Aromatic amine derivative inhibitor, preparation method therefor and use thereof

Abstract

An aromatic amine derivative inhibitor, a preparation method therefor and the use thereof. A compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof in the treatment of cancers, immune diseases, and / or inflammatory diseases.

Description

Aromatic amine derivative inhibitors, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to an aromatic amine derivative inhibitor, its preparation method, and its application. Background Technology

[0002] The phosphatidylinositol 3-kinase (PI3K) protein family is divided into four major classes: I, II, III, and IV. These classes participate in the regulation of various cellular functions, including cell growth, proliferation, differentiation, survival, and energy metabolism. The four classes of PI3K proteins have distinct structures and functions. Class I PI3K is the most extensively studied, and it is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. PI3Kα exhibits activating mutations and amplification in various tumors and is closely related to tumorigenesis and development. Reports have demonstrated that PI3Kβ can activate platelets and plays an important role in the development of diseases such as thrombosis. PI3Kδ and PI3Kγ are mainly expressed in the blood system and are closely related to the immune system and inflammation. Additionally, PI3Kγ is also closely related to blood pressure stability and smooth muscle contraction.

[0003] PI3Kα is composed of the p110α catalytic subunit and the p85 regulatory subunit. The p110α subunit is encoded by the PIK3CA gene. When PI3Kα is regulated by upstream receptor tyrosine kinases (such as insulin receptor, platelet-derived growth factor receptor, etc.) and Ras protein, it is activated and catalyzes the conversion of phosphatidylinositol 2-phosphate (PIP2) to phosphatidylinositol 3-phosphate (PIP3). PIP3 can further activate protein kinase B (AKT) and its downstream signaling pathways, thereby regulating cell differentiation, migration, and metabolic homeostasis. Mutations or amplifications of PI3Kα can lead to persistent activation of the AKT pathway, rapid cell proliferation, and thus tumorigenesis. PI3Kα is also a key protein in the insulin / insulin receptor pathway, regulating glucose metabolism in tissues such as the liver and skeletal muscle. Inhibition of PI3Kα can lead to reduced liver glycogen synthesis, increased blood glucose, and increased insulin levels in the body.

[0004] PI3Kα is one of the most frequently mutated kinases in cancer, with a total mutation rate of 14% across all cancers. It is widely distributed, appearing frequently in cancers such as breast cancer, head and neck cancer, ovarian cancer, and gastric cancer. PIK3CA gene mutations are diverse, with the three most common hotspot mutations being H1047R (kinase region), E542K (helical region), and E545K (helical region). Currently, clinical PI3Kα inhibitors exhibit strong inhibitory activity against PI3Kα mutants, but lack selectivity for wild-type PI3Kα. They also show some inhibition of PI3Kβ / γ / δ, leading to severe hyperglycemia mediated by wild-type PI3Kα and side effects such as rash and diarrhea involving the PI3K / AKT pathway in clinical trials. Furthermore, increased insulin levels and activation of the insulin receptor pathway enhance PI3K pathway activation, thus affecting the efficacy of PI3Kα inhibitors. Currently approved PI3Kα inhibitors, including Novartis' Alpelisib (BYL-719) and Roche's GDC-0077, are non-selective for inhibiting wild-type PI3Kα. Although they have good clinical efficacy, they also have serious side effects such as hyperglycemia.

[0005] In summary, PI3Kα inhibitors have shown significant therapeutic effects in indications such as breast cancer and possess promising market prospects. However, existing PI3Kα inhibitors, due to their lack of selectivity for wild-type PI3Kα, result in severe hyperglycemic side effects, limiting clinical dosage and efficacy. Therefore, the development of PI3Kα mutation-selective inhibitors is of great significance. Summary of the Invention

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

[0007] M1 is selected from N and NR. a CR a or CR a R a1 Preferred from N and NR a or CR a ;

[0008] M2 is selected from N and NR. b CR b or CR a R a1 Preferred from N and NR b or CR b ;

[0009] M3 is selected from N and NR. c CR c or CR a R a1Preferred from N and NR b or CR c ;

[0010] L1 is selected from key, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1- 6-eneyl, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0011] L2 is selected from bond, -O-, -C(O)-, -C(O)O-, -C(S-), -C(NR) d3 )-、-C(=CR d3 R d4 )-、-NR d2 -, -S-, -S(O)-, -S(O)2-, -C(O)NR d2 -、-C(S)NR d2 -、-C(NR d3 )NR d2 -、-C(=CR d3 R d4 )NR d2 -、C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0012] L3 is selected from bond, -O-, -C(O)-, -C(S)-, -NR d5 -, -S-, -S(O)-, -S(O)2-, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1- 6-eneyl, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0013] Alternatively, L2 and L3 form C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene and 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0014] Alternatively, atoms on L3 and ring A can link to form C. 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene and 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0015] Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0016] R1 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0017] R2 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0018] R3 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR ddC(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0019] Alternatively, any two R3 atoms can form C with adjacent atoms. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0020] R a Or R a1 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff-(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0021] R b Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C.1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0022] R c Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NRff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0023] Or, R a R b and R c Any two substituents in the group can be linked to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents are replaced in C; preferably, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1- 6-alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted, unsubstituted 5-14 membered heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2)n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents are substituted in the C; more preferably, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted, unsubstituted 5-14 membered heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2)n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents in it are replaced;

[0024] R d1 R d2 R d3 R d4 and R d5 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 Ree -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0025] R aa and R bb Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0026] Or, R aa With R bb Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0027] R cc and R dd Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0028] Or, R cc With R dd Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0029] R ee and R ff Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0030] Or, R ee With R ff Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0031] n1 is selected from 0, 1, 2, 3, 4 or 5; n2 is selected from 0, 1, 2, 3, 4 or 5; n3 is selected from 0, 1, 2, 3, 4 or 5; a is selected from 0, 1, 2, 3, 4, 5 or 6; b is selected from 0, 1, 2, 3, 4, 5 or 6.

[0032] In some embodiments of the invention, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is further represented as shown in general formula (II):

[0033] M4 is selected from O and NR. e , S or CR e1 R e2 ; Preferred O;

[0034] Alternatively, M4 and L3 may link to form a 3-12-membered heterocyclic group or a 5-14-membered heterocyclic group, wherein the 3-12-membered heterocyclic group and the 5-14-membered heterocyclic group may optionally be further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0035] R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C.1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0036] R e1 R e2 and R e3 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ffC(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted by one or more substituents in the aryl group and substituted or unsubstituted 5-14 heteroaryl groups.

[0037] In some embodiments of the present invention Selected from

[0038] Preferred

[0039] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0040] R 2a and R 2b Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0041] R 2c Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee-(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6- 14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff ;

[0042] Or, any two R 2c Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NRff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents are replaced in C; preferably, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1- 6-alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2Ree -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents in it are replaced;

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

[0044] In some embodiments of the present invention Selected from

[0045] or, Selected from

[0046] or, for

[0047] M5 is selected from -(CR) f1 R f2 ) n4 -、-CR f1 -、-CR f1 =CR f2 -, -C(O)-, -O-, -S-, -S(O)2-, =S(R f1 (O)-, -N-, or -NR f1 -; Preferred from -(CR) f1 R f2 ) n4 -、-CR f1 -、-CRf1 =CR f2 -、-C(O)-、-O-、-S-、-N- or -NR f1 -;

[0048] M6 is selected from -(CR) f1 R f2 ) n5 -、-CR f1 -、-CR f1 =CR f2 -, -C(O)-, -O-, -S-, -S(O)2-, =S(R f1 (O)-, -N-, or -NR f1 -; Preferred from -(CR) f3 R f4 ) n5 -、-CR f3 -、-CR f3 =CR f4 -、-C(O)-、-O-、-S-、-N- or -NR f3 -;

[0049] M7 is selected from -(CR) f1 R f2 ) n6 -、-CR f1 -、-CR f1 =CR f2 -, -C(O)-, -O-, -S-, -S(O)2-, =S(R f1 (O)-, -N-, or -NR f1 -; Preferred from -(CR) f5 R f6 ) n6 -、-CR f5 -、-CR f5 =CR f6 -、-C(O)-、-O-、-S-、-N- or -NR f5 -;

[0050] Ring C is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0051] Ring D is selected from C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0052] R 2d Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6- 14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NRee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff More preferably, C is derived from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1- 6-alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2)n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff ;

[0053] Or, any two R 2d Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0054] R f1 R f2 R f3 R f4 R f5 Or R f6 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C.1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee-NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2)n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6- 14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2Ree -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0055] n4 is selected from 0, 1, 2 or 3; n5 is selected from 0, 1, 2 or 3; n6 is selected from 0, 1, 2 or 3; d is selected from 0, 1, 2, 3, 4 or 5.

