Pyrimidine-containing polycyclic biological inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a pyrimidine-containing polycyclic biological inhibitor as well as a preparation method and application thereof. Particularly, the invention relates to a pyrimidine-containing polycyclic compound or a stereoisomer thereof, a preparation method of the pyrimidine-containing polycyclic compound, a pharmaceutical composition containing the pyrimidine-containing polycyclic compound, and application of the pyrimidine-containing polycyclic compound or the stereoisomer thereof in preparation of drugs for treating cancers and other related diseases.

Description

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

[0001] The present invention belongs to the field of medicine, and specifically relates to a pyrimidine-containing polycyclic bioregulator, a preparation method and application thereof, and also relates to the application of a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in treating cancer and other related diseases. 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 huge clinical need, no drug directly targeting KRAS has been marketed to date. Currently, patients with KRAS mutations can only undergo chemotherapy. The development of KRAS inhibitors is difficult due to two main factors. First, the RAS protein structure is smooth, making it difficult for small molecules to bind to the protein surface. Second, the affinity of RAS GTPase for GTP is as high as picomolar (pM) level, and the endogenous GTP level is high, making it difficult for small molecule drugs to block the binding of the two. Currently, Mirati Therapeutics' MRTX-1133 is the fastest-progressing clinical trial and is in Phase 1b / 2.

[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 the general formula (XV) or (XV-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009] Ring E is selected from C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; preferably 5-8 membered saturated or unsaturated heterocyclic group, 7-10 membered fused heterocyclic group or 6-10 membered bridged heterocyclic group; more preferably 5 membered heterocyclic group, 6 membered heterocyclic group, 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; further preferably Further optimization

[0010] R j 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 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, =CR4R5, =N-R4 or =N-OR4, 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, 5-14 membered heteroaryl, -C(O)(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)R4、-(CR EE R DD ) n1 C(O)OR4、-C(O)O(CR EE R DD ) n1 R4, -(CREE R DD ) n1 C(O)NR4R5、-(CR EE R DD ) n1 OC(O)NR4R5、-(CR EE R DD ) n1 P(=O)R4R5 or -(CR EE R DD ) n1 OP(=O)R4R5 is substituted by one or more substituents; preferably hydrogen, 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 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, =N-R4 or =N-OR4, 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -(CH2) n1 C(O)R4, -(CH2)n1 C(O)OR4, -C(O)O(CH2) n1 R4, -(CH2) n1 C(O)NR4R5, -(CH2) n1 OC(O)NR4R5, -(CH2) n1 P(=O)R4R5 or -(CH2) n1 substituted by one or more substituents in OP(=O)R4R5;

[0011] In the present invention, when R j When selected from =CR4R5, the structure it represents includes but is not limited to the following types

[0012] In the present invention, when R j When selected from =N-R4 or =N-OR4, the structure represented by it includes but is not limited to the following types

[0013] Or any two R j Linked to its adjacent atoms to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in alkynyl; preferably forming cyclopropyl, optionally further substituted by one or more substituents selected from deuterium or hydroxy;

[0014] R a1 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 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, 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 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) n9 R4, -C(O)O(CH2) n9 R4 or -C(O)[(CH2NR FF C(O))] n10 (CH2) n9 R4, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group;

[0015] R b1 and R b2 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 Alkylthio, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, 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, 5-14 membered heteroaryl, -OC(O)(CH2) n1 R4, -OC(O)(CH2) n1 OR4 and -O(CH2) n1 R4 is substituted by one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, 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 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 and C2-4 substituted by one or more substituents in the alkynyl group;

[0016] R e2 Selected from hydrogen, 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 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, C6-14 Aryl, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 R4 is substituted by one or more substituents; 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 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, 5-10 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4;

[0017] R e1 、R e3 、R e4 、R e5 、R e6 and R e7 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 3-12Cycloalkyl, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group;

[0018] R4 or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0019] Or R4 and R5 are linked to their adjacent atoms to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl is substituted by one or more substituents; preferably linked to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group;

[0020] R DD 、R EE or R FF are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0021] n1 is selected from 0, 1, 2, 3, 4 or 5;

[0022] n9 is selected from 0, 1, 2, 3 or 4;

[0023] n10 is selected from 0, 1, 2, 3 or 4;

[0024] t is selected from 1, 2, 3, 4, 5 or 6.

[0025] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is further represented by the general formula (XVI), (XVI-A) or (XVI-B):

[0026] The present invention also provides a compound represented by general formula (XIX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0027] X1 is selected from N or CH;

[0028] X2 selected from CR c2 R c3 N-OR c1 ;

[0029] Ring G is selected from 5-8 membered saturated or unsaturated heterocyclic groups, 7-10 membered fused heterocyclic groups or 6-10 membered bridged heterocyclic groups; preferably 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; further preferably

[0030] R m 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 1-6Hydroxyalkyl, 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, =CR4R5, =N-R4 or =N-OR4, 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, 5-14 membered heteroaryl, -C(O)(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)R4、-(CR EE R DD ) n1 C(O)OR4、-C(O)O(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)NR4R5、-(CR EE R DD ) n1 OC(O)NR4R5、-(CR EE R DD ) n1 P(=O)R4R5 or -(CREE R DD ) n1 OP(=O)R4R5 is substituted by one or more substituents; preferably 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 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =CR4R5, =N-R4 or =N-OR4, 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 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with C 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 Haloalkoxy, -C(O)(CH2) n1 R4, -(CH2) n1 C(O)R4, -(CH2) n1 C(O)OR4, -C(O)O(CH2) n1 R4, -(CH2) n1 C(O)NR4R5, -(CH2) n1 OC(O)NR4R5, -(CH2) n1 P(=O)R4R5 or -(CH2) n1 substituted by one or more substituents in OP(=O)R4R5;

[0031] Or any two R m Linked to its adjacent atoms to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in alkynyl; preferably forming cyclopropyl, optionally further substituted by one or more substituents selected from deuterium or hydroxy;

[0032] R a1 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 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) n9 R4, -C(O)O(CH2) n9 R4 or -C(O)[(CH2NR FF C(O))] n10 (CH2) n9 R4, 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 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 6-10Aryl, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group;

[0033] R a2 Selected from hydrogen, 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 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 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 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 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, 5-14 membered heteroaryl, C 1-6 Alkylaminocarbonyl and -O(CH2) n1 R4 is substituted by one or more substituents; 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, C1-3 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, 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, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group;

[0034] R b1 and R b2 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 Alkylthio, 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 Alkylthio, 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 Aryl, 5-14 membered heteroaryl, -OC(O)(CH2) n1 R4, -OC(O)(CH2) n1 OR4 and -O(CH2) n1 R4 is substituted by one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group;

[0035] R d1 and R d2 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 and 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, C6-10 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 and C 2-4 substituted by one or more substituents in the alkynyl group;

[0036] Or, R d1 and R d2 Linked to its adjacent atoms to form C 3-8 Cycloalkyl, 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 2-4 Alkenyl and C 2-4 Alkynyl is substituted with one or more substituents; preferably linked to form a cyclopropyl or cyclobutyl group, 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 and C 2-4 substituted by one or more substituents in the alkynyl group;

[0037] R e2 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, 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 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2)n1 R4 is substituted by one or more substituents; 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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 6-10Aryl, 5-10 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4;

[0038] R e1 、R e3 、R e4 、R e5 、R e6 and R e7 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 and 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group;

[0039] R c1 、R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0040] or R c2 and R c3 Linked to its adjacent atoms to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl is substituted by one or more substituents; preferably linked to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group;

[0041] R4 or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0042] R DD 、R EE or R FF are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0043] v is selected from 0, 1, 2, 3, 4 or 5;

[0044] x1 is selected from 0, 1, 2, 3, 4 or 5;

[0045] n1 is selected from 0, 1, 2, 3, 4 or 5;

[0046] n9 is selected from 0, 1, 2, 3 or 4; and

[0047] n10 is selected from 0, 1, 2, 3 or 4.

[0048] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is further represented by general formula (XVIII):

[0049] X1 is selected from N or CH;

[0050] X2 selected from CR c2 Rc3 N-OR c1 ;

[0051] R a1 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 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, 5-10 membered heteroaryl, -C(O)(CH2) n9 R4, -C(O)O(CH2) n9 R4 or -C(O)[(CH2NR FF C(O))] n10 (CH2) n9 R4, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group;

[0052] R b1 and R b2 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 Alkylthio, 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 Alkylthio, 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, 5-14 membered heteroaryl, -OC(O)(CH2) n1 R4, -OC(O)(CH2) n1 OR4 and -O(CH2) n1 R4 is substituted by one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group;

[0053] R e2 Selected from hydrogen, 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 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, the amino group, 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 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 R4 is substituted by one or more substituents; 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1OP(=O)R4R5, 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 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, 5-10 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4;

[0054] R e1 、R e3 、R e4 、R e5 、R e6 and R e7 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 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 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 and C2-4 substituted by one or more substituents in the alkynyl group;

[0055] R4 or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0056] R FF Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0057] R c1 、R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0058] or R c2 and R c3 Linked to its adjacent atoms to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl is substituted by one or more substituents; preferably linked to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group;

[0059] R k 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 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 substituted by one or more substituents in aryl or 5-14 membered heteroaryl; preferably 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 3-6Cycloalkyl or 3-6 membered heterocyclic group, 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 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with C 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 or C 1-3 substituted by one or more substituents in a haloalkoxy group;

[0060] Or any two R k Linked to its adjacent atoms to form C 3-6 Saturated or unsaturated cycloalkyl or 3-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl is substituted by one or more substituents; preferably linked to form a cyclopropyl, 5-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group;

[0061] u is selected from 0, 1, 2, 3, 4 or 5;

[0062] n1 is selected from 0, 1, 2, 3, 4 or 5;

[0063] n9 is selected from 0, 1, 2, 3 or 4;

[0064] n10 is selected from 0, 1, 2, 3 or 4;

[0065] n11 is selected from 1, 2 or 3; and

[0066] n12 is selected from 1, 2 or 3.

[0067] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that, in the general formula (XVIII) The structure is selected from u R k The substituted 3-8 membered N-containing heterocyclic group; preferably, selected from 3-8 membered N-containing heterocyclic group; more preferably, selected from 4-8 membered N-containing heterocyclic group; further preferably, selected from

[0068] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that the compound is further represented by general formula (XVII):

[0069] R k 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 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, 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 substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0070] 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, 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 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with C 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 or C 1-3 substituted by one or more substituents in a haloalkoxy group;

[0071] Or any two R k Linked to its adjacent atoms to form C 3-6 Saturated or unsaturated cycloalkyl or 3-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl is substituted by one or more substituents; preferably linked to form a cyclopropyl, 5-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group;

[0072] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0073] u is selected from 0, 1, 2, 3, 4 or 5;

[0074] y is selected from 0, 1, 2 or 3;

[0075] n11 is selected from 1, 2 or 3; and

[0076] n12 is selected from 1, 2 or 3.

[0077] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that the compound is further represented by general formula (XVII-1):

[0078] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R c1 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, preferably methyl;

[0079] R c2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, preferably hydrogen or fluorine;

[0080] R c3 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, preferably hydrogen or fluorine.

[0081] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R b1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably fluorine or chlorine;

[0082] R b2is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl or methylthio, optionally further selected from deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, thiol, methoxy, ethoxy, propoxy, isopropyloxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropyloxy, substituted with one or more substituents selected from propoxy, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxyisopropyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or methylthio, wherein the methyl, ethyl, propyl, and isopropyl are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, or trifluoromethoxy;

[0083] R e1 、R e3 、R e6 and R e7 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydrogen, fluorine, chlorine, methyl or trifluoromethyl;

[0084] R e2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydroxy, amino, fluorine, chlorine, methyl or trifluoromethyl;

[0085] R e4 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydroxy, amino, cyano, fluorine, chlorine, methyl, ethyl, ethynyl or trifluoromethyl;

[0086] R e5Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydroxy, amino, fluorine, chlorine, methyl or trifluoromethyl.

[0087] The present invention also provides a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0088] R1 is selected from C 6-12 Aryl or 5-12 membered heteroaryl, the C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl or benzo 5-6-membered heteroaryl are substituted with one or more substituents of aryl and 5-12-membered heteroaryl; preferably phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl or benzo 5-6-membered heteroaryl, wherein the phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl and benzo 5-6-membered heteroaryl are optionally substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 membered heteroaryl group are substituted by one or more substituents.

[0089] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n4a OR d 、-(CH2) n4a SR d 、-(CH2) n4a NR d R e 、-(CH2) n4a C(O)R d or -(CH2) n4a C(O)NR d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR d 、-NR d R e 、-C(O)R d or -C(O)NR d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0090] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

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

[0092] R 5a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0093] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n5a R m 、-(CH2) n5a OR m 、-(CH2) n5a SR m 、-(CH2) n5a NR m R n 、-(CH2) n5a C(O)R m 、-(CH2) n5a C(O)NR m R n 、-(CH2) n5a NR n C(O)R m 、-(CH2) n5a (O) m1 NR m R n or -(CH2) n5a NR n S(O) m1 Rm , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0094] R b 、R c 、R d and R e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0095] Or any two R c Linked to its adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0096] R m and R n are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0097] n1a is selected from 0, 1, 2 or 3;

[0098] n2a is selected from 0, 1, 2 or 3;

[0099] n4a is selected from 0, 1, 2 or 3;

[0100] n5a is selected from 0, 1, 2 or 3;

[0101] m1 is selected from 0, 1 or 2;

[0102] x is selected from 0, 1, 2, 3, 5 or 6;

[0103] y is selected from 0, 1, 2, 3, 5 or 6; and

[0104] z is selected from 0, 1, 2, 3, 5 or 6.

[0105] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that the compound is further represented by general formula (II):

[0106] R 2a Selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR d 、-NRd R e 、-C(O)R d or -C(O)NR d R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR d 、-NR d R e 、-C(O)R d or -C(O)NR d R e , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0107] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f or R 6g 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 6-14Aryl 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 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 The aryl group and the 5-10 membered heteroaryl group are substituted by one or more substituents.

[0108] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that the compound is further represented by general formula (III):

[0109] R 7a 、R 7b 、R 7c 、R 7d or R 7e 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 1-3Halogenated 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, C 1-3 Alkyl, C 1-3 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 The aryl group and the 5-10 membered heteroaryl group are substituted by one or more substituents.

[0110] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl, methoxy, ethoxy, deuterated methoxy, deuterated ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl, preferably hydrogen or fluorine;

[0111] y is 0, 1, or 2.

[0112] The present invention also provides a compound represented by general formula (XVII-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0113] X2, R b 、R k , n11, n12, y and u are as defined in any of the above embodiments.

[0114] The present invention also provides a compound represented by general formula (XVII-E), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0115] R x Selected from halogen, C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, 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, 5-14 membered heteroaryl, C 1-6 Alkylaminocarbonyl or (C 1-6 alkyl)3-Si-C 2-6 substituted by one or more substituents in the alkynyl group;

[0116] Preferred are fluorine, chlorine, bromine, iodine, C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or (C 1-3 alkyl)3Si-C 2-4 substituted by one or more substituents in the alkynyl group;

[0117] R y is selected from hydrogen or Pg;

[0118] The Pg is selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, p-toluenesulfonyl, p-methoxybenzyl, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably tert-butyloxycarbonyl;

[0119] X2, Ra2 、R b1 、R b2 、R b 、R k , n11, n12, y and u are as defined in any of the above embodiments.

