Multi-component fused ring derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a polynary fused ring derivative inhibitor as well as a preparation method and application thereof. Particularly, the invention relates to a compound shown in a general formula, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound to treatment of cancers and other related diseases.

Description

Technical Field

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

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

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

[0004] RAS was the first oncogene to be identified and also has the highest mutation rate, 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, G13, and Q61 of the Switch II region (aa59-76) within the p-loop (aa 10-17), with G12 mutations being the most common (83%).

[0005] 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 between the two.

[0006] Currently, AMG-510 and MRTX-849, drugs that specifically target KRAS G12C, have been approved for marketing. However, there are currently no specific targeted drugs for KRASG12D and KRAS G12V, and there is a large clinical demand. In addition, pan-KRAS inhibitors can simultaneously target multiple KRAS pathogenic mutations, are applicable to more patients, may have a wider range of indications, and have broad market prospects. Summary of the Invention

[0007] The object of the present invention is to provide a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the structure of which is as follows:

[0008]

[0009] Wherein: X1 is selected from N or CR3;

[0010] X2 selected from CR 1a R 1b NR 1a 、N-OR 1a , CR 1a R 1b -CR 1c R 1d , S or O; preferably CR 1a R 1b NR 1a 、N-OR 1a , CR 1a -CR 1c R 1d or O

[0011] Ring A is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0012] L1 is selected from -O-, -S-, -NR 1e -, -C(O)-, -S(O)- or -SO2-;

[0013] L2 is selected from a bond or C1-C4 alkylene, wherein the C1-C4 alkylene is optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0014] Alternatively, two substituents on the same carbon atom in a C1-C4 alkylene group are linked to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0015] R1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl may optionally be further substituted with 1, 2, 3, 4, 5 or 6 R b replace;

[0016] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0017] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, 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 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0018] R4 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl may optionally be further substituted with 1, 2, 3, 4, 5 or 6 R c replace;

[0019] Ra Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CR aa R bb ) n1 -3-12 membered heterocyclic group, -(CR aa R bb ) n1 -C 6-14 Aryl, -(CR aa R bb ) n1 -5-14 membered heteroaryl, -(CR aa R bb ) n1 -OR 2a 、-(CR aa R bb ) n1 -C(O)R 2a 、-(CR aa R bb ) n1 -C(O)OR 2a 、-(CR aa R bb ) n1 -NR 2a R 2b 、-(CR aa R bb ) n1 -P(O)R 2a R 2b 、-(CR aa R bb ) n1 -NR 2c C(O)R 2a 、-(CR aa R bb ) n1 -C(O)NR 2a R 2b 、-(CR aa R bb )n1 -S(O)2R 2a 、-(CR aa R bb ) n1 -S(O)2NR 2a R 2b 、-(CR aa R bb ) n1 -NR 2c S(O)2R 2a 、-(CR aa R bb ) n1 -S(O)R 2a (=NR 2c ) or -(CR aa R bb ) n1 -N=S(O)R 2a R 2b or =CR 2a R 2b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 2d R 2e One or more substitutions; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-14 Aryl, -(CH2) n1 -5-14 membered heteroaryl, -(CH2) n1 -OR 2a 、-(CH2) n1 -C(O)R 2a 、-(CH2) n1 -C(O)OR 2a 、-(CH2) n1 -NR 2a R 2b 、-(CH2) n1 -P(O)R 2a R 2b 、-(CH2) n1 -NR 2c C(O)R 2a 、-(CH2) n1 -C(O)NR 2a R 2b 、-(CH2) n1 -S(O)2R 2a 、-(CH2) n1 -S(O)2NR 2a R 2b 、-(CH2) n1 -NR 2c S(O)2R 2a 、-(CH2) n1 -S(O)R 2a (=NR 2c ) or -(CH2) n1 -N=S(O)R 2a R 2b or =CR 2a R 2b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 2d R 2e One or more substitutions in ;

[0020] Or, any two R a Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl-OR 2a 、-C(O)R 2a 、-C(O)OR 2a 、-NR 2a R 2b 、-P(O)R 2a R 2b 、-NR 2c C(O)R2a 、-C(O)NR 2a R 2b 、-S(O)2R 2a 、-S(O)2NR 2a R 2b 、-NR 2c S(O)2R 2a 、-S(O)R 2a (=NR 2c ),-N=S(O)R 2a R 2b Sum = CR 2a R 2b One or more substitutions in ;

[0021] 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0022] Or, any two R b Link Form 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 groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b One or more substitutions in ;

[0023] R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c 、-(CH2) n2S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0024] Or, any two R c Link Form 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 groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0025] R a-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-14 Aryl, -(CH2) n1 -5-14 membered heteroaryl, -(CH2) n1 -OR 1a 、-(CH2) n1 -C(O)R 1a 、-(CH2) n1 -C(O)OR 1a 、-(CH2) n1 -NR 1a R 1b 、-(CH2) n1 -P(O)R 1a R 1b 、-(CH2) n1 -NR 1c C(O)R 1a 、-(CH2) n1 -C(O)NR 1a R 1b 、-(CH2) n1 -S(O)2R 1a 、-(CH2) n1 -S(O)2NR 1a R 1b 、-(CH2) n1 -NR 1cS(O)2R 1a 、-(CH2) n1 -S(O)R 1a (=NR 1c ), -(CH2) n1 -N=S(O)R 1a R 1b 、=CR 1a R 1b 、=NR 1a 、=N-OR 1a or =CR 1a -CR 1c R 1d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 1d R 1e One or more substitutions in ;

[0026] Or, any two R a-1 Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl-OR 1a 、-C(O)R 1a 、-C(O)OR 1a 、-NR 1a R 1b 、-P(O)R 1a R 1b 、-NR 1c C(O)R 1a 、-C(O)NR 1a R 1b 、-S(O)2R 1a 、-S(O)2NR 1a R 1b 、-NR 1c S(O)2R 1a 、-S(O)R 1a (=NR 1c ),-N=S(O)R 1a R 1b Sum = CR 1a R 1b One or more substitutions in ;

[0027] R 1a 、R 1b 、R 1c and R 1d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0028] Or, R 1a and R 1b Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0029] R 2a 、R 2b 、R 2c 、R 2d and R 2eare each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0030] R 3a 、R 3b and R 3c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0031] R 4a 、R 4b and R 4c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0032] R 1e Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0033] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

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

[0035] n1 is selected from 0, 1, 2, 3 or 4; and n2 is selected from 0, 1, 2, 3 or 4.

[0036] In certain embodiments of the present invention, ring A is selected from 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-14-membered fused heterocyclyl or 5-14-membered spiro heterocyclyl; preferably 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-8-membered heterocyclyl and 4-8-membered heterocyclyl, 5-8-membered heterocyclyl spiro 4-8-membered heterocyclyl

[0037] Preferably, ring A is selected from Preferred

[0038] Ring B is selected from a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl;

[0039] Ring C is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0040] Ring D is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0041] R dSelected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CR aa R bb ) n3 -3-12 membered heterocyclic group, -(CR aa R bb ) n3 -C 6-14 Aryl, -(CR aa R bb ) n3 -5-14 membered heteroaryl, -(CR aa R bb ) n3 -OR 8a 、-(CR aa R bb ) n3 -C(O)R 8a 、-(CR aa R bb ) n3 -C(O)OR 8a 、-(CR aa R bb ) n3 -NR 8a R 8b 、-(CR aa R bb ) n3 -P(O)R 8a R 8b 、-(CR aa R bb ) n3 -NR 8c C(O)R 8a 、-(CR aa R bb ) n3 -C(O)NR 8a R 8b 、-(CR aa R bb ) n3-S(O)2R 8a 、-(CR aa R bb ) n3 -S(O)2NR 8a R 8b 、-(CR aa R bb ) n3 -NR 8c S(O)2R 8a 、-(CR aa R bb ) n3 -S(O)R 8a (=NR 8c ) or -(CR aa R bb ) n3 -N=S(O)R 8a R 8b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 8d R 8e One or more substitutions; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n3 -3-12 membered heterocyclic group, -(CH2) n3 -C 6-14 Aryl, -(CH2) n3 -5-14 membered heteroaryl, -(CH2) n3 -OR 8a 、-(CH2) n3 -C(O)R 8a 、-(CH2) n3 -C(O)OR 8a 、-(CH2) n3 -NR 8a R 8b 、-(CH2) n3 -P(O)R 8a R 8b 、-(CH2) n3 -NR 8c C(O)R 8a 、-(CH2) n3 -C(O)NR 8a R 8b 、-(CH2) n3 -S(O)2R 8a 、-(CH2) n3 -S(O)2NR 8a R 8b 、-(CH2) n3 -NR 8c S(O)2R 8a 、-(CH2) n3 -S(O)R 8a (=NR 8c ) or -(CH2) n3 -N=S(O)R 8a R 8b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 8d R 8e One or more substitutions in ;

[0042] R 8a 、R 8b 、R 8c 、R 8d and R 8e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

[0043] In certain embodiments of the present invention, L2 is selected from

[0044] R g-1 and R g-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0045] R g-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0046] R g-4 、R g-5 、R g-6 and R g-7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are substituted by one or more; q is selected from 0, 1, 2, 3 or 4.