[0056] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is further shown as in general formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), or (III-7):

[0057] In some embodiments of the invention, the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, further as shown in general formula (III-7):

[0058] M8 is selected from key, -CR h1 =CR h2 -、-O-、-S-、-NR h3 -、-C(O)NR h3 -、-NR h3 C(O)-、-S(O)2NR h3 -、-NR h3 S(O)2- or -S(O)(=NR h3 )-;

[0059] M9 is selected from key, -CR h1 =CR h2 -、-O-、-S-、-NR h3 -、-C(O)NR h3 -、-NR h3 C(O)-、-S(O)2NR h3 -、-NR h3 S(O)2- or -S(O)(=NR h3 )-;

[0060] R h1 R h2 and R h3 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0061] n7 is selected from 0, 1, 2 or 3; n8 is selected from 0, 1, 2 or 3; n9 is selected from 0, 1, 2 or 3.

[0062] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is further shown as in general formula (V):

[0063] Ring E is selected from 3-8 member submonocyclic heterocyclic group, 7-11 member subspirocyclic heterocyclic group, 7-10 member subfused heterocyclic group or 5-10 member subheteroaryl group;

[0064] R5 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0065] e can be selected from 0, 1, 2, 3, 4 or 5.

[0066] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is further shown as in general formula (V-1) or (V-2):

[0067] In some embodiments of the present invention, ring A is selected from C. 3-8 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 7-10 Fused cycloalkyl groups, 3-8 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic groups, 7-10 membered fused heterocyclic groups, C 6-10 Aryl, 5-6 membered monocyclic heteroaryl or 7-14 membered polycyclic heteroaryl;

[0068] In some embodiments of the present invention, ring A is selected from... Preferred from

[0069] In some embodiments of the present invention Selected from

[0070] X1 and X2 are each independently selected from O, S, Se, N, C(O), NR g1CR g1 or CR g1 R g2 Preferred from O, S, N, C(O), NR g1 CR g1 or CR g1 R g2 ;

[0071] X3 is selected from N and NR. g3 CR g3 or C(R) g3 )2; N or CR g3 ;

[0072] X4 is selected from N or CR g4 X5 is selected from N or CR g5 X6 is selected from N or CR g6 X7 is selected from N or C; X8 is selected from N or C;

[0073] R g1 R g2 R g3 R g4 R g5 and R g6 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0074] Or, R g1 With R g3 R g4 R g5 Or R g6 Any substituent in the chain forms C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0075] Or, R g3 R g4 R g5 and R g6 Any substituent in the chain forms C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0076] Preferably, Selected from Preferred from Better self Further optimization

[0077] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is further shown as in general formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), or (IV-10):

[0078] R 3a R 3b R 3c R 3d and R 3e Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2)n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0079] Or, any two R 3a Or R 3b It can form carbon with adjacent atoms. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0080] b1 is selected from 0, 1, 2, 3, 4 or 5; b2 is selected from 0, 1, 2, 3, 4 or 5.

[0081] In some embodiments of the present invention, L1 is selected from bond, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, wherein the C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0082] In some embodiments of the present invention, L1 is selected from a key or C. 1-3 Alkylene, wherein the C 1-3 Alkylene, optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0083] In some embodiments of the invention, L1 is selected from -CH2-, wherein the -CH2- is optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0084] In some embodiments of the present invention, L3 is selected from bond, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10arylene or 5-10 heteroarylene, wherein the C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0085] In some embodiments of the present invention, L3 is selected from a key or C. 1-3 Alkylene, wherein the C 1-3 Alkylene, optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0086] In some embodiments of the invention, L3 is selected from -CH2-, wherein the -CH2- is optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0087] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is further shown as in general formulas (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), or (V-8):

[0088] R6 and R7 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0089] Or R6 and X1 are linked to form C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene and 5-14 heteroarylene, optionally further converted by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0090] In some embodiments of the present invention, R2, R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-3 Alkyl, C 1- 3-Hydroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted with one or more substituents from aryl and 5-14 heteroaryl groups; preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl.

[0091] In some embodiments of the present invention, R3, R 3a R 3b R 3c R 3d and R 3e Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2)n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents selected from aryl and 5-14 heteroaryl groups; preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl.

[0092] Or, any two R3, R 3a Or R3b It can form carbon with adjacent atoms. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0093] In some embodiments of the present invention, R1 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14It is substituted with one or more substituents from aryl and 5-14 heteroaryl groups; preferably hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl.

[0094] The present invention also provides a compound of general formula (A) or a pharmaceutically acceptable salt thereof:

[0095] X1 and X2 are each independently selected from O, S, N, C(O), and NR. g1 CR g1 or CR g1 R g2 ;

[0096] X3 is selected from N or CR g3 X4 is selected from N or CR g4 X5 is selected from N or CR g5 X6 is selected from N or CR g6 ;

[0097] L1 is selected from key, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1- 6-eneyl, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0098] L4 is selected from bond, -O-, -C(O)-, -C(O)O-, -C(S-), -C(NR)-. d3 )-、-C(=CR d3 R d4 )-、-NR d2 -, -S-, -S(O)-, -S(O)2-, -C(O)NR d2 -、-C(S)NR d2 -、-C(NR d3 )NR d2 -、-C(=CR d3 R d4 )NR d2 -、C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0099] Alternatively, L1 and L4 form C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C6-14 arylene and 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0100] Ring F is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0101] R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0102] R6 and R7 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2)n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0103] Alternatively, R6 and R7 form C with adjacent atoms. 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0104] R8 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)C(O)R cc -(CH2) n2 C(O)OR cc -C(O)(CH2) n2 OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -S(O)2(CH2) n2 OR cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 C(O)C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -(CH2) n2 S(O)(R cc ) = NR dd -NR dd (CH2)n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2)n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0105] Alternatively, any two R8 atoms can form C with adjacent atoms. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0106] R d1 R d2 R d3 and R d4 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 ORee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0107] R g1 R g2 R g3 R g4 R g5 and R g6 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0108] Or, Rg1 With R g3 R g4 R g5 Or R g6 Any substituent in the chain forms C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0109] R aa and R bb Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0110] Or, R aa With R bb Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0111] R cc and R dd Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0112] Or, R cc With R dd Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0113] R ee and Rff Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0114] Or, R ee With R ff Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0115] n1 is selected from 0, 1, 2, 3, 4 or 5; n2 is selected from 0, 1, 2, 3, 4 or 5; n3 is selected from 0, 1, 2, 3, 4 or 5; f is selected from 0, 1, 2, 3, 4, 5 or 6.

[0116] In some embodiments of the present invention, -L4-L1- is selected from key,

[0117] R9 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff-(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0118] R 10 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted by one or more substituents in the aryl group and substituted or unsubstituted 5-14 heteroaryl groups.

[0119] In some embodiments of the invention, the compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, further as shown in general formulas (A-1), (A-3), or (A-4):

[0120] In some embodiments of the present invention, ring F is selected from C. 3-8 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 7-10 Fused cycloalkyl groups, 3-8 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic groups, 7-10 membered fused heterocyclic groups, C 6-10 Aryl, 5-6 membered monocyclic heteroaryl or 7-14 membered polycyclic heteroaryl;

[0121] In some embodiments of the present invention, ring F is selected from...

