

[0055] R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0056] p is selected from 0, 1, 2, 3 or 4;

[0057] R 1a 、R 1d , R2, R 3a 、R 3b , R5, X1, X2, X3, x and z are as defined in any of the above embodiments.

[0058] In a preferred embodiment, the compound is further represented by formula (III):

[0059] R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0060] R 4a 、R 4c 、R 4d or R 4e are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0061] R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0062] R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0063] R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0064] R 7a Selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0065] R 7b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

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

[0067] n8 is selected from 0, 1 or 2;

[0068] R 1a 、R 1d , R2, R 3a , R5, X2, X3, x and z are as defined in any embodiment.

[0069] In a preferred embodiment, the compound is further represented by formula (II-B) or (II-C):

[0070] Preferably, the compound is further represented by the general formula (II-B-1) or (II-C-1):

[0071] X2 is selected from N-OR 6a or CR 6b R 6c ; preferably N-OR 6a ;

[0072] X4 is selected from N or CR 9a ;

[0073] R 9aSelected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0074] R 9b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] R 9c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0076] R 9d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0077] R 9e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0078] R6 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0079] p is selected from 0, 1, 2, 3 or 4;

[0080] R 1a 、R 1d , R2, R 3a 、R 3b , R5, X1, X2, X3, x and z are as defined in any of the above embodiments.

[0081] In a preferred embodiment, the compound is further represented by formula (V):

[0082] X2 is selected from N-OR 6a or CR 6b R 6c ;

[0083] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably 5-8 membered saturated or unsaturated heterocyclic group, 7-10 membered fused heterocyclic group or 6-10 membered bridged heterocyclic group;

[0084] Pg is selected from trityl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxyphenyl, -C(O)O(CR aa R bb ) n9 OC(O)(CR dd R ee ) n10 R b 、-C(O)(CR aa R bb ) n9 R b 、-C(O)O(CR aa R bb ) n9 R b or -C(O)[(CR aa R bb NR cc C(O))] n9 (CR dd R ee ) n10 R b ;

[0085] R b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0086] R aa 、R bb 、R cc 、R dd or R ee are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl or isopropyl;

[0087] R2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] R 3aSelected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)Rd R e , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d Re 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] R 4a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0091] R 4c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0092] R 4d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] R 4e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0094] R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0095] R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0096] R5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0097] R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0098] R 6aSelected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0099] R 6b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0100] R 6c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 7a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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;

[0102] R 7b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0103] R d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] R e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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] n5 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0106] n8 is selected from 0, 1 or 2;

[0107] n9 is selected from 0, 1 or 2;

[0108] n10 is selected from 0, 1 or 2;

[0109] x is selected from 0, 1, 2, 3, 4, 5 or 6;

[0110] z is selected from 0, 1, 2, 3, 4, 5 or 6;

[0111] p is selected from 0, 1, 2, 3 or 4.

[0112] In a preferred embodiment, the compound is further represented by formula (IV):

[0113] Preferably, the compound is further represented by general formula (IV-1):

[0114] R 1d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen;

[0115] R2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or cyclopropyl;

[0116] Or two R2 substituents are linked to their adjacent atoms to form a C 3-8 Cycloalkyl; preferably forming cyclopropyl;

[0117] R 3a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl or isopropyl; more preferably hydrogen or fluorine;

[0118] R 4a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0119] R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC(O)C 1-6 Alkyl or C 3-8Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, acetoxy, propionyloxy, butyryloxy, p-pivaloyloxy or cyclopropyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, methyl, acetoxy, propionyloxy, butyryloxy or p-pivaloyloxy;

[0120] R 4c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0121] R 4d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0122] R 4e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0123] R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0124] R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, ethyl or ethynyl;

[0125] R5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, amino, hydroxy, cyano, methyl or ethyl;

[0126] R 6b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, fluorine, difluoromethyl or trifluoromethyl;

[0127] R 7c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, deuterated methoxy, deuterated ethoxy, hydroxymethyl, hydroxyethyl, vinyl, halovinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, deuterated methoxy, deuterated ethoxy, vinyl, monofluorovinyl or difluorovinyl;

[0128] R 7b Hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or deuterium;

[0129] x is selected from 0, 1 or 2;

[0130] z is selected from 0, 1, 2, 3, 4, 5 or 6;

[0131] p is selected from 0, 1 or 2;

[0132] n8 is selected from 0, 1 or 2.

[0133] In a preferred embodiment, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that ring B is selected from a 5-8 membered saturated or unsaturated monocyclic heterocyclic group, a 5-6 membered heterocyclic group and C 3-6 Cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, or 6-10 membered bridged heterocyclyl;

[0134] Selected from

[0135] In a preferred embodiment, the compound is further represented by formula (III-A) or (III-B):

[0136] Preferably, the compound is further represented by the general formula (III-A-1) or (III-B-1):

[0137] X2 is selected from N-OR 6a or CR 6b R 6c ; CR is preferred 6b R 6c ;

[0138] R 1d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen;

[0139] R2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or cyclopropyl;

[0140] Or two R2 substituents are linked to their adjacent atoms to form a C3-8 Cycloalkyl; preferably forming cyclopropyl;

[0141] R 3a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or fluorine;

[0142] R 4a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0143] R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC(O)C 1-6 Alkyl or C 3-8Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, acetoxy, propionyloxy, butyryloxy, p-pivaloyloxy or cyclopropyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, methyl, acetoxy, propionyloxy, butyryloxy or p-pivaloyloxy;

[0144] R 4c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0145] R 4d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0146] R 4e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0147] R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0148] R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, ethyl or ethynyl;

[0149] R6 hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen;

[0150] R 6a Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably methyl, ethyl, -CH2CH2F, -CH2CHF2, -CH2CF3 or cyclopropyl;

[0151] R 6b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, fluorine, difluoromethyl or trifluoromethyl;

[0152] R 6cSelected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or fluorine;

[0153] R 7c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, deuterated methoxy, deuterated ethoxy, hydroxymethyl, hydroxyethyl, vinyl, halovinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, deuterated methoxy, deuterated ethoxy, vinyl, monofluorovinyl or difluorovinyl;

[0154] R 7b Hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or deuterium;

[0155] R8 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, amino, hydroxy, cyano, methyl or ethyl;

[0156] Or any two R8 substituents are linked to their adjacent atoms to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably forming cyclopropyl, 5 membered nitrogen-containing heterocyclic group or 6 membered nitrogen-containing heterocyclic group;

[0157] x is selected from 0, 1 or 2;

[0158] p is selected from 0, 1 or 2;

[0159] q is selected from 0, 1, 2, 3, 4, 5 or 6;

[0160] n8 is selected from 0, 1 or 2.

[0161] The present invention also provides a method for preparing the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps:

[0162] The compound represented by general formula (VI) reacts with the compound represented by general formula (VI-A) in the presence of a halide salt and a base to obtain the compound represented by general formula (I);

[0163] R L1 is selected from hydrogen or a hydroxy protecting group;

[0164] Ring A, Ring B, X1, X2, X3, L1, L2, R 1a 、R1b 、R 1c 、R 1d , R2, R 3a , R4, R5, x, y, z, n1 and n2 are as described in any of the above embodiments.

[0165] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (II-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0166] The compound represented by the general formula (VI-B) reacts with the compound represented by the general formula (VI-A) in the presence of a halide salt and a base to obtain the compound represented by the general formula (II-D);

[0167] R L1 is selected from hydrogen or a hydroxy protecting group;

[0168] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium;

[0169] Ring B, X1, X2, X3, R 1a 、R 1d , R2, R 3a 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R5, R6, x, p or z are as described in any of the above embodiments;

[0170] When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution.

[0171] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (II-E), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0172] The compound represented by the general formula (VI-C) reacts with the compound represented by the general formula (VI-A) in the presence of a halide salt and a base, and the protecting group is further removed to obtain the compound represented by the general formula (II-E);

[0173] R L1 is selected from hydrogen or a hydroxy protecting group;

[0174] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium;

[0175] Ring B, X1, X2, X3, X4, R 1a 、R 1d , R2, R 3a 、R 9a 、R 9b 、R 9c 、R 9d 、R 9e , R5, R6, x, p or z are as described in any of the above embodiments.

[0176] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0177] The compound represented by the general formula (VI-D) reacts with the compound represented by the general formula (VI-E) in the presence of a halide salt and a base, and the protecting group is further removed to obtain the compound represented by the general formula (III-A);

[0178] R L1 is selected from hydrogen or a hydroxy protecting group;

[0179] Ring B, X1, X2, X3, R 1a 、R 1d , R2, R 3a 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R6, R 7b 、R 7c , R8, x, p, q, n8 and Pg are as described in any of the above embodiments;

[0180] When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution.

[0181] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0182] The compound represented by the general formula (VI-D) reacts with the compound represented by the general formula (VI-G) in the presence of a halide salt and a base, and the protecting group is further removed to obtain the compound represented by the general formula (IV);

[0183] R L1 is selected from hydrogen or a hydroxy protecting group;

[0184] Ring B, X1, X2, X3, R 1a 、R 1d , R2, R 3a 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R5, R6, R 6b 、R 7b 、R 7c , x, p, z, n8 and Pg are as described in any of the above embodiments;

[0185] When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution.

[0186] In a preferred embodiment, the hydroxy protecting group is selected from methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, acetyl, benzoyl or p-toluenesulfonyl; preferably trimethylsilyl or tert-butyldimethylsilyl;

[0187] In a preferred embodiment, the halogenated salt is selected from potassium iodide, sodium iodide, potassium bromide, sodium bromide, potassium chloride or sodium chloride; preferably potassium iodide or sodium iodide;

[0188] In a preferred embodiment, the base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine or N,N-diisopropylethylamine; preferably N,N-diisopropylethylamine.

[0189] The present invention also provides a compound represented by general formula (VII-F), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0190] R L2 is selected from halogen; preferably chlorine or bromine;

[0191] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium;

[0192] Ring B, X1, X2, X3, R 1a 、R 1d , R2, R 3a , R5, R6, x, p and z are as described in any of the above embodiments.

[0193] The present invention also provides a method for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following step 1:

[0194] The compound represented by general formula (VII-B) and the compound represented by general formula (VII-C) are subjected to coupling reaction to obtain the compound represented by general formula (I);

[0195] Optionally, further comprising step 2:

[0196] The compound represented by general formula (VII) reacts with the compound represented by general formula (VII-A) under alkaline conditions to obtain the compound represented by general formula (VII-B);

[0197] R L4 Selected from -OH, -SH; preferably -OH;

[0198] R L2 is selected from halogen; preferably chlorine or bromine;

[0199] R L3 Selected from halogen, hydroxyl or -S(O) m1 -C 1-3 Alkyl; preferably chlorine, bromine, -S(O)-CH3 or -S(O)2-CH3;

[0200] R L5 is selected from boronic acid, borate, chain borate or cyclic borate;

[0201] m1 is selected from 0, 1 or 2;

[0202] Ring A, Ring B, X1, X2, X3, L1, L2, R 1a 、R 1b 、R 1c 、R 1d , R2, R 3a , R4, R5, x, y, z, n1 and n2 are as described in any of the above embodiments.

[0203] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (II-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step 1:

[0204] The compound represented by the general formula (VII-F) and the compound represented by the general formula (VII-G) are subjected to a coupling reaction to obtain the compound represented by the general formula (II-D);

[0205] Optionally, further comprising step 2:

[0206] The compound represented by general formula (VII-D) reacts with the compound represented by general formula (VII-E) under alkaline conditions to obtain the compound represented by general formula (VII-F);

[0207] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium;

[0208] R L2 is selected from halogen; preferably chlorine or bromine;

[0209] R L3 Selected from halogen, hydroxyl or -S(O) m1 -C 1-3 Alkyl; preferably chlorine, bromine, -S(O)-CH3 or -S(O)2-CH3;

[0210] R L5 is selected from boronic acid, borate, chain borate or cyclic borate;

[0211] m1 is selected from 0, 1 or 2;

[0212] Ring B, X1, X2, X3, R 1a 、R 1d , R2, R 3a 、R 4a 、R4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R5, R6, x, p or z are as described in any of the above embodiments;

[0213] When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution.

[0214] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (II-E), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step 1:

[0215] The compound represented by the general formula (VII-F) and the compound represented by the general formula (VII-H) are subjected to a coupling reaction to obtain the compound represented by the general formula (II-E);

[0216] Optionally, further comprising step 2:

[0217] The compound represented by general formula (VII-D) reacts with the compound represented by general formula (VII-E) under alkaline conditions to obtain the compound represented by general formula (VII-F);

[0218] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium;

[0219] R L2 is selected from halogen; preferably chlorine or bromine;

[0220] R L3 Selected from halogen, hydroxyl or -S(O) m1 -C 1-3 Alkyl; preferably chlorine, bromine, -S(O)-CH3 or -S(O)2-CH3;

[0221] R L5 is selected from boronic acid, borate, chain borate or cyclic borate;

[0222] m1 is selected from 0, 1 or 2;

[0223] Ring B, X1, X2, X3, X4, R1a 、R 1d , R2, R 3a 、R 9a 、R 9b 、R 9c 、R 9d 、R 9e , R5, R6, x, p or z are as described in any of the above embodiments.

[0224] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0225] The compound represented by the general formula (VII-I) reacts with the compound represented by the general formula (VII-J) under alkaline conditions to obtain the compound represented by the general formula (VII-K); the compound represented by the general formula (VII-K) and the compound represented by the general formula (VII-G) undergo a coupling reaction to obtain the compound represented by the general formula (VII-L), and the protecting group is further removed to obtain the compound represented by the general formula (III-A);

[0226] R L2 is selected from halogen; preferably chlorine or bromine;

[0227] R L3 Selected from halogen, hydroxyl or -S(O) m1 -C 1-3 Alkyl; preferably chlorine, bromine, -S(O)-CH3 or -S(O)2-CH3;

[0228] R L5 is selected from boronic acid, borate, chain borate or cyclic borate;

[0229] m1 is selected from 0, 1 or 2;

[0230] Ring B, X1, X2, R 1a 、R 1d , R2, R 3a 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R6, R 7b 、R 7c , R8, x, p, q, n8 and Pg are as described in any of the above embodiments;

[0231] When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution;.