[0120] The present invention also provides a method for preparing a compound represented by general formula (XVII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0121] The compound represented by general formula (XVII-C) reacts with the compound represented by general formula (XVII-D) in the presence of a base to obtain the compound represented by general formula (XVII-E) or its stereoisomer and a pharmaceutically acceptable salt thereof;

[0122] R x Selected from halogen, C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, 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, 5-14 membered heteroaryl, C 1-6 Alkylaminocarbonyl or (C 1-6 alkyl)3Si-C 2-6 substituted by one or more substituents in the alkynyl group;

[0123] Preferred are fluorine, chlorine, bromine, iodine, C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or (C 1-3 alkyl)3-Si-C 2-4 substituted by one or more substituents in the alkynyl group;

[0124] R z is selected from halogen, preferably chlorine, bromine or iodine;

[0125] R y is selected from hydrogen or Pg;

[0126] The Pg is selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, p-toluenesulfonyl, p-methoxybenzyl, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably tert-butyloxycarbonyl;

[0127] 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 sodium hydride;

[0128] When R x When selected from halogen, the compound represented by general formula (XVII-E) is further reacted with the compound represented by general formula (XVII-F) in the presence of a palladium catalyst and a base to obtain the compound represented by general formula (XVII-G) or its stereoisomer and a pharmaceutically acceptable salt thereof;

[0129] R w is selected from boronic acid, borate, chain borate or cyclic borate;

[0130] 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 sodium hydroxide or potassium hydroxide;

[0131] The palladium catalyst is selected from (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, palladium acetate or methanesulfonate [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II); preferably methanesulfonate [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II);

[0132] The compound represented by general formula (XVII-E) or the compound represented by general formula (XVII-G) is optionally deprotected to obtain the compound represented by general formula (XVII) or its stereoisomers and pharmaceutically acceptable salts thereof;

[0133] X2, Ra2 、R b1 、R b2 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R e7 、R b 、R k , y and u are as defined in any of the above embodiments.

[0134] The present invention also provides a method for preparing a compound represented by general formula (XIX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0135] The compound represented by the general formula (XIX-A) reacts with the compound represented by the general formula (XIX-B) in the presence of a halide salt and a base to obtain the compound represented by the general formula (XIX) or its stereoisomer and a pharmaceutically acceptable salt thereof;

[0136] R 6 Selected from hydrogen or a hydroxyl protecting group; the hydroxyl 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 selected from trimethylsilyl or tert-butyldimethylsilyl;

[0137] 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;

[0138] 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;

[0139] Ring G, X1, X2, R a1 、R a2 、R b1 、R b2 、R d1 、R d2 、R e1 、R e2 、R e3 、R e4 、R e5 、 R e6 、R e7 、R m , x1 and v are as described in any of the above embodiments.

[0140] The present invention also provides a method for preparing a compound represented by general formula (XV) or (XV-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0141] The compound represented by the general formula (XV-1) or the compound represented by the general formula (XV-2) reacts with the compound represented by the general formula (XV-3) in the presence of a halide salt and a base to obtain a compound represented by the general formula (XV) or the general formula (XV-A) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

[0142] R 6 Selected from hydrogen or a hydroxyl protecting group; the hydroxyl 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 selected from trimethylsilyl or tert-butyldimethylsilyl;

[0143] 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;

[0144] 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;

[0145] Ring E, R a1 、R b1 、R b2 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R e7 、R j and t as described in any of the above embodiments.

[0146] The present invention also provides a method for preparing a compound represented by general formula (XVIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0147] The compound represented by the general formula (XVIII-A) reacts with the compound represented by the general formula (XVIII-B) in the presence of a halide salt and a base to obtain the compound represented by the general formula (XVIII) or its stereoisomer and a pharmaceutically acceptable salt thereof;

[0148] R 6Selected from hydrogen or a hydroxyl protecting group; the hydroxyl 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 selected from trimethylsilyl or tert-butyldimethylsilyl;

[0149] 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;

[0150] 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;

[0151] X1, X2, R a1 、R b1 、R b2 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R e7 、R k , n11, n12 and u are as described in any of the above embodiments.

[0152] The present invention also provides a method for preparing a compound represented by general formula (XVII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0153] The compound represented by the general formula (XVII-A) reacts with the compound represented by the general formula (XVII-B) in the presence of a halide salt and a base to obtain the compound represented by the general formula (XVII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

[0154] R 6 Selected from hydrogen or a hydroxyl protecting group; the hydroxyl 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 selected from trimethylsilyl or tert-butyldimethylsilyl;

[0155] 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;

[0156] 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;

[0157] X2, R a2 、R b1 、R b2 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R e7 、R b 、R k , y and u are as described in any of the above embodiments.

[0158] 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.

[0159] The present invention further relates to the use of any of the compounds described in the above texts, their stereoisomers or pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical compositions described above in the preparation of KRAS inhibitor drugs; preferably, in drugs for KRAS G12D, KRAS G12V, and KRAS G13D mutations.

[0160] 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 a compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt or prodrug, or its pharmaceutical composition.

[0161] 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%.

[0162] 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.

[0163] In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0164] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0165] 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.

[0166] 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.

[0167] The present invention also provides a preferred embodiment, involving the use of any 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.

[0168] 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.

[0169] In some embodiments, the present invention provides a method of treating a cancer condition comprising administering a compound or composition of the present invention to a patient suffering from a cancer condition.

[0170] 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.

[0171] Detailed Description of the Invention

[0172] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0173] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 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, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, pentyl, 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. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which 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, n-heptyl, 4-heptyl, 1-propylbutyl, 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, and the like.The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0174] The term "alkylene" refers to a divalent alkyl group formed by further replacing one of the hydrogen atoms of an alkyl group, where alkyl is as defined above. For example, "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, and so on. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbon atoms within the chain. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0175] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and is a straight or branched chain group comprising 2 to 20 carbon atoms, preferably an alkenyl group containing 2 to 12 carbon atoms, more preferably an alkenyl group containing 2 to 8 carbon atoms, further preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 4 carbon atoms. For example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0176] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and is a straight or branched chain group containing 2 to 20 carbon atoms, preferably an alkynyl group containing 2 to 12 carbon atoms, more preferably an alkynyl group containing 2 to 8 carbon atoms, further preferably an alkynyl group containing 2 to 6 carbon atoms, and most preferably an alkynyl group containing 2 to 4 carbon atoms. For example, ethynyl, propynyl, 1-butynyl, 2-butynyl or 3-butynyl, etc. Alkynyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0177] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0178] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O) or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; most preferably, it contains 3 to 8 ring atoms; more preferably, it contains 3 to 6 ring atoms; and further preferably, it is a 3-6 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0179] Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide, etc.; preferably oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydrothiopyran dioxide, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepanyl, 1,4-diazepanyl and piperazinyl; more preferably piperidinyl, Piperazinyl, pyrrolidinyl, morpholinyl, oxetanyl or azetidinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups; wherein the spirocyclic, fused ring and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0180] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 5 to 12 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include: wait.

[0181] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include: wait.

[0182] The term "bridged heterocyclyl" refers to a 5- to 14-membered 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 selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include: wait.

[0183] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

[0184] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0185] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, more preferably 6- to 10-membered, further preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including a benzo 5- to 10-membered heterocyclic group, a benzo 3- to 8-membered cycloalkyl group, a benzo 3- to 8-membered heterocyclic group, and a naphtho 5- to 6-membered heteroaryl group, preferably a benzo 5- to 6-membered heteroaryl group, a benzo 3- to 6-membered cycloalkyl group, and a benzo 3- to 6-membered heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, an oxygen atom, or a sulfur atom; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0186] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0187] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5 to 10-membered, further preferably 5 to 8-membered, and even more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, 2-pyridonyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridinyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazolyl; more preferably tetrazolyl, thienyl, pyridinyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl.

[0188] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0189] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and alkoxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0190] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0191] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0192] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0193] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and alkylthio may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0194] "Aminocarbonyl" refers to NH2-C(O)-.

[0195] "Alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both hydrogen atoms are replaced by an alkyl group, wherein alkyl is as defined above.

[0196] "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 is as defined above.

[0197] "Alkylcarbonyl" or "acyl" refers to an (alkyl)-C(O)- group in which alkyl is as previously described.

[0198] "Chain borate group" means R and R' are selected from alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy or haloalkoxy, and each substituent is as defined above.

[0199] "Cyclic boronate group" refers to The ring may be a 5-membered ring, a 6-membered ring or a 7-membered ring, and optionally, one or more hydrogen atoms on the ring are substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, etc., and the definitions of each substituent are as described above; preferably substituted or unsubstituted More preferred

[0200] 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.

[0201] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0202] "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 an 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.

[0203] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0204] 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.

[0205] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0206] 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.

[0207] Example

[0208] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0209] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0210] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0211] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0212] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0213] Intermediate 1

[0214] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0215] Step 1: Preparation of 4,6-dichloro-5-fluoronicotinamide

[0216] Dissolve 4,6-dichloro-5-fluoronicotinic acid (25 g, 119 mmol) in THF (100 mL). Add N,N'-carbonyldiimidazole (21.2 g, 131 mmol) portionwise and stir at 50°C for 2 hours. Cool the reaction mixture to 25°C, add toluene (100 mL), and concentrate to 80 mL. Cool the concentrate to 0°C, add aqueous ammonia (30 mL) dropwise, and gradually warm the reaction mixture to room temperature and stir for 2 hours. Add a large amount of water and extract with ethyl acetate. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which is then purified by column chromatography to yield the desired product, 4,6-dichloro-5-fluoronicotinamide (17 g, 68% yield).

[0217] MS m / z(ESI):209.1[M+H] + ,211.1[M+H+2] + .

[0218] Step 2: Preparation of N-carbamoyl-4,6-dichloro-5-fluoronicotinamide

[0219] Oxalyl chloride (5 g, 36 mmol) was added dropwise to a solution of 4,6-dichloro-5-fluoronicotinamide (5 g, 23.8 mmol) in tetrahydrofuran (100 mL) at room temperature. The temperature was raised to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and triethylamine (10 g, 99 mmol) was added, followed by aqueous ammonia (15 mL), and stirred for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield the desired product, N-carbamoyl-4,6-dichloro-5-fluoronicotinamide (3.2 g, 53% yield).

[0220] MS m / z(ESI):252.1[M+H] + ,254.1[M+H+2] + .

[0221] Step 3: Preparation of 7-chloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-2(1H)-one

[0222] To a solution of N-carbamoyl-4,6-dichloro-5-fluoronicotinamide (2.5 g, 9.9 mmol) in tetrahydrofuran (50 mL) was added potassium hexamethyldisilazane (25 mL, 25 mmol) dropwise at 0°C and stirred for 2 hours. The reaction was quenched with aqueous ammonium chloride (40 mL) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford the desired product, 7-chloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-2(1H)-one (1.7 g, 79% yield).

[0223] MS m / z(ESI):216.1[M+H] + ,218.1[M+H+2] + .

[0224] Step 4: Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0225] To a solution of 7-chloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-2(1H)-one (500 mg, 2.3 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (4.5 g, 34.9 mmol) and phosphorus oxychloride (1.8 g, 11.8 mmol) at room temperature. The mixture was stirred at 80°C for 1 hour to obtain crude 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine, which was used directly in the next reaction.

[0226] Intermediate 2

[0227] Preparation of 8-(2,4-dimethoxybenzyl)-3,8-diazabicyclo[3.2.1]oct-6-ene

[0228] Step 1: Preparation of tert-butyl bis(2-carbonylethyl)carbamate

[0229] To a solution of tert-butyl rac-(3R,4R)-3,4-dihydroxypyrrolidine-1-carboxylate (4.1 g, 20.2 mmol) in THF (30 mL) and water (12 mL) was added sodium periodate (6.47 g, 30.3 mmol) at 0°C under nitrogen. The mixture was warmed to 20°C and stirred for 12 hours. Saturated aqueous NaCl was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl di(2-carbonylethyl)carbamate (4 g, 98% yield) as a colorless oil, which was used directly in the next reaction.

[0230] Step 2: Preparation of tert-butyl N,N-di(2-hydroxybut-3-enyl)carbamate

[0231] To a solution of tert-butyl bis(2-carbonylethyl)carbamate (4 g, 19.88 mmol) in THF (80 mL) was added dropwise vinylmagnesium bromide (1 M, 119.27 mL) at 0°C under nitrogen. The temperature was slowly raised to 20°C and stirred for 12 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution and adjusted to pH 5-7 with dilute aqueous hydrochloric acid (1 M). The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford tert-butyl N,N-bis(2-hydroxybut-3-enyl)carbamate (1.3 g, 25% yield) as a colorless oil.

[0232] 1 H NMR(400MHz,Chloroform-d)δ5.90-5.78(m,2H),5.35-5.19(m,2H),5.18-5.15(m,2H),4 .54-4.35(m,2H),3.71-3.59(m,1H),3.58-3.40(m,2H),2.94-2.90(m,1H),1.48(s,9H).

[0233] Step 3: Preparation of 1-[[tert-butoxycarbonyl-[2-(2,2,2-trichloroethyleneimidate)oxybut-3-enyl]amino]methyl]allyl 2,2,2-trichloroethyleneimidate

[0234] To a solution of tert-butyl N,N-bis(2-hydroxybut-3-enyl)carbamate (1.2 g, 4.7 mmol) in dichloromethane (25 mL) at 0°C under nitrogen was added 2,2,2-trichloroacetonitrile (4.04 g, 28.0 mmol) and DBU (355 mg, 2.33 mmol, 348 μL). The temperature was slowly raised to 20°C and stirred for 12 hours. The reaction mixture was filtered, concentrated, and purified by column chromatography to afford 1-[[tert-butoxycarbonyl-[2-(2,2,2-trichloroethylimidoyl)oxobut-3-enyl]amino]methyl]allyl 2,2,2-trichloroethylimidate (1.2 g, 47% yield) as a colorless oil. This was immediately used in the next reaction.

[0235] 1 H NMR(400MHz,Chloroform-d)δ8.38(s,2H),5.95-5.77(m,2H),5.67-5.60(m,2H),5.4 6-5.38(m,2H),5.28-5.25(m,2H),3.84-3.77(m,2H),3.71-3.58(m,2H),1.48(s,9H).

[0236] Step 4: Preparation of tert-butyl rac-(3R,5S)-4-[(2,4-dimethoxyphenyl)methyl]-3,5-divinyl-piperazine-1-carboxylate

[0237] Under nitrogen, [Ir(COD)Cl]2 (74 mg, 110 μmol) was added to a solution of 1-[[tert-butoxycarbonyl-[2-(2,2,2-trichloroethylimidoyl)oxobut-3-enyl]amino]methyl]allyl 2,2,2-trichloroethylimidate (1.2 g, 2.2 mmol) in MeCN (30 mL). The temperature was slowly raised to 60°C and stirred for 12 hours. The reaction mixture was filtered, concentrated, and purified by column chromatography to afford tert-butyl rac-(3R,5S)-4-[(2,4-dimethoxyphenyl)methyl]-3,5-divinylpiperazine-1-carboxylate (0.22 g, 24% yield) as a colorless oil.