[0122] In some embodiments of the present invention, ring F is selected from...

[0123] Or preferably, ring F is selected from

[0124] Y1 is selected from N, O, S, or CR. 8a Preferred from N, O, S or CH;

[0125] Y2 is selected from N, O, S, C or CR 8a Preferred from N, O, S, C or CH;

[0126] Y3 is selected from N or C;

[0127] Y4 is selected from N, O, S, C or CR 8a Preferred from N, O, S, C or CH;

[0128] Ring G is selected from C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0129] R 8a R 8c and R 8d Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0130] R 8b Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)C(O)R cc -(CH2) n2 C(O)OR cc -C(O)(CH2) n2 OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -S(O)2(CH2) n2 OR cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 C(O)C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -(CH2) n2 S(O)(R cc ) = NR dd -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NRdd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)ORcc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0131] Or, any two R 8b It can form carbon with adjacent atoms. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0132] g is selected from 0, 1, 2, 3, 4, 5, or 6;

[0133] Preferably, ring F is selected from

[0134] In some embodiments of the invention, the compound represented by general formula (A) or a pharmaceutically acceptable salt thereof is further represented as shown in general formula (A-5) or (A-6):

[0135] R1 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0136] R 8a Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0137] R 8b Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)C(O)R cc -(CH2) n2 C(O)OR cc -C(O)(CH2) n2 OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -S(O)2(CH2) n2 OR cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2C(O)C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -(CH2) n2 S(O)(R cc ) = NR dd -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents from a group consisting of aryl and substituted or unsubstituted 5-14 heteroaryl groups; preferably from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0138] Or, any two R 8b It can form carbon with adjacent atoms. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0139] g is selected from 0, 1, 2, 3, 4, 5 or 6.

[0140] In some embodiments of the present invention, R6 and R7 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0141] Alternatively, R6 and R7 form C with adjacent atoms. 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0142] In some embodiments of the present invention, R g1 R g2 R g3 R g4 R g5 and R g6 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10aryl or 5-10 heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0143] In some embodiments of the present invention, R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted with one or more substituents from aryl and 5-14 heteroaryl groups; preferably hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl.

[0144] The present invention also provides a compound of formula (III-4-1) or a pharmaceutically acceptable salt thereof:

[0145] Preferably, compounds of the general formula (V-2-1) or their pharmaceutically acceptable salts are preferred:

[0146] R L1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Hydroxyalkyl;

[0147] R1, L1, Ring D, M6, M7, R 2a R 2b R 2d And d is as defined in any of the above implementation schemes.

[0148] The present invention also provides a method for preparing compounds of general formula (III-4) or pharmaceutically acceptable salts thereof, characterized in that:

[0149] The compound of general formula (III-4-1) or its pharmaceutically acceptable salt reacts with the compound of general formula (III-4-2) or its pharmaceutically acceptable salt in the presence of a base to give the compound of general formula (III-4) or its pharmaceutically acceptable salt.

[0150] Preferably, the method is a method for preparing a compound of general formula (V-2) or a pharmaceutically acceptable salt thereof:

[0151] The compound of general formula (V-2-1) or its pharmaceutically acceptable salt reacts with the compound of general formula (V-2-2) or its pharmaceutically acceptable salt in the presence of a base to give the compound of general formula (V-2) or its pharmaceutically acceptable salt.

[0152] R L1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Hydroxyalkyl;

[0153] R L2 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0154] Ring A, R1, R3, L1, L3, b, R4, Ring D, M6, M7, R 2a R 2b R 2d , d, X1, R g1 ~R g6 R6 and R7 are as defined in any of the above embodiments.

[0155] In some embodiments of the present invention, the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia, triethylamine, diisopropylethylamine, pyridine, or imidazole; preferably triethylamine, diisopropylethylamine, pyridine, or imidazole.

[0156] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds of the general formula shown or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0157] In some embodiments of the present invention, the pharmaceutical composition comprises the general formulas described in the present invention and their compounds or pharmaceutically acceptable salts thereof as active ingredients, wherein the weight percentage of the active ingredients is 1% to 95%, preferably 1% to 90%, 5% to 85%, 5% to 80%, 5% to 75%, 10% to 70%, 10% to 60%, or 10% to 50%.

[0158] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0159] This invention also relates to the use of any of the compounds of the general formula shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating diseases related to PI3Kα.

[0160] The present invention further relates to any of the compounds of the general formula shown or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a method for treating diseases associated with PI3Kα kinase dysfunction.

[0161] The present invention also relates to a method for treating, preventing and / or treating diseases associated with PI3Kα kinase dysfunction, comprising administering to a patient a therapeutically effective dose of any compound of the general formula or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0162] The present invention also provides a method for treating disease conditions using the compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, including but not limited to conditions related to PI3Kα kinase dysfunction.

[0163] The present invention also relates to a method for treating a condition in mammals associated with PI3Kα kinase dysfunction, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0164] In some embodiments, the disease is selected from the treatment of cancer, PROS (PIK3CA-related overgrowth spectrum), immune disorders, or inflammatory disorders; wherein the cancer, PROS, immune disorders, or inflammatory disorders are caused by PI3Kα kinase dysfunction.

[0165] In some embodiments, the cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer, and multiple myeloma; preferably clear cell ovarian cancer or breast cancer.

[0166] Detailed description of the invention

[0167] 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, and in particular, the terms used in the specification and claims have the following meanings.

[0168] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 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 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 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 A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6 Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C... 1-6The alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-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 isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0169] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described 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 alkylene as described elsewhere herein.

[0170] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 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 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C3-15 ), 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 A branched unsaturated hydrocarbon group with 16 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. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0171] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 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 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 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 A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkyne 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. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0172] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 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 comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenedyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group, as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0173] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 11 (C 7-11 (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0174] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl 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 rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0175] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, 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 rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0176] The term "heterocyclic group" 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, sulfur, or selenium, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen but excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 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 heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0177] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group 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; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0178] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0179] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; 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:

[0180] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0181] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0182] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 7 to 20, 5 to 14, 7 to 14, 5 to 10, or 7 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, the heteroaryl 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 comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl,

[0183] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0184] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions 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. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0185] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0186] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0187] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3,

[0188] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0189] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0190] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0191] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0192] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0193] The term "aminocarbonyl" refers to NH2-C(O)-.

[0194] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

[0195] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0196] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0197] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotope-enriched analogs may be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atom described in this patent comprises its isotopes (H) and / or mixtures thereof. 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0198] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0199] The term "substituted or unsubstituted" indicates that the modified substituent may optionally be further substituted by one or more of the following substituents, selected from alkyl, deuteralkyl, haloalkyl, alkenyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkoxy, -(CH2) n -、-(CH2) n R, -(CH2) n OR, -O(CH2) n R, -(CH2) n SR, -SR5, -(CH2) n C(O)R、-(CH2) n C(O)OR, -(CH2) n S(O)R、-(CH2) n S(O)2R、-(CH2) n NRR'、-(CH2) n C(O)NRR'、-(CH2) n NR'C(O)R、-(CH2) n NR'S(O)R、-(CH2) n NR'S(O)2R、-OC(R'R”) n (CH2) m R、-NR'(CH2) n R, -CH=CH(CH2) n R, -CH=CH(CH2) n NRR'、-CH=CH(CH2) n NR'C(O)R、-CH=CH(CH2) n NR"C(O)NRR', =N-OR or =CRR';

[0200] R, R', and R" are each independently selected from alkyl, deuterated alkyl, haloalkyl, alkenyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, carboxyl, carboxylic ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocyclic alkoxy, cycloalkylthio, or heterocyclic alkoxy;

[0201] n is selected from 0, 1, 2, 4 or 5; m is selected from 0, 1, 2, 3, 4 or 5.

[0202] The different terms 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.

[0203] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0204] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the 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 "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0205] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0206] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0207] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0208] "Medicinal salts" refers to salts of the compounds of this invention that are safe and effective when used in mammals and have the appropriate biological activity.