[0047] In certain embodiments of the present invention, R4 is selected from 5-7 membered monocyclic heterocyclic group, 7-10 membered fused heterocyclic group or 7-10 membered bridged heterocyclic group, which may be further substituted by 1, 2, 3, 4, 5 or 6 R e replace;

[0048] Preferably, R4 is selected from Optionally, it may be further replaced by 1, 2, 3, 4, 5 or 6 R e replace;

[0049] R e Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR4b R 4c 、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

[0050] In certain embodiments of the present invention, -L2-R4 is selected from

[0051]

[0052] R e-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c 、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0053] R e-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; r-1 is selected from 0, 1, 2 or 3; r-2 is selected from 0, 1, 2 or 3;

[0054] r is selected from 0, 1, 2, 3, 4, 5 or 6; R e 、R g-1 、R g-2 、R g-3 、R g-4 、R g-5 、R g-6 、R g-7 and q are as defined in the above embodiments.

[0055] In certain embodiments of the present invention, X1 is selected from N, CH, CCH3, CCH2CH3, C-Cl, CF, C-CF3 or C-CHF2; preferably N, CH, CCH3, CCH2CH3, C-Cl or CF.

[0056] In certain embodiments of the present invention, R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, 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 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Alkylamino; preferably, R2 is selected from hydrogen, deuterium, fluorine, chlorine or bromine; more preferably, R2 is selected from fluorine.

[0057] In certain embodiments of the present invention, R1 is selected from

[0058] Preferably, R1 is selected from

[0059] Preferred

[0060] R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 and R 5-7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0061] R 6-1 、R 6-2 、R 6-3 、R 6-4 and R 6-5are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0062] R 7-1 、R 7-2 、R 7-3 、R 7-4 and R 7-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0063] R 8-1 、R 8-2 、R 8-3 and R 8-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

[0064] In certain embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is further represented by the general formula (III-1) or (III-2):

[0065]

[0066] n3 is selected from 1, 2 or 3.

[0067] The present invention also provides a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof:

[0068]

[0069] Preferably, the general formula (IV) is further represented by the general formula (IV-1) or (IV-2)

[0070]

[0071] Arc A' is selected from

[0072] R L1 is selected from halogen; preferably chlorine or bromine; R L2 is selected from halogen; preferably chlorine or bromine;

[0073] R L3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0074] Ring B, Ring C, Ring D, R d ,X1,X2,L1,L2,R1,R2,R4,R a and x is as described in any of the above embodiments.

[0075] The present invention also provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0076]

[0077] The compound represented by general formula (IV) is subjected to coupling reaction ① to obtain the compound represented by general formula (II);

[0078] Preferably, the preparation method is a method for preparing a compound represented by general formula (V-1) or an acceptable salt thereof, comprising the following steps 1):

[0079]

[0080] The compound represented by the general formula (IV-1) is subjected to coupling reaction ① to obtain the compound represented by the general formula (V-1);

[0081] Optionally, further comprising step 2):

[0082]

[0083] The compound represented by the general formula (V-1) and the compound represented by the general formula (VI-1) are subjected to a coupling reaction ② to obtain the compound represented by the general formula (III-1);

[0084] Or preferably, the preparation method is a method for preparing a compound represented by general formula (V-2) or an acceptable salt thereof, comprising the following steps 1):

[0085]

[0086] The compound represented by the general formula (IV-2) is subjected to coupling reaction ① to obtain the compound represented by the general formula (V-2);

[0087] Optionally, further comprising step 2):

[0088]

[0089] The compound represented by the general formula (V-2) and the compound represented by the general formula (VI-2) are subjected to a coupling reaction ② to obtain the compound represented by the general formula (III-2);

[0090] R L4 is selected from boronic acid, borate, chain borate or cyclic borate; L1 、RL2 、R L3 ,X1,X2,L1,L2,R1,R2,R4,R a ,x,R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 6-1 、R 6-2 、R 6-3 、R 6-4 and R 6-5 As described in any of the above embodiments.

[0091] In certain embodiments of the present invention, R L4 Selected from substituted or unsubstituted Preferred

[0092] R L5 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl or C 3-8 Cycloalkyl;

[0093] n4 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0094] In certain embodiments of the present invention, the coupling reaction ① or the coupling reaction ② is carried out in the presence of a palladium catalyst;

[0095] In certain embodiments of the present invention, the palladium catalyst is selected from palladium on carbon, palladium acetate, diphenylphosphinoferrocene palladium dichloride, tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [(bis(1-adamantyl)butylphosphino)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, methanesulfonate (dimethyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct or methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II);

[0096] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0097] In certain embodiments of the present invention, the weight percentage of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0098] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations, injections, suspensions, powders, granules or lozenges, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0099] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0100] The present invention further relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of KRAS inhibitor drugs; preferably, the use in KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRASG13D inhibitor drugs.

[0101] The present invention further relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, 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 tumors, breast cancer, lung cancer, pancreatic cancer and colorectal cancer; preferably, the use of the above-mentioned compound or a pharmaceutical composition thereof in the preparation of a medicament for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer and head and neck tumors.

[0102] The present invention further relates to a method for preparing the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck cancer, breast cancer, lung cancer, pancreatic cancer and colorectal cancer; preferably, a method for preparing a method for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer and head and neck cancer.

[0103] The present invention also relates to a method for treating, preventing and / or treating diseases or conditions such as Noonan syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer and colorectal cancer, which comprises administering to the patient a therapeutically effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; preferably, in the preparation of a method for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer and head and neck tumors.

[0104] In certain embodiments of the present invention, the above-mentioned disease or condition is a disease or condition mediated by a KRAS mutation; the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation.

[0105] In certain embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof can be administered by any convenient method, for example, orally, parenterally, buccally, sublingually, nasally, rectally, intrathecally or transdermally, and the pharmaceutical compositions adjusted accordingly.

[0106] Detailed Description of the Invention

[0107] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

[0108] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". For example, C 1-6Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6 Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0109] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0110] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be located at any position within the alkenyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkenyl group is an unsaturated aliphatic hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0111] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0112] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a particular embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0113] The term "spiroalkyl" refers to an aliphatic hydrocarbon polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroalkyl group contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl is divided into mono-, di-, or poly-spirocycloalkyl according to the number of shared spiro atoms between the rings, and in one embodiment, is mono- and di-spirocycloalkyl. In one embodiment, it is a 4-, 3-, 5-, 4-, 5-, 4-, 6-, 5-, or 5-membered mono-spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

[0114]

[0115] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the fused cycloalkyl group comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, and in one embodiment, it is bicyclic or tricyclic, and further in one embodiment, it is a 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. In one embodiment, the fused cycloalkyl group is an optionally substituted fused cycloalkyl group described elsewhere herein or a fused cycloalkyl group optionally fused with a heterocyclic group, an aryl group or a heteroaryl group. Non-limiting examples of fused cycloalkyl groups include:

[0116]

[0117] The term "bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the bridged cycloalkyl group comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of constituent rings, the bridged cycloalkyl group may be bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl group is an optionally substituted bridged cycloalkyl group described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include:

[0118]

[0119] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxygen, but does not include the ring portion of -OO- or -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl group contains 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl group contains 3 to 8, 5 to 10, or 6 to 11 ring atoms; in one embodiment, the heterocyclyl group contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.In one embodiment, described heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0120] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl according to the number of spirohetero atoms shared between the rings; monospiroheterocyclyl and bispiroheterocyclyl are preferred; in one embodiment, the spiroheterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:

[0121]

[0122] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclyl is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl is an optionally substituted or fused heterocyclyl described elsewhere herein, or a cycloalkyl, heterocyclyl, aryl or heteroaryl group; non-limiting examples of fused heterocyclyls include:

[0123]

[0124]

[0125] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In specific embodiments, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups; preferably bicyclic, tricyclic or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0126]

[0127] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted with one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is aromatic and the other rings may be saturated, partially unsaturated, or a ring containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl group, a benzo 3-10 membered cycloalkyl group, or a benzo 3-10 membered heterocyclyl group. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl group, a benzo 3-6 membered cycloalkyl group, or a benzo 3-6 membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

[0128]

[0129] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

[0130] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, the heteroaryl group contains 5 to 20, 5 to 14 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in particular embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from a heteroaryl group with 6-10 members, a heteroaryl group with 3-10 members, or a heteroaryl group with 3-10 members, and a heterocyclyl group with 3-10 members. In another embodiment, the heteroaryl group is selected from a 5- or 6-membered heteroaryl group with 6-10 members, a 5- or 6-membered heteroaryl group with 3-6 members, and a 5- or 6-membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothienyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0131] The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

[0132] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0133] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

[0134] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0135] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH2CF3,

[0136] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0137] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0138] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.

[0139] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0140] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

[0141] The term "aminocarbonyl" refers to NH2-C(O)-.

[0142] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0143] The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0144] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0145] The term "hydroxy" refers to an -OH group. The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "oxo" or "oxo" refers to =0.

[0146] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atoms described in this patent include their isotopes ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0147] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituents are selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

[0148] 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.

[0149] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0150] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0151] " substituted " refers to that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment in one embodiment. When a substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" refers to that it may be substituted or not, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical achievable. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0152] In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

[0153] 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.

[0154] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0155] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0156] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0157] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

[0158] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0159] "Optically active" and "enantiomeric active" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.

[0160] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of the optical rotations (+) and (-) have nothing to do with the absolute configuration, R or S, of the molecule.

