Pyrimidine polycyclic derivative inhibitor, preparation method therefor and use thereof

Abstract

Provided are a pyrimidine polycyclic derivative inhibitor, a preparation method therefor and the use thereof. In particular, provided are a compound as shown in the general formula, a preparation method therefor, a pharmaceutical composition comprising the compound, and the use thereof in the treatment of cancers and other related diseases.

Description

Pyrimidine polycyclic derivative inhibitor, preparation method and application thereof Technical Field

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

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

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

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

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

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

[0007] The object of the present invention is to provide a compound represented by general formula (A), its nitrogen oxide, its oxo product or a pharmaceutically acceptable salt thereof:

[0008] in:

[0009] X1 is selected from N or CR 2b ; preferably N; L1 is selected from O, S or NH; preferably O;

[0010] L2 is selected from C1-C4 alkylene, said C1-C4 alkylene being optionally substituted by 1, 2, 3, 4, 5 or 6 R a replace;

[0011] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0012] R is selected from -OR b 、-CH2OR b 、-C(O)R b 、-C(O)OR b , 3-10 membered heterocyclyl or 5-12 membered heteroaryl, the 3-10 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R 4a Substituent substitution;

[0013] R 1a 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 1-6Alkoxy, 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 b 、-OC(O)R b 、-OC(O)NR b R c 、-OS(O)2R b or-OS(O)2NR b R c , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, 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;

[0014] R 1b 、R 1c 、R 1d and R 1e 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, C1-6 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;

[0015] or R 1b and R 1c It is linked to adjacent atoms to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, optionally substituted by 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, C1-6 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;

[0016] R 2a 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, 5-14 membered heteroaryl or -(CH2)n1OR e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 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 6-10one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0017] or R 2a With R 1e Linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, optionally substituted 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;

[0018] R 2b 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, 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 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;

[0019] R 2c 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 1-6Halogenated 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;

[0020] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0021] Alternatively, any two R3 links form a 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;

[0022] R 4a 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, 5-14 membered heteroaryl, =CR aa R bb N-OR cc , 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, C1-6 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;

[0023] Or, any two R 4a 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, 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 of aryl or 5-10 membered heteroaryl;

[0024] 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, 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;

[0025] or two R with the same carbon atom or different carbon atoms a Link Form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further 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 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 6-10one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0026] 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 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;

[0027] R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, 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 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;

[0028] R e 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 1-6Halogenated 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;

[0029] R aa 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 or 5-14 membered heteroaryl, the amino, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, 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 bb 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 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 1-6Halogenated 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(O)OC 1- 6 alkyl, C 1-6 Silane group, 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 cc 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 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, C1-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, 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] n1 is selected from 0, 1, 2 or 3; x is selected from 0, 1, 2, 3, 4, 5 or 6.

[0033] In certain embodiments of the present invention, the compound represented by general formula (A), its nitrogen oxide, its oxo product, or a pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (A-1):

[0034] Ring B is selected from 3-10 membered heterocyclyl or 5-12 membered heteroaryl; q is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0035] In certain embodiments of the present invention, the compound represented by general formula (A), its nitrogen oxide, its oxo product, or a pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (A-2):

[0036] X2 is selected from O, CR 5a R 5b N-OR 5c ; Ring B is selected from a 3-10 membered heterocyclyl or a 5-12 membered heteroaryl;

[0037] Pg is selected from hydrogen or a hydroxyl protecting group; the hydroxyl protecting group is selected from methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzoyl, p-toluenesulfonyl, -C(O)R b 、-C(O)NR b R c 、-S(O)2R b or -S(O)2NR b R c ;

[0038] R4 is selected from 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 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 1-6Hydroxyalkyl, -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;

[0039] Alternatively, any two R4s 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 of aryl or 5-10 membered heteroaryl;

[0040] R 5a 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 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 1-6Alkylamino, 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0041] R 5b 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 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0042] R 5c 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 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, C2-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0043] R dd 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 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 1-6Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0044] R ee 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 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(O)OC1- 6 alkyl, C 1-6 Silane group, 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 ff Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0046] n1 is selected from 0, 1, 2, 3 or 4; and y is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0047] In certain embodiments of the present invention, the compound represented by general formula (A), its nitrogen oxide, its oxo product, or its pharmaceutically acceptable salt is characterized by being further represented by general formula (I) or (IA):

[0048] in:

[0049] X2 is selected from O, CR 5a R 5b N-OR 5c ; Ring B is selected from a 3-10 membered heterocyclyl or a 5-12 membered heteroaryl;

[0050] R4 is selected from 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 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 1-6Deuterated 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;

[0051] Alternatively, any two R4s 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, 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 of aryl or 5-10 membered heteroaryl;

[0052] R 5a 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 or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, 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 5b 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 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, C1-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0054] R 5c 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 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0055] y is selected from 0, 1, 2, 3, 4, 5 or 6.

[0056] In certain embodiments of the present invention, R 1b and R 1c Linked with its adjacent atoms to form the following structure Preferably, the following structure is formed More preferably, the following structure is formed

[0057] R 1f and R 1g are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 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.

[0058] In certain embodiments of the present invention, the compound represented by general formula (A), its nitrogen oxide, its oxo product, or its pharmaceutically acceptable salt is characterized by being further represented by general formula (II-A) or (II-B):

[0059] R6 is selected from 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 or 5-10 membered heteroaryl;

[0060] R7 is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C(O)R b 、-C(O)NR b R c 、-S(O)2R b or -S(O)2NR b R c ;

[0061] R b 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 or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3Alkylthio, 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 1-6 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;

[0062] R c 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 or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 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 6-10The aryl or 5-10 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;

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

[0064] In certain embodiments of the present invention, the compound represented by general formula (A), its nitrogen oxide, its oxo product, or a pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (III-A) or (III-B):

[0065] R6 is selected from 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 or 5-10 membered heteroaryl; p is selected from 0, 1, 2, 3 or 4.

[0066] In certain embodiments of the present invention, R 5a Selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, 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 3-8Cycloalkyl or 3-8 membered heterocyclic group, the C 1-3 Alkyl 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 3-8 The cycloalkyl and 3-8 membered heterocyclic 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 of aryl and 5-10 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl or cyclopropyl;

[0067] R 5b Selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, 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 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 1-3 Alkyl 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 3-8 The cycloalkyl and 3-8 membered heterocyclic 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 2-6Alkynyl, 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 of aryl and 5-10 membered heteroaryl are substituted; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl or cyclopropyl.

[0068] In certain embodiments of the present invention, R 5c Selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 3-8 The cycloalkyl and 3-8 membered heterocyclic 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 of aryl and 5-10 membered heteroaryl are substituted; preferably methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl, cyclopropyl or cyclopropylmethyl.

[0069] In certain embodiments of the present invention, Ring B is selected from a 3-8 membered monocyclic heterocyclyl, a 7-10 membered fused heterocyclyl, a 7-11 membered spiroheterocyclyl, or a 7-10 membered bridged heterocyclyl;

[0070] The following groups are preferred:

[0071] In certain embodiments of the present invention, R4 is selected from 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 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 or 5-10 membered heteroaryl, the 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 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;

[0072] Preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl.