[0209] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0210] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0211] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0212] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0213] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer 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 a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0214] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule.

[0215] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers".

[0216] The general formula of this invention includes the contents described above; specifically, when general formula (V-2) is used... When R6 and R7 are different substituents, the general formula further includes the general formula of its isomers. Detailed Implementation

[0217] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0218] Example

[0219] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0220] The determinations were performed using LC-MS with an Agilent 1200 Infinity Series mass spectrometer. The determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C). 18 150×4.6mm chromatographic column) and Waters 2695-2996 high-performance liquid chromatograph (Gimini C) 18 (150×4.6mm chromatographic column).

[0221] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0222] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0223] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0224] Intermediate A

[0225] (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine

[0226] Step 1: 1-(3,5-difluoro-2-hydroxyphenyl) ethyl ketone (200.0 g, 1.2 mol) was dissolved in N,N-dimethylformamide (1.0 L), and methyl 2-bromoacetate (267.0 g, 1.7 mol) and potassium carbonate (241.0 g, 1.7 mol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and 1,8-diazacyclo[5,4,0]undecene-7 (176.8 g, 173.4 mL) was added to the filtrate. The mixture was stirred at 80 °C for 1 hour. The reaction solution was poured into water, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give methyl 5,7-difluoro-3-methylbenzofuran-2-carboxylate (76.0 g, yield 28.8%). MS m / z (ESI): 227 [M+H].

[0227] Step 2: Compound A-2 (40.0 g, 176.9 mmol) was dissolved in tetrahydrofuran (400 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (176.9 mL, 1 M) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Sodium sulfate decahydrate was slowly added to the system at 0 °C to quench the reaction. Extraction was performed with water and ethyl acetate. The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give (5,7-difluoro-3-methylbenzofuran-2-yl)methanol (26.0 g, yield 74.2%). MS m / z (ESI): 199 [M+H].

[0228] Step 3: Compound A-3 (70.0 g, 353.2 mmol) was dissolved in acetonitrile (700 mL), and 2-iodobenzoic acid (148.0 g, 529.8 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 5,7-difluoro-3-methylbenzofuran-2-carboxaldehyde (68.0 g, crude product). MS m / z (ESI): 197 [M+H].

[0229] Step 4: Compound A-4 (70.0 g, 356.9 mmol) was dissolved in N,N-dimethylformamide (700 mL), and (trifluoromethyl)trimethylsilane (101.5 g, 713.7 mmol) and potassium carbonate (73.9 g, 535.3 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Extraction was performed with water and ethyl acetate, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography to give 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethanol (80.0 g, yield 84.2%). MS m / z (ESI): 311 [M+46-H].

[0230] Step 5: Compound A-5 (80.0 g, 300.6 mmol) was dissolved in acetonitrile (1 L), and 2-iodobenzoic acid (168.0 g, 601.1 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroacetone (72.0 g, crude product). MS m / z (ESI): 265 [M+H].

[0231] Step 6: Compound A-6 (72.0 g, 272.6 mmol) was dissolved in ethanol (800 mL). Hydroxylamine hydrochloride (38.0 g, 545.2 mmol) and sodium acetate (55.9 g, 681.4 mmol) were added at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered. Zinc powder (168.7 g, 2.6 mol) and ammonium chloride (138.0 g, 2.6 mol) were added to the filtrate. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove ethanol. Ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography and then separated by chiral supercritical chromatography to obtain intermediate A (20.0 g). MS m / z (ESI): 266 [M+H].

[0232] Intermediate B

[0233] (S)-1-(6,8-difluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroethylamine

[0234] Step 1: 3,5-Difluoropyridine-2-amine (10.0 g, 76.9 mmol) was dissolved in 1,4-dioxane (150 mL), and ethyl 3-bromo-2-oxobutyrate (16.0 g, 76.9 mmol) was added. The mixture was stirred at 100 °C for 16 hours. The solution was filtered to give ethyl 6,8-difluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylate hydrochloride (12.0 g, yield 49.9%). MS m / z (ESI): 241 [M+H].

[0235] Step 2: Compound B-2 (13.0 g, 40.5 mmol) was dissolved in tetrahydrofuran (100 mL), and a tetrahydrofuran solution of lithium aluminum hydride (40 mL, 40.5 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction solution was quenched by slowly adding 2 M sodium hydroxide aqueous solution, extracted with dichloromethane, and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give (6,8-difluoro-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (5.2 g, yield 64.2%). MS m / z (ESI): 199 [M+H].

[0236] Step 3: Compound B-3 (5.2 g, 25.9 mmol) was dissolved in dichloromethane (80 mL). Under nitrogen protection, manganese dioxide (22.6 g, 259.9 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 6,8-difluoro-3-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (5.0 g, yield 98.1%). MS m / z (ESI): 197 [M+H].

[0237] Step 4: Dissolve trifluoromethyltrimethylsilane (5.8 g, 40.8 mmol) in dichloromethane (10 mL), and slowly add compound B-4 (1.0 g, 5.1 mmol) at 0 °C under nitrogen protection. Then add tetrabutylammonium fluoride in tetrahydrofuran solution (0.5 mL, 51.0 μmol, 1 M), and stir at 0 °C for 2 hours. Concentrate the reaction solution under reduced pressure, dissolve the residue in methanol (10 mL), add concentrated hydrochloric acid (1 mL), stir at 45 °C for 4 hours, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 1-(6,8-difluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroethanol-1-ol (0.7 g, yield 51.6%). MS m / z (ESI): 267 [M+H].

[0238] Step 5: Compound B-5 (0.7 g, 2.6 mmol) was dissolved in acetonitrile (10 mL), and 2-iodobenzoic acid (1.1 g, 3.9 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 1-(6,8-difluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroethane-1-one (0.7 g, yield 99.3%). MS m / z (ESI): 283 [M+H+H2O].

[0239] Step 6: Compound B-6 (0.5 g, 1.9 mmol) was dissolved in ethanol (5 mL), and hydroxylamine hydrochloride (921 mg, 13.3 mmol) and sodium acetate (1.6 g, 18.9 mmol) were added. The mixture was stirred at 80 °C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give crude 1-(6,8-difluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroethane-1-one oxime (528 mg, crude). MS m / z (ESI): 280 [M+H].

[0240] Step 7: Compound B-7 (0.53 g, 1.9 mmol) was dissolved in ethanol (5 mL), and water (5 mL), zinc powder (1.2 g, 18.9 mmol), and ammonium chloride (1.1 g, 18.9 mmol) were added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate aqueous solution and dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography and then separated by chiral supercritical chromatography to obtain intermediate B (120 mg). MS m / z (ESI): 266 [M+H].

[0241] Intermediate C

[0242] (R)-1-(6,8-difluoro-3-methylindoleazin-2-yl)-2,2,2-trifluoroethane-1-amine

[0243] Step 1: At room temperature, thionyl chloride (44.8 g, 377.1 mmol) was added to a methanol (500 mL) solution of 3,5-difluoropyridine acid (60.0 g, 377.1 mmol), and the mixture was stirred at 40 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate aqueous solution were added. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3,5-difluoromethylpyridine ester (60.0 g, yield 91.9%). MS m / z (ESI): 174 [M+H].

[0244] Step 2: At room temperature, sodium borohydride (17.5 g, 462.1 mmol) was added to a solution of compound C-2 (80.0 g, 462.1 mmol) in methanol (160 mL) and tetrahydrofuran (320 mL). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. 1 M hydrochloric acid aqueous solution was slowly added to the reaction mixture until the pH reached 5–6. Ethyl acetate was added for extraction, and the organic phase was collected. The mixture was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give (3,5-difluoro-2-pyridyl)methanol (65.0 g, yield 96.9%). MS m / z (ESI): 146 [M+H].