[0238] 1 H NMR(400MHz,Chloroform-d)δ7.49-7.47(d,J=8.0Hz,1H),6.46-6.44(d,J=8.0Hz,1H),6.35(s,1H),5.60-5.53 (m,2H),5.24-5.19(m,2H),4.98-4.95(m,2H),3.79-3.73(d,8H),3.64(s,2H),2.95-2.79(m,4H),1.48(s,9H).

[0239] Step 5: Preparation of tert-butyl rac-(1S,5R)-8-[(2,4-dimethoxyphenyl)methyl]-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate

[0240] Under nitrogen, Grubbs 2nd catalyst (55 mg, 64.4 μmol) was added to a solution of tert-butyl rac-(3R,5S)-4-[(2,4-dimethoxyphenyl)methyl]-3,5-divinylpiperazine-1-carboxylate (250 mg, 643.5 μmol) in toluene (40 mL). The temperature was slowly raised to 120°C and stirred for 12 hours. The reaction mixture was filtered, concentrated, and purified by column chromatography to afford tert-butyl rac-(1S,5R)-8-[(2,4-dimethoxyphenyl)methyl]-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (127 mg, 55% yield) as a colorless oil.

[0241] 1 H NMR(400MHz,Chloroform-d)δ7.42(bs,1H),6.50-6.48(m,1H),6.44-6.42(m,1H),6.06-6.01(m,2H ),3.85(s,3H),3.83(s,3H),3.75-3.71(m,1H),3.62-3.52(m,5H),3.23-3.19(m,2H),1.42(s,9H).

[0242] Step 6: Preparation of N-(2-(6-chloro-7-methoxynaphthalen-1-yl)ethyl)acetamide

[0243] To a solution of tert-butyl rac-(1S,5R)-8-[(2,4-dimethoxyphenyl)methyl]-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylate (127 mg, 352 μmol) in dichloromethane (5 mL) was added TFA (1 mL) at 0°C under nitrogen, and the mixture was stirred at 20°C for 1 hour. The mixture was concentrated to give (1R,5S)-8-(2,4-dimethoxybenzyl)-3,8-diazabicyclo[3.2.1]oct-6-ene trifluoroacetate (200 mg).

[0244] MS m / z(ESI):261.1[M+H] + .

[0245] Intermediate 3

[0246] Preparation of [6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate

[0247] Step 1: Preparation of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol

[0248] To a mixture of 2-bromoethynyl(triisopropyl)silane (15.4 g, 58.94 mmol), 7-fluoro-1,3-naphthalenediol (10 g, 56.13 mmol), potassium acetate (11.0 g, 112.26 mmol), and dioxane (70 mL) was added dichlorobis(4-methylisopropylphenyl)ruthenium(II) (3.44 g, 5.61 mmol). After nitrogen purging, the mixture was reacted at 110°C for 2 hours. The reaction solution was filtered and the filtrate was concentrated to obtain the crude product. The target compound, 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol, was obtained by rapid separation and purification via silica gel chromatography (18 g, 89.4% yield).

[0249] Step 2: Preparation of [6-fluoro-4-hydroxy-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate

[0250] Dissolve 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (6 g, 16.74 mmol) and diisopropylethylamine (6.5 g, 50.21 mmol) in dichloromethane (60 mL). Add pivaloyl chloride (2.3 g, 19.25 mmol) dropwise under ice-cooling. Mix thoroughly and allow to react at 0°C for 0.5 hours. The reaction mixture is quenched with saturated sodium bicarbonate solution. The organic phase is concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The target compound, [6-fluoro-4-hydroxy-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate (5.91 g, 79.8% yield), is separated by silica gel column chromatography.

[0251] Step 3: Preparation of [6-fluoro-4-(trifluoromethylsulfoxy)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate

[0252] Dissolve [6-fluoro-4-hydroxy-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate (6.4 g, 14.47 mmol) in dichloromethane (90 mL), and add diisopropylethylamine (5.6 g, 43.42 mmol). Add trifluoromethanesulfonic anhydride (7.4 g, 26.05 mmol) dropwise at -40°C. After mixing thoroughly, the mixture was allowed to react at -40°C for 0.5 hour. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography afforded the target compound, [6-fluoro-4-(trifluoromethylsulfoxy)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate (7.24 g, 87.1% yield).

[0253] Step 4: Preparation of [6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate

[0254] Combine pinacol diboronate (4.4 g, 17.40 mmol), [6-fluoro-4-(trifluoromethylsulfoxy)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate (5 g, 8.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane adduct (707 mg, 870.02 μmol), potassium acetate (2.6 g, 26.10 mmol), and toluene (60 mL). Purge with nitrogen and react at 130°C for 3 hours. The solid was removed by filtration, and the filtrate was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel chromatography to obtain the target compound [6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate (2.4 g, yield 49.9%).

[0255] 1 H NMR (400MHz, CDCl3) δ7.71(dd,J=9.0,5.7Hz,1H),7.56(d,J=2.4Hz,1H),7.47(d,J =2.4Hz,1H),7.26(d,J=2.1Hz,1H),1.42(s,12H),1.39(s,9H),1.18–1.11(m,21H).

[0256] Intermediate 4

[0257] Preparation of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0258] Step 1: Preparation of 2-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0259] Under nitrogen, to a solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (9.5 g, 18.54 mmol) in acetonitrile (100 mL) was added cesium fluoride (28.16 g, 185.35 mmol), and the mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography to afford 2-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (5 g, 75.7% yield).

[0260] MS m / z(ESI):357[M+1].

[0261] Step 2: Preparation of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0262] 2-[8-Ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 14.04 mmol) was dissolved in MeOH (100 mL). Under nitrogen, Pd / C (1.70 g) was added. The atmosphere was replaced with hydrogen three times, and the mixture was heated to 30°C and stirred for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered, washed with methanol, and the organic phase was concentrated to provide 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.1 g, 81.1% yield).

[0263] MS m / z(ESI):361[M+1].

[0264] Intermediate 5

[0265] Preparation of [5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate

[0266] Step 1: Preparation of [5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate

[0267] In an eggplant-shaped flask, [6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)-2-naphthyl] 2,2-dimethylpropanoate (5.5 g, 9.95 mmol) was dissolved in acetonitrile (150 mL). Cesium fluoride (5.26 g, 79.62 mmol) was added and the mixture was heated to 80°C and stirred for 30 minutes. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography to yield [5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate (1.1 g, 27.8% yield).

[0268] MS m / z(ESI):397[M+1].

[0269] Step 2: Preparation of [5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate

[0270] [5-Ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate (300 mg, 0.76 mmol) was dissolved in MeOH (10 mL). Under nitrogen, Pd / C (600 mg) was added, and the atmosphere was replaced with hydrogen three times. The mixture was heated to 20°C and stirred for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered, washed with methanol, and the organic phase was concentrated to provide [5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate (300 mg, 99.0% yield).

[0271] MS m / z(ESI):401[M+1].

[0272] Intermediate 6

[0273] Preparation of tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0274] Step 1: Preparation of tert-butyl (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0275] Dissolve tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 g, 188.42 mmol) in MeOH (800 mL). Add K2CO3 (65.10 g, 471.06 mmol). Replace the mixture with nitrogen three times and cool to 0°C in an ice bath. Add BnBr (38.67 g, 226.11 mmol) dropwise to the reaction mixture. Allow to warm to room temperature and react overnight. Pour the reaction mixture into water (800 mL) and extract three times with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and the mother liquor is concentrated. Purification by silica gel column chromatography affords tert-butyl (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.7 g, 66.2% yield) as a colorless oil.

[0276] MS m / z(ESI):303[M+1].

[0277] Step 2: Preparation of tert-butyl 3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0278] To a 1L three-necked flask, add tert-butyl (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.7 g, 124.67 mmol). Dissolve the mixture in ultra-dry THF (500 mL). Replace the atmosphere with nitrogen three times. Cool the system to -78°C and add TMEDA (16.66 g, 143.36 mmol). Then, slowly add s-BuLi (144 mL, 187.00 mmol, 1.3 M in hexane) dropwise. Maintain the reaction at -78°C and stir for 1 hour. Then, slowly add MeI (26.54 g, 187.00 mmol) dropwise. Allow the mixture to warm to room temperature and react for 2 hours. Water was slowly poured into the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The mother liquor was concentrated and separated by silica gel column chromatography to obtain a colorless oily product, tert-butyl 3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (39.2 g, yield 99.4%).

[0279] MS m / z(ESI):317[M+1].

[0280] Step 3: Preparation of tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0281] Dissolve tert-butyl 3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12 g, 37.92 mmol) in MeOH (200 mL), add Pd(OH)2 / C (2.4 g), replace the atmosphere with hydrogen three times, and allow to react overnight at room temperature. The reaction mixture was filtered, and the mother liquor was concentrated and separated by silica gel column chromatography to afford tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.0 g, 81.6% yield) as a colorless oil.

[0282] MS m / z(ESI):227[M+1].

[0283] Intermediate 7

[0284] Preparation of tert-butyl 1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0285] Step 1: Preparation of tert-butyl 3-benzyl-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0286] To a 1L three-necked flask, add tert-butyl 3-benzyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (27 g, 85.33 mmol). Dissolve the mixture in ultra-dry THF (500 mL). Replace the atmosphere with nitrogen three times. Cool the system to -78°C and add TMEDA (11.40 g, 98.12 mmol). Then, slowly add s-BuLi (98.4 mL, 127.99 mmol, 1.3 M in hexane) dropwise. Maintain the temperature at -78°C and stir for 1 hour. Then, slowly add MeI (18.17 g, 127.99 mmol) dropwise. Allow the mixture to warm to room temperature and react for 2 hours. Water was slowly poured into the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The mother liquor was concentrated and separated by silica gel column chromatography to obtain a colorless oily substance, tert-butyl 3-benzyl-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11.9 g, yield 42.2%).

[0287] MS m / z(ESI):331[M+1].

[0288] Step 2: Preparation of tert-butyl 1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0289] Dissolve tert-butyl 3-benzyl-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11.9 g, 36.01 mmol) in MeOH (200 mL). Add Pd(OH)2 / C (2.4 g). Replace the mixture with hydrogen three times and allow to react overnight at room temperature. The reaction mixture is filtered, and the mother liquor is concentrated and separated by silica gel column chromatography to afford tert-butyl 1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil (7.3 g, 84.4% yield).

[0290] MS m / z(ESI):241[M+1].

[0291] Intermediate 8

[0292] Preparation of tert-butyl 3-[7-[3-(2,2-dimethylpropyloxo)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0293] Step 1: Preparation of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0294] Dissolve [1-(Hydroxymethyl)cyclopropyl]methanol (1.07 g, 10.51 mmol) in tetrahydrofuran (100 mL). Add 60% sodium hydride (841 mg, 21.01 mmol) under ice-cooling. Mix thoroughly and stir at 0°C for 0.5 hour. Then add a solution of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 3.50 mmol) in tetrahydrofuran (10 mL) and stir under ice-cooling for 0.5 hour. The reaction solution was quenched with aqueous ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel chromatography to give the target compound, tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, yield 17%).

[0295] MS m / z(ESI):494[M+1].

[0296] Step 2: Preparation of tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0297] Tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (480 mg, 0.97 mmol), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- )-2-naphthyl] 2,2-dimethylpropanoate (450 mg, 1.1 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, dichloromethane adduct (95 mg, 0.13 mmol) and potassium phosphate (550 mg, 2.6 mmol) were stirred in tetrahydrofuran (15 mL) at 100°C in a microwave for 45 minutes. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and purified by column chromatography to give tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, yield 35%).

[0298] MS m / z(ESI):732[M+H].

[0299] Step 3: Preparation of tert-butyl 3-[7-[3-(2,2-dimethylpropyloxo)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0300] Methanesulfonyl chloride (250 mg, 2.19 mmol) was added to a solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.09 mmol) and triethylamine (332 mg, 3.28 mmol) in dichloromethane (30 mL) at 0°C. After addition, the mixture was stirred at 0°C for 1 hour. The reaction was quenched with aqueous ammonium chloride (30 mL), extracted with dichloromethane, and the organic phase was washed with aqueous sodium bicarbonate, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to give tert-butyl 3-[7-[3-(2,2-dimethylpropyloxo)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (885 mg, 100% yield).

[0301] MS m / z(ESI):810[M+H].

[0302] Example 1

[0303] Preparation of 1-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyloxime

[0304] Step 1: Preparation of tert-butyl 4-(methoxyimino)piperidine-1-carboxylate

[0305] 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%).

[0306] MS m / z(ESI):229[M+H].

[0307] Step 2: Preparation of N-methoxypiperidin-4-imine trifluoroacetate

[0308] Dissolve tert-butyl 4-(methoxyimino)piperidine-1-carboxylate (1.2 g, 5.26 mmol) in dichloromethane (10 mL), add TFA (599.35 mg, 5.26 mmol), and stir at room temperature for 4 hours. The reaction mixture is concentrated to obtain the target compound, N-methoxypiperidin-4-imine trifluoroacetate (910 mg, crude product).

[0309] MS m / z(ESI):129[M+H].

[0310] Step 3: Preparation of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0311] N-Methoxypiperidin-4-imine trifluoroacetate (910 mg, crude product) was dissolved in acetonitrile (10 mL), and DIPEA (825.95 mg, 6.39 mmol, 1.11 mL) was added and stirred for 10 minutes. Then, tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (984 mg, 1.28 mmol) and NaI (383.17 mg, 2.56 mmol) were added. Under nitrogen protection, the mixture was heated to 60°C and stirred for 8 hours. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to give the crude target compound, which was purified by column chromatography to give the target compound tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (910 mg, 88.78%).

[0312] MS m / z(ESI):802[M+H].

[0313] Step 4: Preparation of 1-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyloxime

[0314] Tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (910 mg, 1.13 mmol) was dissolved in dichloromethane (10 ml), TFA (129.39 mg, 1.13 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by preparative HPLC to give the target product, 1-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyloxime (450 mg, 60.29%).

[0315] 1 H NMR(400MHz,MeOD)δ9.10(d,J=9.7Hz,1H),7.68(dd,J=9.1,5.8Hz,1H),7.34–7.23(m,2H) ,7.03(d,J=2.6Hz,1H),4.82–4.74(m,3H),4.60(s,2H),4.50(s,2H),4.19(d,J=11.2Hz,2H ),3.89(dd,J=25.7,14.0Hz,2H),3.78(s,3H),2.93(d,J=30.4Hz,4H),2.79(s,2H),2.67( s,2H),2.52–2.38(m,3H),2.21–2.14(m,1H),2.10(s,4H),0.82–0.78(m,3H),0.64(s,1H).

[0316] MS m / z(ESI):658[M+H]

[0317] The syntheses of Examples 2 to 25 refer to Example 1.