[0232] In a preferred embodiment, the preparation method is a method for preparing a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0233] The compound represented by the general formula (VII-I) reacts with the compound represented by the general formula (VII-K) under alkaline conditions to obtain the compound represented by the general formula (VII-M); the compound represented by the general formula (VII-M) reacts with the compound represented by the general formula (VII-G) through a coupling reaction to obtain the compound represented by the general formula (VII-N), and the protecting group is further removed to obtain the compound represented by the general formula (IV);

[0234] R L2 is selected from halogen; preferably chlorine or bromine;

[0235] R L3 Selected from halogen, hydroxyl or -S(O) m1 -C 1-3 Alkyl; preferably chlorine, bromine, -S(O)-CH3 or -S(O)2-CH3;

[0236] R L5 is selected from boronic acid, borate, chain borate or cyclic borate;

[0237] m1 is selected from 0, 1 or 2;

[0238] Ring B, X1, X2, R 1a 、R 1d , R2, R 3a 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R6, R 6b 、R 7b 、R 7c , x, p, n8 and Pg are as described in any of the above embodiments;

[0239] When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution.

[0240] In a preferred embodiment, R L4 Selected from substituted or unsubstituted Preferred

[0241] R L6Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl;

[0242] a is selected from 0, 1, 2, 3, 4, 5 or 6;

[0243] In a preferred embodiment, the coupling reaction is carried out in the presence of a palladium catalyst;

[0244] In a preferred embodiment, the palladium catalyst is selected from palladium carbon, palladium acetate, diphenylphosphinoferrocene palladium dichloride, tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [(bis(1-adamantyl)butylphosphino)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, methanesulfonate (dimethyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct or methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II);

[0245] In a preferred embodiment, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide or lithium bis(trimethylsilyl)amide; preferably sodium hydride or lithium bis(trimethylsilyl)amide.

[0246] The present invention also provides a preferred embodiment, which relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds described in the above texts, its stereoisomers or pharmaceutically acceptable salts or prodrugs thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0247] The present invention further relates to the use of the compound described in the above text, its stereoisomers or pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition in the preparation of KRAS inhibitor drugs; preferably, in drugs for KRAS G12D, KRAS G12V, and KRAS G13D mutations.

[0248] The present invention also provides a preferred embodiment, and also relates to a method for treating, preventing and / or treating a condition mediated by a KRAS inhibitor using the compound, its stereoisomer or its pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition, which comprises administering to a patient a therapeutically effective dose of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt or prodrug, or its pharmaceutical composition.

[0249] The present invention also provides a preferred embodiment, involving the use of the compound described herein, its stereoisomer or pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition in the preparation of a drug for treating diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer and colon cancer; preferably non-small cell lung cancer, colon cancer, esophageal cancer and head and neck tumors.

[0250] The present invention also provides a preferred embodiment, relating to the use of the compounds and compositions of the present invention in treating diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer.

[0251] In some embodiments, the present invention provides a method of treating a cancer condition comprising administering to a patient suffering from the cancer condition a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0252] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60% or 50%.

[0253] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0254] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0255] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0256] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0257] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0258] In some embodiments, the cancer treated by the compounds or compositions of the present invention is Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck cancer, gastric cancer, lung cancer and colon cancer; preferably non-small cell lung cancer, colon cancer, esophageal cancer, head and neck cancer.

[0259] Detailed Description of the Invention

[0260] 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.

[0261] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C3-6 ) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6 Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0262] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0263] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be located at any position within the alkenyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkenyl group is an unsaturated aliphatic hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0264] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C2-6 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.

[0265] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a particular embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0266] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxygen, but does not include the ring portion of -OO- or -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl group contains 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl group contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclyl group contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.In one embodiment, described heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0267] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclyl is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl is an optionally substituted or fused heterocyclyl described elsewhere herein, or a cycloalkyl, heterocyclyl, aryl or heteroaryl group; non-limiting examples of fused heterocyclyls include:

[0268] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In specific embodiments, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups; preferably bicyclic, tricyclic or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0269] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted with one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is aromatic and the other rings may be saturated, partially unsaturated, or a ring containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl group, a benzo 3-10 membered cycloalkyl group, or a benzo 3-10 membered heterocyclyl group. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl group, a benzo 3-6 membered cycloalkyl group, or a benzo 3-6 membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

[0270] 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.

[0271] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, the heteroaryl group contains 5 to 20, 5 to 15 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in particular embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from a heteroaryl group with 6-10 members, a heteroaryl group with 3-10 members, or a heteroaryl group with 3-10 members, and a heterocyclyl group with 3-10 members. In another embodiment, the heteroaryl group is selected from a 5- or 6-membered heteroaryl group with 6-10 members, a 5- or 6-membered heteroaryl group with 3-6 members, and a 5- or 6-membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothienyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0272] 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.

[0273] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0274] 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.

[0275] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0276] 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,

[0277] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0278] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0279] 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.

[0280] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0281] 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.

[0282] The term "aminocarbonyl" refers to NH2-C(O)-.

[0283] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0284] The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0285] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0286] The term "hydroxy" refers to an -OH group.

[0287] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0288] The term "acetyl" refers to -C(O)CH3.

[0289] The term "oxo" or "oxo" refers to =0.

[0290] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

[0291] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituents are selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

[0292] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0293] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0294] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0295] " substituted " refers to 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 a substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" refers to that it may be substituted or not, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical achievable. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0296] 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.

[0297] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0298] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0299] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0300] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0301] "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.

[0302] "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.

[0303] "Optically active" and "enantiomerically active" refer to a composition of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate. When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). (+) 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., it rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., it rotates the plane of polarized light to the right or clockwise. However, the signs of optical rotation (+) and (-) have nothing to do with the absolute configuration of the molecule, R or S. DETAILED DESCRIPTION

[0304] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0305] Example

[0306] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0307] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0308] HPLC determination was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0309] Average kinase inhibition rate and IC50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0310] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0311] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0312] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0313] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0314] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0315] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0316] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0317] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0318] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0319] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0320] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0321] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0322] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0323] Intermediate 1

[0324] Preparation of 4-(difluoromethylene)piperidine trifluoroacetate

[0325] Step 1: tert-Butyl 4-(difluoromethylene)piperidine-1-carboxylate

[0326] THF (300 mL) was added to a three-necked flask. After nitrogen replacement, the temperature was lowered to 0°C, and dibromodifluoromethane (42.12 g, 200.76 mmol) was added. The mixture was stirred for 10 minutes, followed by HMPT (32.76 g, 200.76 mmol). Stirring continued for 1 hour, followed by tert-butyl 4-carbonylpiperidine-1-carboxylate (10 g, 50.19 mmol). The temperature was gradually warmed to room temperature and stirred for 1 hour. Zinc powder (12.85 g, 200.76 mmol) and HMPT (2 mL) were added, and the mixture was heated to 70°C and refluxed for 3 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (4.5 g, 38.4% yield).

[0327] Step 2: Preparation of 4-(difluoromethylene)piperidinium trifluoroacetate

[0328] Tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (380 mg, 1.63 mol) was added to dichloromethane (20 mL), and TFA (3 mL) was added dropwise under ice bath. After the reaction solution was evenly mixed, it was reacted at room temperature for 1 hour and concentrated under reduced pressure to obtain the crude compound 4-(difluoromethylene)piperidine trifluoroacetate (400 mg, TF salt, yield 99%).

[0329] MS m / z(ESI):134[M+H].

[0330] Intermediate 2

[0331] Step 1: tert-Butyl 4-(methoxyimino)piperidine-1-carboxylate

[0332] Dissolve tert-butyl 4-carbonylpiperidine-1-carboxylate (1.59 g, 8 mmol) and O-methylhydroxylamine hydrochloride (801.77 mg, 9.60 mmol) in EtOH (20 mL). Under nitrogen purge, add K2CO3 (3.32 g, 24.00 mmol) and heat under reflux for 3 hours. Concentrate the reaction mixture and extract with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the organic phase to yield tert-butyl 4-(methoxyimino)piperidine-1-carboxylate (1.2 g, 65.71%).

[0333] MS m / z(ESI):229[M+H].

[0334] Step 2: N-methoxypiperidin-4-imine trifluoroacetate

[0335] To a solution of tert-butyl 4-methoxyiminopiperidine-1-carboxylate (3 g, 13.1 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL) at room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford N-methoxypiperidin-4-imine trifluoroacetate (3.18 g, 100% yield).

[0336] MS m / z(ESI):129[M+H].

[0337] Intermediate 3

[0338] Step 1: Preparation of tert-butyl 3-(fluoromethylene)pyrrolidine-1-carboxylate

[0339] The substrate (fluoromethyl)triphenylphosphonium tetrafluoroborate (14.91 g, 39.02 mmol) was dissolved in THF (100 mL) and purged under nitrogen. The mixture was cooled to -25°C and NaHMDS (7.16 g, 39.02 mmol) was added dropwise. After complete addition, the mixture was stirred for 10 minutes. Then, a solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (5.56 g, 30.02 mmol) in THF (60 mL) was added dropwise. After complete addition, the mixture was stirred for 10 minutes, then warmed to room temperature and stirred for 3 hours. The reaction mixture was slowly added to saturated aqueous NH4Cl solution for quenching. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to yield the target compound, 3-(fluoromethylene)pyrrolidine-1-carboxylate (3.1 g, 51.3% yield).

[0340] MS m / z(ESI):202[M+H].

[0341] Step 2: Preparation of 3-(fluoromethylene)pyrrolidine trifluoroacetate

[0342] The substrate, 3-(fluoromethylene)pyrrolidine-1-carboxylate (150 mg, 745.39 μmol), was dissolved in anhydrous dichloromethane (2 mL). TFA (0.5 mL) was added and stirred at room temperature for 1 hour. Concentration afforded the crude target compound, 3-(fluoromethylene)pyrrolidine trifluoroacetate (140 mg, crude), which was used directly in the next step.

[0343] MS m / z(ESI):102[M+H].

[0344] Intermediate 4

[0345] Step 1: Preparation of tert-butyl 4-(fluoromethylene)azacyclohexane-1-carboxylate

[0346] (Fluoromethyl)triphenylphosphonium tetrafluoroborate (23.29 g, 60.95 mmol) was added to tetrahydrofuran (300 mL), followed by 18-crown-6 (2.48 g, 9.38 mmol) and a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (56.27 mL, 56.27 mmol). The mixture was cooled to 0°C, and tert-butyl 4-oxoazacyclopentane-1-carboxylate (10 g, 46.89 mmol) was added. The mixture was maintained at 0°C for 20 minutes and then heated to room temperature overnight. Water was added, the mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give tert-butyl 4-(fluoromethylene)azacyclohexane-1-carboxylate (9.58 g, 89.1% yield).

[0347] MS m / z(ESI):230[M+H].

[0348] Step 2: Preparation of 4-(fluoromethylene)azacyclohexane hydrochloride

[0349] Tert-butyl 4-(fluoromethylene)azepane-1-carboxylate (9.58 g, 41.78 mmol) was added to dichloromethane (50 mL), followed by a 4.0 M hydrochloric acid ethyl acetate solution (70 mL), and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain 4-(fluoromethylene)azepane hydrochloride (3.8 g, 99.7% yield).

[0350] MS m / z(ESI):130[M+H].

[0351] Step 3: Preparation of methyl 1-(4-(fluoromethylene)aziridine-1-carbonyl)cyclopropane-1-carboxylate

[0352] 1-Methoxycarbonylcyclopropanecarboxylic acid (7.31 g, 50.71 mmol) was added to dichloromethane (70 mL), followed by N,N-diisopropylethylamine (16.39 g, 126.78 mmol). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (17.54 g, 46.49 mmol) was added portionwise at room temperature. 4-(Fluoromethylene)azacyclohexane hydrochloride (7 g, 42.26 mmol) was added portionwise at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added, the mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to afford methyl 1-(4-(fluoromethylene)azacyclohexane-1-carbonyl)cyclopropane-1-carboxylate (4.8 g, 44.5% yield).

[0353] MS m / z(ESI):256[M+H].

[0354] Step 4: Preparation of (1-((4-(fluoromethylene)azepan-1-yl)methyl)cyclopropyl)methanol

[0355] Methyl 1-(4-(fluoromethylene)azepan-1-carbonyl)cyclopropane-1-carboxylate (4.8 g, 18.80 mmol) was added to tetrahydrofuran (50 mL). Under nitrogen, a 2.5 M solution of lithium aluminum hydride (15.47 mL, 21.45 mmol) in tetrahydrofuran was added dropwise at 0-10°C. The mixture was allowed to react at room temperature for 2 hours. Sodium sulfate decahydrate (9.6 g, 29.80 mmol) was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain the compound (1-((4-(fluoromethylene)azepan-1-yl)methyl)cyclopropyl)methanol (3.4 g, 86.6% yield).

[0356] MS m / z(ESI):214[M+H].

[0357] Intermediate 5

[0358] Step 1: Preparation of 1-tert-butyl 4-methyl-5-oxo-azacyclohexane-1,4-dicarboxylate

[0359] NaH (1.55 g, 64.59 mmol) was dissolved in DMF (60 mL) and stirred. The mixture was cooled to 0°C under nitrogen atmosphere and a solution of 1-Boc-5-oxoazacycloheptane-carboxylic acid ethyl ester (10 g, 35.05 mmol) in DMF (40 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0°C and iodomethane (12.5 g, 88.03 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by slowly adding 200 mL of water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-tert-butyl 4-methyl-5-oxoazacyclohexane-1,4-dicarboxylate (10.7 g, crude product), which was used directly in the next reaction.