[0245] Step 3: At room temperature, dimethyl sulfoxide (1.6 g, 22.4 mmol) and dichlorosulfoxide (63.9 g, 537.5 mmol) were added to a solution of compound C-3 (65.0 g, 447.9 mmol) in dichloromethane (500 mL). The reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 2-(chloromethyl)-3,5-difluoropyridine (70.0 g, yield 95.5%). MS m / z (ESI): 164 [M+H].

[0246] Step 4: At room temperature, sodium hydride (18.8 g, 470.8 mmol, 60% purity) was added to a solution of ethyl acetoacetate (61.2 g, 470.8 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at 25 °C for 0.5 h under nitrogen protection. Compound C-4 (70.0 g, 428.0 mmol) was added to the reaction mixture, and the mixture was stirred at 60 °C for 16 h under nitrogen protection. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give ethyl 2-((3,5-difluoropyridin-2-yl)methyl)-3-oxobutyrate (70.0 g, yield 63.5%). MS m / z (ESI): 258 [M+H].

[0247] Step 5: At room temperature, Burgess reagent (83.4 g, 349.9 mmol) was added to a tetrahydrofuran (600 mL) solution of compound C-5 (60.0 g, 233.2 mmol). The reaction mixture was stirred at 40 °C for 5 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give ethyl 6,8-difluoro-3-methylindoleazine-2-carboxylate (10.0 g, yield 17.9%). MS m / z (ESI): 240 [M+H].

[0248] Step 6: At -70°C, a solution of diisobutylaluminum hydride tetrahydrofuran (167.2 mL, 1 M) was added dropwise to a tetrahydrofuran solution of compound C-6 (20.0 g, 83.6 mmol) (120 mL). The reaction mixture was stirred at 25°C for 1 hour under nitrogen protection. The reaction mixture was extracted with saturated sodium potassium tartrate aqueous solution and ethyl acetate. The organic phase was collected, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give (6,8-difluoro-3-methylindoleazine-2-yl)methanol (13.0 g, yield 78.8%). MS m / z (ESI): 214 [M+H].

[0249] Step 7: At room temperature, a solution of compound C-7 (13.0 g, 65.9 mmol) in dichloromethane (200 mL) was added with Dys-Martin oxidant (30.8 g, 72.5 mmol), and the mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected. The phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 6,8-difluoro-3-methylindoleazine-2-carboxaldehyde (7.0 g, yield 54.4%). MS m / z (ESI): 196 [M+H].

[0250] Step 8: At room temperature, tetraethyl titanate (10.6 g, 46.6 mmol) was added to a tetrahydrofuran (100 mL) solution of compound C-8 (7.0 g, 35.9 mmol) and tert-butylsulfinamide (5.6 g, 46.6 mmol). The reaction mixture was stirred at 75 °C for 16 hours under nitrogen protection. The reaction mixture was quenched with water, filtered, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give (E)-N-((6,8-difluoro-3-methylindoleazin-2-yl)methylene)-2-methylpropane-2-sulfinamide (5.5 g, yield 51.4%). MS m / z (ESI): 299 [M+H].

[0251] Step 9: Compound C-9 (5.0 g, 16.7 mmol), cesium fluoride (3.8 g, 25.1 mmol), and (trifluoromethyl)trimethylsilane (8.3 g, 58.6 mmol) were mixed in tetrahydrofuran (75 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1.5 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give N-(1-(6,8-difluoro-3-methylindoleazin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfonamide (3.0 g, yield 48.6%). MS m / z (ESI): 368 [M+H].

[0252] Step 10: At room temperature, add 5.0 mL of dioxane hydrochloride solution (4 M) to a solution of compound C-10 (3.0 g, 8.1 mmol) in dichloromethane (50 mL). Stir the reaction mixture at 25 °C for 1 hour under nitrogen protection. Filter the reaction mixture and collect the filter cake. Separate the filter cake using chiral supercritical chromatography to give intermediate C (820 mg, yield 38.1%). MS m / z (ESI): 265 [M+H].

[0253] Intermediate D

[0254] (R)-1-(8-chloro-6-fluoro-3-methylindoleazin-2-yl)-2,2,2-trifluoroethane-1-amine

[0255] Intermediate D was prepared using the same method as intermediate C. MS m / z (ESI): 281 [M+H].

[0256] Intermediate E

[0257] (R)-1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethylamine

[0258] Intermediate E was prepared using the same method as intermediate A. MS m / z (ESI): 282 [M+H].

[0259] intermediate F

[0260] (S)-1-(5,7-difluoro-3-methylbenzothiophene-2-yl)-2,2,2-trifluoroethanol-1-amine

[0261] Step 1: 1-(2,3,5-trifluorophenyl)ethyl-1-one (25.0 g, 143.5 mmol) was dissolved in acetonitrile (200 mL), and methyl 2-mercaptoacetate (24.1 g, 201.1 mmol) and potassium carbonate (39.6 g, 287.1 mmol) were added at room temperature. The mixture was stirred at 80 °C for 10 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Extraction was performed with water and ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain ethyl 5,7-difluoro-3-methylbenzothiophene-2-carboxylate (26.0 g, yield 70.1%). MS m / z (ESI): 257 [M+H].

[0262] Step 2: Compound F-2 (26.0 g, 101.4 mmol) was dissolved in tetrahydrofuran (200 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (49.0 mL, 2.5 M) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Sodium sulfate decahydrate was slowly added to the reaction mixture at 0 °C, filtered, and the filtrate was concentrated under reduced pressure to obtain (5,7-difluoro-3-methylbenzothiophene-2-yl)methanol (16.0 g, crude product). MS m / z (ESI): 215 [M+H].

[0263] Step 3: Compound F-3 (16.0 g, 74.7 mmol) was dissolved in dichloromethane (200 mL), and manganese dioxide (32.5 g, 373.4 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5,7-difluoro-3-methylbenzothiophene-2-carboxaldehyde (15.0 g, crude product). MS m / z (ESI): 213 [M+H].

[0264] Step 4: Compound F-4 (14.0 g, 65.9 mmol) was dissolved in N,N-dimethylformamide (200 mL). (Trifluoromethyl)trimethylsilane (37.5 g, 263.8 mmol) and potassium carbonate (18.2 g, 131.9 mmol) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Extraction was performed with water and ethyl acetate. The organic phase was concentrated under reduced pressure. The crude product was stirred in hydrochloric acid aqueous solution (6 M) for 1 hour, extracted with water and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1-(5,7-difluoro-3-methylbenzothiophene-2-yl)-2,2,2-trifluoroethanol-1-ol (9.0 g, yield 48.3%). MS m / z (ESI): 283 [M+H].

[0265] Step 5: Compound F-5 (7.0 g, 24.8 mmol) was dissolved in dichloromethane (200 mL), and Dys-Martin oxidant (15.8 g, 37.2 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give 1-(5,7-difluoro-3-methylbenzothiophene-2-yl)-2,2,2-trifluoroethane-1-one (6.5 g, yield 93.5%). MS m / z (ESI): 281 [M+H].

[0266] Step 6: Compound F-6 (6.5 g, 23.2 mmol) was dissolved in ethanol (50 mL), and hydroxylamine hydrochloride (6.5 g, 92.8 mmol) and pyridine (9 mL) were added at room temperature. The reaction mixture was stirred at 85 °C for 10 hours. The reaction mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to give (5,7-difluoro-3-methylbenzothiophene-2-yl)-2,2,2-trifluoroethane-1-one oxime (5.5 g, yield 80.3%). MS m / z (ESI): 296 [M+H].

[0267] Step 7: Compound F-7 (4.7 g, 15.9 mmol) was dissolved in ethanol (50 mL) and saturated ammonium chloride aqueous solution (50 mL), and zinc powder (10.3 g, 159.2 mmol) was added. The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove ethanol. Water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. Then, it was separated by chiral supercritical chromatography to obtain intermediate F (1.2 g). MS m / z (ESI): 282 [M+H].

[0268] intermediate G

[0269] (S)-1-(7-chloro-5-fluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethylamine

[0270] Intermediate G was prepared using the same method as intermediate F. MS m / z (ESI): 298 [M+H].