[0318] Example 28

[0319] Preparation of 3-chloro-5-[4-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-(trifluoromethyl)aniline

[0320] Step 1: Preparation of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0321] Methanesulfonyl chloride (118 mg, 1.03 mmol) was added to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 688.32 μmol) and triethylamine (209 mg, 2.06 mmol) in dichloromethane (30 mL) at 0°C. After addition, the mixture was stirred at 0°C for 1 hour. The reaction solution was quenched with saturated aqueous NaHCO3 solution, extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (480 mg, 100% yield).

[0322] MS m / z(ESI):572[M+H].

[0323] Step 2: Preparation of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0324] Tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 699.24 μmol), N-methoxypiperidin-4-imine trifluoroacetate (0.8 g, 3.30 mmol), diisopropylethylamine (320 mg, 2.48 mmol) and sodium iodide (105 mg, 699.24 μmol) were stirred in acetonitrile (20 mL) at 50 °C for 12 hours. To the reaction solution was added aqueous ammonium chloride (40 mL), extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to give tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, yield 61.6%).

[0325] MS m / z(ESI):604[M+H].

[0326] Step 3: Preparation of tert-butyl (1R,5S)-3-[7-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0327] To a solution of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 82.77 μmol) in dioxane (5 mL) was added methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (12.05 mg, 16.55 μmol), and the mixture was stirred at 80°C for 0.5 hour. The mixture was cooled to 20°C, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (70 mg, 217.71 μmol) was added, and then NaOH (2M, 206.91 μL) was added. Under nitrogen protection, the mixture was stirred at 70°C for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to give tert-butyl (1R,5S)-3-[7-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (41 mg, yield 64.9%).

[0328] MS m / z(ESI):763[M+H].

[0329] Step 4: Preparation of 3-chloro-5-[4-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-(trifluoromethyl)aniline

[0330] To a solution of tert-butyl (1R,5S)-3-[7-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (41 mg, 53.72 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred at room temperature for 0.5 h. The reaction solution was added with saturated aqueous NaHCO3 solution, extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by acid preparative separation method to obtain 3-chloro-5-[4-[(1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-(trifluoromethyl)aniline (10 mg, yield 26.7%).

[0331] MS m / z(ESI):663[M+H].

[0332] 1 H NMR(400MHz,MeOD)δ8.98(s,1H),7.09(m,1H),7.02(d,J=4Hz,1H),4.78–4.60(m,2H),4.50–4.41(m,2H),3.99(s,2H),3.81( t,J=12Hz,1H),3.76(s,3H),2.76–2.49(m,8H),2.32(t,J=4Hz,2H),2.09–1.92(m,5H),0.79–0.70(m,2H),0.58–0.48(m,2H).

[0333] The synthesis of Examples 26-27 refers to Example 28.

[0334] Example 29

[0335] Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro-naphthalen-2-amine

[0336] Step 1: Preparation of tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-[3-(2,2-dimethylpropyloxo)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0337] In a microwave tube, [5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl] 2,2-dimethylpropanoate (900 mg, 2.25 mmol), tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl] 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (1.65 g, 2.25 mmol), 2N aqueous sodium hydroxide solution (3.37 mL, 6.74 mmol), and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (245.61 mg, 337.26 μmol) were dissolved in 30 mL of tetrahydrofuran and the atmosphere was replaced with nitrogen. The reaction was carried out in a microwave oven at 100°C for 45 minutes. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-[3-(2,2-dimethylpropyloxo)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.18 g, yield 100%).

[0338] Step 2: Preparation of tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0339] In an eggplant-shaped flask, tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-[3-(2,2-dimethylpropyloxo)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 1.24 mmol) was dissolved in 15 mL of methanol, and cesium carbonate (2.01 g, 6.18 mmol) was added and reacted at room temperature for 2 hours. The reaction mixture was quenched by adding 20 mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.10 g, yield 100%).

[0340] Step 3: Preparation of tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-[8-ethyl-7-fluoro-3-(trifluoromethylsulfoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0341] To an eggplant-shaped flask, tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.24 g, 1.40 mmol), N,N-diisopropylethylamine (723.42 mg, 5.60 mmol), and dichloromethane (15 mL) were added dropwise. Trifluoromethanesulfonic anhydride (592.23 mg, 2.10 mmol) was added dropwise in an ice bath and the mixture was allowed to react for 30 minutes. The reaction mixture was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-[8-ethyl-7-fluoro-3-(trifluoromethylsulfonyl)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.39 mmol, 100% yield).

[0342] Step 4: Preparation of tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0343] To an eggplant flask were added tert-butyl carbamate (653.51 mg, 5.58 mmol), tert-butyl 3-[2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-7-[8-ethyl-7-fluoro-3-(trifluoromethylsulfoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.39 mmol), tris(dibenzylideneacetone)dipalladium (255.42 mg, 278.93 μmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (403.49 mg, 697.33 μmol), cesium carbonate (1.36 g, 4.18 mmol) and 40 mL of toluene. Under a nitrogen atmosphere, the reaction mixture was heated to 100°C for 16 hours. The mixture was cooled, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.37 g, 1.39 mmol, 100% yield).

[0344] Step 5: Preparation of tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0345] To an eggplant-shaped flask, add tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-2-[[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.47 g, 1.49 mmol), cesium fluoride (1.81 g, 11.94 mmol), and 20 mL of N,N-dimethylformamide. Incubate in an oil bath at 80°C for 1 hour. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, yield 26.9%).

[0346] MS m / z(ESI):747[M+H].

[0347] Step 6: Preparation of tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0348] In an eggplant-shaped flask, tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 267.79 μmol) and N,N-diisopropylethylamine (103.83 mg, 803.38 μmol) were dissolved in 4 mL of dichloromethane. Methanesulfonyl chloride (46.01 mg, 401.69 μmol) was added dropwise under ice-cooling, and the mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220.91 mg, yield 100.00%).

[0349] Step 7: Preparation of tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0350] In an eggplant flask, N-methoxypiperidin-4-imine (68.36 mg, 533.38 μmol), tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-(methylsulfonyloxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 133.34 μmol), sodium iodide (59.96 mg, 400.03 μmol) and N,N-diisopropylethylamine (86.17 mg, 666.72 μmol) were dissolved in 10 mL of acetonitrile and heated in an oil bath at 55°C for 16 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative chromatography to give tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, yield 70.0%).

[0351] MS m / z(ESI):857[M+H].

[0352] Step 8: Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro-naphthalene-2-amine

[0353] Under ice bath, to tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 93.35 μmol) in an eggplant flask was added 10 mL of a mixed solvent of dichloromethane / trifluoroacetic acid (3 / 1), and the mixture was allowed to react at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and purified by preparative HPLC to give 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro-naphthalen-2-amine (24 mg, yield 34.7%).

[0354] MS m / z(ESI):657[M+H]

[0355] 1 H NMR(400MHz,MeOD)δ9.05(s,1H),7.58(dd,J=9.1,5.8Hz,1H),7.24–7.12(m,2H),6.9 8(d,J=2.5Hz,1H),4.74(t,J=12.2Hz,2H),4.54–4.43(m,2H),3.84(t,J=13.5Hz,2H), 3.76(s,2H),2.70(d,J=29.5Hz,4H),2.58(s,3H),2.31(t,J=5.9Hz,2H),2.02(d,J=1 2.0Hz,4H),1.33-1.29(m,5H),0.94-0.85(m,2H),0.78(t,J=7.1Hz,4H),0.55(s,2H).

[0356] The syntheses of Examples 30 to 47 were prepared with reference to Example 29.

[0357] Example 48

[0358] Preparation of 1-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyl-d3 oxime

[0359] Step 1: Preparation of tert-butyl 4-oximinopiperidine-1-carboxylate

[0360] To a solution of tert-butyl 4-carbonylpiperidine-1-carboxylate (2 g, 10.04 mmol) and hydroxylamine hydrochloride (1.05 g, 15.06 mmol) in MeOH (10 mL) was added K2CO3 (3.85 g, 27.86 mmol) under nitrogen. The mixture was heated to 60°C and stirred for 12 hours. The reaction mixture was concentrated, added with saturated aqueous NaCl, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield tert-butyl 4-oximinopiperidine-1-carboxylate (2 g, 93% yield).

[0361] MS m / z(ESI):215[M+H].

[0362] Step 2: Preparation of tert-butyl 4-((methoxy-d3)imino)piperidine-1-carboxylate

[0363] Under nitrogen, a solution of tert-butyl 4-hydroxyiminopiperidine-1-carboxylate (0.5 g, 2.33 mmol) in THF (10 mL) was cooled to 0°C, and NaH (1.61 g, 40.26 mmol, 60% purity) was added. The mixture was stirred at 0°C for 0.5 hours, followed by the addition of CD3I (676.54 mg, 4.67 mmol, 294.15 mL), and stirred at 20°C for 1 hour. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 4-((methoxy-d3)imino)piperidine-1-carboxylate (0.5 g, 92.6% yield).

[0364] MS m / z(ESI):232[M+H].

[0365] Step 3: Preparation of piperidin-4-one O-methyl-d3 oxime trifluoroacetate

[0366] To a solution of tert-butyl 4-((methoxy-d3)imino)piperidine-1-carboxylate (0.4 g, 1.73 mmol) in dichloromethane (8 mL) was added TFA (197.18 mg, 1.73 mmol) at 0°C under nitrogen. The mixture was gradually warmed to 20°C and stirred for 1 hour. The reaction mixture was concentrated to afford piperidin-4-one O-methyl-d3-oxime trifluoroacetate (0.4 g, 94.3% yield).

[0367] MS m / z(ESI):132[M+H].

[0368] Step 4: Preparation of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-((methoxy-d3)imino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0369] Under nitrogen protection, tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 61.73 μmol), piperidin-4-one O-methyl-d3 oxime trifluoroacetate (151.38 mg, 663.35 μmol), diisopropylethylamine (79.79 mg, 617.35 μmol) and sodium iodide (1.85 mg, 12.35 μmol) were stirred in acetonitrile (20 mL) at 50 °C for 12 hours. The mixture was cooled to room temperature, quenched by addition of aqueous ammonium chloride (40 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the organic phase concentrated, and purified by column chromatography to give tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-((methoxy-d3)imino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, yield 57.5%).

[0370] MS m / z(ESI):845[M+H].

[0371] Step 5: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-((methoxy-d3)imino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivaloyl indanedionate

[0372] To a solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-((methoxy-d3)imino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 35.50 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with saturated aqueous NaHCO3 solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-((methoxy-d3)imino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivaloyl indane dione ester (25 mg, yield 94.5%).

[0373] MS m / z(ESI):745[M+H].

[0374] Step 6: Preparation of 1-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyl-d3 oxime

[0375] To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-((methoxy-d3)imino)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivaloylindane dione (25 mg, 33.56 μmol) in MeOH (3 mL) was added K2CO3 (23.16 mg, 167.81 μmol) at room temperature and stirred at 20°C for 1 hour. The reaction solution was concentrated and purified by preparative HPLC to give 1-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyl-d3 oxime (11 mg, 46.4% yield).

[0376] 1H NMR (400MHz, MeOD) δ8.94 (s, 1H), 7.66–7.55 (m, 1H), 7.23 (d, J = 4Hz, 1H), 7.18 (t, J = 8 Hz,1H),6.99(d,J=2.6Hz,1H),4.71–4.59(m,2H),4.52(s,1H),4.12–3.91(m,2H),3. 88–3.63(m,5H),3.51–3.46(m,1H),3.45–3.29(m,1H),3.10–2.98(m,4H),2.69–2.55 (m,4H), 1.89–1.69(m,4H),0.75–0.66(m,3H),0.64–0.55(m,2H),0.51–0.43(m,2H).

[0377] MS m / z(ESI):661[M+H].

[0378] The syntheses of Examples 49 to 84 were prepared with reference to Example 48.

[0379] Example 85

[0380] Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0381] Step 1: Preparation of tert-butyl 4-(fluoromethylene)piperidine-1-carboxylate

[0382] tert-Butyl 4-carbonylpiperidine-1-carboxylate (100 mg, 500 μmol) was dissolved in THF (120 mL). Under nitrogen, (fluoromethyl)triphenylphosphine tetrafluoroborate (280 mg, 750 μmol) and NaHMDS (1N, 750 μml) were added. The reaction mixture was mixed thoroughly and stirred at room temperature for 1 hour. The mixture was quenched with water, extracted, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to obtain the target compound, tert-butyl 4-(fluoromethylene)piperidine-1-carboxylate (50 mg, 46% yield).

[0383] MS m / z(ESI):216[M+H].

[0384] Step 2: Preparation of 4-(fluoromethylene)piperidine

[0385] Tert-butyl 4-(fluoromethylene)piperidine-1-carboxylate (50 mg, 232 μmol) and TFA (0.5 mL) were added to dichloromethane (5 mL). The reaction solution was uniformly mixed and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude compound 4-(fluoromethylene)piperidine (26 mg, yield 97%).

[0386] MS m / z(ESI):116[M+H].

[0387] Step 3: Preparation of tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0388] Tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 74 μmol), 4-(fluoromethylene)piperidine (26 mg, 225 μmol), NaI (11 mg, 74 μmol), DIPEA (30 mg, 232 μmol) were added to acetonitrile (10 mL) and the mixture was heated under nitrogen. The reaction solution was reacted at 50° C. overnight, cooled to room temperature, added with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash silica gel column chromatography to give the compound tert-butyl (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, yield 48%).

[0389] MS m / z(ESI):829[M+H].

[0390] Step 4: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivaloyl indanedionate

[0391] To a solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 36 μmol) in dichloromethane (5 mL) was added TFA (1 mL) was added, reacted at room temperature for 1 hour, and concentrated under reduced pressure to give a crude product of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ylpivaloylindane dione ester (25 mg, yield 94%).

[0392] MS m / z(ESI):729[M+H].

[0393] Step 5: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0394] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivaloyl indane dione ester (25 mg, 34 μmol) was dissolved in MeOH (5 mL), and K2CO3 (25 mg, 180 μmol) was added. l), reacted at room temperature for 1 hour, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative HPLC to give compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol (17 mg, yield 69%).

[0395] MS m / z(ESI):645[M+H].

[0396] 1 H NMR (400MHz, MeOD) δ9.05 (s, 1H), 7.67 (dd, J1=9.2Hz, J2=3.2Hz, 1H), 7.30- 7.22(m,2H),7.04(d,J=2.4Hz,1H),6.52(d,J=86Hz,1H),4.68-6.63(m,2H), 4.49-4.42(m,2H),3.78-3.72(m,4H),2.63-2.47(m,7H),2.37-2.23(m,2H), 2.21-2.11(m,4H),1.94-1.85(m,4H),0.81-0.75(m,5H),0.56-0.53(m,2H).

[0397] The synthesis of Examples 86 to 90 refers to Example 85.

[0398] Example 91

[0399] Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-amine

[0400] Step 1: Preparation of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalene-2-ol

[0401] To a solution of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (6 g, 11.7 mmol) in methanol (10 mL) was added hydrochloric acid (4 M, 30 mL) under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by column chromatography to afford 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (5 g, 91% yield).

[0402] MS m / z(ESI):469[M+H].