[0360] MS m / z(ESI):300[M+H].

[0361] Step 2: Preparation of tert-butyl 4-methyl-5-oxo-azacyclopentane-1-carboxylate

[0362] The substrate, 1-tert-butyl 4-methyl-5-oxo-azacyclopentane-1,4-dicarboxylate (8.0 g, 26.72 mmol), was dissolved in dioxane (80 mL). A solution of KOH (7.5 g, 133.68 mmol) in water (56 mL) was added, and the mixture was heated to 100°C and stirred overnight. The mixture was diluted with 300 mL of water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the target compound, tert-butyl 4-methyl-5-oxo-azacyclopentane-1-carboxylate (3.8 g).

[0363] MS m / z(ESI):228[M+H].

[0364] Step 3: Preparation of tert-butyl 4-(difluoromethylene)-5-methyl-azacyclopentane-1-carboxylate

[0365] 4-Methyl-5-oxo-azacyclopentane-1-carboxylic acid tert-butyl ester (1.0 g, 4.4 mmol) was dissolved in THF (20 mL) and cooled to 0°C under nitrogen purge. HMPT (2.87 g, 17.61 mmol) and CF2Br2 (3.7 g, 17.63 mmol) were added. The reaction mixture was warmed to room temperature, and zinc powder (1.15 g, 17.69 mmol) and HMPT (10 mg, 0.06 mmol) were added. The mixture was heated to 70°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered, and rinsed with dichloromethane (50 mL) to obtain a filtrate. The filtrate was concentrated and purified by silica gel chromatography to obtain tert-butyl 4-(difluoromethylene)-5-methyl-azacyclopentane-1-carboxylate (350 mg, 30.4% yield).

[0366] MS m / z(ESI):262[M+H].

[0367] Step 4: Preparation of 4-(difluoromethylene)-5-methylazacyclohexane hydrochloride

[0368] 4-(Difluoromethylene)-5-methyl-azacyclohexane-1-carboxylic acid tert-butyl ester (250 mg, 0.96 mmol) was dissolved in DCM (5 mL), and HCl / EtOAc (4 M, 5 mL) was added dropwise. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated to give 4-(difluoromethylene)-5-methylazacyclohexane hydrochloride (240 mg, crude product), which was used directly in the next reaction.

[0369] MS m / z(ESI):162[M+H].

[0370] Intermediate 6

[0371] Step 1: Preparation of tert-butyl 5-(fluoromethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0372] (Fluoromethyl)triphenylphosphine tetrafluoroborate (52.9 g, 138.49 mmol) and 18-crown-6 (6.06 g, 22.93 mmol) were added to tetrahydrofuran (500 mL). Potassium tert-butoxide solution (128 mL, 1 M in THF) was added under nitrogen. The reaction mixture was cooled to 0°C, and tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate solution (24 g, 106.5 mmol) was added dropwise at 0°C. The reaction mixture was gradually allowed to return to room temperature and stirred overnight. Upon completion, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to afford tert-butyl 5-(fluoromethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (17 g, 66.1% yield).

[0373] MS m / z(ESI):242[M+H].

[0374] Step 2: Preparation of 5-(fluoromethylene)octahydrocyclopentadiene

[0375] tert-Butyl 5-(fluoromethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (17 g, 70.45 mmol) was added to 10 mL of ethyl acetate. A solution of hydrogen chloride in ethyl acetate (141 mL, 563 mmol, 4 M in EtOAc) was added to the reaction flask. After 1 hour of reaction, the mixture was concentrated under reduced pressure, adjusted to neutrality with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 5-(fluoromethylene)octahydrocyclopentadiene (9.9 g, 99% yield).

[0376] MS m / z(ESI):142[M+H].

[0377] Step 3: Preparation of methyl 1-(5-(fluoromethylene)octahydrocyclopenta[c]pyrrole-2-carbonyl)cyclopropane-1-carboxylate

[0378] The raw materials 1-methoxycarbonylcyclopropanecarboxylic acid (12 g, 85 mmol), diisopropylethylamine (28 g, 216 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29 g, 77 mmol) were added to 170 mL of dichloromethane. The mixture was stirred at room temperature for 5 minutes. 5-(Fluoromethylene)octahydrocyclopentadiene (9.9 g, 70 mmol) was dissolved in dichloromethane and slowly added dropwise to the reaction flask at 0°C. The mixture was slowly allowed to return to room temperature and stirred for 2 hours. Upon completion of the reaction, water was added to quench the reaction, followed by extraction with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to yield methyl 1-(5-(Fluoromethylene)octahydrocyclopenta[c]pyrrole-2-carbonyl)cyclopropane-1-carboxylate (17 g, 89.8% yield).

[0379] MS m / z(ESI):268[M+H].

[0380] Step 4: Preparation of (1-((5-(fluoromethylene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methanol

[0381] Lithium aluminum hydride (51 mL, 126 mmol, 2.5 M in THF) was added to 160 mL of tetrahydrofuran solution, the atmosphere was replaced with nitrogen, and the solution was cooled to 0°C. Methyl 1-(5-(fluoromethylene)octahydrocyclopenta[c]pyrrol-2-carbonyl)cyclopropane-1-carboxylate (16 g, 60 mmol) was slowly added to the reaction system. After stirring for 5 minutes, the solution was returned to room temperature and stirred for 1 hour. After completion of the reaction, 32 g of sodium tartrate was added to the reaction system in small portions to quench the reaction. The reaction system was filtered through celite and washed with ethyl acetate. The organic phase was concentrated under reduced pressure to provide (1-((5-(fluoromethylene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methanol (12.7 g, 94.2% yield).

[0382] MS m / z(ESI):226[M+H].

[0383] Intermediate 7

[0384] Step 1: Preparation of tert-butyl (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0385] Tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (354 g, 1.46 mol) was added to acetonitrile (2100 mL) and water (525 mL), and potassium carbonate (404.03 g, 2.92 mol) and benzyl bromide (275.01 g, 1.61 mol) were added. The mixture was stirred at room temperature for 1 hour, the layers were separated, and the mixture was concentrated and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound tert-butyl (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (410 g, yield 84.4%).

[0386] MS m / z(ESI):333[M+H].

[0387] Step 2: Preparation of tert-butyl (1S,2S,5R)-3-benzyl-2-((methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0388] To tert-butyl (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13 g, 39.11 mmol) and N,N-diisopropylethylamine (22.74 g, 175.97 mmol) were added to dichloromethane (130 mL), and bromomethyl methyl ether (19.55 g, 156.42 mmol) was added at 0-10°C. The mixture was stirred at room temperature for 16 hours, and water was added. The aqueous layer was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the compound tert-butyl (1S,2S,5R)-3-benzyl-2-((methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.7 g, yield 65.9%).

[0389] MS m / z(ESI):377[M+H].

[0390] Step 3: Preparation of tert-butyl (1R,4S,5S)-3-benzyl-1-formyl-4-((methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0391] (1S, 2S, 5R) -3-benzyl -2- ((methoxymethoxy) methyl) -3,8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (9.7 g, 25.76 mmol) and N, N, N', N'-tetramethylethylenediamine (14.97 g, 128.82 mmol) were added to tetrahydrofuran (100 mL), and sec-butyl lithium (1.3 M cyclohexane solution, 39.64 mL) was added dropwise at -40 ° C under nitrogen protection. Stir at -40 ° C for 2 hours. Methyl formate (7.74 g, 128.82 mmol) was added dropwise to the reaction mixture at -40 ° C under nitrogen protection, and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution was added dropwise to quench the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give tert-butyl (1R,4S,5S)-3-benzyl-1-formyl-4-((methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.7 g, yield 54.7%).

[0392] MS m / z(ESI):405[M+H].

[0393] Step 4: Preparation of tert-butyl (1R,4S,5S)-3-benzyl-1-(hydroxymethyl)-4-(methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0394] Tert-butyl (1R,4S,5S)-3-benzyl-1-formyl-4-((methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.7 g, 14.09 mmol) was added to methanol (57 mL). NaBH4 (1.07 g, 28.18 mmol) was added at 0-10°C and stirred at room temperature for 1 hour. Water was added, and the mixture was concentrated to remove methanol to obtain a crude product. Ethyl acetate was added, and the separated aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain tert-butyl (1R,4S,5S)-3-benzyl-1-(hydroxymethyl)-4-(methoxymethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 82.1% yield).

[0395] MS m / z(ESI):407[M+H].

[0396] Step 5: Preparation of tert-butyl (1R,4S,5S)-3-benzyl-4-((methoxymethoxy)methyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0397] Tert-butyl (1R,4S,5S)-3-benzyl-1-(hydroxymethyl)-4-(methoxymethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 11.56 mmol) was added to tetrahydrofuran (47 mL), and 60% sodium bicarbonate (1.83 g, 76.31 mmol) was added under ice bath. The mixture was reacted at room temperature for 1 hour, and iodomethane (49.25 g, 346.85 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give the compound (1R,4S,5S)-3-benzyl-4-((methoxymethoxy)methyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.4 g, yield 69.9%).

[0398] MS m / z(ESI):421[M+H].

[0399] Step 6: Preparation of tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0400] Tert-butyl (1R,4S,5S)-3-benzyl-4-((methoxymethoxy)methyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.4 g, 8.09 mmol) was added to ethyl acetate (20 mL), followed by a 4.0 M hydrochloric acid ethyl acetate solution (31.36 mL, 125.44 mmol), and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and dichloromethane (30 mL) was added, along with N,N-diisopropylethylamine (5.40 g, 41.82 mmol) and di-tert-butyl dicarbonate (2.74 g, 12.55 mmol), and stirred at room temperature for 1 hour. The residue was concentrated under reduced pressure and purified by silica gel chromatography to give tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, yield 82.0%).

[0401] MS m / z(ESI):377[M+H].

[0402] Step 7: Preparation of tert-butyl (1R,4S,5S)-4-(hydroxymethyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0403] (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.5 g, 6.64 mmol) was added to methanol (20 mL), and 10% palladium hydroxide (1.30 g, 9.30 mmol) was added. The mixture was stirred at room temperature for 16 hours under a 0.3-0.4 MPa hydrogen atmosphere. The mixture was heated to 80°C and stirred for 8 hours. The mixture was filtered through a celite pad, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound (1R,4S,5S)-4-(hydroxymethyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.8 g, 94.7% yield).

[0404] MS m / z(ESI):287[M+H].

[0405] Step 8: Preparation of tert-butyl (1R, 4S, 4S, 5S)-4-[(7-chloro-8-fluoro-4-hydroxy-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-yl)oxymethyl]-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0406] Tert-butyl (1R,4S,5S)-4-(hydroxymethyl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.88 g, 6.57 mmol) was added to tetrahydrofuran (25 mL), and 60% sodium hydroxide (1.13 g, 28.23 mmol) was added under ice-cooling. The mixture was allowed to react under ice-cooling for 1 hour. 5,7-Dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-ol (2.21 g, 7.88 mmol) was added portionwise at 0-10°C over 2 minutes, and the mixture was stirred at 65°C for 1 hour. Water and ethyl acetate were added for extraction, the layers were separated, the aqueous phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound tert-butyl (1R, 4S, 4S, 5S) -4- [(7-chloro-8-fluoro-4-hydroxy-2-methylsulfanyl-pyrido [4, 3-d] pyrimidin-5-yl) oxymethyl] -1- (methoxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (3.48 g, yield 100%).

[0407] MS m / z(ESI):530[M+H].

[0408] Step 9: Preparation of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-9-(methoxymethyl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0409] Tert-butyl (1R,4S,4S,5S)-4-[(7-chloro-8-fluoro-4-hydroxy-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-yl)oxymethyl]-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.48 g, 6.57 mmol) and N,N-diisopropylethylamine (4.24 g, 32.83 mmol) were added to chloroform (40 mL), and bis(2-oxo'-3-oxazolidinyl)phosphinoyl chloride (3.34 g, 13.13 mmol) was added, and the mixture was stirred at 65° C. for 1 hour. The mixture was cooled to room temperature, and water and dichloromethane were added. The aqueous phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give the compound (5aS,6S,9R)-2-chloro-1-fluoro-9-(methoxymethyl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphthalene[1,8-ab]heptene-4-carboxylic acid tert-butyl ester (2.17 g, yield 64.6%).

[0410] MS m / z(ESI):512[M+H].

[0411] Intermediate 8

[0412] Step 1: Preparation of tert-butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0413] Dissolve (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (28 g, 83.97 mmol) in dichloromethane (280 mL) and water (280 mL), add 2,2,6,6-tetramethylpiperidinoxide (1.26 g, 8.08 mmol) and sodium bicarbonate (33.95 g, 404.08 mmol), and add 2,2,6,6-tetramethylpiperidinoxide (1.26 g, 8.08 mmol) and 1,0-dextrose (2,0-dextrose) under ice-cooling. Aqueous sodium hypochlorite solution (42.11 g, 565.72 mmol) was added, and the reaction was carried out under ice bath for 20 minutes. The mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (10.5 g, yield 37.7%).

[0414] MS m / z(ESI):331[M+H].

[0415] Step 2: Preparation of tert-butyl (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0416] Dissolve (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (10.5 g, 31.78 mmol) in tetrahydrofuran (100 mL), replace with nitrogen, cool to -60°C, add methylmagnesium bromide (4.73 g, 39.63 mmol) dropwise, slowly warm to 0°C and react for 2 hours. Quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel chromatography to obtain the compound (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (9.64 g, yield 87.7%).