[0271] Example 1

[0272] (R)-1-(4-aminophenyl)-3-(1-(6,8-difluoro-3,4-dihydro-5-oxa-1,2a-diazanaphth-2-yl)-2,2,2-trifluoroethyl)urea

[0273] Step 1: At room temperature, 1,2-dibromoethane (18.8 g, 100.0 mmol) and potassium carbonate (13.8 g, 100.0 mmol) were added to a solution of 2-amino-4,6-difluorophenol (14.5 g, 100.0 mmol) in N,N-dimethylformamide (100 mL), and the mixture was stirred at 80 °C for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 6,8-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (15.1 g, yield 88.2%). MS m / z (ESI): 172 [M+H].

[0274] Step 2: Under ice bath conditions, nitric acid (25 mL) was added in portions to a 100 mL solution of acetic acid containing compounds 1-3 (15.1 g, 88.3 mmol), and the mixture was stirred for 5 hours. The solution was diluted with water, and the product precipitated. The mixture was filtered, the filter cake was dried, and recrystallized to give 6,8-difluoro-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (13.5 g, yield 70.6%). MS m / z (ESI): 217 [M+H].

[0275] Step 3: At room temperature, compounds 1-4 (13.5 g, 62.3 mmol) were dissolved in methanol (50 mL), and wet palladium on carbon (2 g, 5% palladium content) was added. The mixture was hydrogenated and stirred at room temperature for 6 hours. The solution was filtered through diatomaceous earth, and the filtrate was collected and concentrated to give 6,8-difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-amine (10.1 g, yield 87.1%). MS m / z (ESI): 187 [M+H].

[0276] Step 4: At room temperature, compound 1-6 (23.5 g, 162.3 mmol) was added to a 1,4-dioxane solution (10.1 g, 54.1 mmol) of compounds 1-5 (10.1 g, 54.1 mmol) and stirred at 100 °C for 10 hours. The reaction solution was neutralized to alkaline with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1-(6,8-difluoro-3,4-dihydro-5-oxa-1,2-diazaacenaphthene-2-yl)-2,2,2-trifluoroethane-1-one (7.3 g, yield 46.5%). MS m / z (ESI): 293 [M+H].

[0277] Step 5: At room temperature, sodium triacetoxyborohydride (26.4 g, 124.5 mmol) was added in portions to a methanol (100 mL) solution of compounds 1-7 (7.3 g, 24.9 mmol) and ammonium acetate (19.1 g, 249.2 mmol), and the mixture was stirred at 70 °C for 10 hours. The reaction mixture was concentrated, extracted with water and ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 1-(6,8-difluoro-3,4-dihydro-5-oxa-1,2-diazaacenaphthene-2-yl)-2,2,2-trifluoroethane-1-amine (4.6 g, yield 63.1%). MS m / z (ESI): 294 [M+H].

[0278] Step 6: Under ice bath conditions, triphosgene (2.8 g, 9.4 mmol) was added in portions to a solution of compounds 1-8 (2.3 g, 7.8 mmol) and triethylamine (2.4 g, 23.4 mmol) in dichloromethane (30 mL). Under nitrogen protection, the mixture was stirred for 1 hour. Then, compounds 1-9 (2.4 g, 7.8 mmol) were added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain tert-butyl(tert-butyloxycarbonyl)(4-(3-(1-(6,8-difluoro-3,4-dihydro-5-oxa-1,2-diazaacenaphthene-2-yl)-2,2,2-trifluoroethyl)ureo)phenyl)carbamate (1.5 g, yield 30.5%). MS m / z (ESI): 628 [M+H].

[0279] Step 7: Under ice bath conditions, add 5 mL of ethyl hydrochloric acid solution (2M) to a 10 mL solution of compound 1-10 (628 mg, 1.0 mmol) in dichloromethane, and stir for 1 hour under ice bath conditions. Concentrate the reaction solution, neutralize with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, collect the organic phase, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify by silica gel column chromatography, and then resolve by chiral supercritical chromatography to obtain Example 1 (130 mg). MS m / z (ESI): 428 [M+H].

[0280] The following embodiments can also be synthesized using the following methods:

[0281] Example 18

[0282] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1',2,3,3',5,6-hexahydrospiro[pyrrolo-4,2'-pyrrolo[2,3-b]pyridin]-5'-yl)urea

[0283] Step 1: At room temperature, 2-amino-3-iodo-5-bromopyridine (8.0 g, 26.8 mmol), 4,4,5,5-tetramethyl-2-((tetrahydro-4H-pyran-4-yl)methyl)-1,3,2-dioxoborane (6.0 g, 26.8 mmol), and potassium carbonate (7.4 g, 53.5 mmol) were added to a solution of water (20 mL) and dioxane (100 mL), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (979 mg, 1.3 mmol). The mixture was stirred at 100 °C for 6 hours under nitrogen protection. The reaction solution was cooled, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 5-bromo-3-((tetrahydro-4H-pyran-4-yl)methyl)pyridine-2-amine (4.5 g, yield 62.4%). MS m / z (ESI): 239 [M+H].

[0284] Step 2: At room temperature, compound 18-2 (4.0 g, 14.9 mmol) was added to concentrated sulfuric acid (30 mL), and the reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate, washed successively with 6 M sodium hydroxide aqueous solution and saturated saline solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5'-bromo-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrole[2,3-b]pyridine] (2.4 g, yield 60.0%). MS m / z (ESI): 239 [M+H].

[0285] Step 3: At room temperature, 4-methoxybenzyl chloride (2.8 g, 17.8 mmol) and sodium hydride (713 mg, 17.8 mmol, 60% purity) were added sequentially to a solution of compound 18-3 (2.4 g, 8.9 mmol) in N,N-dimethylformamide (30 mL). The mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5'-bromo-1'-(4-methoxybenzyl)-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrolo[2,3-b]pyridine] (1.7 g, yield 49.0%). MS m / z (ESI): 389 [M+H].

[0286] Step 4: At room temperature, a solution of compound 18-4 (400 mg, 1.0 mmol), cesium carbonate (837 mg, 2.6 mmol), benzophenone imine (372 mg, 2.1 mmol) in dioxane (10 mL) was mixed with tris(dibenzylacetone)dipalladium (70 mg, 77.1 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (178 mg, 308.3 μmol). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give N-(1'-(4-methoxybenzyl)-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrolo[2,3-b]pyridin]-5'-yl)-1,1-diphenyltoluidine (100 mg, yield 19.8%). MS m / z(ESI): 490 [M+H].

[0287] Step 5: At room temperature, add 1 mL of dioxane hydrochloride solution (4 M) to a solution of compound 18-5 (100 mg, 204.2 μmol) in dichloromethane (4 mL), and stir at 25 °C for 1 hour. Pour the reaction solution into a saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, collect the organic phase, dry to anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography to give 1'-(4-methoxybenzyl)-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrolo[2,3-b]pyridine]-5'-amine (30 mg, yield 45.1%). MS m / z (ESI): 326 [M+H].

[0288] Step 6: At room temperature, phenyl chloroformate (16 mg, 101.4 μmol) was added to a 2 mL solution of compound 18-6 (30 mg, 92.2 μmol) in tetrahydrofuran, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give phenyl (1'-(4-methoxybenzyl)-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrolo[2,3-b]pyridin]-5'-yl)carbamate (40 mg, crude product). MS m / z (ESI): 491 [M+H].

[0289] Step 7: At room temperature, intermediate A (37 mg, 138.0 μmol) was added to a pyridine (2 mL) solution of compound 18-7 (41 mg, 92.0 μmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1'-(4-methoxybenzyl)-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrolo[2,3-b]pyridine]-5'-yl)urea (40 mg, yield 70.5%). MS m / z (ESI): 617 [M+H].

[0290] Step 8: At room temperature, trifluoromethanesulfonic acid (0.1 mL) was added to a trifluoroacetic acid (1 mL) solution of compound 18-8 (40 mg, 64.9 μmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and separated by high performance liquid chromatography to obtain Example 18 (5 mg). MS m / z (ESI): 467 [M+H].