[0073] In certain embodiments of the present invention, L2 is selected from Preferred Or, L2 is selected from Preferred

[0074] R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 1-6 Hydroxyalkyl; preferably hydrogen or deuterium;

[0075] R5 is selected from 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 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 of aryl and 5-10 membered heteroaryl are substituted; z is selected from 0, 1, 2, 3 or 4.

[0076] In certain embodiments of the present invention, R 1d Selected from 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 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Alkylamino, 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 and C 1-3 The alkylamino 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 1-6Hydroxyalkyl, -C(O)-C 1- 6 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-10 membered heteroaryl are substituted; preferably hydrogen, deuterium, fluorine, chlorine, or methyl.

[0077] In certain embodiments of the present invention, R 1e Selected from 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 Alkylthio, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 1-3 Alkylamino, 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 and C 1-3 The alkylamino 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 of aryl and 5-10 membered heteroaryl are substituted; preferably hydrogen, deuterium, fluorine, chlorine, or methyl.

[0078] In certain embodiments of the present invention, R 2a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4Alkenyl, 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 or -(CH2) n1 OR e , 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 or C 1-3 The alkylamino 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;

[0079] R e 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, C6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 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 1-6 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 of aryl and 5-10 membered heteroaryl are substituted; n1 is selected from 0, 1, 2 or 3.

[0080] In certain embodiments of the present invention, R 2c 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, R 2c is selected from hydrogen, deuterium, fluorine, chlorine or bromine; more preferably, R 2c Selected from fluorine.

[0081] In certain embodiments of the present invention, the compound, its nitrogen oxide, its oxo compound, or its pharmaceutically acceptable salt is characterized by being further represented by formula (IV) or (V):

[0082] n2 is selected from 0, 1, 2 or 3; n3 is selected from 0, 1, 2 or 3.

[0083] In certain embodiments of the present invention, R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, 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(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0084] Preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl or haloethyl;

[0085] In certain embodiments of the present invention, Selected from

[0086] M1 is selected from CR 7-5 or N; M2 is selected from CR 8-1 or N;

[0087] Selected from

[0088] R 6-1 、R 6-2 、R 56-3 、R 6-4 、R 6-5 、R 6-6 and R 6-7 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, C3-8 Cycloalkyl, 3-8 membered heterocyclic group or C 6-10 Aryl, 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 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 1-6 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(O)OC 1-6 Alkyl, C 1-6 Silane group, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0089] 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 or C6-10 Aryl, 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 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 1-6 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(O)OC 1-6 Alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0090] R 8-1 、R 8-2 、R 8-3 、R 8-4 and R 8-5 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 or C 6-10 Aryl, 5-10 membered heteroaryl, the amino, C1-3 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 1-6 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(O)OC 1-6 Alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

[0091] The present invention also provides a compound represented by general formula (IV-C), its nitrogen oxide, its oxo product or a pharmaceutically acceptable salt thereof:

[0092] R9 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, 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, C2-6 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(O)OC 1- 6 alkyl, C 1-6 Silane group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0093] Ring A, X2, R3, R4, R6, n2, n3, x and y are as described in any of the above embodiments.

[0094] The present invention also provides a compound represented by general formula (VB), its nitrogen oxide, its oxo product or a pharmaceutically acceptable salt thereof:

[0095] Pg is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-dimethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0096] Ring A, X2, R3, R4, R6, n2, n3, x and y are as described in any of the above embodiments.

[0097] The present invention also provides a method for preparing a compound represented by general formula (II-B), its nitrogen oxide, its oxo product or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0098] The compound represented by general formula (II-B-1) reacts with a peroxide compound to obtain a compound represented by general formula (II-B);

[0099] Ring A, Ring B, L1, L2, X1, X2, R 1d 、R 2a 、R 2c , R3, R4, R6, R7, p, x and y are as described in any of the above embodiments.

[0100] In certain embodiments of the present invention, the preparation method is a method for preparing a compound represented by general formula (IV):

[0101] The compound represented by general formula (IV-1) reacts with a peroxide compound to obtain a compound represented by general formula (IV);

[0102] Optionally, when R7 is -C(O)R9, the compound represented by general formula (IV) is further subjected to ester hydrolysis under alkaline conditions to obtain the target compound; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, triethylamine or pyridine;

[0103] Ring A, Ring B, L1, L2, X1, X2, R 1d 、R 2a 、R 2c , R3, R4, R6, R7, R9, p, x, y, n2 and n3 are as described in any of the above embodiments.

[0104] The present invention also provides a method for preparing a compound represented by general formula (III-B), its nitrogen oxide, its oxo product or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0105] The compound represented by the general formula (III-B-1) reacts with a peroxide compound to obtain a compound represented by the general formula (III-B);

[0106] Ring A, Ring B, L1, L2, X1, X2, R 1d 、R 2a 、R 2c , R3, R4, R6, R7, p, x and y are as described in any of the above embodiments.

[0107] In certain embodiments of the present invention, the preparation method is a method for preparing a compound represented by general formula (V):

[0108] The compound represented by general formula (V-1) reacts with a peroxide compound to obtain a compound represented by general formula (V);

[0109] Optionally, when R 1a When Pg is present, the compound represented by general formula (V) is further subjected to acidic conditions to remove Pg to obtain the target compound; the acid is selected from hydrochloric acid, sulfuric acid or trifluoroacetic acid;

[0110] Ring A, Ring B, Pg, L1, L2, X1, X2, R 1d 、R 2a 、R 2c , R3, R4, R6, R7, p, x, y, n2 and n3 are as described in any of the above embodiments.

[0111] In certain embodiments of the present invention, the peroxy compound in the preparation method is selected from hydrogen peroxide, sodium peroxide, perbenzoic acid, m-chloroperbenzoic acid or benzoyl peroxide.

[0112] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above compound, its nitrogen oxide, its oxygenate or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0113] In certain embodiments of the present invention, the weight percentage of the above-mentioned compound, its nitrogen oxide, its oxygenate or pharmaceutically acceptable salt 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).

[0114] 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.

[0115] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0116] The present invention further relates to the use of the above-mentioned compound, its nitrogen oxide, its oxygenate or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of KRAS inhibitor drugs; preferably, the use in KRAS G12D, KRAS G12V or KRAS G13D inhibitor drugs.

[0117] The present invention further relates to the use of the above-mentioned compound, its nitrogen oxide, its oxygenate or pharmaceutically acceptable salt thereof, or its pharmaceutical composition 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, brain cancer, breast cancer, lung cancer, liver cancer, gastric cancer, kidney cancer, bile duct cancer, prostate cancer, ovarian cancer, pancreatic cancer, small intestine cancer and colon cancer; preferably, the use of the above-mentioned compound in the preparation of a medicament for treating non-small cell lung cancer, colon cancer, pancreatic cancer, esophageal cancer and head and neck tumors.

[0118] The present invention further relates to methods for preparing the above-mentioned compounds, their nitrogen oxides, their oxygenates or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for treating diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, brain cancer, breast cancer, lung cancer, liver cancer, gastric cancer, kidney cancer, bile duct cancer, prostate cancer, ovarian cancer, pancreatic cancer, small intestine cancer and colon cancer; preferably, methods for preparing methods for treating non-small cell lung cancer, colon cancer, pancreatic cancer, esophageal cancer and head and neck tumors.