[0161] The compounds of the present invention include all "stereoisomers," "stereomerically pure," "stereomerically enriched," "enantiomerically pure," "optically active," "enantiomerically active," and "optical isomers" thereof. DETAILED DESCRIPTION

[0162] 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.

[0163] Example

[0164] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0165] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0166] HPLC determination was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0167] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0168] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0169] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0170] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0171] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0172] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0173] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0174] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0175] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0176] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0177] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0178] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0179] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0180] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0181] Intermediate A

[0182] 5-Bromo-4,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0183]

[0184] Step 1: Preparation of 2,7-dichloro-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine

[0185] Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10.00 g, 39.61 mmol) in tetrahydrofuran

[0186] (50 mL) was cooled to -40°C. Sodium methoxide (2.14 g, 39.61 mmol) was dissolved in methanol (10 mL) and added dropwise to the reaction solution. The reaction was allowed to react at -40°C for 1 hour. The reaction solution was concentrated, poured into water, and the solid was collected by filtration and dried to give 2,7-dichloro-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine (9.60 g, 97.71% yield). MS m / z (ESI): 248 [M+H].

[0187] Step 2: Preparation of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxypyridin[4,3-d]pyrimidine

[0188] 2,7-Dichloro-8-fluoro-4-methoxy-pyrido[4,3-d]pyrimidine (7.00 g, 28.22 mmol) and [(2R,

[0189] 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (4.49 g, 28.22 mmol) was dissolved in tetrahydrofuran

[0190] (200mL), nitrogen protection, add sodium hexamethyldisilazide tetrahydrofuran solution (14.22

[0191] mL, 2mol / L), reacted in an ice bath for 1 hour, quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 7-chloro-8-fluoro-2-(((2R,7aS)-

[0192] 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxypyrido[4,3-d]pyrimidine (3.8 g, yield 36.32%). MS m / z (ESI): 371 [M+H].

[0193] Step 3: 5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-

[0194] Preparation of 4-methoxypyridinyl[4,3-d]pyrimidine

[0195] 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxypyridin[4,3-d]pyrimidine (3.60 g, 9.71 mmol) was dissolved in tetrahydrofuran (100 mL). A tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium magnesium chloride lithium chloride complex (38.84 mL, 1 mol / L) was added under ice-cooling and stirred for 0.5 h. 1,2-dibromo[4,3-d]pyrimidine was added under ice-cooling. Tetrachloroethane (12.62 g, 38.84 mmol) was reacted for 0.5 h, then quenched with aqueous ammonium chloride. The reaction was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxypyrido[4,3-d]pyrimidine (3.80 g, yield 87.04%). MS m / z (ESI): 449 [M+H].

[0196] Step 4: Preparation of 5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol

[0197] 5-Bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-

[0198] 4-Methoxypyrido[4,3-d]pyrimidine (4.10 g, 9.12 mmol) was dissolved in glacial acetic acid (20 mL), and sodium iodide (5.47 g, 36.47 mmol) was added. The mixture was reacted at 70°C for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by silica gel chromatography to obtain 5-bromo-7-chloro

[0199] -8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-

[0200] 4-ol (3.60 g, yield 90.63%). MS m / z (ESI): 435 [M+H].

[0201] Step 5: Preparation of 5-bromo-4,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0202] 5-Bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (800 mg, 1.84 mmol) was dissolved in phosphorus oxychloride (9.20 mL), and N,N-diisopropylethylamine (237.3 mg, 1.84 mmol) was added. The mixture was reacted at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain 5-bromo-4,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (830 mg, yield 99.5%). MS m / z (ESI): 453 [M+H].

[0203] Example 1

[0204] 5-Ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaza[4,3-g]pyrimido[4,5,6-de][1,6]naphthypyridin-5-yl)naphthalen-2-ol

[0205]

[0206] Step 1: Preparation of tert-butyl (R)-3-(hydroxymethyl)-1,4-oxacyclopropane-4-carboxylate

[0207] Dissolve (2R)-4-tert-Butyloxycarbonyl-1,4-oxocyclopentene-2-carboxylic acid (1.00 g, 4.08 mmol) in anhydrous tetrahydrofuran (8 mL). Slowly add a solution of lithium aluminum tetrahydride in tetrahydrofuran (1.96 mL, 2.5 mol / L) dropwise under ice-cooling. Stir under ice-cooling for 1 hour. Slowly add sodium sulfate decahydrate under ice-cooling to quench the mixture. Filter and wash the filter cake with ethyl acetate. The organic phase is collected and concentrated under reduced pressure to yield tert-butyl (R)-3-(hydroxymethyl)-1,4-oxacyclopropane-4-carboxylate (766 mg, 81.2% yield). MS m / z (ESI): 232 [M+H].

[0208] Step 2: Preparation of tert-butyl (2R)-2-formyl-1,4-oxol-4-carboxylate

[0209] Dissolve (2R)-tert-butyl 2-(hydroxymethyl)-1,4-oxol-4-carboxylate (0.94 g, 4.06 mmol) in dichloromethane (15 mL), then add Dess-Martin periodinane (2.24 g, 5.28 mmol). React at room temperature for 2 hours, then filter and collect the filtrate. Add saturated aqueous sodium bicarbonate to the filtrate, stir for a period of time, separate the layers, collect the organic phase, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain tert-butyl (2R)-2-formyl-1,4-oxol-4-carboxylate (445 mg, 47.8% yield). MS m / z (ESI): 230 [M+H].

[0210] Step 3: Preparation of tert-butyl (3R)-3-vinyl-1,4-oxol-4-carboxylate

[0211] Bromomethyltriphenylphosphine (1.04 g, 2.91 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Potassium tert-butoxide (326.69 mg, 2.91 mmol) was added under ice-cooling. The mixture was allowed to react for 0.5 h. Then, a solution of (2R)-2-formyl-1,4-oxol-4-carboxylic acid tert-butyl ester (445 mg, 1.94 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 1.5 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to afford (3R)-3-vinyl-1,4-oxol-4-carboxylic acid tert-butyl ester (325 mg, 73.7% yield). MS m / z (ESI): 228 [M+H].

[0212] Step 4: Preparation of (3R)-3-vinyl-1,4-oxacyclopropane

[0213] Dissolve tert-butyl (3R)-3-vinyl-1,4-oxol-4-carboxylate (325 mg, 1.43 mmol) in dichloromethane (5 mL). Add a solution of hydrogen chloride (3.00 mL, 4 mol / L) in dioxane. Stir at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure to obtain (3R)-3-vinyl-1,4-oxol-4-carboxylate (230 mg, 98.3% yield). MS m / z (ESI): 128 [M+H].

[0214] Step 5: Preparation of (3R)-4-(5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-vinyl-1,4-oxacyclopropane

[0215] (3R)-3-Vinyl-1,4-oxirane (233 mg, 1.83 mmol) was dissolved in dichloromethane (15 mL). N,N-Diisopropylethylamine (3.55 g, 27.48 mmol) and Intermediate A (831.90 mg, 1.83 mmol) were added sequentially under ice-cooling. The mixture was stirred under ice-cooling for 1 hour. Water was added and the mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to give (3R)-4-(5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-vinyl-1,4-oxirane (273 mg, 27.4% yield). MS m / z (ESI): 544 [M+H].

[0216] Step 6: Preparation of (R)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaza[4,3-g]pyrimido[4,5,6-de][1,6]naphthyridine

[0217] (3R)-4-(5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-vinyl-1,4-oxacyclopropane (260 mg, 477 μmol) was dissolved in a mixture of tetrahydrofuran (0.5 mL) and water (0.25 mL), and cesium carbonate (465 mg, 1.43 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (39 mg, 477 μmol) were added. The reaction mixture was stirred at 90°C for 0.5 hours, cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to yield (R)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazin[4,3-g]pyrimido[4,5,6-de][1,6]naphthyridine (90 mg, 40.5% yield). MS m / z (ESI): 464 [M+H].

[0218] Step 7: Preparation of 6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaza[4,3-g]pyrimidinyl[4,5,6-de][1,6]naphthyridin-5-yl)-5-(((triisopropylsilyl)ethynyl)naphthalene-2-ol

[0219] (R)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaza[4,3-g]pyrimido[4,5,6-de][1,6]naphthyridine (70 mg, 150.89 μmol), 6 -fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (106.04 mg, 226.34 μmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium(II) (10.99 mg, 15.09 μmol) mol) and sodium hydroxide aqueous solution (226.34 μl, 2 mol / L) were mixed in a microwave tube, tetrahydrofuran (2 mL) was added, and nitrogen was bubbled for 5 minutes. The reaction was carried out in a microwave oven at 100°C for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to give 6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaazepinyl[4,3-g]pyrimidinyl[4,5,6-de][1,6]naphthypyridin-5-yl)-5-(((triisopropylsilyl)ethynyl)naphthalen-2-ol (70 mg, yield 60.3%). MS m / z(ESI):770[M+H].

[0220] Step 8: Preparation of 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaza[4,3-g]pyrimido[4,5,6-de][1,6]naphthypyridin-5-yl)naphthalen-2-ol

[0221] 6-Fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaazepin[4,3-g]pyrimidinyl[4,5,6-de][1,6]naphthyridin-5-yl)-5-(((triisopropylsilyl)ethynyl)naphthalen-2-ol (70 mg, 90.91 μmol) was dissolved in tetrahydrofuran (2 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (363.6 μmol) was added. The mixture was stirred at room temperature for 0.5 h, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and purified to obtain 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxaza[4,3-g]pyrimido[4,5,6-de][1,6]naphthypyridin-5-yl)naphthalen-2-ol (14.7 mg, yield 26.4%). MS m / z (ESI): 614 [M+H].