[0403] Step 2: Preparation of N-methoxypiperidin-4-imine trifluoroacetate

[0404] 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).

[0405] MS m / z(ESI):129[M+H].

[0406] Step 3: Preparation of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0407] To a solution of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3 g, 5.9 mmol) and triethylamine (1.84 g, 18.2 mmol) in dichloromethane (70 mL) was added methanesulfonyl chloride (1 g, 8.7 mmol) under ice cooling. After addition, the mixture was stirred at 0°C for 0.5 hour. The reaction was quenched with aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was washed with aqueous ammonium chloride, then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.47 g, 100% yield).

[0408] MS m / z(ESI):572[M+H].

[0409] Step 4: Preparation of tert-butyl 3-[7-chloro-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0410] Tert-butyl 3-[7-chloro-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.47 g, 6.1 mmol), N-methoxypiperidin-4-imine trifluoroacetate (2.94 g, 12.1 mmol), diisopropylethylamine (7.8 g, 60.7 mmol) and sodium iodide (2.7 g, 18.2 mmol) were added to acetonitrile (100 mL), heated to 50°C and stirred for 13 hours. To the reaction solution was added aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[7-chloro-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.2 g, yield 87%).

[0411] MS m / z(ESI):604[M+H].

[0412] Step 5: Preparation of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0413] Tert-butyl 3-[7-chloro-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.83 mmol) The product was dissolved in tetrahydrofuran (10 mL), and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (504 mg, 1.08 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium (66.3 mg, 0.09 mmol), and sodium hydroxide (2M, 2.07 mL) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred in a microwave at 90°C for 40 min. The mixture was poured into aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, yield 93%).

[0414] MS m / z(ESI):910[M+H].

[0415] Step 6: Preparation of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(trifluoromethylsulfoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0416] To a solution of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 2.31 mmol) in dichloromethane (50 mL) was added triethylamine (700 mg, 6.92 mmol) under ice bath, and trifluoromethanesulfonic anhydride (976 mg, 3.46 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour under nitrogen protection. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with aqueous ammonium chloride solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(trifluoromethylsulfonyl)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 100% yield).

[0417] MS m / z(ESI):1042[M+H].

[0418] Step 7: Preparation of tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0419] tert-Butyl 3-[8-fluoro-7-[7-fluoro-3-(trifluoromethylsulfoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d] Pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 2.30 mmol) was dissolved in toluene (50 mL). Under nitrogen protection, tert-butylcarbamate (1.08 g, 9.21 mmol), trisdibenzylideneacetone dipalladium (210.8 mg, 0.23 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (266 mg, 0.46 mmol) and cesium carbonate (2.25 g, 6.9 mmol) were added. The atmosphere was replaced with nitrogen and the mixture was heated to 100 ° C with stirring for 8 hours. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.8 g, yield 77%).

[0420] MS m / z(ESI):1009[M+H].

[0421] Step 8: Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalene-2-amine

[0422] To a solution of tert-butyl 3-[7-[3-(tert-butoxycarbonylamino)-7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.12 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalene-2-amine (96 mg, yield 100%).

[0423] MS m / z(ESI):809[M+H].

[0424] Step 9: Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalene-2-amine

[0425] 4-[4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2-amine (96 mg, 0.12 mmol) was dissolved in N,N-dimethylacetamide (3 mL), cesium fluoride (180 mg, 1.2 mmol) was added, and the mixture was heated to 80°C and stirred for 30 minutes. The reaction mixture was cooled to room temperature, filtered, washed with dichloromethane, concentrated, and purified by preparative HPLC to give 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalene-2-amine (20 mg, 26% yield).

[0426] 1H NMR(400MHz,MeOD)δ9.00(s,1H),7.87-7.84(m,1H),7.35-7.32(m,2H),7.20(d,J=4 Hz,1H),6.81(d,J=4Hz,1H),4.74(t,J=12Hz,2H),4.54–4.43(m,3H),3.90-3.87(m,2 H),3.80(t,J=12Hz,2H),2.71-2.61(m,2H),2.58-2.53(m,2H),2.31(t,J=4Hz,2H), 2.00-1.94(m,4H),1.33(s,2H),0.94-0.85(m,2H),0.78(t,J=8Hz,4H),0.55(s,2H).

[0427] MS m / z(ESI):653[M+H].

[0428] The syntheses of Examples 92 to 113 refer to Example 91.

[0429] Example 114

[0430] Preparation of 5-(2-chloroethynyl)-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-naphthalen-2-ol

[0431] Step 1: Preparation of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0432] Tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 126 μmol) and cesium fluoride (50 mg, 329 μmol) were added to 5 mL of acetonitrile and reacted in an oil bath at 80°C for 1 hour. The reaction mixture was cooled to room temperature, added with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 49.8% yield).

[0433] MS m / z(ESI):798[M+H].

[0434] Step 2: Preparation of tert-butyl 3-[7-[8-(2-chloroethynyl)-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0435] To an eggplant-shaped flask, tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 62.67 μmol), tetrabutylammonium fluoride trihydrate (20 mg, 71.56 μmol), cesium carbonate (61.25 mg, 188.00 μmol) and 3 mL of carbon tetrachloride were added and reacted at room temperature for 2 hours. The reaction solution was concentrated and dissolved in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 3-[7-[8-(2-chloroethynyl)-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (52.16 mg, yield 100%), which was directly used in the next reaction.

[0436] MS m / z(ESI):832[M+H].

[0437] Step 3: Preparation of 5-(2-chloroethynyl)-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-naphthalen-2-ol

[0438] To tert-butyl 3-[7-[8-(2-chloroethynyl)-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (52.16 mg, 62.67 μmol) was added 4 mL of a 3 / 1 dichloromethane / trifluoroacetic acid mixture in an eggplant-shaped flask and allowed to react at room temperature for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate solution, the organic phase was concentrated, and the insoluble solid was filtered. The obtained solid was purified by preparative HPLC to give 5-(2-chloroethynyl)-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[1-[(4-methoxyimino-1-piperidinyl)methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-naphthalen-2-ol (11.5 mg, 25.0% yield).

[0439] MS m / z(ESI):688[M+H].

[0440] 1 H NMR(400MHz,MeOD)δ9.15(s,1H),7.90(dd,J=9.2,5.8Hz,1H),7.39–7.31(m,2H),7.21(d,J=2.6Hz,1H),4.76(d,J=14.4Hz,2H),4.59–4.47(m,2 H),4.24(s,2H),3.92(t,J=14.4Hz,2H),3.80(s,3H),2.22–2.12(m,4H) ,2.06-1.98(s,4H),1.62-1.56(s,2H),1.03–0.84(m,6H),0.75(s,2H).

[0441] The synthesis of Examples 115 to 142 refers to Example 114.

[0442] Example 143

[0443] 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0444] The synthesis of Example 143 can be prepared with reference to Example 114, or by the following method:

[0445] Step 1: tert-Butyl 4-(difluoromethylene)piperidine-1-carboxylate

[0446] 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).

[0447] Step 2: Preparation of 4-(difluoromethylene)piperidine

[0448] 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. The reaction solution was evenly mixed and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude compound 4-(difluoromethylene)piperidine (400 mg, TF salt, yield 99%).

[0449] MS m / z(ESI):134[M+H].

[0450] Step 3: Preparation of tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0451] Tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15 g, 0.03 mol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (12.15 g, 0.034 mol) were added to dioxane (150 mL) and stirred to dissolve. H2O (30 mL) and Cs2CO3 (21.43 g, 0.06 mol) were added. The atmosphere was replaced with nitrogen three times. CataCXium A Pd G3 (1.11 g, 1.52 mmol) was replaced with nitrogen three times, heated to 100°C and stirred for 16 hours, then washed with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15 g, yield 58.5%).

[0452] Step 4: Preparation of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0453] In a round-bottom flask, tert-butyl 3-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.8 g, 3.32 mmol) was dissolved in THF (20 mL), and TBAF (1 M, 6.63 mL) was added dropwise. After nitrogen substitution, the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash column chromatography to give tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.2 g, yield 96.4%).

[0454] MS m / z(ESI):688[M+H].

[0455] Step 5: Preparation of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(methylsulfoxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0456] Methanesulfonyl chloride (133.3 mg, 1.16 mmol) was added to a solution of tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 581.62 μmol) and triethylamine (176.6 mg, 1.74 mmol) in dichloromethane (30 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h. The reaction was quenched with aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was washed with aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(methylsulfonyloxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (445 mg, 99.9% yield).

[0457] Step 6: Preparation of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0458] Tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(methylsulfonyloxymethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (445 mg, 581.08 μmol), 4-(difluoromethylene)piperidine (215.4 mg, 871.61 μmol, TF), DIEA (751 mg, 5.81 mmol) and NaI (261.3 mg, 1.74 mmol) were stirred in acetonitrile (15 mL) at 50 °C for 13 hours. To the reaction solution was added aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (430 mg, yield 92.2%).

[0459] MS m / z(ESI):803[M+H].

[0460] Step 7: Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalene-2-ol

[0461] To a solution of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 685.06 μmol) in dichloromethane (6 mL) and MeOH (1.5 mL) was added HCl (4 M, 6 mL) at 0°C. The mixture was stirred at room temperature for 45 minutes and then the mixture was added to a 1% HCl solution. The reaction solution was slowly added to an aqueous sodium bicarbonate solution, extracted with dichloromethane / methanol (v / v=10 / 1), and the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to give 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (288 mg, yield 63.9%).

[0462] MS m / z(ESI):659[M+H].

[0463] 1 H NMR(400MHz,MeOD)δ9.03(s,1H),7.87(dd,J=8Hz,1H),7.38–7.28(m,2H),7.20(d,J=4Hz,1H),4.80–4.66(m,2H),4.45(q,J=12Hz,2H),4.12–4.01(m ,2H),3.85(d,J=12Hz,2H),3.36(s,1H),2.86–2.75(m,4H),2.71(s,2H),2 .37–2.27(m,4H),2.11–1.99(m,4H),0.83–0.76(m,2H),0.64–0.56(m,2H).

[0464] Example 148

[0465] Preparation of 8-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-8-azabicyclo[3.2.1]oct-6-en-3-one O-methyloxime

[0466] Step 1: Preparation of tert-butyl 2,4-dibromo-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate

[0467] To a solution of tert-butyl 1H-pyrrole-1-carboxylate (3 g, 17.94 mmol) and 1,1,3,3-tetrabromoacetone (13.41 g, 35.88 mmol) in toluene (50 mL) was added dropwise a solution of diethylzinc in n-hexane (32.3 mL, 32.3 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 25°C for 16 hours. The mixture was cooled in an ice bath and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 2,4-dibromo-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (5 g, 73% yield).

[0468] MS m / z(ESI):382[M+H].

[0469] Step 2: Preparation of tert-butyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate

[0470] To a saturated solution of 2,4-dibromo-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylic acid tert-butyl ester (2 g, 5.25 mmol) in ammonium chloride in methanol (20 mL) at 0°C under nitrogen was added freshly prepared zinc-copper coupling agent (4 g, 40 mmol) and stirred at 25°C for 1 hour. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (0.2 g, 17.1% yield).

[0471] MS m / z(ESI):224[M+H].

[0472] Step 3: Preparation of tert-butyl 3-methoxyimino-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate

[0473] Under nitrogen, potassium carbonate (370 mg, 2.7 mmol) was added to a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (0.2 g, 0.90 mmol) and hydroxylamine hydrochloride (97 mg, 1.4 mmol) in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash silica gel chromatography to afford tert-butyl 8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate-3-keto-O-methyloxime (0.16 g, 70.8% yield).

[0474] MS m / z(ESI):253[M+H].

[0475] Step 4: Preparation of 8-azabicyclo[3.2.1]oct-6-en-3-one-O-methyloxime trifluoroacetate

[0476] To a solution of tert-butyl 8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate-3-one-O-methyloxime (0.16 g, 0.64 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (98.06 mg, 0.87 mmol) under ice-cooling, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to afford 8-azabicyclo[3.2.1]oct-6-ene-3-one-O-methyloxime trifluoroacetate (0.16 g, 95.3% yield).

[0477] MS m / z(ESI):153[M+H].

[0478] Step 5: Preparation of tert-butyl 8-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-8-azabicyclo[3.2.1]oct-6-ene-3-one-O-methyloxime-8-carboxylate

[0479] Tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(pivaloylindanedionyloxy)naphthalen-1-yl)-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 130.6 μmol), 8-azabicyclo[3.2.1]oct-6-en-3-one-O-methyloxime trifluoroacetate (160 mg, 61.1 μmol), diisopropylethylamine (85 mg, 652.89 μmol) and sodium iodide (58.72 mg, 391.74 μmol) were stirred in acetonitrile (8 mL) at 50°C for 12 hours. The reaction solution was added with aqueous ammonium chloride (40 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to give tert-butyl 8-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-8-azabicyclo[3.2.1]oct-6-en-3-one-O-methyloxime-8-carboxylate (60 mg, yield 55.9%).

[0480] MS m / z(ESI):822[M+H].

[0481] Step 6: Preparation of 8-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-8-azabicyclo[3.2.1]oct-6-en-3-one O-methyloxime

[0482] Under ice-cooling, to a solution of tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxy-methoxy)naphthalen-1-yl)-8-fluoro-2-((1-((3-(methoxyimino)-8-azabicyclo[3.2.1]oct-6-en-8-yl)methyl)cyclopropyl)methoxypyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 73.10 μmol) in dichloromethane (1 mL) and methanol (0.3 mL) was added hydrochloric acid-dioxane solution (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with saturated aqueous NaHCO3 solution, extracted with a mixed solution of dichloromethane and methanol, dried over anhydrous sodium sulfate, filtered, concentrated, separated by high performance liquid chromatography, and freeze-dried to give 8-((1-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-8-azabicyclo[3.2.1]oct-6-en-3-one O-methyloxime (10.5 mg, yield 23.6%).

[0483] MS m / z(ESI):678[M+H].

[0484] 1 H NMR(400MHz,MeOD)δ9.01(s,1H),7.87(dd,J=9.1,5.7Hz,1H),7.42–7.15(m,3H),6.04(s,2H),4.71–4.48(m,4H), 3.99–3.69(m,7H),3.39–3.33(m,3H),2.70–2.20(m,6H),2.02–1.78(m,4H),0.78–0.65(m,2H),0.56–0.43(m,2H).

[0485] The synthesis of Examples 144 to 187 may refer to Example 114 or 143.

[0486] Example 188

[0487] 4-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-1,6-naphthyridin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0488] Step 1: Preparation of tert-butyl 4-cyclopropylidenepiperidine-1-carboxylate

[0489] Potassium tert-butoxide (6.75 g, 60.23 mmol) was added to THF (200 mL). The reaction temperature was lowered to 0°C. (3-Bromopropyl)triphenylphosphonium bromide (12.23 g, 30.11 mmol) was added to the reaction solution and the reaction was continued for 1 hour. Tert-butyl 4-carbonylpiperidine-1-carboxylate (5 g, 25.09 mmol) was added to the reaction solution. The reaction temperature was raised to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column chromatography to obtain the target compound, tert-butyl 4-cyclopropylidenepiperidine-1-carboxylate (800 mg, 14.3% yield).