[0417] MS m / z(ESI):347[M+H].

[0418] Step 3: Preparation of tert-butyl (1S,2S,5R)-2-acetyl-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0419] Tert-butyl (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.64 g, 27.81 mmol) was dissolved in dichloromethane (100 mL). Dess-Martin periodinane (17.01 g, 40.11 mmol) was added portionwise under ice-cooling. After addition, the mixture was heated to room temperature and reacted for 2 hours. The mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain tert-butyl (1S,2S,5R)-2-acetyl-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.1 g, yield 94.9%).

[0420] MS m / z(ESI):345[M+H].

[0421] Step 4: Preparation of tert-butyl (1S,2S,5R)-3-benzyl-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0422] Dissolve (1S,2S,5R)-2-acetyl-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (9.10 g, 26.42 mmol) in tetrahydrofuran (100 mL), replace with nitrogen, cool to -60°C, add methylmagnesium bromide (3.94 g, 33.00 mmol) dropwise, slowly warm to 0°C and react for 2 hours. Quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel chromatography to obtain the compound (1S,2S,5R)-3-benzyl-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2 g, yield 21.0%).

[0423] MS m / z(ESI):361[M+H].

[0424] Step 5: Preparation of tert-butyl (1S,2S,5R)-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0425] Tert-butyl (1S,2S,5R)-3-benzyl-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 g, 5.55 mmol) was dissolved in methanol (20 mL), and palladium hydroxide (1 g, 10%) was added. The mixture was replaced with hydrogen and reacted at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel chromatography to obtain tert-butyl (1S,2S,5R)-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (903 mg, yield 60.2%).

[0426] MS m / z(ESI):271[M+H].

[0427] Intermediate 9

[0428] Step 1: Preparation of tert-butyl (1S,2S,5R)-3-benzyl-2-((S)-cyclopropyl(hydroxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0429] Dissolve tert-butyl (1R,2R,5S)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 4.24 mmol) in tetrahydrofuran (30 mL), replace the atmosphere with nitrogen, and cool to 0°C. Cyclopropylmagnesium bromide solution (8.5 mL, 8.47 mmol, 1 M in THF) is slowly added dropwise. The reaction is incubated for half an hour, then slowly warmed to room temperature and stirred for 3 hours. After completion of the reaction, the mixture is quenched with water, extracted with ethyl acetate, and washed with saturated brine. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel chromatography to afford tert-butyl (1S,2S,5R)-3-benzyl-2-((S)-cyclopropyl(hydroxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 76.0% yield).

[0430] MS m / z(ESI):373[M+H].

[0431] Step 2: Preparation of tert-butyl (1S,2S,5R)-2-((S)-cyclopropyl(hydroxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0432] The raw material (1S,2S,5R)-3-benzyl-2-((S)-cyclopropyl(hydroxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.18 g, 3.17 mmol) was dissolved in 20 mL of methanol, and 600 mg of palladium hydroxide / carbon (10% wt) was weighed and added to the reaction solution. The reaction flask was placed in a hydrogen bomb, set to a pressure of 65 psi, and the hydrogen was replaced three times. After reacting for 4 hours at room temperature, the reaction solution was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain (1S,2S,5R)-2-((S)-cyclopropyl(hydroxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (810 mg, 90.6% yield).

[0433] MS m / z(ESI):283[M+H].

[0434] Intermediate 10

[0435] Step 1: Preparation of 1-(tert-butyl)-2-methyl(R)-4-(difluoromethylene)pyrrolidine-1,2-dicarboxylate

[0436] To a solution of dibromo(difluoro)methane (10.35 g, 49.3 mmol, 4.5 mL) in tetrahydrofuran (300 mL) was added hexamethylphosphorus triamide (8.83 g, 49.3 mmol, 10.6 mL) at 0°C. Stir at 0°C for 1 hour. Add dropwise a solution of 1-(tert-butyl)-2-methyl(R)-4-oxopyrrolidine-1,2-dicarboxylate (3 g, 12.3 mmol) in tetrahydrofuran (200 mL) at 0°C. After addition, slowly warm to room temperature and stir for 1 hour. Add zinc powder (3.23 g, 49.3 mmol) and hexamethylphosphorus triamide (550 mg, 3.07 mmol). After addition, stir at 70°C for 4 hours. Water (300 mL) was added, extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give 1-(tert-butyl) 2-methyl (R)-4-(difluoromethylene) pyrrolidine-1,2-dicarboxylate (2 g, yield: 58%).

[0437] MS m / z(ESI):278[M+H].

[0438] Step 2: Preparation of tert-butyl (2R)-4-(difluoromethylene)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0439] To a solution of 1-(tert-butyl)-2-methyl (R)-4-(difluoromethylene)pyrrolidine-1,2-dicarboxylate (2 g, 7.21 mmol) in tetrahydrofuran (20 mL) was added lithium borohydride (1.43 g, 65.66 mmol) at 0°C and stirred at room temperature for 2 hours. Aqueous ammonium chloride (50 mL) was slowly added dropwise to the reaction mixture at 0°C and stirred for another hour. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl (2R)-4-(difluoromethylene)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.7 g, 95% yield).

[0440] MS m / z(ESI):250[M+H].

[0441] Step 3: Preparation of [(2R)-4-(difluoromethylene)pyrrolidin-2-yl]methanol trifluoroacetate

[0442] To a solution of tert-butyl (2R)-4-(difluoromethylene)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (200 mg, 0.8 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford [(2R)-4-(difluoromethylene)pyrrolidin-2-yl]methanol trifluoroacetate (211 mg, 100% yield).

[0443] MS m / z(ESI):150[M+H].

[0444] Intermediate 11

[0445] Step 1: Preparation of (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one

[0446] In an eggplant-shaped flask, 4-methoxyaniline (12.68 g, 102.99 mmol) and (S)-proline (3.23 g, 28.09 mmol) were dissolved in 240 mL of DMSO. The atmosphere was purged with nitrogen, and paraformaldehyde (13.16 M, 7.11 mL) and 2-cyclohexen-1-one (18 g, 187.25 mmol) were quickly added. The mixture was reacted in an oil bath at 50°C for 24 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one (2.3 g, 10.6% yield).

[0447] MS m / z(ESI):246[M+H].

[0448] Step 2: Preparation of (1S,4R)-5-(difluoromethylene)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane

[0449] In a 250 mL three-necked flask, add THF (60 mL), replace the atmosphere with nitrogen, and cool in an ice bath for 5 minutes. After cooling, add dibromo(difluoro)methane (10.43 g, 49.72 mmol). Using a separate syringe, slowly inject tri(dimethylamino)phosphine (8.11 g, 49.72 mmol) into the reaction mixture and allow to react in an ice bath for 1 hour. Dissolve (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one (2.30 g, 9.94 mmol) in 20 mL of tetrahydrofuran and slowly add to the reaction mixture. After addition, bring the reaction mixture to room temperature and stir for 1 hour. Add zinc powder (3.25 g, 49.72 mmol) and an additional 0.5 mL of tri(dimethylamino)phosphine. Allow to react in an oil bath at 75°C overnight. The reaction mixture was cooled to room temperature, and water was added to quench the reaction mixture. The filtrate was filtered and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give (1S,4R)-5-(difluoromethylene)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane (900 mg, yield: 34.1%).

[0450] MS m / z(ESI):280[M+H].

[0451] Step 3: Preparation of (1S,4R)-5-(difluoromethylene)-2-azabicyclo[2.2.2]octane

[0452] In an eggplant-shaped flask, (1S,4R)-5-(difluoromethylene)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octane (945 mg, 3.39 mmol) was dissolved in 20 mL of acetonitrile and 10 mL of water. Separately, cerium ammonium nitrate (3.60 g, 6.78 mmol) was dissolved in 1 mL of water using an EP tube. This was added to the reaction mixture under ice for 30 minutes. After completion of the reaction, the mixture was quenched with saturated sodium sulfite solution, and the filtrate was lyophilized. The resulting solid was diluted with ethyl acetate, filtered, and the organic phase concentrated to yield (1S,4R)-5-(difluoromethylene)-2-azabicyclo[2.2.2]octane (530 mg, 98.2% yield).

[0453] MS m / z(ESI):160[M+H].

[0454] Intermediate 12

[0455] Step 1: Preparation of tert-butyl 4-(2,2,2-trifluoroethylidene)piperidine-1-carboxylate

[0456] A Schlenk tube was charged with tert-butyl 4-(2,2,2-trifluoroethylidenepiperidine-1-carboxylate (500 mg, 2.53 mmol), tris(2-phenylpyridine)iridium (49.79 mg, 76.04 μmol), S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate (1.03 g, 3.04 mmol), and 25 mL of N,N-dimethylformamide. The atmosphere was purged with nitrogen and the reaction was allowed to proceed overnight in a photoreactor. After completion of the reaction, the mixture was diluted with water and then ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford tert-butyl 4-(2,2,2-trifluoroethylidene)piperidine-1-carboxylate (359 mg, 53.4% ​​yield).

[0457] MS m / z(ESI):210[M-tBu].

[0458] Step 2: Preparation of 4-(2,2,2-trifluoroethylidene)piperidine

[0459] In an eggplant-shaped flask, add 4 mL of a 3 / 1 dichloromethane / trifluoroacetic acid mixture to tert-butyl 4-(2,2,2-trifluoroethylidene)piperidine-1-carboxylate (150 mg, 565.46 μmol) and allow to react at room temperature for 1 hour. Concentrate the reaction mixture to obtain crude 4-(2,2,2-trifluoroethylidene)piperidine (93.39 mg), which is used directly in the next reaction.

[0460] MS m / z(ESI):166[M+H].

[0461] Intermediate 13

[0462] Step 1: Preparation of tert-butyl 4-(2,2,2-trifluoroethylidene)piperidine-1-carboxylate

[0463] To a suspension of (fluoromethyl) tetrafluoroboryl triphenylphosphine (43.15 g, 112.93 mmol) in THF (120 mL) was added dropwise NaHMDS (1 M, 112.93 mL) at -20°C. The reaction was continued at -20°C for 20 minutes. Separately, tert-butyl 4-carbonylpiperidine-1-carboxylate (15 g, 75.28 mmol) was dissolved in THF (10 mL) and added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to react at room temperature for 40 minutes. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and rapidly purified by silica gel chromatography to afford tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (7.5 g, 46.3% yield).

[0464] MS m / z(ESI):216[M+H].

[0465] Step 2: Preparation of 4-(fluoromethylene)piperidinium trifluoroacetate

[0466] Tert-butyl 4-(fluoromethylene)piperidine-1-carboxylate (7.2 g, 33.47 mol) was added to dichloromethane (50 mL), and TFA (10 mL) was added dropwise under ice bath. After the reaction solution was evenly mixed, it was reacted at room temperature for 1 hour and concentrated under reduced pressure to obtain the crude compound 4-(difluoromethylene)piperidine trifluoroacetate (7.1 g, TF salt, yield 100%).

[0467] MS m / z(ESI):116[M+H].

[0468] Intermediate 14

[0469] Step 1: Preparation of (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol

[0470] [1-(Hydroxymethyl)cyclopropyl]methanol (29.73 g, 291.06 mmol) and TEA (44.10 g, 436.59 mmol) were added to dichloromethane (400 mL) and mixed thoroughly. Tert-butyldiphenylsilyl chloride (40 g, 145.53 mmol) was then added dropwise to the reaction mixture at 25°C. The mixture was reacted at 25°C for 16 hours. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and rapidly purified by silica gel chromatography to obtain (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanol (45 g, 45.4% yield).

[0471] Intermediate 15

[0472] Step 1: Preparation of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0473] Under nitrogen protection, potassium acetate (5.18 g, 52.83 mmol) and Pd(dppf)Cl2.DCM (871.69 mg, 1.06 mmol) were added to a solution of 3-bromo-5-chloro-4-(trifluoromethyl)aniline (2.9 g, 10.57 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (6.71 g, 26.41 mmol) in dioxane (30 mL), and the mixture was stirred at 120°C for 12 hours. The reaction solution was concentrated, saturated aqueous NaCl solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (2.6 g, yield 76.5%).

[0474] MS m / z(ESI):322[M+H].

[0475] Example 1-1

[0476] Step 1: Methyl (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate

[0477] Methyl (R)-5-carbonylpyrrolidine-2-carboxylate (5 g, 34.93 mmol) and dimethyl sulfate (6.6 g, 52.33 mmol) were added to a round-bottom flask and heated to 60°C with stirring under nitrogen for 16 hours. The mixture was cooled and then added dropwise to a solution of MTBE / TEA (100 mL / 20 mL) at 0°C. The mixture was quenched with saturated aqueous potassium carbonate solution and extracted with MTBE. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford methyl (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (4.3 g, 78.2% yield).

[0478] MS m / z(ESI):158[M+H].

[0479] Step 2: Preparation of methyl (R,E)-5-(2-ethoxy-1-nitro-2-carbonylethylidene)pyrrolidine-2-carboxylate

[0480] Methyl (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (4.0 g, 25.45 mmol) was added to ethyl nitroacetate (15 mL), heated to 60°C, and stirred for 16 hours. The solution was concentrated under reduced pressure and purified by silica gel chromatography to afford methyl (R,E)-5-(2-ethoxy-1-nitro-2-carbonylethylidene)pyrrolidine-2-carboxylate (2.1 g, 31.9% yield).

[0481] MS m / z(ESI):259[M+H].

[0482] Step 3: Preparation of ethyl (1S,5R)-4-carbonyl-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0483] Methyl (R,E)-5-(2-ethoxy-1-nitro-2-carbonylethylidene)pyrrolidine-2-carboxylate (2 g, 7.75 mmol) was added to ethanol (30 mL), and Pd / C (2 g) was added. The mixture was reacted under a hydrogen atmosphere for 48 hours, filtered, washed with ethanol, and the organic phase was concentrated under reduced pressure. The mixture was purified by silica gel chromatography to obtain the compound ethyl (1S,5R)-4-carbonyl-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (1.3 g, yield 84.4%).