[0222] 1 H NMR(400MHz, DMSO-d)δ8.26(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.1Hz,1H),7.41(d,J=2.6Hz,1H),7.21(dt,J=5.9 ,2.8Hz,1H),6.17(d,J=7.9Hz,1H),5.50(d,J=6.3Hz,1H),5.38–5.21(m,1H),4.93(ddd,J=11.8,7.5,4.3Hz,1H),4.57(dd,J=1 3.3,7.2Hz,1H),4.18–4.11(m,2H),4.07–3.95(m,2H),3.86(dd,J=12.0,4.6Hz,1H),3.52(ddd,J=21.3,10.7,3.6Hz,2H),3.15 –3.01(m,4H),2.84(q,J=7.8Hz,1H),2.16(dd,J=8.2,4.2Hz,1H),2.09–2.06(m,1H),2.01(p,J=8.4Hz,2H),1.89–1.73(m,4H).

[0223] The synthesis of Examples 2 to 260 is carried out according to the synthesis method of Example 1:

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] Alternatively, the following examples are synthesized using the following method:

[0245] Example 53

[0246] 5-Ethyl-6-fluoro-4-((S)-9-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-6-methylene-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthalen-2-ol

[0247] Step 1: Preparation of compound 53-2

[0248] (S)-N-Methylbut-3-en-2-amine (84 mg, 991.0 μmol), Intermediate A (300 mg, 660.6 μmol), and N,N-diisopropylethylamine (427 mg, 3.3 mmol) were dissolved in dichloromethane (5 mL) and stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 5-bromo-N-((S)-but-3-en-2-yl)-7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrido[4,3-d]pyrimidin-4-amine (182 mg, 54.7% yield). MS m / z (ESI): 503 [M+H].

[0249] Step 2: Preparation of compound 53-3

[0250] Compound 53-2 (180 mg, 358.0 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 35.8 μmol), and cesium carbonate (233 mg, 716.0 μmol) were mixed in 1,4-dioxane (5 mL) and water (0.5 mL) at room temperature. The atmosphere was replaced with nitrogen and stirred at 90°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain (S)-8-chloro-9-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-6-methylene-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridine (80 mg, 52.9% yield). MS m / z (ESI): 422 [M+H].

[0251] Step 3: Preparation of compound 53-4

[0252] At room temperature, compound 53-3 (80 mg, 189.6 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (133 mg, 284.4 μmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (14 mg, 19.0 μmol) and sodium hydroxide (190 μL, 2 mol / L) were mixed in a microwave tube, tetrahydrofuran (5 mL) and water (0.2 mL) were added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 6-fluoro-4-((S)-9-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-6-methylene-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (50 mg, 36.2% yield). MS m / z (ESI): 728 [M+H].

[0253] Step 4: Preparation of Example 53

[0254] Compound 53-4 (30 mg, 41.2 μmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, and tetrabutylammonium fluoride (41 μL, 2 mol / L) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by HPLC and lyophilized to obtain Example 53 (7.2 mg). MS m / z (ESI): 572 [M+H].

[0255] 1 H NMR (400MHz, CDCl3) δ9.88(s,1H),8.63(s,1H),7.68(s,1H),7.44–7.01(m,3H),6.23(d,J=8Hz,1H),5.33(d,J=8Hz,1H ),5.33–5.30(m,2H),4.49–4.38(m,3H),3.50–3.26(m,3H),2.63–2.30(m,4H),1.75–1.34(m,5H),1.12(d,J=4Hz,3H).

[0256] Example 82

[0257] 5-Ethynyl-6-fluoro-4-((R)-4'-fluoro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7a',8',11',12'-tetrahydro-10'H-spiro[cyclopropane-1,7'-[1,4]oxazepin[4,3-g]pyrimido[4,5,6-de][1,6]naphthyridine]-5'-yl)naphthalen-2-ol

[0258]

[0259] Step 1: Preparation of compound 82-1

[0260] At room temperature, trimethylsulfoxide iodide (36 mg, 161.7 μmol) and potassium tert-butoxide (18 mg, 161.7 μmol) were dissolved in anhydrous tetrahydrofuran (8 mL). The mixture was stirred for a few minutes. A solution of compound 1-7 (50 mg, 107.8 μmol) in tetrahydrofuran (1 mL) was added. The atmosphere was replaced with nitrogen and stirred at room temperature for 2 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford (R)-5'-chloro-4'-fluoro-2'-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7a',8',11',12'-tetrahydro-10'H-spiro[cyclopropane-1,7'-[1,4]oxazepine[4,3-g]pyrimido[4,5,6-de][1,6]naphthyridine] (27 mg, 52.4% yield). MS m / z (ESI): 479 [M+H].

[0261] Step 2: Preparation of compound 82-2

[0262] At room temperature, compound 82-1 (27 mg, 56.5 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (40 mg, 84.7 μmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (4 mg, 5.6 μmol) and sodium hydroxide (7 mg, 169.5 μmol) were mixed in a microwave tube, tetrahydrofuran (1.5 mL) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 6-fluoro-4-((R)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)-7a',8',11',12'-tetrahydro-10'H-spiro[cyclopropane-1,7'-[1,4]oxazolopyrimidin[4,3-g]pyrimidin[4,5,6-de][1,6]naphthyridine]-5'-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (20 mg, crude). The crude product was used directly in the next reaction without purification.

[0263] Step 3: Preparation of Example 82

[0264] Compound 82-2 (20 mg, 25.5 μmol) was dissolved in tetrahydrofuran (1.5 mL) at room temperature. A solution of tetrabutylammonium fluoride (102 μL, 1 mol / L) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 0.5 hours. Ethyl acetate and water were added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by HPLC and lyophilized to obtain Example 82 (5.3 mg). MS m / z (ESI): 629 [M+H].

[0265] Example 113

[0266] 2-Amino-4-((5R,7aR)-6-chloro-4-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazolo[4',3':1,6]pyrido[2,3,4-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0267]

[0268] Step 1: Preparation of compound 113-2

[0269] Compound 113-1 (prepared according to the synthetic method of compound 170-5) (15.0 g, 33.6 mmol), compound 1-5 (1.5 g, 9.2 mmol), and N,N-diisopropylethylamine (11.9 g, 91.7 mmol) were dissolved in dichloromethane (200 mL) under ice-cooling and stirred at room temperature for 2 hours. Water and dichloromethane were added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (3R)-4-(5,7-dibromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-vinyl-1,4-oxazepane (2.8 g, 54.9% yield). MS m / z (ESI): 500 [M+H].

[0270] Step 2: Preparation of compound 113-3

[0271] At room temperature, compound 113-2 (1.8 g, 3.6 mmol), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (5.7 g, 36.1 mmol), triethylenediamine (121 mg, 1.1 mmol) and cesium carbonate (2.3 g, 7.2 mmol) were mixed in N,N-dimethylformamide (50 mL), replaced with nitrogen, and stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (3R)-4-[5,7-dibromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3-vinyl-1,4-oxazepane (1.1 g, 49.1% yield). MS m / z (ESI): 501 [M+H].

[0272] Step 3: Preparation of compound 113-4

[0273] At room temperature, compound 113-3 (50 mg, 80.2 μmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (39 mg, 96.3 μmol), dichloro[bis(diphenylphosphinophenyl) ether]palladium(II) (6 mg, 8.2 μmol) and cesium carbonate (52 mg, 160.6 μmol) were mixed in toluene (2 mL), replaced with nitrogen, and stirred at 110 ° C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (4-((7aR)-6-chloro-4-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazepine[4',3':1,6]pyrido[2,3,4-de]quinazolin-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (30 mg, crude). The crude product was used directly in the next reaction without purification. MS mz (ESI): 753 [M+H].

[0274] Step 4: Preparation of Example 113

[0275] Compound 113-4 (30 mg, crude) was dissolved in dichloromethane (0.5 mL) at room temperature, and trifluoroacetic acid (0.5 mL) was added, followed by stirring at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, extracted with aqueous sodium bicarbonate and dichloromethane, and the organic phase was collected and concentrated under reduced pressure. The crude product was separated by HPLC (column: SuperLu C18 (10 μm*250 mm*30 mm); mobile phase: water (0.1% formic acid), acetonitrile; gradient ratio: 20%-40% acetonitrile; flow rate: 35 mL / min; column temperature: room temperature) and lyophilized to obtain a pair of atropisomers, with Example 113 (1.4 mg) eluting first. MS mz (ESI): 653 [M+H].

[0276] 1H NMR(400MHz,DMSO-d)δ7.13–7.27(m,2H),6.67(s,2H),6.17(s,1H),5.93(s,1H),5 .31–5.34(m,2H),5.20–5.21(m,1H),4.78–4.80(m,1H),4.59–4.64(m,1H),4.06–4 .11(m,1H),4.00–4.09(m,1H),3.80–3.83(m,2H),3.08–3.11(m,1H),2.81–2.87(m ,1H),1.92–2.10(m,3H),1.76–1.81(m,5H),1.71–1.73(m,2H),1.43–1.45(m,1H).