[0490] MS m / z(ESI):168[M-55].

[0491] Step 2: Preparation of 4-cyclopropylidenepiperidine

[0492] Tert-butyl 4-cyclopropylidenepiperidine-1-carboxylate (150 mg, 0.67 mmol) was added to dichloromethane (10 mL), and TFA (1 mL) was added to the reaction solution. The mixture was reacted at room temperature for 1 hour, and concentrated under reduced pressure to obtain crude 4-cyclopropylidenepiperidine (80 mg, yield 96%).

[0493] MS m / z(ESI):124[M+H].

[0494] Step 3: Preparation of tert-butyl 3-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-1,6-naphthyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0495] Tert-butyl 3-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-1,6-naphthyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.2 mmol), 4-cyclopropylidenepiperidine (80 mg, 0.65 mmol), DIPEA (130 mg, 1 mmol), and NaI (30 mg, 0.2 mmol) were added to acetonitrile (5 mL) and reacted at 50°C overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash silica gel column chromatography to give the target compound tert-butyl 3-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-1,6-naphthyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, yield 64%).

[0496] MS m / z(ESI):793[M+H].

[0497] Step 4: Preparation of 4-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-1,6-naphthyridin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0498] Tert-butyl 3-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-1,6-naphthyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol) was added to dichloromethane (5 mL), and dioxane hydrochloric acid solution (4N, 5 mL) was added to the reaction solution, and the reaction was continued for 0.5 hours. Then, saturated The pH of the aqueous NaHCO3 solution was adjusted to 8, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative HPLC to give the target compound 4-[2-[[1-[(4-cyclopropylidene-1-piperidinyl)methyl]cyclopropyl]methoxy]-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-1,6-naphthyridin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (30 mg, yield 36%).

[0499] MS m / z(ESI):649[M+H].

[0500] 1 H NMR (400MHz, MeOD) δ9.04 (s, 1H), 8.48 (s, 1H), 7.87 (dd, J = 9.2, 5.7Hz, 1H), 7. 38–7.30(m,2H),7.20(d,J=2.6Hz,1H),4.76–4.49(m,4H),4.42(d,J=11.6Hz,1 H),3.89–3.69(m,4H),3.35(s,1H),3.16–2.93(m,4H),2.60(s,3H),1.99–1.81 (m,4H),1.45–1.20(m,2H),1.06(s,3H),0.96–0.84(m,2H),0.80–0.65(m,2H).

[0501] The synthesis of Examples 189 to 193 refers to Example 188.

[0502] Synthesis of Examples 194-216 Reference Example 143

[0503] Example 217

[0504] Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0505] Step 1: Preparation of (2,5,7-trichloro-8-fluoro-3H-pyrido[4,3-d]pyrimidin-4-one

[0506] Under nitrogen, DIEA (60.00 mmol, 10.45 mL) was added to a solution of 5,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (5 g, 20.00 mmol) in POCl₃ (140 mL), and the mixture was stirred at 100°C for 12 hours. The reaction mixture was concentrated, 1,4-dioxane (60 mL) was added, and 20% aqueous K₂CO₃ solution (500 mL) was added dropwise. The mixture was stirred at 20°C for 2 hours, cooled to 0°C, and the pH was adjusted to 2-3 with dilute hydrochloric acid (1 M). A solid precipitated and was filtered. The filter cake was washed with water and dried in vacuo to afford 2,5,7-trichloro-8-fluoro-3H-pyrido[4,3-d]pyrimidin-4-one (4.5 g, 83.8% yield).

[0507] MS m / z(ESI):266[MH].

[0508] Step 2: Preparation of 2,7-dichloro-8-fluoro-5-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0509] Under nitrogen, sodium thiomethoxide (1.10 g, 14.90 mmol, 95% purity) was added to a solution of 2,5,7-trichloro-8-fluoro-3H-pyrido[4,3-d]pyrimidin-4-one (2 g, 7.45 mmol) in DMA (10 mL). The mixture was stirred at 100°C for 2 hours. The mixture was cooled to 0°C, and ethyl acetate (200 mL) was added to the reaction mixture. The mixture was washed with dilute aqueous HCl (1 M) and extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford 2,7-dichloro-8-fluoro-5-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.2 g, 57.5% yield).

[0510] MS m / z(ESI):278[MH].

[0511] Step 3: Preparation of 2,4,7-trichloro-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidine

[0512] Under nitrogen, POCl₃ (2.30 g, 14.99 mmol, 1.37 mL) and DIEA (1.66 g, 12.85 mmol) were added to a solution of 2,7-dichloro-8-fluoro-5-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-ol (1.2 g, 4.28 mmol) in acetonitrile (32 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated to yield 2,4,7-trichloro-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidine (1.2 g, 93.8% yield).

[0513] Step 4: Preparation of (3-(2,7-dichloro-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0514] Under nitrogen, DIEA (2.60 g, 20.10 mmol) was added to a solution of 2,4,7-trichloro-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidine (1.2 g, 4.02 mmol) in acetonitrile (15 mL) until the pH reached 8-9. Tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.71 g, 8.04 mmol) was then stirred at 20°C for 2 hours. The reaction mixture was added with saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were washed with sodium chloride solution, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford tert-butyl 3-(2,7-dichloro-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 52.5% yield).

[0515] MS m / z(ESI):474[M+H].

[0516] Step 5: Preparation of tert-butyl 3-[7-chloro-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0517] Under nitrogen protection, NaH (84.31 mg, 2.11 mmol, 60% purity) was added to a solution of tert-butyl 3-(2,7-dichloro-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 1.05 mmol) and [1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methanol (297.7 mg, 1.37 mmol) in THF (10 mL), and the mixture was stirred at 20°C for 12 hours. The reaction solution was added with saturated aqueous NH4Cl solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl 3-[7-chloro-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.3 g, yield 43.4%).

[0518] MS m / z(ESI):655[M+H].

[0519] Step 6: Preparation of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0520] Under nitrogen protection, 3-[7-chloro-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.28 g, 427.37 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 5-(2-triisopropylsilylethynyl)naphthalen-2-ol (300.3 mg, 641.05 μmol) in THF (5 mL) were added methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (31.1 mg, 42.74 μmol) and NaOH (2 M, 641.05 μL), and the mixture was stirred in a microwave at 90 °C for 40 min. After concentration, the product was purified by preparative thin layer chromatography to give tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 48.7% yield).

[0521] MS m / z(ESI):961[M+H].

[0522] Step 7: Preparation of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0523] Under nitrogen, TBAF (1 M, 416.13 μL) was added to a solution of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 208.07 μmol) in THF (4 mL), and the mixture was stirred at 20°C for 30 min. The reaction solution was added with saturated aqueous NH4Cl solution, extracted with dichloromethane, and the organic layer was washed with aqueous sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to give tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.1 g, yield 59.7%).

[0524] MS m / z(ESI):805[M+H].

[0525] Step 8: Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0526] Under nitrogen protection, a solution of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.1 g, 124.24 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (6 mL) was stirred in microwave at 100°C for 6 h. After concentration, the product was purified by preparative liquid phase to give 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-methylsulfanyl-pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (3.5 mg, 3.75% yield).

[0527] 1H NMR(400MHz,MeOD)δ7.93(dd,J=8Hz,1H),7.42–7.29(m,2H),7.22(d,J=4Hz,1H),4.80–4.66(m,2H),4.45(q,J=12Hz,2H),4.12–4.01(m,2H),3.85(d ,J=12Hz,2H),3.36(s,1H),2.86–2.75(m,4H),2.82(s,3H),2.71(s,2H),2 .37–2.27(m,4H),2.11–1.99(m,4H),0.83–0.76(m,2H),0.64–0.56(m,2H).

[0528] MS m / z(ESI):705[M+H].

[0529] The synthesis of Examples 218 to 222 is described with reference to Example 143 or 217:

[0530] Example 223

[0531] Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0532] Step 1: Preparation of 2-chloro-3-fluoro-4-iodo-6-methylpyridine

[0533] To a solution of 2-chloro-3-fluoro-6-methylpyridine (10 g, 68.7 mmol) in THF (100 mL) was added a 2M solution of LDA in THF (68.7 mL, 137.4 mmol) dropwise under nitrogen at -65°C. The reaction mixture was stirred at -65°C for 1 hour. A fresh solution of I2 (34.87 g, 137.4 mmol) in THF (10 mL) was then added dropwise to the reaction mixture, and stirring continued at -65°C for 1 hour. The mixture was warmed to 0°C, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2-chloro-3-fluoro-4-iodo-6-methylpyridine (18 g, 96.5% yield).

[0534] MS m / z(ESI):272[M+H].

[0535] Step 2: Preparation of tert-butyl (2-chloro-3-fluoro-6-methylpyridine)-4-carbamate

[0536] To a solution of 2-chloro-3-fluoro-4-iodo-6-methylpyridine (18 g, 66.3 mmol) in 1,4-dioxane (200 mL) at 0°C under nitrogen was added Pd(dba) (3 g, 3.3 mmol), XtanPhos (3.84 g, 6.63 mmol), tert-butyl carbamate (9.3 g, 79.6 mmol), and cesium carbonate (54 g, 165 mmol). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate. The filtrate was collected, concentrated, and purified by silica gel chromatography to afford tert-butyl (2-chloro-3-fluoro-6-methylpyridine)-4-carbamate (15 g, 86.7% yield).

[0537] MS m / z(ESI):261[M+H].

[0538] Step 3: Preparation of 2-chloro-3-fluoro-6-methylpyridin-4-amine

[0539] To a solution of tert-butyl (2-chloro-3-fluoro-6-methylpyridinyl)-4-carbamate (15 g, 57.6 mmol) in acetonitrile (150 mL) was added dropwise a solution of hydrochloric acid in dioxane (2 M, 90 mL, 180 mmol) at 0°C. The reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was cooled to 0°C, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2-chloro-3-fluoro-6-methylpyridin-4-amine (9 g, 97.7% yield).

[0540] MS m / z(ESI):161[M+H].

[0541] Step 4: Preparation of 2-chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine

[0542] Under nitrogen, to a solution of 2-chloro-3-fluoro-6-methylpyridin-4-amine (9 g, 56.3 mmol) in acetonitrile (90 mL) were added NIS (16.5 g, 73.2 mmol) and p-toluenesulfonic acid monohydrate (0.98 g, 5.63 mmol), and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with saturated sodium sulfite solution, water, and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford 2-chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine (14 g, 86.8% yield).

[0543] MS m / z(ESI):287[M+H].

[0544] Step 5: Preparation of methyl 4-amino-6-chloro-5-fluoro-2-methylpyridine-3-carboxylate

[0545] 2-Chloro-3-fluoro-5-iodo-6-methylpyridin-4-amine (3 g, 10.47 mmol) was dissolved in methanol (15 mL) and DMF (15 mL). TEA (4.5 mL, 32 mmol) and bistriphenylphosphine palladium dichloride (750 mg, 1.05 mmol) were added. The atmosphere was replaced with nitrogen and then carbon monoxide. The reaction mixture was stirred at 80°C under a carbon monoxide atmosphere for 16 hours. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel chromatography to afford methyl 4-amino-6-chloro-5-fluoro-2-methylpyridine-3-carboxylate (1.5 g, 65.52% yield).

[0546] MS m / z(ESI):219[M+H].

[0547] Step 6: Preparation of methyl 4-amino-2-(bromomethyl)-6-chloro-5-fluoropyridine-3-carboxylate

[0548] Under nitrogen, to a solution of methyl 4-amino-6-chloro-5-fluoro-2-methylpyridine-3-carboxylate (1.5 g, 6.85 mmol) in carbon tetrachloride (60 mL) were added NBS (1.58 g, 8.87 mmol) and AIBN (370 mg, 2.26 mmol). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography to afford methyl 4-amino-2-(bromomethyl)-6-chloro-5-fluoropyridine-3-carboxylate (1.3 g, 63.9% yield).

[0549] MS m / z(ESI):297[M+H].

[0550] Step 7: Preparation of methyl 4-amino-6-chloro-5-fluoro-2-(methoxymethyl)pyridine-3-carboxylate

[0551] At 0°C under nitrogen, methyl 4-amino-2-(bromomethyl)-6-chloro-5-fluoropyridine-3-carboxylate (1.3 g, 4.38 mmol) was dissolved in methanol (15 mL), and sodium methoxide (4.5 mL, 32 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was cooled to 0°C, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford methyl 4-amino-6-chloro-5-fluoro-2-(methoxymethyl)pyridine-3-carboxylate (0.9 g, 82.6% yield).

[0552] MS m / z(ESI):249[M+H].

[0553] Step 8: Preparation of methyl 6-chloro-5-fluoro-2-(methoxymethyl)-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate

[0554] Under nitrogen, methyl 4-amino-6-chloro-5-fluoro-2-(methoxymethyl)pyridine-3-carboxylate (0.9 g, 3.62 mmol) was dissolved in THF (15 mL), and trichloroacetyl isocyanate (2.05 g, 10.86 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness to afford methyl 6-chloro-5-fluoro-2-(methoxymethyl)-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (1.5 g, 94.8% yield).

[0555] MS m / z(ESI):435.9[M+H].

[0556] Step 9: Preparation of 7-chloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidine-2,4-diol

[0557] Under nitrogen, methyl 6-chloro-5-fluoro-2-(methoxymethyl)-4-[(2,2,2-trichloroacetyl)carbamoylamino]pyridine-3-carboxylate (1.5 g, 3.43 mmol) was dissolved in methanol (15 mL), and methanolic ammonia (5 mL, 1 M) was added. The reaction mixture was stirred at 25°C for 6 hours. The reaction mixture was filtered, and the filter cake was collected to yield 7-chloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidine-2,4-diol (0.75 g, 84.2% yield).

[0558] MS m / z(ESI):260[M+H].

[0559] Step 10: Preparation of 2,4,7-trichloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidine

[0560] Under nitrogen, 7-chloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidine-2,4-diol (0.4 g, 1.54 mmol) was dissolved in SOCl2 (4 mL) and DIEA (1 mL) was added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness to afford 2,4,7-trichloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidine (0.45 g, 99.8% yield).

[0561] MS m / z(ESI):296[M+H].

[0562] Step 11: Preparation of tert-butyl 3-[2,7-dichloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0563] 2,4,7-Trichloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidine (420 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL) at 0°C, and DIEA (1.5 mL, 8.6 mmol) was added, followed by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 2.13 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl 3-[2,7-dichloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, yield 67.1%).

[0564] MS m / z(ESI):472[M+H].

[0565] Step 12: Preparation of tert-butyl 3-[7-chloro-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0566] At 0°C, tert-butyl 3-[2,7-dichloro-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.95 mmol) and [1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methanol (310 mg, 1.43 mmol) were dissolved in THF (15 mL), and NaH (45 mg, 1.91 mmol) was added. After replacing the atmosphere with nitrogen, the reaction solution was stirred at 25°C for 1 hour. The reaction solution was cooled to 0°C, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with water and a saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl 3-[7-chloro-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, yield 56.3%).