[0119] 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, brain cancer, breast cancer, lung cancer, liver cancer, stomach cancer, kidney cancer, bile duct cancer, prostate cancer, ovarian cancer, pancreatic cancer, small intestine cancer and colon cancer, which comprises administering to a patient a therapeutically effective dose of the above-mentioned compound, its nitrogen oxide, its oxygenate 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, colon cancer, pancreatic cancer, esophageal cancer and head and neck tumors.

[0120] In certain embodiments of the present invention, the above-mentioned compounds, their nitrogen oxides, their oxygenates 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.

[0121] Detailed Description of the Invention

[0122] 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.

[0123] 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 (C3-8 ) 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 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6 Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0124] 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.

[0125] 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 (C2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3- 10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 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.

[0126] 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 3-6Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0127] 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.

[0128] 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:

[0129] 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:

[0130] 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:

[0131] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxygen, but does not include the ring portion of -OO- or -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl group contains 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl group contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclyl group contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.In one embodiment, described heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0132] 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:

[0133] 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:

[0134] 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:

[0135] 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),

[0136] 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.

[0137] 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,

[0138] 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.

[0139] 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.

[0140] 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.

[0141] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0142] 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,

[0143] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0144] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0145] 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.

[0146] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0147] 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.

[0148] The term "aminocarbonyl" refers to NH2-C(O)-.

[0149] 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.

[0150] 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.

[0151] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0152] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0153] The term "oxo" or "oxo" refers to =0.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] "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.

[0158] 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.

[0159] " 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.

[0160] 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.

[0161] "Oxo" refers to a compound in which the nitrogen atom is further substituted by -OH or -OR substituents, where R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C(O)R x 、-C(O)NR x R y 、-S(O)2R x or -S(O)2NR x R y ;

[0162] R x and R y Each is independently selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, thiol, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio or heterocycloalkylthio.

[0163] 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.

[0164] "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.

[0165] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0166] "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.

[0167] "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.

[0168] "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.

[0169] "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.

[0170] 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.

[0171] 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

[0172] 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.

[0173] Example

[0174] 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), deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard.

[0175] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0176] HPLC determination was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0177] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0178] 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.

[0179] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0180] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0181] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0182] 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.

[0183] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0184] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0185] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0186] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0187] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0188] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0189] 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.

[0190] 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.

[0191] Example 1

[0192] Preparation of (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptan-14-ol

[0193] Step 1: Preparation of 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine

[0194] 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.1 g, 4.40 mmol) was added to POCl3 (20 mL), and the mixture was heated under reflux for 16 hours. The mixture was then concentrated under reduced pressure to obtain crude compound E-1-2 (1.4 g). MS m / z (ESI): 288 [M+H].

[0195] Step 2: Preparation of tert-butyl (1S,2S,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0196] E-1-2 (1.3 g) was added to dichloromethane (20 mL), and tert-butyl (1S, 2S, 5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 4.99 mmol) and triethylamine (1.4 g, 13.84 mmol) were added. The mixture was reacted at room temperature for 3 hours. Water was added and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain E-1-3 (2.8 g).

[0197] Step 3: Preparation of tert-butyl (1S, 2S, 5R) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -3- (2- ((1- (((tert-butyldiphenylsilyl) oxy) methyl) cyclopropyl) methoxy) -5,7-dichloro-8-fluoropyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0198] To a solution of E-1-3 (235.7 mg, 692.05 μmol) in THF (15 mL) was added NaH (27.68 mg, 692.05 μmol, 60% purity) at 0°C. The mixture was warmed to room temperature and stirred for 15 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford E-1-4 (622 mg, 99.8% yield).

[0199] Step 4: Preparation of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0200] To a solution of E-1-4 (622 mg, 600.83 μmol) in THF (20 mL) was added TBAF (1 M, 3.61 mL) at room temperature and stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to afford E-1-5 (210 mg, 66.9% yield). MS m / z (ESI): 522 [M+H].

[0201] Step 5: Preparation of tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0202] E-1-5 (210 mg, 402.32 μmol), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (14.65 mg, 20.12 μmol), and Cs2CO3 (262.17 mg, 804.65 μmol) were added to dioxane (5 mL) and heated to 100°C under nitrogen with stirring for 13 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford E-1-6 (350 mg, 99.8% yield).

[0203] Step 6: Preparation of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0204] To a solution of E-1-6 (350 mg, 401.34 μmol) in THF (10 mL) was added TBAF (1 M, 1.20 mL) at room temperature and stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel plate to afford E-1-7 (120 mg, 41.8% yield). MS m / z (ESI): 716 [M+H].

[0205] Step 7: Preparation of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0206] To a solution of E-1-7 (100 mg, 139.72 μmol) in dichloromethane (15 mL) was added triethylamine (42.41 mg, 419.15 μmol, 58.46 μL) and methanesulfonyl chloride (32.01 mg, 279.43 μmol) at 0°C. The mixture was stirred at 0°C for 30 minutes. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was washed with aqueous ammonium chloride solution and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford E-1-8 (110 mg, 99.2% yield). MS m / z (ESI): 794 [M+H].

[0207] Step 8: Preparation of tert-butyl (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalene-14-carboxylate

[0208] E-1-8 (110 mg, 138.57 μmol), 4-(difluoromethylene)piperidine (55.35 mg, 415.71 μmol), DIPEA (179.09 mg, 1.39 mmol), and NaI (62.31 mg, 415.71 μmol) were added to acetonitrile (8 mL) and heated to 50°C with stirring for 13 hours. Aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification on a silica gel plate afforded E-1-9 (70 mg, 60.8% yield). MS m / z (ESI): 831 [M+H].

[0209] Step 9: Preparation of 4-((5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-2-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0210] To a solution of E-1-9 (70 mg, 84.25 μmol) in dichloromethane (3 mL) and methanol (0.5 mL) was added HCl (3.07 mg, 84.25 μmol, 3 mL) at 0°C. The mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly added to an aqueous sodium bicarbonate solution and extracted with dichloromethane / methanol. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to afford E-1-10 (30 mg, 51.8% yield). MS m / z (ESI): 687 [M+H].

[0211] Step 10: Preparation of (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-14-ylbenzoate

[0212] Benzoyl peroxide (35 mg, 0.14 mmol) was added to a solution of E-1-10 (50 mg, 0.07 mmol) and potassium dihydrogen phosphate (38 mg, 0.22 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford E-1-11 (54 mg, 92% yield). MS m / z (ESI): 807 [M+H].

[0213] Step 11: Preparation of (5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptan-14-ol

[0214] E-1-11 (54 mg, 0.067 mmol) and potassium carbonate (28 mg, 0.2 mmol) were stirred in methanol (5 mL) at room temperature for 1 hour. The reaction solution was filtered, concentrated, purified by HPLC, and lyophilized to obtain E-1 (18 mg, yield: 39%). MS m / z (ESI): 703 [M+H]

[0215] 1H NMR(400MHz,MeOD)δ7.88–7.78(m,1H),7.34–7.14(m,3H),5.18–5.05(m,1H),4.72–4.59(m,1H),4.56–4.32(m,4H), 4.22(d,J=8Hz,1H),3.95–3.79(m,2H),2.98–2.56(m,6H),2.35(s,4H),2.11–1.75(m,5H),0.83(s,2H),0.64(s,2H).