[0484] MS m / z(ESI):199[M+H].

[0485] Step 4: Preparation of 8-(tert-butyl) 2-ethyl (1S,2S,5R)-4-carbonyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate

[0486] Ethyl (1S, 5R)-4-carbonyl-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (1.2 g, 6.05 mmol) was added to dichloromethane (20 mL), and triethylamine (1.84 g, 18.2 mmol) and di-tert-butyl dicarbonate (1.58 g, 7.24 mmol) were added. The reaction solution was uniformly mixed and reacted at room temperature for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain compound 8-(tert-butyl) 2-ethyl (1S, 2S, 5R)-4-carbonyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (920 mg, yield 50.9%).

[0487] MS m / z(ESI):299[M+H].

[0488] Step 5: Preparation of 8-(tert-butyl) 2-ethyl (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate

[0489] 8-(tert-Butyl)-2-ethyl (1S,2S,5R)-4-carbonyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (900 mg, 3.02 mmol) was added to a solution of borane dimethyl sulfide (2M in THF, 10 mL) and reacted at room temperature under nitrogen for 16 hours. The reaction was quenched by adding methanol and heated to 60°C with stirring for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to yield 8-(tert-Butyl)-2-ethyl (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (570 mg, 66.2% yield).

[0490] MS m / z(ESI):285[M+H].

[0491] Step 6: Preparation of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0492] 8-(tert-Butyl) 2-ethyl (1S,2S,5R)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (530 mg, 1.86 mmol) was added to THF (20 mL) under nitrogen protection. LiAlH4 (1M in THF, 3 mL) was added dropwise under ice bath, and the temperature was gradually raised to room temperature. The reaction was carried out for 3 hours, quenched with water, filtered, and the filtrate was concentrated under reduced pressure. The compound tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (380 mg, yield 84.3%) was obtained.

[0493] MS m / z(ESI):243[M+H].

[0494] Step 7: Preparation of tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0495] Tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 1.44 mmol) was added to dichloromethane (20 mL), and DIPEA (930 mg, 7.19 mmol) and TBDPSCl (480 mg, 1.75 mmol) were added. The reaction solution was uniformly mixed and stirred at 25°C for 3 hours. Water was added and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to give tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (630 mg, yield 91.0%).

[0496] Step 8: Preparation of 2,6-dichloro-3-fluoropyridin-4-amine

[0497] 2,6-Dichloropyridin-4-amine (10 g, 61.35 mmol) was added to acetonitrile (100 mL), and Selectfluoro (26.1 g, 73.67 mmol) was added. The mixture was heated to 80°C and stirred for 8 hours. The mixture was cooled to room temperature, and water was added. The mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain 2,6-dichloro-3-fluoropyridin-4-amine (2.5 g, 22.5% yield).

[0498] MS m / z(ESI):181[M+H].

[0499] Step 9: Preparation of 2,6-dichloro-3-fluoro-5-iodopyridin-4-amine

[0500] 2,6-Dichloro-3-fluoropyridin-4-amine (2.4 g, 13.26 mmol) was added to acetonitrile (50 mL), followed by NIS (3.6 g, 16.00 mmol) and p-toluenesulfonic acid hydrate (120 mg, 0.63 mmol). The mixture was heated to 70°C and stirred for 6 hours under nitrogen. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain 2,6-dichloro-3-fluoro-5-iodopyridin-4-amine (3.8 g, 93.4% yield).

[0501] MS m / z(ESI):307[M+H].

[0502] Step 10: Preparation of ethyl 4-amino-2,6-dichloro-5-fluoronicotinate

[0503] 2,6-Dichloro-3-fluoro-5-iodopyridin-4-amine (3.5 g, 11.40 mmol) was added to ethanol (20 mL), along with triethylamine (4.6 g, 45.46 mmol) and Pd(PPh3)2Cl2 (1.6 g, 2.28 mmol). The mixture was heated to 80°C and stirred for 16 hours under a carbon monoxide atmosphere (1.5 MPa). The mixture was cooled to room temperature, filtered, washed with ethanol, concentrated under reduced pressure, and purified by silica gel chromatography to obtain ethyl 4-amino-2,6-dichloro-5-fluoronicotinate (2.1 g, 73.0% yield).

[0504] MS m / z(ESI):253[M+H].

[0505] Step 11: Preparation of ethyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0506] Ethyl 4-amino-2,6-dichloro-5-fluoronicotinate (2 g, 7.90 mmol) was added to THF (50 mL), and a solution of trichloroacetyl isocyanate (1.8 g, 9.55 mmol) in THF (10 mL) was added dropwise under an ice bath. The mixture was reacted at room temperature for 2 hours, concentrated, and recrystallized to obtain ethyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (2.9 g, yield 83.1%).

[0507] MS m / z(ESI):442[M+H].

[0508] Step 12: Preparation of 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol

[0509] Ethyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (2.7 g, 6.12 mmol) was added to methanol (10 mL), and ammonia methanol solution (7 M, 10 mL) was added. The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, washed with water, and slurried to obtain compound 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.2 g, yield 78.4%).

[0510] MS m / z(ESI):250[M+H].

[0511] Step 13: Preparation of 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine

[0512] 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.1 g, 4.40 mmol) was added to POCl3 (20 mL), heated under reflux for 16 hours, and concentrated under reduced pressure to obtain a crude compound 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (1.4 g).

[0513] MS m / z(ESI):288[M+H].

[0514] Step 14: Preparation of tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0515] 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (1.3 g) was added to dichloromethane (20 mL), and tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 4.99 mmol) and triethylamine (1.4 g, 13.84 mmol) were added and reacted at room temperature for 3 minutes. The reaction mixture was stirred for 2 hours, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound tert-butyl (1S, 2S, 5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.8 g).

[0516] Step 15: Preparation of tert-butyl (1S, 2S, 5R) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -3- (2- ((1- (((tert-butyldiphenylsilyl) oxy) methyl) cyclopropyl) methoxy) -5,7-dichloro-8-fluoropyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0517] To a solution of tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methanol (235.67 mg, 692.05 μmol) in THF (15 mL) was added NaH (27.68 mg, 692.05 μmol, 60% purity) at 0°C. After completion of the addition, the mixture was warmed to room temperature and stirred for 15 hours. The reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-((1-((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (622 mg, 99.8% yield).

[0518] Step 16: Preparation of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0519] To a solution of tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-((1-((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (622 mg, 600.83 μmol) in THF (20 mL) was added TBAF (1 M, 3.61 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to give tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (210 mg, yield 66.9%).

[0520] MS m / z(ESI):522[M+H].

[0521] Step 17: Preparation of tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0522] Tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (210 mg, 402.32 μmol), 2-[2- Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (14.65 mg, 20.12 μmol) and Cs2CO3 (262.17 mg, 804.65 μmol) were added to dioxane (5 mL) and heated to 100°C with stirring under nitrogen for 13 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (350 mg, yield 99.8%).

[0523] Step 18: Preparation of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0524] To a solution of tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (350 mg, 401.34 μmol) in THF (10 mL) was added TBAF (1 M, 1.20 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel plate to give tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (120 mg, yield 41.8%).

[0525] MS m / z(ESI):716[M+H].

[0526] Step 19: Preparation of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0527] To a solution of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (100 mg, 139.72 μmol) in dichloromethane (15 mL) was added triethylamine (42.41 mg, 419.15 μmol, 58.46 μL) at 0°C, followed by methanesulfonyl chloride (32.01 mg, 279.43 μmol), and the mixture was stirred at 0°C for 30 min. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was washed with aqueous ammonium chloride solution and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (110 mg, yield 99.2%).

[0528] MS m / z(ESI):794[M+H].

[0529] Step 20: Preparation of tert-butyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0530] To acetonitrile (8 mL) was added tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (110 mg, 138.57 μmol), 4-(difluoromethylene)piperidine (55.35 mg, 415.71 μmol), DIPEA (179.09 mg, 1.39 mmol) and NaI (62.31 mg, 415.71 μmol), the mixture was heated to 50°C and stirred for 13 hours. To the reaction solution was added aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparative silica gel plate to give tert-butyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (70 mg, yield 60.8%) as a yellow solid.

[0531] MS m / z(ESI):831[M+H].

[0532] Step 21: Preparation of 4-((5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-2-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0533] To a solution of tert-butyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (70 mg, 84.25 μmol) in dichloromethane (3 mL) and methanol (0.5 mL) was added HCl (3.07 mg, 84.25 μmol, 3 mL) at 0°C. ), stirred at room temperature for 30 minutes, and the reaction solution was slowly added to a sodium bicarbonate aqueous solution, extracted with dichloromethane / methanol, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give 4-((5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (30 mg, yield 51.8%).

[0534] MS m / z(ESI):687[M+H].

[0535] The following table shows the synthesis of Example 1-1:

[0536] The following examples can also be used in the following synthesis method:

[0537] Example 19-1

[0538] Step 1: Preparation of 3-benzyl 8-tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0539] Tert-butyl (1S, 2S, 5R) -2- (hydroxymethyl) -3, 8- diazabicyclo [3.2.1] octane -8-carboxylate (25 g, 103.17 mmol) was added to ethyl acetate (100 mL) and water (100 mL), and sodium bicarbonate (17.33 g, 206.34 mmol) and benzyl chloroformate (22.88 g, 134.12 mmol) were added. The mixture was stirred at room temperature for 4 hours. The layers were separated and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound 3-benzyl 8-tert-butyl (1S, 2S, 5R) -2- (hydroxymethyl) -3, 8- diazabicyclo [3.2.1] octane -3, 8- dicarboxylate (26 g, yield 66.9%).

[0540] MS m / z(ESI):377[M+H].

[0541] Step 2: Preparation of 3-benzyl 8-tert-butyl (1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0542] 3-Benzyl 8-tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (24.3 g, 64.55 mmol) and 2,2,6,6-tetramethylpiperidinoxide (1.0 g, 6.46 mmol) were added to dichloromethane (240 mL) and water (240 mL), sodium bicarbonate (21.69 g, 258.20 mmol) was added, and the mixture was cooled to 0°C. Sodium hypochlorite solution (1.3 M, 148.96 mL, 258.20 mmol) was added dropwise at 0-10°C, stirred at 0-10°C for 10 minutes, separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound 3-benzyl 8-tert-butyl (1S, 2S, 5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (19 g, yield 78.6%).

[0543] MS m / z(ESI):375[M+H].

[0544] Step 3: Preparation of 3-benzyl 8-tert-butyl (1S,2S,5R)-2-[(1S)-1-hydroxyethyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0545] 3-Benzyl 8-tert-butyl (1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (19 g, 50.74 mmol) was added to tetrahydrofuran (190 mL). Methylmagnesium bromide (3 M solution in tetrahydrofuran, 21.99 mL) was added dropwise at -70°C under nitrogen. The mixture was stirred at -70°C for 2 hours. Saturated ammonium chloride solution was added dropwise, and the separated aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield 3-benzyl 8-tert-butyl (1S,2S,5R)-2-[(1S)-1-hydroxyethyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (16 g, 80.8% yield).

[0546] MS m / z(ESI):391[M+H].

[0547] Step 4: Preparation of tert-butyl (1S,2S,5R)-2-[(1S)-1-hydroxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0548] 3-Benzyl 8-tert-butyl (1S,2S,5R)-2-[(1S)-1-hydroxyethyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (60 g, 153.66 mmol) and 10% palladium on carbon (6.5 g, 61.46 mmol) were added to methanol (480 mL) and stirred for 4 hours under a hydrogen atmosphere (0.34 MPa). The mixture was filtered, washed with methanol, concentrated under reduced pressure, and purified by silica gel chromatography to obtain tert-butyl (1S,2S,5R)-2-[(1S)-1-hydroxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36.6 g, 92.9% yield).

[0549] MS m / z(ESI):257[M+H].

[0550] Step 5: Preparation of tert-butyl (1S,2S,5R)-2-[(S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0551] Tert-butyl (1S,2S,5R)-2-[(1S)-1-hydroxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 g, 156.04 mmol) and imidazole (21.25 g, 312.09 mmol) were added to N,N-dimethylformamide (320 mL), and tert-butyldimethylsilyl chloride (58.80 g, 390.11 mmol) was added under ice bath. The reaction was carried out at room temperature for 40 hours, water and ethyl acetate were added, the layers were separated, the aqueous phase was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound tert-butyl (1S,2S,5R)-2-[(S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.7 g, yield 87.7%).

[0552] MS m / z(ESI):371[M+H].

[0553] Step 6: Preparation of tert-butyl (1S,2S,5R)-2-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0554] 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (36.9 g, 128.61 mmol) and N,N-diisopropylethylamine (24.93 g, 192.92 mmol) were added to DCM (300 mL). Under nitrogen protection, a solution of tert-butyl (1S,2S,5R)-2-[(S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.98 g, 83.60 mmol) in DCM (70 mL) was added dropwise at -65°C. The mixture was then stirred at room temperature for 16 hours. Water was added, the mixture was separated and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound (1S,2S,5R)-2-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (49.3 g, yield 61.7%).

[0555] MS m / z(ESI):602[M+H].

[0556] Step 7: Preparation of tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-hydroxy-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0557] tert-Butyl (1S,2S,5R)-2-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (53.4 g, 88.76 mmol) and cesium carbonate (168.08 g, 515.90 mmol) were added to N,N-dimethylformamide (250 mL), and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (515.90 mL, 515.90 mmol) was added. After the addition, the temperature was raised to 65°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to give (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-hydroxy-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylic acid tert-butyl ester (29.5 g, yield 73.6%).