[0567] MS m / z(ESI):653[M+H].

[0568] Step 13: Preparation of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0569] Tert-butyl 3-[7-chloro-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 535.8 μmol) was dissolved in THF (5 mL), and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (326 mg, 696.6 μmol), Cata A Xium Pd G3 (39 mg, 54 μmol), and NaOH solution (1 mL, 2 M) were added. After replacing the atmosphere with nitrogen, the reaction solution was microwaved at 100°C for 1 hour. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 38.9% yield).

[0570] MS m / z(ESI):959[M+H].

[0571] Step 14: Preparation of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0572] Under nitrogen, tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 208.51 μmol) was dissolved in THF (3 mL), and TBAF (1 mL, 1 M) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with water and a saturated sodium chloride aqueous solution, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, yield 89.6%).

[0573] MS m / z(ESI):803[M+H].

[0574] Step 15: Preparation of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol

[0575] Under ice bath, to a solution of tert-butyl 3-[2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 186.83 μmol) in dichloromethane (3 mL) and methanol (0.6 mL) was added hydrochloric acid-dioxane solution (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with saturated aqueous NaHCO3 solution, extracted with a mixed solution of dichloromethane and methanol, dried over anhydrous sodium sulfate, filtered, concentrated, separated by high performance liquid chromatography, and freeze-dried to give 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-[[1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methoxy]-8-fluoro-5-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (33 mg, yield 23.6%).

[0576] MS m / z(ESI):703[M+H].

[0577] 1 H NMR(400MHz,MeOD)δ7.85(d,J=4Hz,1H),7.38–7.16(m,3H),4.72–4.53(m,4H),4.47–4.23(m,2H),4.11–4.03(m,2H),3.83 (s,3H),3.79–3.43(m,3H),2.78–2.70(m,6H),2.34–2.21(m,4H),2.04–1.93(m,4H),0.86–0.76(m,2H),0.62–0.55(m,2H).

[0578] The synthesis of Examples 224 to 249 is described with reference to Example 143 or 223:

[0579] Synthesis of Examples 250-253 Reference Examples Example 143 or 217:

[0580] Synthesis Reference Example of Examples 254 to 262 Example 143:

[0581] Biological test evaluation

[0582] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0583] 1. Determination of the activity of the compounds of the present invention in blocking KRAS G12D-SOS1 protein binding

[0584] 1. Experimental purpose:

[0585] The purpose of this assay is to test the ability of compounds to block the binding of KRAS G12D and SOS1 proteins.

[0586] 2. Experimental Reagents and Instruments

[0587] 2.1 Experimental instruments:

[0588] Centrifuge (5810R) was purchased from Eppendorf; liquid analyzers were purchased from Eppendorf or Rainin;

[0589] The microplate reader was purchased from BioTek, USA, and the model is SynergyH1 full-function microplate reader.

[0590] 2.2 Experimental reagents:

[0591] KRAS-G12D / SOS1 Binding Assay Kit was purchased from Cisbio, catalog number 63ADK000CB17PEG;

[0592] GTP was purchased from Sigma, catalog number G8877; 384-well plate was purchased from Perkin Elmer, catalog number 6007299.

[0593] 3. Experimental methods:

[0594] The compound was diluted into 10× compound solution with different concentrations using Diluent buffer in the kit, and 2uL was added to each well of the 384-well plate. Tag2-KRAS G12D protein and GTP were prepared into 5×KRAS G12D-GTP protein mixed solution using Diluent buffer, and Tag1-SOS1 protein was prepared into 5×SOS1 protein solution, and added to 384-well plate, 4uL per well, and incubated at room temperature for 15 minutes. 2×anti-Tag1-Tb prepared with detection buffer was added. 3+ The mixed solution of anti-Tag2-XL665 was added to a 384-well plate at 10 μL per well and incubated at 4°C in the dark for 3 hours. The plate was read using the time-resolved fluorescence program of the Biotek Synergy H1 instrument, and fluorescence values ​​at emission wavelengths of 665 nm and 620 nm were measured.

[0595] 4. Experimental treatment methods:

[0596] The signal ratio (665 nm / 620 nm*10,000) was calculated and the signal ratio and sample concentration were nonlinearly fitted using a four-parameter equation in GraphPad Prism 6 to obtain the IC 50 value.

[0597] 5. Experimental results:

[0598] Table 1. Compounds' activity in blocking KRAS G12D-SOS1 protein binding

[0599] 6. Experimental conclusions:

[0600] The compounds of the present invention can effectively block the binding between KRAS G12D and SOS1 proteins and have good selectivity for the wild type.

[0601] II. Determination of the proliferation inhibitory activity of the compounds of the present invention on KRAS G12D mutant tumor cell lines

[0602] 1. Experimental purpose:

[0603] The proliferation inhibitory activity of the example compounds on five KRAS G12D mutant cell lines, SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D, was determined.

[0604] 2. Experimental instruments:

[0605] 2.1 Instruments:

[0606] Microplate reader (BioTek Synergy H1); pipette (Eppendorf & Rainin).

[0607] 2.2 Reagents:

[0608] HPAF-II, PANC0403, AsPC-1, and GP2D were purchased from Nanjing Kebai Biotechnology Co., Ltd.;

[0609] SNU-1 was purchased from the Cell Bank of the Chinese Academy of Sciences, and Cell Titer-Glo was purchased from Promega, catalog number G7573;

[0610] RPMI 1640 was purchased from Gibco, catalog number 22400089;

[0611] DMEM was purchased from Gibco, catalog number 11995065; FBS was purchased from Gibco, catalog number 10091148;

[0612] PBS was purchased from Gibco, catalog number 10010023; trypsin was purchased from Gibco, catalog number 25200056;

[0613] Cell culture plates were purchased from Corning, catalog number 3610.

[0614] 3. Experimental methods:

[0615] When SNU-1, HPAF-II, Panc0403, AsPC-1, or GP2D cells were cultured to an appropriate confluence, the cells were harvested and adjusted to an appropriate cell density using complete medium. The cell suspension was plated into a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of varying concentrations were prepared using DMSO and culture medium. Vehicle controls were set up and the compound solutions were added to each well of the 96-well plate at 10 μL. The plates were cultured in a 37°C, 5% CO2 incubator for approximately 72 hours. CellTiter-Glo solution was then added and mixed thoroughly with vortexing. The plates were incubated in the dark for 10 minutes and read using a BioTek Synergy H1 microplate reader.

[0616] 4. Experimental data processing method:

[0617] The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the EC 50 value.

[0618] 5. Experimental results:

[0619] Table 2. Antiproliferative activity of compounds against KRAS G12D mutant tumor cell lines

[0620] 6. Experimental conclusions:

[0621] The compounds of the present invention have significant proliferation inhibitory effects on SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D cells.

[0622] III. Inhibitory activity of the compounds of the present invention on p-ERK in AsPC-1 cells

[0623] 1. Experimental purpose:

[0624] The inhibitory activity of the example compounds on the level of phosphorylated ERK in KRAS G12D mutant cells AsPC-1 was determined.

[0625] 2. Experimental instruments:

[0626] 2.1 Instruments:

[0627] Microplate reader (BioTek Synergy H1)

[0628] Pipette (Eppendorf & Rainin)

[0629] 2.2 Reagents:

[0630] Phosphorylated ERK1 / 2 (T202-Y204) LANCE Ultra Cellular Detection Kit was purchased from PerkinElmer, catalog number TRF4000M;

[0631] DMEM was purchased from Gibco, catalog number 11995065;

[0632] FBS was purchased from Gibco, catalog number 10091148;

[0633] PBS was purchased from Gibco, catalog number 10010023;

[0634] Pancreatin was purchased from Gibco, catalog number 25200056;

[0635] Cell culture plates were purchased from Corning, catalog number 3610;

[0636] White opaque OptiPlate TM -384 plate was purchased from PerkinElmer, catalog number 6007290.

[0637] 3. Experimental methods:

[0638] When AsPC-1 cells reached an appropriate confluence, they were harvested and the cell density was adjusted to 1 × 10 6 / mL, the cell suspension was plated in a 96-well plate, 50 μL per well, and placed in a 37°C, 5% CO2 incubator to adhere overnight. Different concentrations of compound solutions were prepared using DMSO and complete culture medium. As a vehicle control, 25 μL of compound solution was added to each well of the 96-well plate. The plate was incubated in a 37°C, 5% CO2 incubator for another 2 hours. The supernatant was discarded and 50 μL of lysis buffer was added to each well. The cells were shaken and lysed at room temperature for 30 minutes. The cells were centrifuged at 1000 rpm for 1 minute. 15 μL of supernatant was transferred to a 384-well plate. 5 μL of detection mixture (Eu-labeled anti-ERK1 / 2 (T202-Y204) Antibody with a final detection concentration of 0.5 nM and ULight labeled anti-ERK1 / 2 Antibody with a final detection concentration of 5 nM) was added to each well. The cells were centrifuged at 1000 rpm for 1 minute to mix well. The cells were reacted overnight at room temperature and detected using BioTek Synergy H1 reads the plate and uses a time-resolved fluorescence program to detect the signal values ​​at emission wavelengths of 620 nm and 665 nm.

[0639] 4. Experimental data processing method:

[0640] The ratio of the signal values ​​at the emission wavelengths of 665 nm and 620 nm was calculated, and the inhibition rate was calculated using the ratio. The concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.

[0641] 5. Experimental results:

[0642] Table 3. Inhibitory activity of compounds on p-ERK in AsPC-1 cells

[0643] 6. Experimental conclusion:

[0644] The compounds of the present invention have a good inhibitory effect on pERK in AsPC-1 cells.

[0645] Pharmacokinetics in mice

[0646] 1. Research objectives:

[0647] Balb / c mice were used as test animals to study the pharmacokinetic behavior of the compound in mice (plasma) after oral administration.

[0648] 2. Experimental Plan

[0649] 2.1 Investigational Drugs:

[0650] The compounds of the present invention were prepared in-house;

[0651] 2.2 Experimental Animals

[0652] Balb / c male mice were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd. with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0653] 2.3 Drug preparation:

[0654] Oral administration preparation: 10% Captisol in 50mM citrate buffer pH 5.0

[0655] Prepare 50 mM citric acid: weigh 4.8 g of citric acid into a 1000 ml glass bottle, add ultrapure water to 300 ml, stir magnetically to completely dissolve, and add ultrapure water to 500 ml to prepare 50 mM citric acid.

[0656] Preparation of 50 mM citric acid (10% Captisol, pH = 5): Weigh 50 g Captisol powder and add it to a 1000 ml glass bottle. Add 300 ml of 50 mM citric acid and stir magnetically to completely dissolve it. Add citric acid to 500 ml and adjust the pH to 5 with 10 M NaOH.

[0657] The example compounds were weighed and added to 4-mL glass bottles, 2.4 mL of the solution was added, and ultrasonication was performed for 10 minutes to obtain a colorless clear solution with a concentration of 3 mg / mL.

[0658] 2.4 Administration:

[0659] Three male Balb / c mice were fasted overnight and PO-administered at a dose of 30 mg / kg in a dosing volume of 10 mL / kg.

[0660] 2.5 Sample collection:

[0661] Before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, 0.04 mL of blood was collected from the orbital cavity. The blood was placed in an EDTA-2K tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -20°C. Food was consumed 4 h after administration.

[0662] 3. Measurement results:

[0663] The final determination results were obtained using LCMS / MS method.

[0664] Table 4. Pharmacokinetic parameters of the compounds in mice after oral administration

[0665] 4. Experimental conclusions:

[0666] The results show that the example compounds have higher oral exposure and higher bioavailability. Compared with the compound MRTX-1133 that needs to be administered intravenously in clinical practice, the present invention provides a class of compounds that can be used for oral administration.

[0667] 5. Anti-tumor efficacy experiments in a human colorectal cancer cell line (GP2D) mouse transplant tumor model

[0668] 1. Purpose of the experiment

[0669] Female BALB / c nude mice aged 8-10 weeks weighing 18-22 g were used as experimental animals. In vivo efficacy experiments were conducted using a human colorectal cancer cell line (GP2D) transplanted tumor model to test the anti-tumor effects of the example compounds by oral administration.

[0670] 2. Experimental instruments and reagents:

[0671] 2.1 Instruments:

[0672] Clean bench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0673] CO2 incubator (Thermo-311, Thermo)

[0674] Centrifuge (Centrifuge 5720R, Eppendorf)

[0675] Automated cell counter (Countess II, Life Technologies)

[0676] Pipette (10-20 μL, Eppendorf)

[0677] Microscope (TS 2, Nikon); Vernier caliper (CD-6" AX, Mitutoyo, Japan)

[0678] Cell culture flasks (T25 / T75 / T225, Corning); constant temperature water bath (HWS12, Shanghai Yiheng Science)

[0679] 2.2 Reagents:

[0680] DMEM (11995-065, Gibco); Fetal bovine serum (FBS) (10091-148, Gibco)

[0681] 0.25% trypsin (25200-056, Gibco); penicillin-streptomycin double antibody (P / S) (SV30010, GE)

[0682] Phosphate buffered saline (PBS) (10010-023, Gibco); Matrigel (356234, Corning)

[0683] Gln (25030-081, Gibco)

[0684] 3. Experimental Methods

[0685] 3.1 Experimental compounds

[0686] The compound implemented by the present invention is self-made.

[0687] 3.2 Preparation of compounds

[0688] A certain amount of the example compound was weighed, and an appropriate amount of 10% solvent (solutol HS15) was added, and the mixture was stirred on a magnetic stirrer for 0.5 hours to prepare a uniform suspension solution of the desired concentration.

[0689] 3.3 Cell culture and passaging

[0690] The human colorectal cancer cell line (GP2D) was obtained from Nanjing Kebo and cultured in DMEM medium (Gibco, 11995-065) supplemented with 10% fetal bovine serum (Gibco, 10091-148) and 1% penicillin / streptomycin (Gibco, 15140-122). The cells were observed under a microscope (Thermo Fisher Scientific, 311). When the cells filled the culture flask to a density of 80%-90%, the cells were routinely passaged and cultured in a 37°C, 5% CO2 incubator (Thermo Fisher Scientific, 311).

[0691] 3.4 Cell inoculation and group administration

[0692] Under sterile conditions, human colorectal cancer cells (GP2D) in the logarithmic growth phase were digested with 0.25% trypsin-EDTA (Gibco, 25200-056), washed and suspended with phosphate buffered saline, mixed with Matrigel (Corning, 356234) at a ratio of 1:1, and then transplanted subcutaneously on the right anterior flank of the back of immunodeficient mice (BALB / c nude). Each mouse was inoculated with 5*10 6 After inoculation, the tumor volume was grown to 100-200 mm. 3 At the same time, the mice were randomly divided into 5 groups according to the tumor size, with 5 mice in each group for in vivo efficacy experiments. The positive control group was the compound MRTX-1133, and the negative control group was the solvent group.

[0693] Administration: The positive control group received intraperitoneal injection, and the example compounds were administered orally. The dosage and administration cycle are shown in the table.