[0216] Example 17

[0217] Preparation of (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-14-ol

[0218] Step 1: Preparation of (1S,2S,5R)-2-[(1S)-1-(7-chloro-8-fluoro-4-hydroxy-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-yl)oxy-ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0219] 5,7-Dichloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-ol (5 g, 17.9 mmol) was dissolved in tetrahydrofuran (100 mL), and tert-butyl (1S,2S,5R)-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.3 g, 16.8 mmol) was added. The mixture was cooled to 0°C, and sodium hydroxide (2.3 g, 57.5 mmol, 60% purity) was added. After addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly poured into 10% aqueous ammonium chloride (100 mL) and ethyl acetate (100 mL). A solid precipitated, which was filtered, washed with water, and dried to give E-17-2 (5.2 g, 58.2% yield). MS m / z (ESI): 500 [M+H].

[0220] Step 2: Preparation of tert-butyl (5S,5aS,6R,9S)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0221] To a solution of E-17-2 (5.1 g, 10.2 mmol) in dichloromethane (250 mL) at 0°C was added N,N-diisopropylethylamine (6.5 g, 50.3 mmol), followed by dropwise addition of phosphorus oxychloride (3.7 g, 24.1 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with aqueous ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford E-17-3 (3.9 g, 79.3% yield). MS m / z (ESI): 482 [M+H].

[0222] Step 3: Preparation of tert-butyl (5S,5aS,6R,9S)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0223] E-17-3 (3.8 g, 7.88 mmol) was dissolved in dichloromethane (100 mL), cooled to 0-5°C, and m-chloroperbenzoic acid (4.0 g, 19.7 mmol, 85% purity) was added. Stir for 1.5 hours after addition. The reaction mixture was filtered, and aqueous sodium thiosulfate (100 mL) and ethyl acetate (100 mL) were added to the filtrate. The mixture was stirred for 30 minutes. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford E-17-4 (3.3 g, 81.5% yield). MS m / z (ESI): 514 [M+H].

[0224] Step 4: Preparation of tert-butyl (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0225] E-17-4 (3.2 g, 6.23 mmol) and [1-[[4-(difluoromethylene)-1-piperidinyl]methyl]cyclopropyl]methanol (1.76 g, 8.10 mmol) were dissolved in tetrahydrofuran (70 mL). The atmosphere was purged with nitrogen and lithium bistrimethylsilylamide (1 M, 18.7 mL) was added dropwise under ice-cooling. The reaction was allowed to proceed under ice-cooling for 30 minutes. Saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford E-17-5 (2.7 g, 66.7% yield). MS m / z (ESI): 651 [M+H].

[0226] Step 5: Preparation of tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate

[0227] In an eggplant-shaped flask, 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyboran-2-yl)-1-naphthyl]ethynyltriisopropylsilane (2.05 g, 4.0 mmol), E-17-5 (2.6 g, 3.99 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (73 mg, 0.1 mmol), and cesium carbonate (3.9 g, 11.97 mmol) were dissolved in a mixture of dioxane (30 mL) and water (6 mL). The atmosphere was replaced with nitrogen and the reaction was carried out in an oil bath at 85°C for 1 hour. After completion of the reaction, the mixture was concentrated and purified by silica gel chromatography to afford E-17-6 (1.8 g, 57.1% yield). MS m / z(ESI):1001[M+H].

[0228] Step 6: Preparation of tert-butyl (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphthalene[1,8-ab]heptene-4-carboxylate

[0229] In an eggplant-shaped flask, E-17-6 (1.8 g, 1.80 mmol) was dissolved in tetrahydrofuran (120 mL). Tetrabutylammonium fluoride (1 M, 10 mL) was added and allowed to react at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography to afford E-17-7 (1.4 g, 92.1% yield). MS m / z (ESI): 845 [M+H].

[0230] Step 7: Preparation of 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalene-2-ol

[0231] E-17-7 (200 mg, 0.24 mmol) was dissolved in dichloromethane (20 mL) and methanol (4 mL), cooled in an ice bath for 10 minutes, replaced with nitrogen, and slowly added with 4N hydrochloric acid in dioxane (10 mL). The mixture was allowed to react in an ice bath for 1.5 hours. Sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane / methanol. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford E-17-8 (140 mg, 84.3% yield). MS m / z (ESI): 701 [M+H].

[0232] Step 8: Preparation of (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-14-ylbenzoate

[0233] Benzoyl peroxide (82 mg, 0.34 mmol) was added to a solution of E-17-8 (120 mg, 0.17 mmol) and dipotassium hydrogen phosphate (90 mg, 0.52 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford E-17-9 (150 mg). MS m / z (ESI): 821 [M+H].

[0234] Step 9: Preparation of (5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-14-ol

[0235] E-17-9 (150 mg) was dissolved in methanol (5 mL), potassium carbonate (70 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, concentrated, purified by HPLC, and lyophilized to obtain E-17 (27 mg, 22% yield). MS m / z (ESI): 717 [M+H]

[0236] 1 H NMR(400MHz,MeOD)δ7.89–7.77(m,1H),7.37–7.26(m,2H),7.25–7.06(m,1H),5.46 –5.37(m,1H),4.63–4.51(m,1H),4.50–4.29(m,2H),4.12(d,J=8.7Hz,1H),3.74–3 .64(m,1H),3.59(s,1H),3.49–3.34(m,1H),3.27–3.14(m,1H),2.84–2.53(m,6H), 2.37–2.23(m,4H),2.20–1.87(m,3H),1.67-1.50(m,4H),0.79(s,2H),0.59(s,2H).

[0237] Alternatively, Examples 21, 33, 102 and 263 were prepared as follows.

[0238] Example 21

[0239] Preparation of 4-(difluoromethylene)-1-(1-(((5S,5aR,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)piperidine 1-oxide

[0240] Step 1: Preparation of the compound tert-butyl (5S,5aR,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptane-14 carboxylate

[0241] To a solution of 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (1 g, 1.43 mmol) in dichloromethane (20 mL) were added triethylamine (433 mg, 4.28 mmol) and di-tert-butyl dicarbonate (467 mg, 2.14 mmol), and the reaction was carried out at room temperature for 1 hour. The mixture was washed with saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. Purification by silica gel column chromatography afforded E-21-2 (1.14 g, 100% yield). MS m / z (ESI): 801 [M+H].

[0242] Step 2: Preparation of compound 1-(1-(((5S,5aR,6S,9R)-14-(tert-butoxycarbonyl)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine 1-oxide

[0243] To a solution of E-21-2 (1 g, 1.25 mmol) in dichloromethane (30 mL) was added m-chloroperbenzoic acid (323 mg, 1.87 mmol) and allowed to react at room temperature for 1 hour. The reaction solution was washed with sodium thiosulfate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford E-21-3 (1.02 g, 100% yield). MS m / z (ESI): 817 [M+H].

[0244] Step 3: Preparation of compound 4-(difluoromethylene)-1-(1-(((5S,5aR,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)piperidine 1-oxide

[0245] E-21-3 (1 g, 1.22 mmol) was dissolved in a mixture of dichloromethane (10 mL) and MeOH (2.5 mL) at 0°C. HCl (4 M, 10 mL) was added and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated and purified by preparative liquid chromatography to afford E-21 (619 mg, 55% yield). MS m / z (ESI): 717 [M+H].