[0558] MS m / z(ESI):452[M+H].

[0559] Step 8: Preparation of tert-butyl (5S,5aS,6S,9R)-2,12-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0560] Tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-hydroxy-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (29.5 g, 65.28 mmol) was dissolved in phosphorus oxychloride (180.18 g, 1.18 mol) at room temperature. Under nitrogen protection, N,N-diisopropylethylamine (16.87 g, 130.57 mmol) was added at 10-25 °C, and the mixture was stirred at 100 °C for 0.5 hour. The reaction mixture was concentrated to give a crude product, which was dissolved in ethyl acetate and quenched with saturated sodium bicarbonate, maintaining pH = 8-9. Methanol and di-tert-butyl dicarbonate (28.50 g, 130.57 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The layers were separated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. After purification by silica gel chromatography, tert-butyl (5S,5aS,6S,9R)-2,12-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (20.5 g, yield 66.8%) was obtained.

[0561] MS m / z(ESI):470[M+H].

[0562] Step 9: Preparation of tert-butyl (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0563] [1-[4-(Difluoromethylene)cyclohexyloxy]cyclopropyl]methanol (16.17 g, 74.10 mmol) was added to tetrahydrofuran (100 mL), and under nitrogen protection, 60% NaH (3.35 g, 139.48 mmol) was added at 0-10°C, and the mixture was stirred at 0-10°C for 0.5 hour. A solution of tert-butyl (5S,5aS,6S,9R)-2,12-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylic acid (20.5 g, 43.59 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was quenched by adding tert-butanol. The mixture was concentrated and purified by silica gel chromatography to give tert-butyl (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (22 g, yield 77.4%).

[0564] MS m / z(ESI):651[M+H].

[0565] Step 10: Preparation of tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy]-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0566] At room temperature, tert-butyl (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (1 .35 g, 2.07 mmol) was added to tetrahydrofuran (13 mL) and water (3 mL), potassium phosphate (2.20 g, 10.37 mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (301.99 mg, 414.67 μmol) and stirred in microwave at 100 ° C under nitrogen protection for 30 minutes. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy]-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (1.8 g, yield 86.7%).

[0567] MS m / z(ESI):1001[M+H].

[0568] Step 11: Preparation of tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0569] Tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy]-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (1.8 g, 1.80 mmol) was added to tetrahydrofuran (18 mL), and 1 M tetrabutylammonium fluoride (8.99 ml, 8.99 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and then purified by preparative chromatography to give tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (1.2 g, yield 79%).

[0570] MS m / z(ESI):845[M+H].

[0571] Step 12: Preparation of 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0572] Tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (1.2 g, 1.42 mmol) was added to dichloromethane (12 mL), and 4.0 M hydrochloric acid and ethyl acetate were added. The ester solution (8.88 mL, 65.52 mmol) was stirred at room temperature for 1 hour. After concentration, it was purified by preparative column chromatography to give 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (0.46 g, 46.2% yield).

[0573] MS m / z(ESI):701[M+H].

[0574] Example 21-1

[0575] Step 1: Preparation of tert-butyl 4-methoxyiminopiperidine-1-carboxylate

[0576] To an eggplant-shaped flask, add tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.51 mmol), methoxyamine hydrochloride (272.46 mg, 3.26 mmol), potassium carbonate (1.04 g, 7.53 mmol), and 10 mL of ethanol. Allow to react overnight at room temperature. Filter, wash the filter cake with ethanol, and concentrate the filtrate to obtain tert-butyl 4-methoxyiminopiperidine-1-carboxylate (573 mg, 99.7% yield).

[0577] MS m / z(ESI):229[M+H].

[0578] Step 2: Preparation of N-methoxypiperidin-4-imine

[0579] To an eggplant-shaped flask, tert-butyl 4-methoxyiminopiperidine-1-carboxylate (720 mg, 3.15 mmol) and 9 mL of a 2 / 1 dichloromethane / trifluoroacetic acid mixture were added and allowed to react at room temperature for 1 hour. The crude product was quenched with 2 mL of N,N-diisopropylethylamine in an ice bath. The reaction solution was concentrated to afford N-methoxypiperidin-4-imine (404 mg, 100% yield).

[0580] MS m / z(ESI):129[M+H].

[0581] Step 3: Preparation of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0582] To an eggplant-shaped flask, tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-1-fluoro-12-((1-(methylsulfonyl)oxy)methyl)cyclopropyl)methoxy-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (998.2 mg, 1.26 mmol), sodium iodide (565.4 mg, 3.77 mmol), N,N-diisopropylethylamine (812.6 mg, 6.29 mmol), and 30 mL of acetonitrile were added. The atmosphere was replaced with nitrogen and the reaction was carried out in an oil bath at 55°C overnight. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative column chromatography to give tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (190 mg, yield 18.3%).

[0583] MS m / z(ESI):826[M+H].

[0584] Step 4: Preparation of 1-((1-((((5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one-oxy-methyloxime

[0585] In an eggplant flask, tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (190 mg, 230.05 μmol) was dissolved in a mixed solvent of 5 mL of dichloromethane and 1.5 mL of methanol. 5 mL of 4N hydrochloric acid in dioxane was slowly added to the reaction solution under ice-cooling, and the reaction was allowed to proceed to room temperature for 30 minutes. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution under ice-cooling, and extracted with a mixed solvent of ethyl acetate / methanol. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative column chromatography to give 1-((1-((((5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one-oxy-methyloxime (124 mg, yield: 79.2%).

[0586] MS m / z(ESI):682[M+H].

[0587] 1 H NMR (400MHz, MeOD) δ7.87–7.79(m,1H),7.36–7.27(m,2H),7.25–7.14(m,1H),5.12(dd,J=12.2,7.5Hz,1H),4.69–4.21(m,6H),3.91(d,J=26.7Hz ,2H),3.77(s,3H),2.78(d,J=26.3Hz,4H),2.64(d,J=13.2Hz,4H),2.41– 2.30(m,2H),1.98(d,J=33.7Hz,5H),0.90(t,J=6.6Hz,2H),0.57(s,2H).

[0588] The following table shows the synthesis of reference example 1-1 or example 21-1:

[0589] The following examples can also be used in the following synthesis method:

[0590] Example 35-1

[0591] Step 1: Preparation of (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0592] Tert-butyl (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (2 g, 2.74 mmol) and DIPEA (1 g, 8.23 ​​mmol) were added to dichloromethane (20 mL) and mixed well. MsCl (470 mg) was added dropwise at 0°C. , 4.11mmol), the reaction was continued for 0.5 hours, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (2 g, yield 90.3%).

[0593] Step 2: Preparation of tert-butyl (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0594] (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (2 g, 2.47 mmol), piperidin-4-one O-methyloxime (950 mg, 7.41 mmol), DIPEA (1.6 g, 12.35 mmol), NaI (1.1 g, 7.41 mmol) were added to acetonitrile (2 The reaction mixture was added into a 50 mL flask (50 mL) and mixed well. The mixture was reacted at 50°C for 16 hours, and water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel chromatography to obtain the target compound, tert-butyl (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (2 g, yield 96.2%).

[0595] MS m / z(ESI):840[M+H].

[0596] Step 3: Preparation of 1-((1-((((5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyloxime formate

[0597] Tert-butyl (5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (2 g, 2.38 mmol) was added to a dichloromethane / methanol solution (20 mL, volume ratio 4:1), mixed well, and then added with a dioxane hydrochloride solution (20 mL, 4 M) at 0°C. ), after completion, the temperature was raised to room temperature, the reaction was continued for 40 minutes, neutralized with saturated NaHCO3 aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by preparative chromatography to give 1-((1-((((5S,5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyloxime formate (600 mg, yield 34%).

[0598] MS m / z(ESI):696[M+H].

[0599] 1 H NMR (400MHz, DMSO) δ10.10(s,1H),8.13(s,1H),7.95(dt,J=9.6,5.7Hz,1H),7.51–7.39(m,1H),7.37 (d,J=2.5Hz,1H),7.12(dd,J=50.6,2.5Hz,1H),5.20(d,J=13.1Hz,1H),4.62–4.43(m,1H),4.37–4.2 2(m,2H),4.22–3.90(m,2H),3.83–3.59(m,4H),3.21–3.05(m,2H),2.55(s,2H),2.48–2.30(m,6H),2 .20(d,J=5.6Hz,2H),1.98–1.59(m,4H),1.45(t,J=6.9Hz,3H),0.73–0.59(m,2H),0.49–0.25(m,2H).

[0600] Example 37-1

[0601] Step 1: Preparation of tert-butyl (5aS, 6S, 9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methylnaphtho[1, 8-ab]heptene-14 carboxylate

[0602] To the microwave tube were added tert-butyl (5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (100 mg, 156.96 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1, The reaction mixture was stirred for 1 h under a microwave oven. The mixture was stirred for 1 h. The mixture was stirred for 2 h. 3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (95.59 mg, 204.05 μmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (11.43 mg, 15.70 μmol), 2N aqueous sodium hydroxide solution (156.96 μL, 313.92 μmol) and 2 mL of tetrahydrofuran. The atmosphere was replaced with nitrogen and the reaction was carried out under microwave oven at 100°C for 1 hour. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to give tert-butyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14carboxylate (110 mg, 74.3% yield).

[0603] MS m / z(ESI):943[M+H].

[0604] Step 2: Preparation of tert-butyl (5aS, 6S, 9R) -12- ((1- ((4- (difluoromethylene) piperidin-1-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-3- ((trifluoromethyl) sulfonyl) oxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5a, 6, 7, 8, 9, 10- hexahydro -5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methyl naphtho [1, 8-ab] heptene-4-carboxylate

[0605] Tert-butyl (5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate (110 mg, 116.63 μmol), N,N-diisopropylethylamine (60.29 mg, 466.52 μmol) and 2.5 mL of dichloromethane were added dropwise after cooling in an ice bath, and the reaction was continued in an ice bath for 30 minutes. After the reaction, saturated NaHCO3 was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane and washed with saturated ammonium chloride solution. The organic phase was dried and concentrated to give tert-butyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-((trifluoromethyl)sulfonyl)oxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (125.4 mg, 100.00% yield).

[0606] MS m / z(ESI):1075[M+H].

[0607] Step 3: Preparation of tert-butyl (5aS, 6S, 9R) -2- (3- ((tert-butoxycarbonyl) amino) -7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -12- (1- ((4- (difluoromethylene) piperidin-1-yl) methyl) cyclopropyl) methoxy -1-fluoro-5a, 6, 7, 8, 9, 10- hexahydro -5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methylnaphthalene [1, 8-ab] heptene-4-carboxylate

[0608] In the eggplant flask, tert-butyl (5aS, 6S, 9R) -12- ((1- ((4- (difluoromethylene) piperidin-1-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-3- ((trifluoromethyl) sulfonyl) oxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -5a, 6, 7, 8, 9, 10- hexahydro -5H-4-oxa-3, 10a, 11, 13, 14- Pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (125.4 mg, 116.63 μmol), tris(dibenzylideneacetone)dipalladium (21.36 mg, 23.33 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.74 mg, 58.31 μmol), cesium carbonate (114.00 mg, 349.88 μmol), and 4 mL of toluene were added. The atmosphere was replaced with nitrogen and the reaction was carried out in an oil bath at 100°C for 8 hours. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, and the organic phase was washed with water. The organic phase was dried and concentrated, and separated by column chromatography (mobile phase: ethyl acetate / dichloromethane = 2 / 1) to give tert-butyl (5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphthalene[1,8-ab]heptene-4-carboxylate (70 mg, 57.6% yield).

[0609] MS m / z(ESI):1042[M+H].

[0610] Step 4: Preparation of tert-butyl (5aS, 6S, 9R)-2-(3-((tert-butoxycarbonyl)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate

[0611] In an eggplant flask, tert-butyl (5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphthalene[1,8-ab]heptene-4-carboxylate (70 mg, 67.16 μmol) was dissolved in 2 mL of tetrahydrofuran, and 1N tetrabutylammonium fluoride (134.32 μL, 134.32 μmol) was added and reacted at room temperature for 2 h. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated to give tert-butyl (5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14carboxylate (59.5 mg).

[0612] MS m / z(ESI):886[M+H].

[0613] Step 5: Preparation of tert-butyl (5aS,6S,9R)-2-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate

[0614] In an eggplant flask, 4 mL of a 3 / 1 mixture of dichloromethane and trifluoroacetic acid was added to tert-butyl (5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14carboxylate (59.5 mg, 67.16 μmol) under ice bath, and the mixture was allowed to react at room temperature for 30 min. After the reaction, the reaction solution was concentrated and purified by preparative chromatography to give tert-butyl (5aS,6S,9R)-2-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14carboxylate (13.8 mg, yield 25.7%).

[0615] MS m / z(ESI):686[M+H].

[0616] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=7.7Hz,1H),7.28–7.17(m,2H),7.12(d,J=21.7Hz,1H),5.25–5.17(m,1H),4.62(d,J=35.3 Hz,4H),4.49–4.25(m,4H),4.20–4.05(m,2H),2.48(s,4H),2.03(s,5H),1.60(s,2H),0.90(t,J=6.6Hz,4H),0.80(s,2H).

[0617] Examples 38 to 50, 70 to 73 are synthesized with reference to Example 1-1 or Example 37-1; Examples 51 to 69 are synthesized with reference to Example 1-1:

[0618] The following examples can also be used in the following synthesis method:

[0619] Example 57-1

[0620] Step 1: Preparation of 1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine

[0621] 4-(Difluoromethylene)piperidine hydrochloride (3.2 g, 18.87 mmol) and [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methyl methanesulfonate (7.90 g, 18.87 mmol) were dissolved in acetonitrile (30 mL), and N,N-diisopropylacetamide (12.19 g, 94.34 mmol, 16.43 mL) and sodium iodide (14.14 g, 94.34 mmol) were added. The temperature was raised to 60°C and the reaction mixture was reacted for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain compound 1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine (6.9 g, yield 80.2%).