[0291] 1 H NMR(400MHz,MeOD)δ7.78(d,J=2.0Hz,1H),7.50–7.48(m,1H),7.25–7.17(m,1H),7.09–7.02(m,1H),5.97(q,J=7 .8Hz,1H),3.90–3.83(m,2H),3.66–3.60(m,2H),3.10(s,2H),2.32(s,3H),1.90–1.82(m,2H),1.81–1.72(m,2H).

[0292] Example 61

[0293] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine]-5'-yl)urea

[0294] Step 1: At room temperature, 1,1-bis(diphenylphosphine)diberane (367 mg, 501.8 μmol) was added to a solution of 5-bromo-3-iodopyridin-2-amine (3.0 g, 10.0 mmol), 2-(cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.0 g, 10.0 mmol), potassium carbonate (2.8 g, 20.1 mmol), water (2 mL), and dioxane (10 mL). The mixture was stirred at 100 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain 5-bromo-3-(cyclobutylmethyl)pyridin-2-amine (850 mg, yield 35.4%). MS m / z (ESI): 239 [M+H].

[0295] Step 2: At room temperature, compound 61-2 (800 mg, 3.4 mmol) was added to concentrated sulfuric acid (8 mL), and the solution was stirred at 25 °C for 16 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate (400 mL), washed successively with 6 M sodium hydroxide aqueous solution (200 mL) and saturated brine (50 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain 5'-bromo-1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine] (300 mg, yield 37.5%). MS m / z (ESI): 239 [M+H].

[0296] Step 3: At room temperature, 3,4-dimethoxybenzyl chloride (351 mg, 1.9 mmol) and sodium hydride (75 mg, 1.9 mmol, 60% purity) were added sequentially to a solution of compound 61-3 (300 mg, 1.2 mmol) in N,N-dimethylformamide (30 mL). The mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution (150 mL), extracted with ethyl acetate, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 5'-bromo-1'-(3,4-dimethoxybenzyl)-1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine] (450 mg, yield 92.1%). MS m / z (ESI): 389 [M+H].

[0297] Step 4: At room temperature, tris(dibenzylacetone)dipalladium (79 mg, 86.7 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (201 mg, 346.8 μmol) were added to a solution of compound 61-4 (450 mg, 1.2 mmol), cesium carbonate (941 mg, 2.9 mmol), and benzophenone imine (314 mg, 1.7 mmol) in dioxane (10 mL). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was cooled, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain N-(1'-(3,4-dimethoxybenzyl)-1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine]-5'-yl)-1,1-diphenyltoluidine (300 mg, yield 53.0%). MS m / z(ESI): 490 [M+H].

[0298] Step 5: At room temperature, a solution of dioxane in hydrochloric acid (4M, 2mL) was added to a solution of compound 61-5 (300mg, 612.7μmol) in dichloromethane (6mL), and the mixture was stirred at 25°C for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (30mL), extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to give 1'-(3,4-dimethoxybenzyl)-1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine]-5'-amine (80mg, yield 40.1%). MS m / z (ESI): 326 [M+H].

[0299] Step 6: At room temperature, p-nitrophenyl chlorocarbamate (50 mg, 246.6 μmol) was added to a tetrahydrofuran (4 mL) solution of compound 61-6 (80 mg, 246.6 μmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give 4-nitrophenyl (1'-(3,4-dimethoxybenzyl)-1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine]-5'-yl)carbamate (120 mg, crude product). MS m / z (ESI): 491 [M+H] + .

[0300] Step 7: At room temperature, intermediate A (34 mg, 130.0 μmol) was added to a pyridine (2 mL) solution of compound 61-7, and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1'-(3,4-dimethoxybenzyl)-1',3'-dihydrospiro[cyclobutane-1,2'-pyrrolo[2,3-b]pyridine]-5'-yl)urea (60 mg, yield 74.8%). MS m / z (ESI): 617 [M+H].

[0301] Step 8: At room temperature, trifluoromethanesulfonic acid (0.2 mL) was added to a 2 mL solution of compound 61-8 (80 mg, 130.0 μmol) in trifluoroacetic acid. The mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was concentrated, separated by high performance liquid chromatography, and lyophilized to obtain Example 61 (35 mg). MS m / z (ESI): 467 [M+H].

[0302] 1 H NMR(400MHz,DMSO)δ8.39(s,1H),7.89–7.62(m,3H),7.45–7.40(m,3H),6.05–5.97(m,1 H),3.16(s,2H),2.29(s,3H),2.28–2.21(m,2H),2.08–2.00(m,2H),1.70–1.58(m,2H).

[0303] Example 74

[0304] (R)-1-[1-(5,7-difluoro-3-methyl-benzofuran-2-yl)-2,2,2-trifluoro-ethyl]-3-(4-methyl-5-oxo-2,3-dihydro-1H-pyrido[2,3-e][1,4]diazepine-7-yl)urea

[0305] Step 1: Under ice bath conditions, 2-chloro-5-nitronicotinic acid (5.0 g, 24.7 mmol) and tert-butyl (2-(methylamino)ethyl)aminocarbamate (4.3 g, 24.7 mmol) were dissolved in dichloromethane (50 mL), and a solution of 1-butylphosphine in ethyl acetate (23.5 g, 37.1 mmol, 50% purity) and diisopropylethylamine (9.6 g, 74.1 mmol) were added. The mixture was stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give tert-butyl (2-(2-chloro-N-methyl-5-nitronicotinamide)ethyl)aminocarbamate (2.5 g, yield 28.2%). MS m / z (ESI): 359 [M+H].

[0306] Step 2: Under ice bath conditions, a solution of dioxane (10 mL) containing 2.0 g (5.6 mmol) of compound 74-2 was added to a solution of dichloromethane (10 mL) and dioxane hydrochloride (20 mL, 4 M). The mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated to give N-(2-aminoethyl)-2-chloro-N-methyl-5-nitro-pyridine-3-carboxylic acid (1.7 g, yield 103.0%). MS m / z (ESI): 259 [M+H].

[0307] Step 3: At room temperature, N,N-diisopropylethylamine (3.7 g, 28.8 mmol) was added to a 2 mL solution of compound 74-3 (1.7 g, 5.7 mmol) in N,N-dimethylformamide, and the mixture was stirred at 90 °C for 13 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give 4-methyl-7-nitro-2,3-dihydro-1H-pyridano[2,3-e][1,4]diazepine-5-one (500 mg, yield 39.1%). MS m / z (ESI): 223 [M+H].

[0308] Step 4: At room temperature, di-tert-butyl dicarbonate (0.6 g, 2.7 mmol) was added to a methanol solution (2 mL) of compound 74-4 (0.5 g, 2.2 mmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain tert-butyl 4-methyl-7-nitro-5-oxo-2,3-dihydropyrido[2,3-e][1,4]diazepine-1-carboxylic acid (500 mg, yield 68.9%). MS m / z (ESI): 323 [M+H].

[0309] Step 5: At room temperature, wet palladium on carbon (0.1 g, 10% purity) was added to a 2 mL solution of compound 74-5 (0.5 g, 1.6 mmol) in ethyl acetate, and the mixture was stirred for 0.5 hours under a hydrogen atmosphere. The mixture was filtered, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give tert-butyl 7-amino-4-methyl-5-oxo-2,3-dihydropyrido[2,3-e][1,4]diazepine-1-carboxylic acid (400 mg, yield 88.2%). MS m / z (ESI): 293 [M+H].

[0310] Step 6: At room temperature, phenyl chloroformate (0.4 g, 2.7 mmol) was added to a 10 mL solution of compound 74-6 (0.4 g, 1.4 mmol) in dichloromethane, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give 4-methyl-5-oxo-7-(phenoxycarbamoamino)-2,3-dihydropyrido[2,3-e][1,4]diazepine-1-carboxylic acid tert-butyl ester (400 mg, yield 70.8%). MS m / z (ESI): 413 [M+H].