[0246] 1 H NMR(400MHz,MeOD)δ7.85(dt,J=9.1,6.1Hz,1H),7.36–7.27(m,2H),7.17(dd,J=40.4,2.6Hz,1 H),5.55(dt,J=14.8,3.4Hz,1H),4.73–4.57(m,3H),4.30(dd,J=8.8,4.1Hz,1H),4.19(d,J=5.8 Hz,1H),4.09(q,J=5.8Hz,1H),3.79(s,2H),3.68(d,J=9.2Hz,2H),3.50–3.36(m,3H),2.80–2. 66(m,2H),2.52(d,J=15.0Hz,2H),2.35–1.91(m,5H),1.60(t,J=6.3Hz,3H),1.04–0.87(m,4H).

[0247] Example 33

[0248] Preparation of (5S,5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptan-14-ol

[0249] Step 1: Preparation of compound (5S,5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-14-ylbenzoate

[0250] Benzoyl peroxide (688 mg, 2.84 mmol) was added to a solution of E-33-1 (1 g, 1.42 mmol) and potassium dihydrogen phosphate (743 mg, 4.26 mmol) in DMF (15 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford E-33-2 (550 mg, 47.0% yield). MS m / z (ESI): 824 [M+H].

[0251] Step 2: Preparation of compound (5S,5aS,6R,9S)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptan-14-ol

[0252] E-33-2 (550 mg, 0.67 mmol) and potassium carbonate (277 mg, 2 mmol) were stirred in methanol (8 mL) at room temperature for 1 hour. The reaction mixture was filtered, concentrated, purified by preparative liquid chromatography, and lyophilized to afford E-33 (200 mg, 37.2% yield). MS m / z (ESI): 720 [M+H].

[0253] 1H NMR (400MHz, MeOD) δ7.90–7.77(m,1H),7.36–7.27(m,2H),7.25(d,J=2.3Hz,0.5H),7.14(d,J= 2.5Hz,0.5H),5.40(dd,J=13.4,3.4Hz,1H),4.61–4.28(m,3H),4.12(d,J=8.8Hz,1H),3.74–3.6 3(m,1H),3.58(d,J=5.6Hz,1H),3.49–3.35(m,1H),3.22(t,J=13.0Hz,1H),2.96–2.67(m,6H),2 .35(d,J=5.2Hz,4H),2.22–1.80(m,3H),1.75–1.49(m,1H),0.83(d,J=4.5Hz,2H),0.64(s,2H).

[0254] Example 102

[0255] Preparation of 1-((1-((((5S,5aS,6R,9S)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one

[0256] Step 1: Preparation of tert-butyl (5S,5aS,6R,9S)-12-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-chloro-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0257] Tert-butyl (5S,5aS,6R,9S)-2-[(1S)-1-(7-chloro-8-fluoro-4-hydroxy-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-5-yl)oxy-ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 g, 3.89 mmol) was dissolved in tetrahydrofuran (20 mL), and [1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]methanol (1.71 g, 5.03 mmol) was added. The mixture was cooled to 0°C, and lithium bis(trimethylsilyl)amide (1 M, 11.6 mL) was added dropwise. The reaction was continued at 0°C for 15 minutes after the addition was complete. The reaction mixture was quenched by pouring into aqueous ammonium chloride (50 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford E-102-2 (2.6 g, 86.4% yield). MS m / z (ESI): 774 [M+H].

[0258] Step 2: Preparation of tert-butyl (5S,5aS,6R,9S)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate

[0259] Tetrabutylammonium fluoride (1M, 20 mL) was added to a solution of E-102-2 (2.5 g, 3.23 mmol) in tetrahydrofuran (30 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford E-102-3 (2 g, 96% yield). MS m / z (ESI): 536 [M+H].

[0260] Step 3: Preparation of tert-butyl (5S,5aS,6R,9S)-2-chloro-1-fluoro-5-methyl-12-(1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-4-carboxylate

[0261] To a solution of E-102-3 (2 g, 3.73 mmol) in dichloromethane (30 mL) was added triethylamine (1.13 g, 11.13 mmol) and methanesulfonyl chloride (850 mg, 7.42 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes. The reaction mixture was added to aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude E-102-4 (2.1 g). MS m / z (ESI): 614 [M+H].

[0262] Step 4: Preparation of tert-butyl (5S,5aS,6R,9S)-2-chloro-1-fluoro-12-((1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate

[0263] E-102-4 (2.1 g), N-methoxypiperidin-4-imine trifluoroacetate (2.07 g, 8.54 mmol), sodium iodide (1.67 g, 11.13 mmol), and N,N-diisopropylethylamine (4.8 g, 37.1 mmol, 6.46 mL) were heated to 50°C and stirred in acetonitrile (40 mL) for 13 hours. After cooling, the reaction mixture was added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford E-102-5 (1.3 g, 53.9% yield over two steps). MS m / z (ESI): 646 [M+H].

[0264] Step 5: Preparation of tert-butyl (5S,5aS,6R,9S)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-(1-((4-(methoxyimino)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14 carboxylate

[0265] E-102-5 (1.2 g, 1.86 mmol) and methanesulfonic acid (dimethyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl) palladium(II) dichloromethane adduct (157 mg, 0.22 mmol) were heated to 80°C and stirred for 0.5 hours in dioxane (20 mL). After cooling to room temperature, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (1.79 g, 5.57 mmol) and aqueous sodium hydroxide solution (2M, 4 mL) were added and heated to 70°C and stirred for 3 hours. After cooling to room temperature, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford E-102-6 (1.1 g, 73.3% yield). MS m / z(ESI):805[M+H].

[0266] Step 6: Preparation of 1-((1-((((5S,5aS,6R,9S)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one

[0267] To a solution of E-102-6 (1.1 g, 1.37 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (6 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. After concentration, the mixture was purified by silica gel column chromatography to afford E-102-7 (750 mg, 77.9% yield). MS m / z (ESI): 705 [M+H].

[0268] Step 7: Preparation of 1-((1-((((5S,5aS,6R,9S)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptaden-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one

[0269] To a solution of E-102-7 (150 mg, 0.21 mmol) in dichloromethane (10 mL) was added dilute hydrochloric acid (1 M, 2 mL) at room temperature. The mixture was stirred at room temperature for 5 hours. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, purified by HPLC, and lyophilized to afford E-102 (62 mg, 43.1% yield). MS m / z (ESI): 676 [M+H].

[0270] Example 263

[0271] 4-(Difluoromethylene)-1-(1-(((5S,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)piperidine 1-oxide

[0272] Step 1: Preparation of compound (5S,6S,9R)-12-(1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptane-14 carboxylate

[0273] To a solution of E-263-1 (500 mg, 0.71 mmol) in dichloromethane (10 mL) were added triethylamine (216 mg, 2.13 mmol) and di-tert-butyl dicarbonate (155 mg, 0.71 mmol). The mixture was allowed to react at room temperature for 1 hour. The mixture was washed with saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to afford E-263-2 (560 mg, 97% yield). MS m / z (ESI): 804 [M+H].

[0274] Step 2: Preparation of compound 1-(5S,6S,9R)-14-(tert-butoxycarbonyl)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)-4-(difluoromethylene)piperidine 1-oxide

[0275] To a solution of E-263-2 (560 mg, 0.69 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (227 mg, 1.12 mmol) and allowed to react at room temperature for 1 hour. The reaction solution was washed with sodium thiosulfate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude product E-263-3 (565 mg, 100% yield). MS m / z (ESI): 820 [M+H].