[0622] MS m / z(ESI):456[M+H].

[0623] Step 2: Preparation of (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methanol

[0624] 1-((1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine (6.9 g, 15.14 mmol) was dissolved in 2M methanolic hydrogen chloride solution (30 mL) and allowed to react at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methanol (2.1 g, 63.8% yield).

[0625] MS m / z(ESI):218[M+H].

[0626] Step 3: Preparation of 1-((1-(chloromethyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine

[0627] (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methanol (2.1 g, 9.67 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (4.60 g, 38.66 mmol) was added dropwise under ice bath. The mixture was allowed to react at room temperature for 3 hours, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 1-((1-(chloromethyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine (1.1 g, yield 48.3%).

[0628] MS m / z(ESI):236[M+H].

[0629] Step 4: Preparation of S-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)ethanethiol

[0630] 1-((1-(chloromethyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine (1.1 g, 4.67 mmol) was dissolved in acetonitrile (10 mL), and cesium carbonate (15.21 g, 46.67 mmol) and potassium thioacetate (5.33 g, 46.67 mmol) were added. The temperature was raised to 30°C and the reaction was allowed to react for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain compound S-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)ethanethiol (1 g, yield 77.8%).

[0631] MS m / z(ESI):276[M+H].

[0632] Step 5: Preparation of (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methylthiol

[0633] S-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)ethanethiol (400 mg, 1.45 mmol) was dissolved in methanol (4 mL), and sodium methoxide (392.36 mg, 7.26 mmol) was added. The mixture was reacted at room temperature for 3 hours, concentrated under reduced pressure, and purified by silica gel chromatography to obtain the compound (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methylthiol (320 mg, yield 94.4%).

[0634] MS m / z(ESI):234[M+H].

[0635] Step 6: Preparation of tert-butyl (5aS,6S,9R)-2-chloro-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0636] (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methanethiol (300 mg, 1.29 mmol) and (5aS,6S,9R)-2,12-dichloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylic acid tert-butyl ester (586.70 mg, 1.29 mmol) were dissolved in ultra-dry tetrahydrofuran (10 mL). Sodium hydroxide (102.86 mg, 2 The reaction mixture was stirred at room temperature for 16 hours, and tert-butanol was added to quench the reaction. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain tert-butyl (5aS,6S,9R)-2-chloro-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (710 mg, yield 84.5%).

[0637] MS m / z(ESI):654[M+H].

[0638] Step 7: Preparation of tert-butyl (5aS,6S,9R)-12-(((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxy-3,10a,11,13,14-pentaaza-6,9-methylaminonaphthalene[1,8-ab]heptene-14-carboxylate

[0639] Tert-butyl (5aS,6S,9R)-2-chloro-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (710 mg, The product was dissolved in tetrahydrofuran (10 mL) and water (3 mL). Potassium phosphate (2.31 g, 10.87 mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (158.33 mg, 217.41 μmol) were added. The atmosphere was replaced with nitrogen. The temperature was raised to 80°C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain the compound tert-butyl (5aS,6S,9R)-12-(((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopentyl)pyridin-1-yl)pyridin-2- ...1-yl)pyridin-2-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyrid

[0145] The mixture was stirred at 400 rpm for 2 h: 30 min.: 10 min.: 5 min.: 35 min.: 45 min.: 5 min.: 3 ...

[0640] MS m / z(ESI):1004[M+H].

[0641] Step 8: Preparation of tert-butyl (5aS,6S,9R)-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-naphthol[1,8-ab]heptene-14-carboxylate

[0642] Tert-butyl (5aS,6S,9R)-12-(((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13,14-pentaaza-6,9-methylaminonaphthalene[1,8-ab]heptene-14-carboxylate (820 mg, 817.33 μmol) was dissolved in DMF (10 mL), and cesium fluoride (1.24 g, 8 The mixture was stirred for 1 h at 4 ℃ for 1 h. The temperature was raised to 90 ° C. and the reaction was carried out for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain the compound tert-butyl (5aS,6S,9R)-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-manaphthol[1,8-ab]heptene-14-carboxylate (610 mg, yield 88.1%).

[0643] MS m / z(ESI):848[M+H].

[0644] Step 9: Preparation of 4-((5aS,6S,9R)-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0645] Tert-butyl (5aS,6S,9R)-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-manaphthol[1,8-ab]heptene-14-carboxylate (200 mg, 235.84 μmol) was dissolved in dichloromethane (2 mL) and added dropwise. Trifluoroacetic acid (0.4 mL) was added, the mixture was reacted at room temperature for 2 hours, and the mixture was concentrated under reduced pressure to give the compound 4-((5aS,6S,9R)-12-(((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methyl)thio)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (51 mg, yield 30.7%).

[0646] MS m / z(ESI):704[M+H].

[0647] Example 58-1

[0648] Step 1: Preparation of tert-butyl (5aS,6R,9S)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0649] To a solution of tert-butyl (5aS,6R,9S)-2-chloro-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (140 mg, 0.28 mmol) and (1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methanol (79 mg, 0.36 mmol) in tetrahydrofuran (10 mL) was added dropwise lithium bis(trimethylsilyl)amide (1 M, 0.85 mL) at 0°C. The mixture was stirred at 0°C for 5 minutes. The reaction solution was poured into aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (5aS,6R,9S)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (178 mg, yield 100%).

[0650] MS m / z(ESI):637[M+H].

[0651] Step 2: Preparation of tert-butyl (5aS, 6R, 9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methylnaphtho[1, 8-ab]heptene-14 carboxylate

[0652] Tert-butyl (5aS,6R,9S)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate (178 mg, 0.28 mmol), 2-(8-ethyl-7-fluoro-3-(methoxy)- The mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (420 mg, 0.42 mmol), (dimethyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonate (20 mg, 0.028 mmol) and cesium carbonate (228 mg, 0.7 mmol) was stirred in dioxane (10 mL) and water (2 mL) at 90 ° C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl (5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14carboxylate (173 mg, yield 74%).

[0653] MS m / z(ESI):835[M+H].

[0654] Step 3: Preparation of 4-((5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0655] To a solution of tert-butyl (5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14carboxylate (173 mg, 0.21 mmol) in dichloromethane (4 mL) and methanol (0.8 mL) was added dropwise a dioxane solution (4 M, 4 mL) (<10°C) at 5°C. The mixture was stirred at room temperature for 0. The reaction mixture was slowly added to an aqueous sodium bicarbonate solution (80 mL), extracted with dichloromethane / methanol = 10 / 1, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by high-performance liquid chromatography to give 4-((5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol (50 mg, 35% yield).

[0656] 1 H NMR(400MHz,MeOD)δ7.69–7.60(m,1H),7.31–7.17(m,2H),7.13–7.06(m,0.5H),7.03– 6.95(m,0.5H),5.21–5.02(m,1H),4.68–4.54(m,3H),4.53–4.33(m,3H),4.26–4.11(m ,1H),3.92–3.71(m,2H),2.86–2.64(m,4H),2.62–2.36(m,2H),2.30(s,3H),2.24–2.1 2(m,1H),2.07–1.76(m,5H),0.89(t,J=8Hz,2H),0.85–0.73(m,3H),0.65–0.46(m,2H).

[0657] MS m / z(ESI):691[M+H].

[0658] Example 74

[0659] Step 1: Preparation of 1-chloroethyl (4-nitrophenyl) carbonate

[0660] To a solution of 4-nitrophenol (5.35 g, 38 mmol) in dichloromethane (100 mL) at 0°C were added triethylamine (4.60 g, 45 mmol) and 1-chloroethyl chloroformate (5 g, 35 mmol). The mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford 1-chloroethyl (4-nitrophenyl) carbonate (7.7 g, 90% yield).

[0661] Step 2: Preparation of 1-iodoethyl (4-nitrophenyl) carbonate

[0662] 1-Chloroethyl (4-nitrophenyl) carbonate (6 g, 24 mmol) and sodium iodide (14.7 g, 97.7 mmol) were stirred in acetone (60 mL) at 50°C for 40 hours. The reaction mixture was filtered, the filtrate was concentrated, ethyl acetate was added, and the mixture was filtered again. The filtrate was concentrated and purified by silica gel chromatography to afford 1-iodoethyl (4-nitrophenyl) carbonate (2 g, 24% yield).

[0663] Step 3: Preparation of silver isobutyrate

[0664] Isobutyric acid (1.5 g, 17 mmol) and silver oxide (2.37 g, 10 mmol) were stirred in acetonitrile (15 mL) and water (7.5 mL) at room temperature for 13 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain silver isobutyrate (1.3 g, 39% yield).

[0665] Step 4: Preparation of 1-(4-nitrophenoxy)carbonyloxyethyl 2-methylpropionate

[0666] 1-Iodoethyl (4-nitrophenyl) carbonate (500 mg, 1.5 mmol) and silver isobutyrate (1.2 g, 5.9 mmol) were stirred in toluene (10 mL) at 50°C for 13 hours. The reaction mixture was concentrated and purified by silica gel chromatography to afford 1-(4-nitrophenoxy)carbonyloxyethyl 2-methylpropanoate (200 mg, 45% yield).

[0667] Step 5: Preparation of 1-(isobutyryloxy)ethyl(5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0668] To a solution of (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene (100 mg, 0.14 mmol) and 1-(4-nitrophenoxy)carbonyloxyethyl 2-methylpropanoate (80 mg, 0.27 mmol) in dichloromethane (15 mL) were added triethylamine (70 mg, 0.70 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) at room temperature. After addition, the temperature was raised to 40°C and stirred for 16 hours. The residue was concentrated and purified by silica gel column chromatography to afford 1-(isobutyryloxy)ethyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (95 mg, 78% yield).

[0669] MS m / z(ESI):889[M+H].

[0670] Step 6: Preparation of 1-(isobutyryloxy)ethyl(5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0671] To a solution of 1-(isobutyryloxy)ethyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (95 mg, 0.11 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0°C, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, redissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to give 1-(isobutyryloxy)ethyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate (36 mg, 39.9% yield).

[0672] MS m / z(ESI):845[M+H].

[0673] Examples 75 to 79 are synthesized with reference to Example 74:

[0674] Examples 80 to 87 are synthesized with reference to Example 1-1 or Example 74:

[0675] Example 89 can also be synthesized using the following method:

[0676] Example 89

[0677] Step 1: Preparation of tert-butyl (2R)-4-(difluoromethylene)-2-methylpiperidine-1-carboxylate

[0678] To a solution of tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate (3 g, 14.1 mmol) in N,N-dimethylformamide (30 mL) was added difluoromethyl-2-pyridinesulfone (2.27 g, 11.8 mmol) at -50°C. Potassium tert-butoxide (2.37 g, 21.1 mmol) was added portionwise at -40--50°C. The mixture was stirred at -40--50°C for 1 hour. Aqueous ammonium chloride (50 mL) was added to the reaction solution, and the pH was adjusted to ~5 with aqueous hydrochloric acid (3 M). The mixture was extracted with ethyl acetate, and the organic phase was washed with aqueous sodium bicarbonate and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and purified by silica gel chromatography to afford tert-butyl (2R)-4-(difluoromethylene)-2-methylpiperidine-1-carboxylate (2.7 g, 78% yield).

[0679] MS m / z(ESI):248[M+H].

[0680] Step 2: Preparation of (2R)-4-(difluoromethylene)-2-methylpiperidinium trifluoroacetate

[0681] To a solution of tert-butyl (2R)-4-(difluoromethylene)-2-methylpiperidine-1-carboxylate (2.7 g, 10.9 mmol) in dichloromethane (21 mL) was added trifluoroacetic acid (7 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford (2R)-4-(difluoromethylene)-2-methylpiperidine trifluoroacetate (2.85 g, 100% yield).

[0682] MS m / z(ESI):148[M+H].

[0683] Step 3: Preparation of methyl 1-chlorocarbonylcyclopropanecarboxylate

[0684] To a solution of 1-methoxycarbonylcyclopropanecarboxylic acid (1.6 g, 11.1 mmol) and N,N-dimethylformamide (162 mg, 2.22 mmol) in dichloromethane (30 mL) was added oxalyl chloride (1.7 g, 13.3 mmol) at 0°C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give methyl 1-chlorocarbonylcyclopropanecarboxylate (1.8 g, 100% yield). Step 4: Preparation of methyl 1-[(2R)-4-(difluoromethylene)-2-methylpiperidine-1-carbonyl]cyclopropanecarboxylate

[0685] To a solution of (2R)-4-(difluoromethylene)-2-methylpiperidine trifluoroacetate (2.81 g, 10.8 mmol) in dichloromethane (50 mL) at 0°C was added triethylamine (5.45 g, 53.8 mmol), followed by a solution of methyl 1-chlorocarbonylcyclopropanecarboxylate (1.75 g, 10.8 mmol) in dichloromethane (10 mL). The mixture was slowly warmed to room temperature and stirred for 13 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with aqueous ammonium chloride and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford methyl 1-[(2R)-4-(difluoromethylene)-2-methylpiperidine-1-carbonyl]cyclopropanecarboxylate (2.5 g, 85% yield).

[0686] MS m / z(ESI):274[M+H]...