[0277] Example 133

[0278] 4-((R)-7-Cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazolidinyl[4,3-g]pyrimidinyl[4,5,6-de][1,6]naphthyl-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0279]

[0280] Step 1: Preparation of compound 133-1

[0281] Under ice, (4-bromobutyl)triphenylphosphonium bromide (10.0 g, 20.9 mmol) and n-butyllithium (26.2 mL, 1.6 mol / L) were dissolved in tetrahydrofuran (100 mL). A solution of compound 1-3 (3.0 g, 13.1 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise. The atmosphere was purged with nitrogen and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain tert-butyl (R)-3-(cyclobutyldienylmethyl)-1,4-oxazepine-4-carboxylate (880 mg, 25.2% yield). MS m / z (ESI): 268 [M+H].

[0282] Step 2: Preparation of compound 133-2

[0283] Compound 133-1 (700 mg, 2.6 mmol) was dissolved in dichloromethane (4 mL) at room temperature. A solution of hydrogen chloride (4.4 mL, 4 mol / L) in dioxane was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain (R)-3-(cyclobutyldimethyl)-1,4-oxazolidinone (530 mg, crude product). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 168 [M+H].

[0284] Step 3: Preparation of compound 133-3

[0285] Compound 133-2 (550 mg, 2.2 mmol) was dissolved in dichloromethane (15 mL) under ice-cooling. N,N-diisopropylethylamine (2.2 g, 17.4 mmol) and intermediate A (1.4 g, 2.4 mmol) were added sequentially, and the mixture was stirred at room temperature for 6 hours. Water and dichloromethane were added for extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (R)-4-(5-bromo-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,3-d]pyrimidin-4-yl)-3-(cyclobutylmethyl)-1,4-oxazane (950 mg, 74.5% yield). MS m / z (ESI): 585 [M+H].

[0286] Step 4: Preparation of compound 133-4

[0287] At room temperature, compound 133-3 (950 mg, 1.6 mmol), cesium carbonate (1.6 g, 4.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (123 mg, 150.5 μmol) were mixed in dioxane (12 mL) and water (4 mL), replaced with nitrogen, and stirred at 90°C for 1 hour. The mixture was extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (R)-5-chloro-7-cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazolopyrimidin[4,3-g]pyrimidinin[4,5,6-de][1,6]naphthyridine (520 mg, 63.5% yield). MS m / z (ESI): 505 [M+H].

[0288] Step 5: Preparation of compound 133-5

[0289] At room temperature, compound 133-4 (90 mg, 178.6 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (167 mg, 357.2 μmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (26 mg, 35.7 μmol) and sodium hydroxide (21 mg, 535.8 μmol) were mixed in a microwave tube, tetrahydrofuran (2 mL) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 100°C for 1 hour. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-((R)-7-cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazolopyrimidin[4,3-g]pyrimidin[4,5,6-de][1,6]naphthyridin-5-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (90 mg, crude). The crude product was used directly in the next reaction without purification.

[0290] Step 6: Preparation of Example 133

[0291] Compound 133-5 (90 mg, 111.1 μmol) was dissolved in tetrahydrofuran (1.5 mL) at room temperature. A solution of tetrabutylammonium fluoride (102 μL, 1 mol / L) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 0.5 hours. Ethyl acetate and water were added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by HPLC and lyophilized to obtain Example 133. MS m / z (ESI): 654 [M+H].

[0292] 1H NMR(400MHz,DMSO-d)δ10.16(d,J=4.8Hz,1H),7.96(dd,J=9.2,5.6Hz,1H),7.46(td,J=9.2 ,5.6Hz,1H),7.37(d,J=2.4Hz,1H),7.18(dd,J=6.8,2.6Hz,1H),5.47–5.25(m,1H),4.68(dd ,J=10.6,4.4Hz,1H),4.52(dd,J=13.6,7.2Hz,1H),4.19(d,J=29.6Hz,2H),4.07–3.94(m,2 H),3.76(dd,J=12.4,4.4Hz,1H),3.55–3.37(m,1H),3.26–2.71(m,8H),2.31–1.88(m,11H).

[0293] Example 170

[0294] 2-Amino-4-((7aR)-4,6-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazopyryl[4',3':1,6]pyridin[2,3,4-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0295]

[0296] Step 1: Preparation of Compound 170-2

[0297] Under ice, 4,6-dibromo-5,7-difluoroindoline-2,3-dione (45.0 g, 132 mmol) was dissolved in aqueous sodium hydroxide (600 mL, 2 mol / L). A solution of hydrogen peroxide (74.8 g, 660.0 mmol, 30% purity) was slowly added dropwise and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite, the pH was adjusted to ~3, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2-amino-4,6-dibromo-3,5-difluorobenzoic acid (30 g, 68.7% yield). MS m / z (ESI): 332 [M+H].

[0298] Step 2: Preparation of Compound 170-3

[0299] Compound 170-2 (17.0 g, 51.4 mmol) was dissolved in dichloromethane (200 mL) under an ice bath. N-(oxymethylene)sulfonyl chloride (18.2 g, 128.4 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain 2,4-dibromo-6-(3-(chlorosulfonyl)ureido)-3,5-difluorobenzoic acid (35.0 g, crude product). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 473 [M+H].

[0300] Step 3: Preparation of Compound 170-4

[0301] Compound 170-3 (24.0 g, crude) was dissolved in an aqueous solution of hydrogen chloride (85 mL, 6 mol / L) under ice and stirred at 100°C for 16 hours. The filter cake was collected by filtration and dried to yield 5,7-dibromo-6,8-difluoro-quinazoline-2,4-diol (33.0 g, crude). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 357 [M+H].

[0302] Step 4: Preparation of Compound 170-5

[0303] Compound 170-4 (2.0 g, 5.6 mmol) was dissolved in phosphorus oxychloride (12 mL) at room temperature, and N,N-diisopropylethylamine (1.9 g, 14.7 mmol) was added. The mixture was stirred at 70°C for 13 hours. The reaction mixture was cooled and concentrated under reduced pressure to obtain 5,7-dibromo-2,4-dichloro-6,8-difluoroquinazoline (1.1 g, crude product). The crude product was used directly in the next reaction without further purification.

[0304] Step 5: Preparation of Compound 170-6

[0305] Compound 170-6 (1.1 g, 8.8 mmol) was dissolved in dichloromethane (15 mL) under ice-cooling. N,N-diisopropylethylamine (5.7 g, 43.9 mmol) and compound 1-5 (2.2 g, 5.6 mmol) were added and stirred at room temperature for 6 hours. Water and dichloromethane were added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (4S)-3(5,7-dibromo-2-chloro-6,8-difluoro-quinazolin-4-yl)-4-vinyl-1,3-oxazolidine (2.2 g, 81.9% yield). MS m / z (ESI): 484 [M+H].

[0306] Step 6: Preparation of Compound 170-7

[0307] Under ice bath, compound 170-6 (260 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (856 mg, 5.4 mmol), 1,4-diazabicyclo[2.2.2]octane (30 mg, 268.8 μmol) and cesium carbonate (526 mg, 1.6 mmol) were added in sequence, and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (4S)-3-[5,7-dibromo-6,8-difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4-vinyl-1,3-oxazolidinone (143 mg, 57.0% yield). MS m / z (ESI): 607 [M+H].

[0308] Step 7: Preparation of Compound 170-8

[0309] At room temperature, compound 170-7 (100 mg, 164.9 μmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxolane-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (133 mg, 329.9 μmol), bis(diphenylphosphinophenyl ether)palladium(II) dichloride (47 mg, 66.0 μmol) and cesium carbonate (108 mg, 330.0 μmol) were mixed in toluene (3 mL), replaced with nitrogen, and stirred at 110 ° C for 3 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl (3-cyano-4-((7aR)-4,6-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7a,8,11,12-tetrahydro-7H,10H-[1,4]oxazolidinonepyrrolidone[4',3':1,6]pyridinone[2,3,4-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (200 mg, crude). The crude product was used directly in the next reaction without purification.

[0310] Step 8: Preparation of Example 170

[0311] Compound 170-8 (200 mg, crude) was dissolved in dichloromethane (3 mL) at room temperature, and trifluoroacetic acid (3.0 g, 26.3 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by HPLC (SuperLu C18 column (10 μm*250 mm*30 mm); mobile phase: water (0.1% formic acid), acetonitrile; gradient ratio: 20%-40% acetonitrile; flow rate: 35 mL / min; column temperature: room temperature) and lyophilized to obtain a pair of atropisomers. The first-eluting isomer was Example 170 (15 mg). MS m / z (ESI): 637 [M+H].

[0312] 1 H NMR (400MHz, DMSO) δ8.16 (d, J=12.8Hz, 2H), 7.40 (ddd, J=27.2, 8.4, 5.2Hz, 1H), 7.24–7.08 (m,1H),5.89(d,J=32.4Hz,1H),5.71(d,J=2.4Hz,1H),5.31(d,J=54.4Hz,1H),4.79(td,J= 11.6,5.2Hz,1H),4.57(dd,J=14.4,7.2Hz,1H),4.14(dd,J=10.4,6.0Hz,1H),4.04(d,J=10 .4Hz,1H),3.97–3.72(m,2H),3.20–3.04(m,3H),2.86(d,J=6.8Hz,1H),2.40–1.66(m,8H).