[0276] Step 3: Preparation of compound 4-(difluoromethylene)-1-(1-(((5S,6S,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-(methyl-d3)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept-12-yl)oxy)methyl)cyclopropyl)methyl)piperidine 1-oxide

[0277] E-263-3 (565 mg, 0.69 mmol) was dissolved in a mixture of dichloromethane (10 mL) and MeOH (3 mL) at 0°C. HCl (4 M, 5 mL) was added and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated and the crude product was purified by preparative chromatography to afford E-263 (275 mg, 50% yield). MS m / z (ESI): 720 [M+H].

[0278] 1 H NMR (400MHz, MeOD) δ7.86 (dt, J=8.9, 6.1Hz, 1H), 7.37–7.25 (m, 2H), 7.18 (dd, J=40.0, 2. 7Hz,1H),5.56(dt,J=14.6,3.0Hz,1H),4.72–4.56(m,3H),4.31(dd,J=8.9,3.6Hz,1H),4. 17(d,J=6.0Hz,1H),4.11(q,J=6.0Hz,1H),3.78(s,2H),3.66(d,J=9.1Hz,2H),3.52–3.38 (m,3H),2.81–2.67(m,2H),2.54(d,J=14.8Hz,2H),2.35–1.93(m,5H),1.05–0.89(m,4H).

[0279] Biological test evaluation

[0280] 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.

[0281] 1. Determination of the activity of the compounds of the present invention in blocking KRAS G12D-SOS1 protein binding

[0282] 1. Experimental purpose: The purpose of this test case is to test the ability of compounds to block the binding between KRAS G12D and SOS1 proteins.

[0283] 2. Experimental Reagents and Instruments

[0284] 2.1 Experimental instruments: Centrifuge (5810R) was purchased from Eppendorf; pipettes were purchased from Eppendorf or Rainin; microplate reader was purchased from BioTek, USA, model number is SynergyH1 full-function microplate reader.

[0285] 2.2 Experimental reagents: KRAS-G12D / SOS1 Binding Assay Kit was purchased from Cisbio, catalog number 63ADK000CB17PEG; GTP was purchased from Sigma, catalog number G8877; 384-well plates were purchased from Perkin Elmer, catalog number 6007299.

[0286] 3. Experimental method: Use the Diluent buffer in the kit to dilute the compound into different concentrations of 10× compound solution, and add 2uL per well to a 384-well plate. Use Diluent buffer to prepare Tag2-KRAS G12D protein and GTP into a 5×KRAS G12D-GTP protein mixed solution, and use Tag1-SOS1 protein to prepare a 5×SOS1 protein solution, and add them to a 384-well plate, 4uL per well, and incubate at room temperature for 15 minutes. Use the 2×anti-Tag1-Tb prepared with detection buffer to 3+ The mixed solution of anti-Tag2-XL665 was added to a 384-well plate at 10 μL per well and incubated at 4°C in the dark for 3 hours. The plate was read using the time-resolved fluorescence program of the Biotek Synergy H1 instrument, and fluorescence values ​​at emission wavelengths of 665 nm and 620 nm were measured.

[0287] 4. Experimental processing method: Calculate the signal ratio (665nm / 620nm*10,000) and perform nonlinear fitting of the signal ratio and sample concentration using a four-parameter equation in GraphPad Prism 6 to obtain the IC 50 value.

[0288] 5. Experimental results:

[0289] According to the above scheme, the compounds of the present invention showed an activity of about 0.01nM to 1000nM (IC 50 )'s biological activity.

[0290] In some embodiments, the compounds of the present invention have an IC of 0. 50 Less than about 50 nM, preferably less than about 10 nM for the compounds, further preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM for the compounds listed in the present invention.

[0291] 6. Experimental conclusion: The compounds of the present invention can effectively block the binding of KRAS G12D and SOS1 proteins.

[0292] II. Determination of the proliferation inhibitory activity of the compounds of the present invention on KRAS G12D mutant tumor cell lines

[0293] 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.

[0294] 2. Experimental instruments:

[0295] 2.1 Instruments: Microplate reader (BioTek Synergy H1); pipette (Eppendorf & Rainin).

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 5. Experimental results:

[0300] Table 1: Inhibitory activity of the compounds of the present invention on GP2D and AsPC-1 cell proliferation

[0301] 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.

[0302] III. Inhibitory activity of the compounds of the present invention on p-ERK in AsPC-1 cells

[0303] 1. Experimental purpose: To determine the inhibitory activity of the example compounds on the level of phosphorylated ERK in KRAS G12D mutant cells AsPC-1.

[0304] 2. Experimental instruments:

[0305] 2.1 Instruments: Microplate reader (BioTek Synergy H1); pipette (Eppendorf & Rainin).

[0306] 2.2 Reagents: Phosphorylated ERK1 / 2 (T202-Y204) LANCE Ultra Cellular Detection Kit was purchased from PerkinElmer, catalog number TRF4000M; 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; White opaque OptiPlate TM -384 plate was purchased from PerkinElmer, catalog number 6007290.

[0307] 3. Experimental method: When AsPC-1 cells reach the appropriate confluence, collect the AsPC-1 cells and adjust the cell density to 1×10 6 / mL, the cell suspension was plated in a 96-well plate, 50 μL per well, and placed in a 37°C, 5% CO2 incubator to adhere overnight. Different concentrations of compound solutions were prepared using DMSO and complete culture medium. As a vehicle control, 25 μL of compound solution was added to each well of the 96-well plate. The plate was incubated in a 37°C, 5% CO2 incubator for another 2 hours. The supernatant was discarded from the cell culture plate, 50 μL of lysis buffer was added to each well, and the cells were shaken and lysed at room temperature for 30 minutes. The cells were centrifuged at 1000 rpm for 1 minute, and 15 μL of supernatant was transferred to a 384-well plate. 5 μL of detection mixture (Eu-labeled anti-ERK1 / 2 (T202-Y204) Antibody with a final detection concentration of 0.5 nM and ULight labeled anti-ERK1 / 2 Antibody with a final detection concentration of 5 nM) was added to each well. The mixture was centrifuged at 1000 rpm for 1 minute to mix well. The cells were reacted overnight at room temperature and detected using BioTek Synergy H1 reads the plate and uses a time-resolved fluorescence program to detect the signal values ​​at emission wavelengths of 620 nm and 665 nm.

[0308] 4. Experimental data processing method: Calculate the ratio of the signal values ​​at 665nm and 620nm emission wavelengths, use the ratio to calculate the inhibition rate, and use Graphpad Prism software to perform nonlinear regression curve fitting on the concentration and inhibition rate to obtain IC 50 value.

[0309] 5. Experimental results: The IC values ​​of the compounds of the present invention for pERK inhibition in AsPC-1 cells were obtained through the above scheme. 50 value.

[0310] In some embodiments, the IC values ​​of the compounds of the present invention for pERK inhibition in AsPC-1 cells are 50 Less 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.

[0311] 6. Experimental conclusion: The compounds of the present invention have a good inhibitory effect on pERK in AsPC-1 cells.

[0312] Pharmacokinetics in mice

[0313] 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).