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: X1 is selected from N or CR 3b ; X2 is selected from N-OR 6a or CR 6b R 6c ; X3 is selected from O, S or NR n1 ; Preferably O or S; L1 is selected from a bond, O, S or NR n2 ; Preferably O or S; More preferably O; L2 is selected from C1-C4 alkylene, said C1-C4 alkylene is optionally substituted by 1-4 R a Substituted; preferably C1-C4 alkylene or C1-C4 deuterated alkylene, the C1-C4 alkylene and C1-C4 deuterated alkylene optionally by 1-4 R a replace; Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably 5-8 membered saturated or unsaturated heterocyclic group, 7-10 membered fused heterocyclic group or 6-10 membered bridged heterocyclic group; R 1a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C(O)(CH2) n3 R b 、-C(O)O(CH2) n3 R b or -C(O)[(CH2NR c C(O))] n4 (CH2) n3 R b , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n3 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) n3 R b 、-C(O)O(CH2) n3 R b or -C(O)[(CH2NR c C(O))] n4 (CH2) n3 R b , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 halogen Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl (CH2) n3 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl; R 1a Preferably hydrogen or Pg, wherein said Pg is selected from trityl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxyphenyl, -C(O)O(CR aa R bb ) n9 OC(O)(CR dd R ee ) n10 R b 、-C(O)(CR aa R bb ) n9 R b 、-C(O)O(CR aa R bb ) n9 R b or -C(O)[(CR aa R bb NR cc C(O))] n9 (CR dd R ee ) n10 R b ; R 1b 、R 1c or R 1d are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1b and R 1c It is linked to adjacent atoms to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, optionally substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -(CH2) n7 -C 1-6 Alkoxy, -(CH2) n7 -C 1-6 Deuterated alkoxy, -(CH2) n7 -C 1-6 Haloalkoxy, -(CH2) n7 -C 2-6 Alkenyl, -(CH2) n7 -C 2-6 Alkynyl, -(CH2) n7 -C 3-12 Cycloalkyl, -(CH2) n7 -3-12 membered heterocyclic group, -(CH2) n7 -C 6-14 Aryl or -(CH2) n7 -substituted by one or more substituents in a 5-14 membered heteroaryl; preferably forming a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered hetero The aryl group is substituted with one or more substituents; more preferably, a C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl or haloethyl; Or any two R2 substituents are linked to their adjacent atoms to form a C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; more preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 or R 3b are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R4 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; R5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n6 R f 、-O(CH2) n6 C(O)R f 、-O(CH2) n1 C(O)OR f 、-OC(O)O(CH2) n6 R f 、-O(CH2) n6 C(O)NR f R g 、-O(CH2) n6 OC(O)NR f R g or -O(CH2) n6 P(=O)R f R g , the amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n6 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n6 R f 、-O(CH2) n6 C(O)R f 、-O(CH2) n6 C(O)OR f 、-OC(O)O(CH2) n6 R f 、-O(CH2) n6 C(O)NR f R g 、-O(CH2) n6 OC(O)NR f R g or -O(CH2) n6 P(=O)R f R g , the amino, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n6 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 any two R5 atoms are linked to their adjacent atoms to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 6a 、R 6b or R 6c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 6b and R 6c Linked to its adjacent atoms to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 n1 or R n2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated Alkyl Oxygen, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 、R e 、R f or R g are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 two R attached to the same carbon atom a Link Form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R aa 、R bb 、R cc 、R dd or R ee are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6; z is selected from 0, 1, 2, 3, 4, 5 or 6; n1 is selected from 0, 1 or 2; n2 is selected from 0, 1 or 2; n3 is selected from 0, 1, 2, 3, 4, 5 or 6; n4 is selected from 0, 1, 2, 3, 4, 5 or 6; n5 is selected from 0, 1, 2, 3, 4, 5 or 6; n6 is selected from 0, 1, 2, 3, 4, 5 or 6; n7 is selected from 0, 1 or 2; n9 is selected from 0, 1 or 2; and n10 is selected from 0, 1 or 2;.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1b and R 1c Linked with its adjacent atoms to form the following structure Preferably, the following structure is formed More preferably, the following structure is formed 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L2 is selected from Preferred R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Hydroxyalkyl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; more preferably hydrogen or deuterium; R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl or 5-14 membered heteroaryl; p is selected from 0, 1, 2, 3 or 4.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from phenyl, pyridyl, naphthyl, benzothienyl, benzopyrazolyl, quinolinyl or isoquinolinyl.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (II) or (II-A): R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OC(O)(CH2) n5 R d 、-O(CH2) n5 C(O)R d 、-O(CH2) n5 C(O)OR d 、-O(CH2) n5 OC(O)OR d 、-OC(O)O(CH2) n5 R d 、-O(CH2) n5 C(O)NR d R e 、-O(CH2) n5 OC(O)NR d R e or -O(CH2) n5 P(=O)R d R e , the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and (CH2) n5 Any CH2 in is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4a 、R 4c 、R 4d or R 4e are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; more preferably C 2-4 Alkynyl; R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; p is selected from 0, 1, 2, 3 or 4; R 1a 、R 1d , R2, R 3a 、R 3b , R5, X1, X2, X3, x and z are as defined in claim 1.

6. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (III): R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated Alkyl Oxygen, C 1-6 Alkyl-C(O)O-, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Alkyl-C(O)O-, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4a 、R 4c 、R 4d or R 4e are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated Alkyl Oxygen, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated Alkyl Oxygen, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 7a Selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 7b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated Alkyl Oxygen, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; p is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1 or 2; R 1a 、R 1d , R2, R 3a , R5, X2, X3, x and z are as defined in claim 1.

7. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (II-B) or (II-C): Preferably, the compound is further represented by the general formula (II-B-1) or (II-C-1): X2 is selected from N-OR 6a or CR 6b R 6c ; preferably N-OR 6a ; X4 is selected from N or CR 9a ; R 9a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 9b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered hetero substituted by one or more substituents in the aryl group; R 9c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 9d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered hetero substituted by one or more substituents in the aryl group; R 9e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; R6 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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; p is selected from 0, 1, 2, 3 or 4; R 1a 、R 1d , R2, R 3a , R5, X2, X3, x and z are as defined in claim 1.

8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (V): Pg is selected from trityl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxyphenyl, -C(O)O(CR aa R bb ) n9 OC(O)(CR dd R ee ) n10 R b 、-C(O)(CR aa R bb ) n9 R b 、-C(O)O(CR aa R bb ) n9 R b or -C(O)[(CR aa R bb NR cc C(O))] n9 (CR dd R ee ) n10 R b ; R b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R aa 、R bb 、R cc 、R dd or R ee are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thioxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, 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 hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl or isopropyl; n9 is selected from 0, 1 or 2; n10 is selected from 0, 1 or 2; X2, Ring B, R 1d , R2, R 3a , R5, R 6a 、R 6b 、R 6c , x and z as defined in claim 1; R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g , R6, R 7a 、R 7b , p and n8 are as defined in claim 6.

9. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (IV): Preferably, the compound is further represented by general formula (IV-1): R 1d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen; R2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or cyclopropyl; Or two R2 substituents are linked to their adjacent atoms to form a C 3-8 Cycloalkyl; preferably forming cyclopropyl; R 3a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl or isopropyl; more preferably hydrogen or fluorine; R 4a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC(O)C 1-6 Alkyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, acetoxy, propionyloxy, butyryloxy, p-pivaloyloxy or cyclopropyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, methyl, acetoxy, propionyloxy, butyryloxy or p-pivaloyloxy; R 4c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, ethyl or ethynyl; R5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, amino, hydroxy, cyano, methyl or ethyl; R 6b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, fluorine, difluoromethyl or trifluoromethyl; R 7c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, deuterated methoxy, deuterated ethoxy, hydroxymethyl, hydroxyethyl, vinyl, halovinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, deuterated methoxy, deuterated ethoxy, vinyl, monofluorovinyl or difluorovinyl; R 7b Hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or deuterium; x is selected from 0, 1 or 2; z is selected from 0, 1, 2, 3, 4, 5 or 6; p is selected from 0, 1 or 2; n8 is selected from 0, 1 or 2.

10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring B is selected from 5-8 membered saturated or unsaturated monocyclic heterocyclic groups, 5-6 membered heterocyclic groups and C 3-6 Cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, or 6-10 membered bridged heterocyclyl; Selected from 11. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (III-A) or (III-B): Preferably, the compound is further represented by the general formula (III-A-1) or (III-B-1): X2 is selected from N-OR 6a or CR 6b R 6c ; CR is preferred 6b R 6c ; R 1d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen; R2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or cyclopropyl; Or two R2 substituents are linked to their adjacent atoms to form a C 3-8 Cycloalkyl; preferably forming cyclopropyl; R 3a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or fluorine; R 4a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC(O)C 1-6 Alkyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, acetoxy, propionyloxy, butyryloxy, p-pivaloyloxy or cyclopropyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, methyl, acetoxy, propionyloxy, butyryloxy or p-pivaloyloxy; R 4c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4d Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4e Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4f Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 4g Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, ethyl or ethynyl; R6 hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen; R 6a Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably methyl, ethyl, -CH2CH2F, -CH2CHF2, -CH2CF3 or cyclopropyl; R 6b Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, fluorine, difluoromethyl or trifluoromethyl; R 6c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or fluorine; R 7c Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, deuterated methoxy, deuterated ethoxy, hydroxymethyl, hydroxyethyl, vinyl, halovinyl or ethynyl; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, deuterated methoxy, deuterated ethoxy, vinyl, monofluorovinyl or difluorovinyl; R 7b Hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen or deuterium; R8 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl; more preferably hydrogen, deuterium, fluorine, chlorine, amino, hydroxy, cyano, methyl or ethyl; Or any two R8 substituents are linked to their adjacent atoms to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably forming cyclopropyl, 5 membered nitrogen-containing heterocyclic group or 6 membered nitrogen-containing heterocyclic group; x is selected from 0, 1 or 2; p is selected from 0, 1 or 2; q is selected from 0, 1, 2, 3, 4, 5 or 6; n8 is selected from 0, 1 or 2.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

13. A method for preparing a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by general formula (VI) reacts with the compound represented by general formula (VI-A) in the presence of a halide salt and a base to obtain the compound represented by general formula (I); Preferably, the preparation method is a method for preparing the compound represented by general formula (II-D), its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps: The compound represented by the general formula (VI-B) reacts with the compound represented by the general formula (VI-A) in the presence of a halide salt and a base to obtain the compound represented by the general formula (II-D); Alternatively, preferably, the preparation method is a method for preparing a compound represented by general formula (II-E), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by the general formula (VI-C) reacts with the compound represented by the general formula (VI-A) in the presence of a halide salt and a base, and the protecting group is further removed to obtain the compound represented by the general formula (II-E); R L1 is selected from hydrogen or a hydroxy protecting group; R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium; Ring A, X1, X2, X3, L1, L2, R 1a 、R 1b 、R 1c 、R 1d , R2, R 3a , R4, R5, x, y, z, n1 and n2 as described in claim 1; Ring B is as described in claim 1 or 11; R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f or R 4g As claimed in claim 5; When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution; R 9a 、R 9b 、R 9c 、R 9d or R 9e As claimed in claim 7; R6 and p are as described in claim 3, 5 or 7.

14. A compound represented by general formula (VII-F), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: R L2 is selected from halogen; preferably chlorine or bromine; R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium; X1, X2, X3, R 1a 、R 1d , R2, R 3a , R5, x and z as described in claim 1; Ring B is as described in claim 1 or 11; R6 and p are as described in claim 3, 5 or 7.

15. The compound according to claim 14, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

16. A method for preparing a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step 1: The compound represented by general formula (VII-B) and the compound represented by general formula (VII-C) are subjected to coupling reaction to obtain the compound represented by general formula (I); Optionally, further comprising step 2: The compound represented by general formula (VII) reacts with the compound represented by general formula (VII-A) under alkaline conditions to obtain the compound represented by general formula (VII-B); R L4 Selected from -OH, -SH; preferably -OH; Preferably, the preparation method is a method for preparing a compound represented by general formula (II-D), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following step 1: The compound represented by the general formula (VII-F) and the compound represented by the general formula (VII-G) are subjected to a coupling reaction to obtain the compound represented by the general formula (II-D); Optionally, further comprising step 2: The compound represented by general formula (VII-D) reacts with the compound represented by general formula (VII-E) under alkaline conditions to obtain the compound represented by general formula (VII-F); Alternatively, preferably, the preparation method is a method for preparing a compound represented by general formula (II-E), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following step 1: The compound represented by the general formula (VII-F) and the compound represented by the general formula (VII-H) are subjected to a coupling reaction to obtain the compound represented by the general formula (II-E); Optionally, further comprising step 2: The compound represented by the general formula (VII-D) reacts with the compound represented by the general formula (VII-E) under alkaline conditions to obtain A compound represented by formula (VII-F); R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or C 1-3 Hydroxyalkyl; preferably hydrogen or deuterium; R L2 is selected from halogen; preferably chlorine or bromine; R L3 Selected from halogen, hydroxyl or -S(O) m1 -C 1-3 Alkyl; preferably chlorine, bromine, -S(O)-CH3 or -S(O)2-CH3; R L5 is selected from boronic acid, borate, chain borate or cyclic borate; m1 is selected from 0, 1 or 2; Ring A, X1, X2, X3, L1, L2, R 1a 、R 1b 、R 1c 、R 1d , R2, R 3a , R4, R5, x, y, z, n1 and n2 as described in claim 1; Ring B is as described in claim 1 or 11; R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g As claimed in claim 5; When R 4g When alkynyl is an alkynyl group, in addition to the above definition, it may be further optionally C 1-6 Silyl substitution; R 9a 、R 9b 、R 9c 、R 9d and R 9e As claimed in claim 7; R6 and p are as described in claim 3, 5 or 7.

17. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 12, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound according to any one of claims 1 to 12, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a KRAS inhibitor drug; preferably in a drug for KRAS G12D, KRAS G12V or KRAS G13D mutations.

19. Use of the compound according to any one of claims 1 to 12, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck cancer, breast cancer, lung cancer and colon cancer; preferably in the preparation of a medicament for treating non-small cell lung cancer, colon cancer, esophageal cancer and head and neck cancer.