[0313] Example 226

[0314] 4-((S)-4-(2,2-difluoroethyl)-9-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-6-methylene-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0315]

[0316] Step 1: Preparation of compound 226-2

[0317] At room temperature, tert-butyl (S)-3-buten-2-ylcarbamate (600 mg, 3.5 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (420 mg, 10.5 mmol, 60% purity) and 2,2-difluoroethyl trifluoromethanesulfonate (1.5 g, 7.1 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain tert-butyl N-(2,2-difluoroethyl)-N-[(1S)-1-methylallyl]carbamate (500 mg, 60.6% yield). MS m / z (ESI): 236 [M+H].

[0318] Step 2: Preparation of compound 226-3

[0319] Compound 226-2 (500 mg, 2.1 mmol) was dissolved in a solution of hydrogen chloride (10 mL, 4 mol / L) in 1,4-dioxane at room temperature and stirred for 0.5 hours. The reaction mixture was concentrated under reduced pressure to afford (2S)-N-(2,2-difluoroethyl)but-3-en-2-amine hydrochloride (400 mg, crude). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 136 [M+H].

[0320] Step 3: Preparation of Compound 226-4

[0321] Compound 226-3 (400 mg, crude), Intermediate A (529 mg, 1.2 mmol), and N,N-diisopropylethylamine (1.5 g, 11.7 mmol) were dissolved in dichloromethane (10 mL) at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 5-bromo-7-chloro-N-(2,2-difluoroethyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-N-[(1S)-1-methylallyl]pyrido[4,3-d]pyrimidin-4-amine (200 mg, 15.5% yield). MS m / z (ESI): 554 [M+H].

[0322] Step 4: Preparation of Compound 226-5

[0323] Compound 226-4 (200 mg, 361.8 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 36.2 μmol), and cesium carbonate (235 mg, 0.7 mmol) were mixed in 1,4-dioxane (5 mL) and water (0.5 mL) at room temperature. The atmosphere was replaced with nitrogen and stirred at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to afford (S)-8-chloro-4-(2,2-difluoroethyl)-9-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-6-methylene-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridine (60 mg, 29.9% yield). MS m / z(ESI):472[M+H].

[0324] Step 5: Preparation of Compound 226-6

[0325] At room temperature, compound 226-5 (50 mg, 106.1 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (50 mg, 106.1 μmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (8 mg, 10.6 μmol) and sodium hydroxide (8 mg, 211.9 μmol) were mixed in water (0.5 mL) and tetrahydrofuran (5 mL), replaced with nitrogen, and stirred at 75 ° C for 1 hour. Water and ethyl acetate were added for extraction, and the organic phase was collected, filtered, and concentrated under reduced pressure to obtain 4-((S)-4-(2,2-difluoroethyl)-9-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-6-methylene-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (100 mg, crude product). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 778 [M+H].

[0326] Step 6: Preparation of Example 226

[0327] Compound 226-6 (100 mg, crude) was dissolved in tetrabutylammonium fluoride (1 mL, 1 mol / L) in tetrahydrofuran at room temperature and stirred for 0.5 hours. The reaction mixture was diluted with ethyl acetate and concentrated under reduced pressure. The crude product was separated by HPLC and lyophilized to obtain Example 226 (17 mg). MS m / z (ESI): 622 [M+H].

[0328] 1 H NMR(400MHz,DMSO-d)δ10.15(s,1H),7.95–8.00(m,1H),7.44–7.49(m,1H),7.40(d,J=2.8Hz, 1H),7.21(d,J=2.8Hz,1H),5.47(s,1H),5.99(s,1H),5.35–5.36(m,1H),4.76–4.82(m,1H),4 .63–4.70(m,1H),4.12(s,1H),4.00–4.09(m,1H),3.77–3.80(m,2H),3.08–3.11(m,1H),2.81 –2.87(m,1H),1.94–2.11(m,3H),1.75–1.84(m,4H),1.43(d,J=6.8Hz,3H),1.24–1.27(m,2H).

[0329] Example 234

[0330] 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7,8,9,10-tetrahydro-1,3,6,10-tetraazacycloheptan-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0331]

[0332] Step 1: Preparation of compound 234-2

[0333] 3-Acetyl-2-chloropyridine (3.0 g, 19.3 mmol), bis-(4-methoxybenzyl)-amine (6.5 g, 25.1 mmol), and N,N-diisopropylethylamine (7.5 g, 57.9 mmol) were dissolved in N-methylpyrrolidone (40 mL) at room temperature and stirred at 140°C for 3 hours. The reaction mixture was cooled, extracted with water and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one (5.0 g, 68.9% yield). MS m / z (ESI): 377 [M+H].

[0334] Step 2: Preparation of compound 234-3

[0335] Compound 234-2 (4.0 g, 10.6 mmol) was dissolved in methanol (30 mL) at room temperature, and sodium borohydride (570 mg, 15.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, concentrated under reduced pressure, and extracted with water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-pyridyl]ethanol (3.7 g, 92.0% yield). MS m / z (ESI): 379 [M+H].

[0336] Step 3: Preparation of Compound 234-4

[0337] Compound 234-3 (3.4 g, 8.9 mmol) was dissolved in dichloromethane (60 mL) at room temperature, and thionyl chloride (2.6 g, 22.0 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 0.5 hours. 3-Butenamine hydrochloride (9.7 g, 89.8 mmol) and N,N-diisopropylethylamine (11.6 g, 89.8 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 3-[1-(but-3-enylamino)ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (3.0 g, 77.4% yield). MS m / z (ESI): 432 [M+H].

[0338] Step 4: Preparation of compound 234-5

[0339] Compound 234-4 (217 mg, 503 μmol), intermediate A (208 mg, 458.1 μmol), and N,N-diisopropylethylamine (237 mg, 1.9 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to afford N-[1-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-5-bromo-N-butyl-3-phenyl-7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,23,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-amine (140 mg, 36.0% yield). MS m / z (ESI): 425 [M+H].

[0340] Step 5: Preparation of Compound 234-6

[0341] At room temperature, compound 234-5 (110 mg, 129.5 μmol), cesium carbonate (127 mg, 389.8 μmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (10 mg, 13.7 μmol) were mixed in 1,4-dioxane (8 mL) and water (2 mL), replaced with nitrogen, and stirred at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 3-(1-(5-chloro-4-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-8,9-dihydro-1,3,6,10-tetraazacycloheptane[de]naphth-10(7H)-alkyl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (50 mg, 50.2% yield). MS m / z (ESI): 768 [M+H].

[0342] Step 6: Preparation of Compound 234-7

[0343] Compound 234-6 (50 mg, 65.1 μmol) was dissolved in trifluoroacetic acid (4.4 g, 38.6 mmol) and trifluoromethanesulfonic acid (170 mg, 1.1 mmol) at room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure, dichloromethane was added, and the mixture was washed twice with saturated sodium bicarbonate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(1-(5-chloro-4-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-8,9-dihydro-1,3,6,10-tetraazacycloheptane[de]naphth-10(7H)-alkyl)ethyl)pyridin-2-amine (30 mg, crude). The crude product was used directly in the next step without purification. MS m / z (ESI): 528 [M+H].

[0344] Step 7: Preparation of Compound 234-8

[0345] At room temperature, compound 234-7 (30 mg, 56.8 μmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (66 mg, 140.8 μmol), sodium hydroxide (9 mg, 225.0 μmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (8 mg, 11.0 μmol) were mixed in tetrahydrofuran (6 mL) and water (0.1 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred at 75 ° C for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methylene-7,8,9,10-tetrahydro-1,3,6,10-tetraazacycloheptane[de]naphth-5-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (15 mg, 31.6% yield). MS m / z (ESI): 834 [M+H].

[0346] Step 8: Preparation of Example 234

[0347] Compound 234-8 (15 mg, 18.0 μmol) was dissolved in tetrahydrofuran (3 mL) at room temperature. A solution of tetrabutylammonium fluoride (0.1 mL, 1 mol / L) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by HPLC and lyophilized to obtain Example 234. MS m / z (ESI): 678 [M+H].

[0348] Biological test evaluation

[0349] 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.

[0350] I. Determination of the proliferation inhibitory activity of the compounds of the present invention against KRAS mutation and amplification tumor cell lines 1. Experimental purpose:

[0351] The proliferation inhibitory activity of the example compounds on KRAS mutation and amplification cell lines SW620 and MKN1 was determined.

[0352] 2. Experimental instruments:

[0353] 2.1 Instruments: nanoliter dispensing system (I-DOT); microplate reader (BioTek Synergy H1); pipette (Eppendorf & Rainin).

[0354] 2.2 Reagents: MKN1 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.; SW620 cells were purchased from ATCC; CellTiter-Glo was purchased from Promega, catalog number G7573; RPMI 1640 was purchased from Gibco, catalog number 22400089; DMEM was purchased from Gibco, catalog number 11995065; FBS was purchased from Gibco, catalog number 10091148; PBS was purchased from Gibco, catalog number 10010023; trypsin was purchased from Gibco, catalog number 25200056; cell culture plates were purchased from Corning, catalog number 3610.

[0355] 3. Experimental Methods: When SW620 and MKN1 cells were cultured to an appropriate degree of 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 100 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of varying concentrations were prepared using DMSO. The compound solutions were then added to the 96-well plate using the nanoliter-scale dispensing system I-DOT at a concentration of 8 nL to 600 nL per well. The plates were cultured in a 37°C, 5% CO2 incubator for 3-6 days. Then, 50 μL of CellTiter-Glo solution was added, the plates were shaken to mix evenly, and the plates were incubated in the dark for 10 minutes. The plates were read using a BioTek Synergy H1 microplate reader.