[0314] 2. Experimental Plan

[0315] 2.1 Test drugs: Compounds of the present invention, homemade;

[0316] 2.2 Experimental Animals

[0317] Balb / c male mice were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd. with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0318] 2.3 Drug preparation: Oral administration drug preparation: 10% Captisol in 50mM citrate buffer pH 5.0

[0319] 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.

[0320] 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.

[0321] 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.

[0322] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0323] 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.

[0324] 2.4 Administration: Three male Balb / c mice were fasted overnight and administered orally at a dose of 30 mg / kg in a volume of 10 mL / kg. Three male Balb / c mice were fasted overnight and administered intravenously at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0325] 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.

[0326] 3. Determination results: The final determination results obtained by LCMS / MS method are shown in the following table:

[0327] Table 2: Pharmacokinetic parameters of the compounds in mice after oral administration

[0328] 4 Experimental conclusion: The results show that the example compounds have a high oral exposure, and nitrogen oxides are mainly converted into non-nitrogen oxides in the body.

[0329] 5. Pharmacokinetics in rats

[0330] 1. Study purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the example compounds in rats (plasma) after oral administration.

[0331] 2. Experimental Plan

[0332] 2.1 Test drugs: Compounds of the present invention, homemade.

[0333] 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).

[0334] 2.3 Drug preparation: Oral administration drug preparation: 10% Captisol in 50mM citrate buffer pH 5.0

[0335] 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.

[0336] 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.

[0337] Weigh the example compound and dissolve it in the solution, shake well, and sonicate for 15 minutes to obtain a colorless clear solution with a concentration of 3 mg / mL. Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0338] 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.

[0339] 2.4 Administration: 3 male SD rats per group were fasted overnight and administered PO at a dose of 30 mg / kg in a 10 mL / kg volume. 3 male SD rats per group were fasted overnight and administered IV at a dose of 1 mg / kg in a 5 mL / kg volume.

[0340] 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.

[0341] 3 Experimental results: The final determination results obtained by LCMS / MS method are shown in the following table:

[0342] Table 3: Pharmacokinetic parameters of the compounds in rats after oral administration

[0343] 4 Experimental conclusions:

[0344] The results showed that the example compounds had a higher oral exposure, and nitrogen oxides were mainly converted into non-nitrogen oxides in the body.

[0345] 6. Anti-tumor efficacy experiments in a human pancreatic cancer cell line (HPAC) mouse transplant tumor model

[0346] 1. Experimental purpose: 8-10 week old female conventional immunodeficient mice (BALB / c nude) weighing 18g-22g were used as experimental animals. The in vivo efficacy experiment was conducted using a human pancreatic cancer cell line (HPAC) transplant tumor model to test the anti-tumor effect of the example compound after oral administration.

[0347] 2. Experimental instruments and reagents:

[0348] 2.1 Instruments: clean bench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); CO2 incubator (Thermo-311, Thermo); centrifuge (Centrifuge 5720R, Eppendorf); automatic cell counter (Countess II, Life Technologies); pipette (10-20 μL, Eppendorf); microscope (TS 2, Nikon); vernier caliper (CD-6" AX, Mitutoyo, Japan); cell culture flasks (T25 / T75 / T225, Corning); constant temperature water bath (HWS12, Shanghai Yiheng Scientific).

[0349] 2.2 Reagents: DMEM / F12 (11330-032, Gibco); fetal bovine serum (FBS) (10091-148, Gibco); Insulin (51500-056, Gibco); EGF (PHG0311, Gibco); 0.25% trypsin (25200-056, Gibco); phosphate buffered saline (PBS) (10010-023, Gibco); Matrigel (356234, Corning); Gln (25030-081, Gibco).

[0350] 3. Experimental Methods

[0351] 3.1 Experimental compounds: Compounds used in the present invention, homemade.

[0352] 3.2 Preparation of compounds: Weigh a certain amount of the example compound, add an appropriate amount of 10% solvent (solutol HS15), and stir on a magnetic stirrer for 0.5 hours to prepare a uniform suspension solution of the desired concentration.

[0353] 3.3 Cell culture and passaging: Human pancreatic cancer cell line (HPAC) was obtained from Nanjing Kebai and cultured in DMEM / F12 medium (Gibco, 11330-032) supplemented with 10% fetal bovine serum (Gibco, 10091-148), 1× Insulin (51500-056, Gibco), and 10 ng / ml EGF (PHG0311, Gibco). Cells were observed under a microscope (Thermo Fisher, 311). When the cells filled the culture flask to a density of 80%-90%, the cells were routinely passaged and cultured in a 37°C, 5% CO2 incubator (Thermo Fisher, 311).

[0354] 3.4 Cell inoculation and group administration: Under sterile conditions, human pancreatic cancer cells (HPAC) in the logarithmic growth phase were digested with 0.25% trypsin-EDTA (Gibco, 25200-056), washed and suspended in phosphate buffered saline, mixed with Matrigel (Corning, 356234) at a ratio of 1:1, and then transplanted subcutaneously on the right anterior flank of the back of immunodeficient mice (BALB / c nude). Each mouse was inoculated with 3*10 6 After inoculation, the tumor volume was grown to 100-200 mm. 3 At the same time, the mice were randomly divided into 5 groups according to the tumor size, with 5 mice in each group for in vivo efficacy experiments, and the negative control group was the solvent group.

[0355] Administration: The example compounds were administered orally. The dosage and administration cycle are shown in the table.

[0356] 3.5 Tumor measurement and calculation of tumor inhibition rate: The long and short diameters of the tumor were measured with a vernier caliper twice a week and the tumor volume (mm 3 ), calculated as: V = 0.5 * D * d * d, where D and d are the major and minor diameters of the tumor, respectively. The antitumor efficacy is determined by dividing the average tumor volume increase of compound-treated animals by the average tumor volume increase of untreated animals. The tumor inhibition rate is calculated as: When the tumor does not regress, TGI (%) = 100-[(V t -V0) treatment group / (V t -V0) vehicle control group]*100%, when the tumor regresses, TGI (%) = [1-(V t -V0) drug-treated group / V0 vehicle control group]*100%. All animals were euthanized after the experiment.

[0357] 4. Experimental results and conclusions

[0358] Table 4: Pharmacological parameters of compounds on tumor-transplanted mice

[0359] As shown in the table above, the Example compounds can inhibit tumor proliferation or cause tumor regression at an oral dose of 100 mg / kg, and the body weight of the mice did not decrease significantly, indicating that the Example compounds have good tumor inhibition effect and safety when administered orally.

Claims

1. A compound represented by the general formula (A), its N-oxide, its oxo form or its pharmaceutically acceptable salt: Wherein: X1 is selected from N or CR 2b ; preferably N; L1 is selected from O, S or NH; preferably O; L2 is selected from C1-C4 alkylene groups, and the C1-C4 alkylene groups are optionally substituted with 1, 2, 3, 4, 5 or 6 R a substituents; Ring A is selected from C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-12 aryl or 5- to 12-membered heteroaryl; R is selected from -OR b 、-CH2OR b 、-C(O)R b 、-C(O)OR b 、a 3- to 10-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein the 3- to 10-membered heterocyclic group or the 5- to 12-membered heteroaryl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 R 4a substituents; R 1a selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl, -OR b , -OC(O)R b , -OC(O)NR b R c , -OS(O)2R b or -OS(O)2NR b R c , wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1- 6deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 1b 、R 1c 、R 1d and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; Or R 1b And R 1c is linked to an adjacent atom to form a 3- to 12-membered heterocyclic group or a 5- to 14-membered heteroaryl group, optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 2a selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl or -(CH2)n1OR e , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; or R 2a and R 1e link to form a 3- to 12-membered heterocyclic group or a 5- to 14-membered heteroaryl group, optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 2b Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 2c Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, and the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; Alternatively, any two R3 linkages form a C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 4a selected from 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 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl, =CR aa R bb or N-OR cc , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; Alternatively, any two R 4a linkages form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, and said C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; R a selected from 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 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; or 2 Rs of the same or different carbon atoms a are linked to form a C 3-12 cycloalkyl or 3- to 12-membered heterocyclic group, optionally further substituted by one or more selected from 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R b Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R c selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R e selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R aa selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R bb selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C ; 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R cc selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; n1 is selected from 0, 1, 2 or 3; x is selected from 0, 1, 2, 3, 4, 5 or 6.