[0694] 3.5 Tumor measurement and calculation of tumor inhibition rate

[0695] The long and short diameters of the tumor were measured with a vernier caliper twice a week and the tumor volume (mm 3 ), calculated as: V = 0.5 * D * d * d, where D and d are the major and minor diameters of the tumor, respectively. The antitumor efficacy is determined by dividing the average tumor volume increase of compound-treated animals by the average tumor volume increase of untreated animals. The tumor inhibition rate is calculated as: When the tumor does not regress, TGI (%) = 100-[(V t -V0) treatment group / (V t -V0) vehicle control group]*100%, when the tumor regresses, TGI (%) = [1-(V t -V0) drug-treated group / V0 vehicle control group]*100%. All animals were euthanized after the experiment.

[0696] 4. Experimental results and conclusions

[0697] Table 5: Pharmacodynamic parameters of compounds in transplanted tumor mice

[0698] As shown in Table 5 above, both the Example compound at an oral dose of 100 mg / kg and the MRTX-1133 compound at an intravenous dose of 10 mg / kg achieved the inhibitory effect of tumor regression. There was no significant decrease in mouse body weight at each dose, demonstrating that the Example compound has excellent tumor inhibition and safety when administered orally, and may provide a new medication regimen for future clinical applications.

Claims

1. A compound represented by general formula (XIX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: X1 is selected from N or CH; X2 selected from CR c2 R c3 N-OR c1 ; Ring G is selected from a 5-8 membered saturated or unsaturated heterocyclic group, a 7-10 membered fused heterocyclic group or a 6-10 membered bridged heterocyclic group; Preferably, 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; Further optimization R m 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 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, =CR4R5, =N-R4 or =N-OR4, 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, 5-14 membered heteroaryl, -C(O)(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)R4、-(CR EE R DD ) n1 C(O)OR4、-C(O)O(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)NR4R5、-(CR EE R DD ) n1 OC(O)NR4R5、-(CR EE R DD ) n1 P(=O)R4R5 or -(CR EE R DD ) n1 substituted by one or more substituents in OP(=O)R4R5; 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =CR4R5, =N-R4 or =N-OR4, 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 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with C 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 Haloalkoxy, -C(O)(CH2) n1 R4, -(CH2) n1 C(O)R4, -(CH2) n1 C(O)OR4, -C(O)O(CH2) n1 R4, -(CH2) n1 C(O)NR4R5, -(CH2) n1 OC(O)NR4R5, -(CH2) n1 P(=O)R4R5 or -(CH2) n1 substituted by one or more substituents in OP(=O)R4R5; Or any two R m Linked to its adjacent atoms to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in alkynyl; preferably forming cyclopropyl, optionally further substituted by one or more substituents selected from deuterium or hydroxy; R a1 Selected from hydrogen, 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 2-4 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) n9 R4, -C(O)O(CH2) n9 R4 or -C(O)[(CH2NR FF C(O))] n10 (CH2) n9 R4, 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 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, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group; R a2 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 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 and 5-14 membered heteroaryl, optionally further deuterated, 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 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, 5-14 membered heteroaryl, C 1-6 Alkylaminocarbonyl and -O(CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, 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 2-4 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, 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, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group; R b1 and R b2 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 Alkylthio, 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 Alkylthio, 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, 5-14 membered heteroaryl, -OC(O)(CH2) n1 R4, -OC(O)(CH2) n1 OR4 and -O(CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R d1 and R d2 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 of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group; Or, R d1 and R d2 Linked to its adjacent atoms to form C 3-8 Cycloalkyl, 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 2-4 Alkenyl and C 2-4 substituted by one or more substituents in the alkynyl group; Preferably the linkage forms a cyclopropyl or cyclobutyl group, 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R e2 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, 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 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 5-10 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4; R e1 、R e3 、R e4 、R e5 、R e6 and R e7 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 of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, 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 2-4 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R c1 、R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R c2 and R c3 Linked to its adjacent atoms to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 substituted by one or more substituents in the alkynyl group; Preferred link formation C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group; R4 or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R DD 、R EE or R FF are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; v is selected from 0, 1, 2, 3, 4 or 5; x1 is selected from 0, 1, 2, 3, 4 or 5; n1 is selected from 0, 1, 2, 3, 4 or 5; n9 is selected from 0, 1, 2, 3 or 4; and n10 is selected from 0, 1, 2, 3 or 4.

2. A compound represented by general formula (XV) or (XV-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Ring E is selected from a 5-8 membered saturated or unsaturated heterocyclic group, a 7-10 membered fused heterocyclic group or a 6-10 membered bridged heterocyclic group; Preferably, a 5-membered heterocyclic group, a 6-membered 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; Further optimization Further optimization R j 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 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, =CR4R5, =N-R4 or =N-OR4, 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, 5-14 Heteroaryl, -C(O)(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)R4、-(CR EE R DD ) n1 C(O)OR4、-C(O)O(CR EE R DD ) n1 R4, -(CR EE R DD ) n1 C(O)NR4R5、-(CR EE R DD ) n1 OC(O)NR4R5、-(CR EE R DD ) n1 P(=O)R4R5 or -(CR EE R DD ) n1 substituted by one or more substituents in OP(=O)R4R5; Preferred are 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, =N-R4 or =N-OR4, 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -(CH2) n1 C(O)R4, -(CH2) n1 C(O)OR4, -C(O)O(CH2) n1 R4, -(CH2) n1 C(O)NR4R5, -(CH2) n1 OC(O)NR4R5, -(CH2) n1 P(=O)R4R5 or -(CH2) n1 substituted by one or more substituents in OP(=O)R4R5; Or any two R j Linked to its adjacent atoms to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in alkynyl; preferably forming cyclopropyl, optionally further substituted by one or more substituents selected from deuterium or hydroxy; R a1 Selected from hydrogen, 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 2-4 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, 5-10 membered heteroaryl, -C(O)(CH2) n9 R4, -C(O)O(CH2) n9 R4 or -C(O)[(CH2NR FF C(O))] n10 (CH2) n9 R4, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group; R b1 and R b2 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 Alkylthio, 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 Alkylthio, 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, 5-14 membered heteroaryl, -OC(O)(CH2) n1 R4, -OC(O)(CH2) n1 OR4 and -O(CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, 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 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R e2 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, 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 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4; R e1 、R e3 、R e4 、R e5 、R e6 and R e7 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 of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, 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 2-4 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R4 or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C substituted with cyano 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Or R4 and R5 are linked to their adjacent atoms to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 substituted by one or more substituents in the alkynyl group; Preferred link formation C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group; R DD 、R EE or R FF are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; n1 is selected from 0, 1, 2, 3, 4 or 5; n9 is selected from 0, 1, 2, 3 or 4; n10 is selected from 0, 1, 2, 3 or 4; t is selected from 1, 2, 3, 4, 5 or 6.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (XVIII): X1 is selected from N or CH; X2 selected from CR c2 R c3 N-OR c1 ; R a1 Selected from hydrogen, 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 2-4 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, 5-10 membered heteroaryl, -C(O)(CH2) n9 R4, -C(O)O(CH2) n9 R4 or -C(O)[(CH2NR FF C(O))] n10 (CH2) n9 R4, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or C 1-3 substituted by one or more substituents of an alkylaminocarbonyl group; R b1 and R b2 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 Alkylthio, 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 Alkylthio, 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, -OC(O)(CH2) n1 R4, -OC(O)(CH2) n1 OR4 and -O(CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio Base, C 1-3 Alkyl, C 1-3 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R e2 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 5-14 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4; Preferred are hydrogen, 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 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) n1 R4, -O(CH2) n1 C(O)R4, -O(CH2) n1 C(O)OR4, -O(CH2) n1 OC(O)OR4, -OC(O)O(CH2) n1 R4, -O(CH2) n1 C(O)NR4R5, -O(CH2) n1 OC(O)NR4R5, -O(CH2) n1 P(=O)R4R5 or -O(CH2) n1 OP(=O)R4R5, 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 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, 5-10 membered heteroaryl, -C(O)(CH2) n1 R4, -C(O)O(CH2) n1 R4 or -C(O)[CH2NR FF C(O)] n1 (CH2) n1 is substituted by one or more substituents in R4; R e1 、R e3 、R e4 、R e5 、R e6 and R e7 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 of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, 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 2-4 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 and C 2-4 substituted by one or more substituents in the alkynyl group; R4 or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R FF are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R c1 、R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 Heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R c2 and R c3 Linked to its adjacent atoms to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, 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 Alkylthio, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 substituted by one or more substituents in the alkynyl group; Preferred link formation C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group; R k 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 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 substituted by one or more substituents of aryl or 5-14 membered heteroaryl; 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, 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 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with C 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 or C 1-3 substituted by one or more substituents in a haloalkoxy group; Or any two R k Linked to its adjacent atoms to form C 3-6 Saturated or unsaturated cycloalkyl or 3-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl is substituted by one or more substituents; preferably linked to form a cyclopropyl, 5-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group; u is selected from 0, 1, 2, 3, 4 or 5; n1 is selected from 0, 1, 2, 3, 4 or 5; n9 is selected from 0, 1, 2, 3 or 4; n10 is selected from 0, 1, 2, 3 or 4; n11 is selected from 1, 2 or 3; and n12 is selected from 1, 2 or 3.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: In the general formula (XVIII) The structure is selected from u R k The substituted 3-8 membered N-containing heterocyclic group, Preferably, it is selected from 3-8 membered N-containing heterocyclic groups, More preferably, it is selected from 4-8 membered N-containing heterocyclic groups, More preferably, selected from 5. 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 (XVII): R k 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 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 substituted by one or more substituents of aryl or 5-14 membered heteroaryl; Deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, C 1-3 alkyl Base, 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 3-6 Cycloalkyl or 3-6 membered heterocyclic group, 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 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted with C 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 or C 1-3 substituted by one or more substituents in a haloalkoxy group; Or any two R k Linked to its adjacent atoms to form C 3-6 Saturated or unsaturated cycloalkyl or 3-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 Alkynyl is substituted by one or more substituents; preferably linked to form a cyclopropyl, 5-6 membered saturated or unsaturated heterocyclic group, optionally further selected from 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 Alkylthio, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl or C 2-4 substituted by one or more substituents in the alkynyl group; R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; u is selected from 0, 1, 2, 3, 4 or 5; y is selected from 0, 1, 2 or 3; n11 is selected from 1, 2 or 3; and n12 is selected from 1, 2 or 3; Preferably, the general formula (XVII) is further represented by general formula (XVII-1):

6. The compound according to any one of claims 1, 3 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R c1 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, preferably methyl; R c2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, preferably hydrogen or fluorine; R c3 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, preferably hydrogen or fluorine.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R b1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably fluorine or chlorine; R b2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl or methylthio, optionally further selected from deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, thiol, methoxy, ethoxy, propoxy, isopropyloxy, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated isopropyloxy, substituted with one or more substituents selected from propoxy, deuterated methoxy, deuterated ethoxy, deuterated propoxy, deuterated isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxyisopropyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or methylthio, wherein the methyl, ethyl, propyl, and isopropyl are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, or trifluoromethoxy; R e1 、R e3 、R e6 and R e7 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydrogen, fluorine, chlorine, methyl or trifluoromethyl; R e2 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydroxy, amino, fluorine, chlorine, methyl or trifluoromethyl; R e4 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydroxy, amino, cyano, fluorine, chlorine, methyl, ethyl, ethynyl or trifluoromethyl; R e5 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl, preferably hydroxy, amino, fluorine, chlorine, methyl or trifluoromethyl.

8. The compound according to any one of claims 5 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, amino, cyano, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl, methoxy, ethoxy, deuterated methoxy, deuterated ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl, preferably hydrogen or fluorine; y is 0, 1, or 2.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

10. A compound represented by general formula (XVII-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: X2, R b 、R k , n11, n12, y and u are as defined in any of the above claims.

11. A compound represented by general formula (XVII-E), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: R x Selected from halogen, C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, 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, 5-14 membered heteroaryl, C 1-6 Alkylaminocarbonyl or (C 1-6 alkyl)3Si-C 2-6 substituted by one or more substituents in the alkynyl group; Preferred are fluorine, chlorine, bromine, iodine, C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or (C 1-3 alkyl)3-Si-C 2-4 substituted by one or more substituents in the alkynyl group; R y is selected from hydrogen or Pg; the Pg is selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, p-toluenesulfonyl, p-methoxybenzyl, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably tert-butyloxycarbonyl; X2, R a2 、R b1 、R b2 、R b 、R k , n11, n12, y and u are as defined in any of the above claims.

12. A method for preparing a compound represented by general formula (XVII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of: The compound represented by general formula (XVII-C) reacts with the compound represented by general formula (XVII-D) in the presence of a base to obtain the compound represented by general formula (XVII-E) or its stereoisomer and a pharmaceutically acceptable salt thereof; R x Selected from halogen, C 6-14 Aryl or 5-14 membered heteroaryl, the C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, 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, 5-14 membered heteroaryl, C 1-6 Alkylaminocarbonyl or (C 1-6 alkyl)3Si-C 2-6 substituted by one or more substituents in the alkynyl group; Preferred are fluorine, chlorine, bromine, iodine, C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or (C 1-3 alkyl)3-Si-C 2-4 substituted by one or more substituents in the alkynyl group; R z is selected from halogen, preferably chlorine, bromine or iodine; R y is selected from hydrogen or Pg; the Pg is selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, p-toluenesulfonyl, p-methoxybenzyl, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably tert-butyloxycarbonyl; 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 sodium hydride; When R x When selected from halogen, the compound represented by general formula (XVII-E) is further reacted with the compound represented by general formula (XVII-F) in the presence of a palladium catalyst and a base to obtain the compound represented by general formula (XVII-G) or its stereoisomer and a pharmaceutically acceptable salt thereof; R w is selected from boronic acid, borate, chain borate or cyclic borate; 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 sodium hydroxide or potassium hydroxide; The palladium catalyst is selected from (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, palladium acetate or methanesulfonate [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II); preferably methanesulfonate [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II); The compound represented by general formula (XVII-E) or the compound represented by general formula (XVII-G) is optionally deprotected to obtain the compound represented by general formula (XVII) or its stereoisomers and pharmaceutically acceptable salts thereof; X2, R a2 、R b1 、R b2 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R e7 、R b 、R k , y and u as described in any of the above claims.

13. A method for preparing a compound represented by general formula (XIX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by the general formula (XIX-A) reacts with the compound represented by the general formula (XIX-B) in the presence of a halide salt and a base to obtain the compound represented by the general formula (XIX) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof; Preferably, the method is as follows: A method for preparing a compound represented by general formula (XVII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof The compound represented by the general formula (XVII-A) reacts with the compound represented by the general formula (XVII-B) in the presence of a halide salt and a base to obtain the compound represented by the general formula (XVII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof; R 6 Selected from hydrogen or a hydroxyl protecting group; the hydroxyl 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 selected from trimethylsilyl or tert-butyldimethylsilyl; 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; 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; Ring G, X1, X2, R a1 、R a2 、R b1 、R b2 、R d1 、R d2 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R e7 、R m 、R k , x1, y, v and u are as described in any of the above claims.

14. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a KRAS inhibitor drug; preferably in a drug for KRAS G12D, KRAS G12V or KRAS G13D mutations.

16. Use of the compound according to any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 14 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.