[0356] 4. Experimental data processing method: The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.

[0357] 5. Experimental results: Table 1: Proliferation inhibition activity of compounds against KRAS mutant tumor cell lines

[0358] Compound number <![CDATA[SW620 IC 50 (nM)]]> <![CDATA[MKN1 IC 50 (nM)]]> Example 1 0.7 2.3 Example 21 1.6 5.8 Example 82 7.5 13 Example 88 0.6 8.3 Example 113 2.0 7.7 Example 125 0.5 2.3 Example 126 0.6 2.5 Example 131 0.9 5.5 Example 133 2.1 / Example 233 2.1 / Example 234 1.3 4.8

[0359] 6. Experimental conclusion: The compounds of the present invention have a significant proliferation inhibitory effect on SW620 and MKN1 cells.

[0360] II. Determination of the proliferation inhibitory activity of the compounds of the present invention on KRAS G12D mutant tumor cell lines

[0361] 1. Experimental purpose: To determine the proliferation inhibitory activity of the example compounds against five KRAS G12D mutant cell lines: SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D.

[0362] 2. Experimental instruments:

[0363] 2.1 Instruments: Microplate reader (BioTek Synergy H1); pipette (Eppendorf & Rainin).

[0364] 2.2 Reagents: HPAF-II, PANC0403, AsPC-1, and GP2D were purchased from Nanjing Kebai Biotechnology Co., Ltd.; SNU-1 was purchased from the Cell Bank of the Chinese Academy of Sciences, and Cell Titer-Glo was purchased from Promega Corporation with the catalog number G7573; RPMI 1640 was purchased from Gibco with the catalog number 22400089; DMEM was purchased from Gibco with the catalog number 11995065; FBS was purchased from Gibco with the catalog number 10091148; PBS was purchased from Gibco with the catalog number 10010023; trypsin was purchased from Gibco with the catalog number 25200056; and cell culture plates were purchased from Corning with the catalog number 3610.

[0365] 3. Experimental Methods: When SNU-1, HPAF-II, Panc0403, AsPC-1, or GP2D cells were cultured to an appropriate confluency, they were harvested and adjusted to an appropriate cell density using complete medium. 90 μL of the cell suspension was plated into a 96-well plate and allowed to adhere overnight in a 37°C, 5% CO2 incubator. Compound solutions of varying concentrations were prepared using DMSO and culture medium. Vehicle controls were set up and compound solutions were added to each well of the 96-well plate at 10 μL. The plates were incubated in a 37°C, 5% CO2 incubator for approximately 72 hours. CellTiter-Glo solution was then added, the plates were mixed thoroughly, and the plates were incubated in the dark for 10 minutes. The plates were then read using a BioTek Synergy H1 microplate reader.

[0366] 4. Experimental data processing method: 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.

[0367] 5. Experimental results: The EC values ​​of the compounds of the present invention for the inhibitory activity against the proliferation of SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D cells were obtained through the above scheme. 50 value.

[0368] In some embodiments, the EC of the compounds of the present invention for the inhibitory activity against SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D cells is 50Less than about 100 nM, preferably less than about 50 nM, more preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM among the compounds listed in the present invention.

[0369] 6. Experimental conclusion: The compounds of the present invention have a significant proliferation inhibitory effect on SNU-1, HPAF-II, Panc0403, AsPC-1 and GP2D cells.

[0370] Pharmacokinetics in mice

[0371] 1. Study purpose: Balb / c mice were used as test animals to study the pharmacokinetic behavior of the compound after oral administration in mice (plasma).

[0372] 2. Experimental Plan

[0373] 2.1 Test drugs: Compounds of the present invention, homemade;

[0374] 2.2 Experimental animals: Male Balb / c mice were purchased from Shanghai JXJ Laboratory Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0375] 2.3 Drug preparation: Oral administration drug preparation: 10% Captisol in 50mM citrate buffer pH5.0

[0376] 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.

[0377] Preparation of 50 mM citric acid (10% Captisol, pH = 5): Weigh 50 g of 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 more citric acid to 500 ml and adjust the pH to 5 with 10 M NaOH.

[0378] 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.

[0379] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0380] The example compound was weighed and first added with 5% DMSO in proportion to the total volume of the compound to be administered. The mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added and vortexed and sonicated for 2 minutes to completely dissolve the compound. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0381] 2.4 Administration:

[0382] 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.

[0383] Three male Balb / C mice were fasted overnight and administered IV at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0384] 2.5 Sample collection: 0.04 mL of blood was collected from the orbit before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was placed in an EDTA-2K tube and centrifuged at 6000 rpm at 4°C for 6 min to separate the plasma, which was then stored at -20°C. Food was consumed 4 h after administration.

[0385] 3. Determination results: The final determination results were obtained using the LCMS / MS method, which showed that the example compound had a higher oral exposure.

[0386] 4. Pharmacokinetics in rats

[0387] 1. Study purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the example compounds after oral administration in rats (plasma).

[0388] 2. Experimental Plan

[0389] 2.1 Test drugs: Compounds of the present invention, homemade.

[0390] 2.2 Experimental Animals: 3 male SD rats per group. Shanghai JXJ Laboratory Animal Co., Ltd., Animal Production License No. (SCXK(Shanghai)2013-0006N0.311620400001794).

[0391] 2.3 Drug preparation: Oral administration drug preparation: 10% Captisol in 50mM citrate buffer pH5.0

[0392] 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.

[0393] Preparation of 50 mM citric acid (10% Captisol, pH = 5): Weigh 50 g of 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 more citric acid to 500 ml and adjust the pH to 5 with 10 M NaOH.

[0394] The example compound was weighed and dissolved in the solution, shaken and sonicated for 15 minutes to obtain a colorless clear solution with a concentration of 3 mg / mL.

[0395] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0396] The example compound was weighed and first added with 5% DMSO in proportion to the total volume of the compound to be administered. The mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added and vortexed and sonicated for 2 minutes to completely dissolve the compound. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0397] 2.4 Administration: 3 male SD rats per group were fasted overnight and PO administration was performed at a dose of 30 mg / kg in a volume of 10 mL / kg.

[0398] Three male SD rats were administered IV after overnight fasting at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0399] 2.5 Sample collection: 0.2 mL of blood was collected from the jugular vein before administration and 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration. 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.

[0400] 3 Experimental results: The final determination results were obtained using the LCMS / MS method, which showed that the example compound had a higher oral exposure.