2. The compound represented by the general formula (A) according to claim 1, its N-oxide, its oxo derivative or its pharmaceutically acceptable salt, characterized in that, Furthermore, as shown by the general formula (I) or (I-A): Wherein: X2 is selected from O, CR 5a R 5b or N-OR 5c ; Ring B is selected from 3- to 10-membered heterocyclic groups or 5- to 12-membered heteroaryl groups; R4 is selected from 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 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; Alternatively, any two R4 linkages form C 3-8 a cycloalkyl group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group and 3-8 membered heterocyclic group may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; R 5a selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 5b selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R 5c selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6-alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6- 14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1- 6-alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; y is selected from 0, 1, 2, 3, 4, 5 or 6.

3. The compound, its N-oxide, its oxo-form or its pharmaceutically acceptable salt according to claim 1 or 2, characterized in that, R 1b and R 1c are linked to the adjacent atoms to form the following structure preferably form the following structure more preferably form the following structure R 1f and R 1g are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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.

4. The compound, its N-oxide, its oxo form or its pharmaceutically acceptable salt according to claims 1 to 3, characterized in that, Furthermore, as shown by general formula (II-A) or (II-B): R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; R7 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C(O)R b , -C(O)NR b R c , -S(O)2R b or -S(O)2NR b R c ; R b Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4-alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; R c selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4-alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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; p is selected from 0, 1, 2, 3 or 4.

5. The compound, N-oxide, oxo-form or pharmaceutically acceptable salt thereof according to claims 1 to 3, characterized in that, Furthermore, as shown in General Formula (III-A) or (III-B): R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; p is selected from 0, 1, 2, 3 or 4.

6. The compound according to any one of claims 1 to 5, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, characterized in that R 5a selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1- 3-alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, wherein the C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl or cyclopropyl; R 5b selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1- 3-alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, wherein the C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl or cyclopropyl;, R 5c selected from C 1-3 alkyl, C 1-3 deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1- 3-hydroxyalkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group, wherein the C 1-3 alkyl, C 1-3 deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; preferably methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl, cyclopropyl or cyclopropylmethyl.

7. The compound according to any one of claims 1 to 6, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, characterized in that Ring B is selected from 3- to 8-membered monocyclic heterocyclic groups, 7- to 10-membered fused heterocyclic groups, 7- to 11-membered spiro heterocyclic groups or 7- to 10-membered bridged heterocyclic groups; Preferred are the following groups:

8. The compound according to any one of claims 1 to 7, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, characterized in that R4 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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; Preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxy, cyano, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl or hydroxyethyl.

9. The compound according to any one of claims 1 to 8, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, characterized in that, L2 is selected from preferably Or, L2 is selected from Preferably R a-1 、R a-2 、R a-3 and R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or C 1-6 hydroxyalkyl; preferably hydrogen or deuterium; R5 is selected from 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 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; z is selected from 0, 1, 2, 3 or 4.

10. The compound according to any one of claims 1 to 9, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, characterized in that R 1d selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or C 1-3 alkylamino, and the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl and C 1-3 alkylamino may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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; Preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 1e selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or C 1-3 alkylamino, and the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl and C 1-3 alkylamino may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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; Preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 2a Selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino or -(CH2) n1 OR e , wherein said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or C 1-3 alkylamino may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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; R e selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4-alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, 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; n1 is selected from 0, 1, 2 or 3; R 2c selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or C 1-3 alkylamino; Preferably, R 2c is selected from hydrogen, deuterium, fluorine, chlorine or bromine; More preferably, R 2c is selected from fluorine.

11. The compound, its N-oxide, its oxo form or its pharmaceutically acceptable salt according to any one of claims 1 to 10, characterized in that, Furthermore, as shown by general formula (IV) or (V): n2 is selected from 0, 1, 2 or 3; n3 is selected from 0, 1, 2 or 3.

12. The compound according to any one of claims 4 to 11, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, characterized in that R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; Preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl or haloethyl.

13. The compound, N-oxide, oxo-form or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that, selected from M1 is selected from CR 7-5 or N; M2 is selected from CR 8-1 or N; Preferably selected from R 6-1 、R 6-2 、R 6-3 、R 6-4 、R 6-5 、R 6-6 and R 6-7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group or C 6-10 aryl, 5- to 10-membered heteroaryl, and the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1- 6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1-6 alkyl, C 1-6 silyl, C 3- 8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 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, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group or C 6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more of 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 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1-6 alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl; R 8-1 、R 8-2 、R 8-3 、R 8-4 and R 8-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group or C 6-10 aryl, 5- to 10-membered heteroaryl, and the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkylamino, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl may optionally be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -C(O)-C 1-6 alkyl, -C(O)O-C 1-6 alkyl, C 1-6 silyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl.

14. The compound, its N-oxide, its oxo form or its pharmaceutically acceptable salt according to any one of claims 1 to 13, characterized in that, Selected from the following compounds:

15. A method for preparing a compound represented by the general formula (II-B), its N-oxide, its oxo form or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by general formula (II-B-1) reacts with a peroxide to obtain the compound represented by general formula (II-B); Ring A, Ring B, L1, L2, X1, X2, R 1d , R 2a , R 2c , R3, R4, R6, R7, p, x and y are as described in any one of claims 1 to 13.

16. A method for preparing a compound of formula (III-B), its N-oxide, its oxo form or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by general formula (III-B-1) reacts with a peroxide to obtain the compound represented by general formula (III-B); Ring A, Ring B, L1, L2, X1, X2, R 1a , R 1d , R 2a , R 2c , R3, R4, R6, R7, p, x and y are as described in any one of claims 1 to 13.

17. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 14, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound according to any one of claims 1 to 14, its N-oxide, its oxo compound or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 17 in the preparation of a KRAS inhibitor drug; preferably in the preparation of a KRAS G12D, KRAS G12V or KRAS G13D inhibitor drug.

19. Use of the compound according to any one of claims 1 to 14, its N-oxide, its oxo form or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating diseases or disorders such as Noonan syndrome, LEOPARD syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, brain cancer, breast cancer, lung cancer, liver cancer, gastric cancer, kidney cancer, cholangiocarcinoma, prostate cancer, ovarian cancer, pancreatic cancer, small intestine cancer and colon cancer; preferably for use in the preparation of a medicament for treating non-small cell lung cancer, colon cancer, pancreatic cancer, esophageal cancer and head and neck tumors.

Images