Claims

1. A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: in: X1 is selected from N or CR3; X2 selected from CR 1a R 1b NR 1a 、N-OR 1a , CR 1a R 1b -CR 1c R 1d , S or O; preferably CR 1a R 1b NR 1a 、N-OR 1a , CR 1a -CR 1c R 1d or O; Ring A is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is selected from -O-, -S-, -NR 1e -, -C(O)-, -S(O)- or -SO2-; L2 is selected from a bond or C1-C4 alkylene, wherein the C1-C4 alkylene is optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; Alternatively, two substituents on the same carbon atom in a C1-C4 alkylene group are linked to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl may optionally be further substituted with 1, 2, 3, 4, 5 or 6 R b replace; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R4 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl may optionally be further substituted with 1, 2, 3, 4, 5 or 6 R c replace; R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CR aa R bb ) n1 -3-12 membered heterocyclic group, -(CR aa R bb ) n1 -C 6-14 Aryl, -(CR aa R bb ) n1 -5-14 membered heteroaryl, -(CR aa R bb ) n1 -OR 2a 、-(CR aa R bb ) n1 -C(O)R 2a 、-(CR aa R bb ) n1 -C(O)OR 2a 、-(CR aa R bb ) n1 -NR 2a R 2b 、-(CR aa R bb ) n1 -P(O)R 2a R 2b 、-(CR aa R bb ) n1 -NR 2c C(O)R 2a 、-(CR aa R bb ) n1 -C(O)NR 2a R 2b 、-(CR aa R bb ) n1 -S(O)2R 2a 、-(CR aa R bb ) n1 -S(O)2NR 2a R 2b 、-(CR aa R bb ) n1 -NR 2c S(O)2R 2a 、-(CR aa R bb ) n1 -S(O)R 2a (=NR 2c ) or -(CR aa R bb ) n1 -N=S(O)R 2a R 2b or =CR 2a R 2b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 2d R 2e One or more substitutions; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-14 Aryl, -(CH2) n1 -5-14 membered heteroaryl, -(CH2) n1 -OR 2a 、-(CH2) n1 -C(O)R 2a 、-(CH2) n1 -C(O)OR 2a 、-(CH2) n1 -NR 2a R 2b 、-(CH2) n1 -P(O)R 2a R 2b 、-(CH2) n1 -NR 2c C(O)R 2a 、-(CH2) n1 -C(O)NR 2a R 2b 、-(CH2) n1 -S(O)2R 2a 、-(CH2) n1 -S(O)2NR 2a R 2b 、-(CH2) n1 -NR 2c S(O)2R 2a 、-(CH2) n1 -S(O)R 2a (=NR 2c ) or -(CH2) n1 -N=S(O)R 2a R 2b or =CR 2a R 2b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 2d R 2e One or more substitutions in ; Or, any two R a Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl-OR 2a 、-C(O)R 2a 、-C(O)OR 2a 、-NR 2a R 2b 、-P(O)R 2a R 2b 、-NR 2c C(O)R 2a 、-C(O)NR 2a R 2b 、-S(O)2R 2a 、-S(O)2NR 2a R 2b 、-NR 2c S(O)2R 2a 、-S(O)R 2a (=NR 2c ),-N=S(O)R 2a R 2b Sum = CR 2a R 2b One or more substitutions in ; 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, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; Or, any two R b Link Form 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 groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b One or more substitutions in ; R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c 、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; Or, any two R c Link Form 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 groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R a-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-14 Aryl, -(CH2) n1 -5-14 membered heteroaryl, -(CH2) n1 -OR 1a 、-(CH2) n1 -C(O)R 1a 、-(CH2) n1 -C(O)OR 1a 、-(CH2) n1 -NR 1a R 1b 、-(CH2) n1 -P(O)R 1a R 1b 、-(CH2) n1 -NR 1c C(O)R 1a 、-(CH2) n1 -C(O)NR 1a R 1b 、-(CH2) n1 -S(O)2R 1a 、-(CH2) n1 -S(O)2NR 1a R 1b 、-(CH2) n1 -NR 1c S(O)2R 1a 、-(CH2) n1 -S(O)R 1a (=NR 1c ), -(CH2) n1 -N=S(O)R 1a R 1b 、=CR 1a R 1b 、=NR 1a 、=N-OR 1a or =CR 1a -CR 1c R 1d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 1d R 1e One or more substitutions in ; Or, any two R a-1 Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl-OR 1a 、-C(O)R 1a 、-C(O)OR 1a 、-NR 1a R 1b 、-P(O)R 1a R 1b 、-NR 1c C(O)R 1a 、-C(O)NR 1a R 1b 、-S(O)2R 1a 、-S(O)2NR 1a R 1b 、-NR 1c S(O)2R 1a 、-S(O)R 1a (=NR 1c ),-N=S(O)R 1a R 1b Sum = CR 1a R 1b One or more substitutions in ; R 1a 、R 1b 、R 1c and R 1d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; Or, R 1a and R 1b Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 The cycloalkyl and 3-8 membered heterocyclic groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 2a 、R 2b 、R 2c 、R 2d and R 2e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 3a 、R 3b and R 3c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 4a 、R 4b and R 4c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 1e Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3 or 4; n1 is selected from 0, 1, 2, 3 or 4; and n2 is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that Ring A is selected from 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-14-membered fused heterocyclyl or 5-14-membered spiro heterocyclyl; preferably 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 5-8-membered heterocyclyl and 4-8-membered heterocyclyl, 5-8-membered heterocyclyl spiro 4-8-membered heterocyclyl; Preferably, ring A is selected from Preferred Ring B is selected from a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl; Ring C is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Ring D is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CR aa R bb ) n3 -3-12 membered heterocyclic group, -(CR aa R bb ) n3 -C 6-14 Aryl, -(CR aa R bb ) n3 -5-14 membered heteroaryl, -(CR aa R bb ) n3 -OR 8a 、-(CR aa R bb ) n3 -C(O)R 8a 、-(CR aa R bb ) n3 -C(O)OR 8a 、-(CR aa R bb ) n3 -NR 8a R 8b 、-(CR aa R bb ) n3 -P(O)R 8a R 8b 、-(CR aa R bb ) n3 -NR 8c C(O)R 8a 、-(CR aa R bb ) n3 -C(O)NR 8a R 8b 、-(CR aa R bb ) n3 -S(O)2R 8a 、-(CR aa R bb ) n3 -S(O)2NR 8a R 8b 、-(CR aa R bb ) n3 -NR 8c S(O)2R 8a 、-(CR aa R bb ) n3 -S(O)R 8a (=NR 8c ) or -(CR aa R bb ) n3 -N=S(O)R 8a R 8b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 8d R 8e One or more substitutions; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n3 -3-12 membered heterocyclic group, -(CH2) n3 -C 6-14 Aryl, -(CH2) n3 -5-14 membered heteroaryl, -(CH2) n3 -OR 8a 、-(CH2) n3 -C(O)R 8a 、-(CH2) n3 -C(O)OR 8a 、-(CH2) n3 -NR 8a R 8b 、-(CH2) n3 -P(O)R 8a R 8b 、-(CH2) n3 -NR 8c C(O)R 8a 、-(CH2) n3 -C(O)NR 8a R 8b 、-(CH2) n3 -S(O)2R 8a 、-(CH2) n3 -S(O)2NR 8a R 8b 、-(CH2) n3 -NR 8c S(O)2R 8a 、-(CH2) n3 -S(O)R 8a (=NR 8c ) or -(CH2) n3 -N=S(O)R 8a R 8b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or =CR 8d R 8e One or more substitutions in ; R 8a 、R 8b 、R 8c 、R 8d and R 8e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that L2 is selected from R g-1 and R g-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R g-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R g-4 、R g-5 、R g-6 and R g-7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; q is selected from 0, 1, 2, 3 or 4.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that R4 is selected from 5-7 membered monocyclic heterocyclic group, 7-10 membered fused heterocyclic group or 7-10 membered bridged heterocyclic group, which may be further substituted by 1, 2, 3, 4, 5 or 6 R e replace; Preferably, R4 is selected from Optionally, it may be further replaced by 1, 2, 3, 4, 5 or 6 R e replace; R e Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c 、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: -L2-R4 is selected from R e-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c 、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R e-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-14 Aryl, -(CH2) n2 -5-14 membered heteroaryl, -(CH2) n2 OR 4a 、-(CH2) n2 C(O)R 4a 、-(CH2) n2 OC(O)R 4a 、-(CH2) n2 NR 4b R 4c 、-(CH2) n2 P(O)R 4b R 4c 、-(CH2) n2 NR 4b C(O)R 4c 、-(CH2) n2 C(O)NR 4b R 4c 、-(CH2) n2 S(O)2R 4a 、-(CH2) n2 S(O)2NR 4b R 4c 、-(CH2) n2 NR 4b S(O)2R 4a 、=N-OR 4a or =CR 4a R 4b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; r-1 is selected from 0, 1, 2 or 3; r-2 is selected from 0, 1, 2 or 3; r is selected from 0, 1, 2, 3, 4, 5 or 6; R g-1 、R g-2 、R g-3 、R g-4 、R g-5 、R g-6 、R g-7 and q as defined in claim 3; R e As defined in claim 4.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that: X1 is selected from N, CH, CCH3, CCH2CH3, C-Cl, CF, C-CF3 or C-CHF2; preferably N, CH, CCH3, CCH2CH3, C-Cl or CF; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, 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 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Alkylamino; Preferably, R2 is selected from hydrogen, deuterium, fluorine, chlorine or bromine; More preferably, R2 is selected from fluorine.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from Preferably, R1 is selected from Preferred R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 and R 5-7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 6-1 、R 6-2 、R 6-3 、R 6-4 and R 6-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 7-1 、R 7-2 、R 7-3 、R 7-4 and R 7-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R 8-1 、R 8-2 、R 8-3 and R 8-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-NR 3a R 3b 、-P(O)R 3a R 3b 、-NR 3c C(O)R 3a 、-C(O)NR 3a R 3b 、-S(O)2R 3a 、-S(O)2NR 3a R 3b 、-NR 3c S(O)2R 3a 、-S(O)R 3a (=NR 3c ) or -N=S(O)R 3a R 3b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (III-1) or (III-2): n3 is selected from 1, 2 or 3.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

10. A compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof: Preferably, the general formula (IV) is further represented by the general formula (IV-1) or (IV-2) Arc A' is selected from R L1 is selected from halogen; preferably chlorine or bromine; R L2 is selected from halogen; preferably chlorine or bromine; R L3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; Ring B, Ring C, Ring D, R d As claimed in claim 2; X1, X2, L1, L2, R1, R2, R4, R a and x as described in claim 1.

11. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by general formula (IV) is subjected to coupling reaction ① to obtain the compound represented by general formula (II); Preferably, the preparation method is a method for preparing a compound represented by general formula (V-1) or an acceptable salt thereof, comprising the following steps 1): The compound represented by the general formula (IV-1) is subjected to coupling reaction ① to obtain the compound represented by the general formula (V-1); Optionally, further comprising step 2): The compound represented by the general formula (V-1) and the compound represented by the general formula (VI-1) are subjected to a coupling reaction ② to obtain the compound represented by the general formula (III-1); Or preferably, the preparation method is a method for preparing a compound represented by general formula (V-2) or an acceptable salt thereof, comprising the following steps 1): The compound represented by the general formula (IV-2) is subjected to coupling reaction ① to obtain the compound represented by the general formula (V-2); Optionally, further comprising step 2): The compound represented by the general formula (V-2) and the compound represented by the general formula (VI-2) are subjected to a coupling reaction ② to obtain the compound represented by the general formula (III-2); R L4 is selected from boronic acid, borate, chain borate or cyclic borate; Arcs A', R L1 、R L2 and R L3 As claimed in claim 10; R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 6-1 、R 6-2 、R 6-3 、R 6-4 and R 6-5 As claimed in claim 7; X1, X2, L1, L2, R1, R2, R4, R a and x as described in claim 1.

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

13. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the preparation of a KRAS inhibitor drug; preferably in the preparation of a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D inhibitor drug.

14. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, 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, pancreatic cancer, and colorectal cancer; preferably, use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer, pancreatic cancer, colon cancer, esophageal cancer, and head and neck cancer.

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