[0311] Step 7: At room temperature, intermediate A (200 mg, 0.7 mmol) was added to a pyridine solution (10 mL) of compound 74-7 (311 mg, 0.7 mmol), and the mixture was stirred at 80 °C for 15 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give (R)-7-(3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)ureo)-4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazaphen-1-carboxylic acid tert-butyl ester (400 mg, yield 90.8%). MS m / z (ESI): 584 [M+H].

[0312] Step 8: At room temperature, compound 74-8 (400 mg, 0.7 mmol) was added to a dioxane hydrochloride solution (4 mL, 4 M), and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was separated by high performance liquid chromatography to obtain Example 74 (200 mg). MS m / z (ESI): 484 [M+H].

[0313] 1H NMR (400MHz, DMSO-d6) δ8.38 (s, 1H), 8.15 (d, 1H, J = 2.8Hz), 7.97 (d, 1H, J = 2.8Hz), 7.67 (d, 1H, J = 9.2Hz), 7. 42(m,2H),6.79(t,1H,J=4Hz),6.04(m,1H),3.49–3.61(m,2H),3.41–3.45(m,2H),3.03(s,3H),2.30(s,3H).

[0314] Example 77

[0315] 1-[(1R)-1-(5,7-difluoro-3-methyl-benzofuran-2-yl)-2,2,2-trifluoro-ethyl]-3-(4-methyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazono-7-yl)urea

[0316] Step 1: At room temperature, sodium hydride (1.1 g, 27.6 mmol, 60% purity) was added to a solution of 2-chloro-5-nitronicotinic acid (1.4 g, 6.9 mmol) and tert-butyl N-2-hydroxyethyl-N-methylcarbamate (1.2 g, 6.9 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into ice water, the pH was adjusted to neutral, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography to give 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-nitro-pyridine-3-carboxylic acid (2.5 g, crude product). MS m / z (ESI): 342 [M+H].

[0317] Step 2: Compound 77-2 (2.5 g, 7.3 mmol) was dissolved in dioxane hydrochloride solution (20 mL, 4 M) at room temperature and stirred for 1 hour. The reaction solution was concentrated to give 2-[2-(methylamino)ethoxy]-5-nitro-pyridine-3-carboxylic acid hydrochloride (2.0 g, crude product). MS m / z (ESI): 242 [M+H].

[0318] Step 3: At room temperature, N,N-diisopropylethylamine (2.8 g, 21.6 mmol) and 1-butylphosphine (7.8 g, 10.8 mmol, 50% purity) were added sequentially to a tetrahydrofuran solution (20 mL) of compound 77-3 (2.0 g, 7.2 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with dichloromethane, the organic phase was concentrated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 4-methyl-7-nitro-2,3-dihydropyrido[3,2-f][1,4]diazepine-5-one (500 mg, yield 31.1%). MS m / z (ESI): 224 [M+H].

[0319] Step 4: At room temperature, wet palladium on carbon (100 mg, 10% purity) was added to a tetrahydrofuran solution (10 mL) of compound 77-4 (500 mg, 2.2 mmol), and the mixture was stirred for 1 hour under a hydrogen atmosphere. The solution was filtered, and the filtrate was concentrated to give 7-amino-4-methyl-2,3-dihydropyrido[3,2-f][1,4]diazepine-5-one (240 mg, 55% yield). MS m / z (ESI): 194 [M+H].

[0320] Step 5: At room temperature, compound 77-5 (100 mg, 0.5 mmol) and phenyl chloroformate (81 mg, 0.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give N-(4-methyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]diazepine-7-yl)phenyl carbamate (90 mg, yield 50%). MS m / z (ESI): 313 [M+H].

[0321] Step 6: At room temperature, compound 77-6 (90 mg, 0.3 mmol) and intermediate A (76 mg, 0.3 mmol) were dissolved in pyridine (10 mL), and stirred at 90 °C for 3 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain Example 77 (50 mg). MS m / z (ESI): 485 [M+H].

[0322] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.83(s,1H),7.80(s,1H),7.27(m,2H),7.00(d,1H ,J=2H),6.04(m,1H),4.63(t,2H,J=4.8H),3.67–3.75(m,2H),3.46(s,3H),2.30(s,3H).

[0323] Example 83

[0324] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1,2,3,5-tetrahydropyrido[2,3-e][1,4]thiazide-7-yl)urea

[0325] Step 1: Under ice bath conditions, 5-bromo-3-(chloromethyl)pyridine-2-amine hydrochloride (6.0 g, 23.3 mmol) and methyl 2-mercaptoacetate (3.0 g, 27.9 mmol) were dissolved in N,N-dimethylformamide (45 mL), and sodium hydride (2.8 g, 70.0 mmol, 60% purity) was added. The mixture was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was poured into ice water, filtered, and the filter cake was collected to obtain 7-bromo-1,5-dihydropyridine[2,3-e][1,4]tiazepine-2(3H)-one (4.5 g, yield 74.6%), which was directly used for the next step of the reaction. MS m / z (ESI): 258 [M+H].

[0326] Step 2: At room temperature, 3,4-dimethoxybenzyl chloride (1.7 g, 9.3 mmol) and sodium hydride (370 mg, 9.3 mmol, 60% purity) were added sequentially to a solution of compound 83-2 (2.0 g, 7.7 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 7-bromo-1-(3,4-dimethoxybenzyl)-1,5-dihydropyridine[2,3-e][1,4]tiazepine-2(3H)-one (1.8 g, yield 56.9%). MS m / z (ESI): 409 [M+H].

[0327] Step 3: At room temperature, borane dimethyl sulfide (2.6 mL, 10 M) was added to a tetrahydrofuran (20 mL) solution of compound 83-3 (1.8 g, 4.4 mmol), and the mixture was stirred at 70 °C for 6 hours under nitrogen protection. The reaction was quenched with methanol, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give 7-bromo-1-(3,4-dimethoxybenzyl)-1,2,3,5-tetrahydropyridine[2,3-e][1,4]tiazepine (1.2 g, yield 69.0%). MS m / z (ESI): 395 [M+H].

[0328] Step 4: At room temperature, tris(dibenzylacetone)dipalladium (87 mg, 95 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (220 mg, 379 μmol) were added to a solution of compound 83-4 (500 mg, 1.3 mmol), cesium carbonate (1.0 g, 3.2 mmol), and benzophenone imine (344 mg, 1.9 mmol) in dioxane (8 mL). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to give N-(1-(3,4-dimethoxybenzyl)-1,2,3,5-tetrahydropyridin[2,3-e][1,4]thiazol-7-yl)-1,1-diphenyltoluidine (100 mg, yield 19.8%). MS m / z (ESI): 496 [M+H].

[0329] Step 5: At room temperature, add 461 μL of dioxane hydrochloride solution (4 M) to a solution of compound 83-5 (70 mg, 141 μmol) in dichloromethane (1.5 mL), and stir at 25 °C for 1 hour. Pour the reaction solution into a saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, collect the organic phase, dry to anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography to give 1-(3,4-dimethoxybenzyl)-1,2,3,5-tetrahydropyridine[2,3-e][1,4]thiazepine-7-amine (15 mg, yield 32.0%). MS m / z (ESI): 332 [M+H].

[0330] Step 6: At room temperature, phenyl chloroformate (9 mg, 45.3 μmol) was added to a 2 mL solution of compound 83-6 (15 mg, 45.3 μmol) in tetrahydrofuran, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give 4-nitrophenyl (1-(3,4-dimethoxybenzyl)-1,2,3,5-tetrahydropyridine[2,3-e][1,4]thiazepine-7-yl)carbamate (22 mg, crude product). MS m / z (ESI): 497 [M+H].

[0331] Step 7: At room temperature, intermediate A (12 mg, 44.3 μmol) was added to a pyridine (2 mL) solution of compound 83-7 (22 mg, 44.3 μmol), and the mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1'-(4-methoxybenzyl)-1',2,3,3',5,6-hexahydrospiro[pyran-4,2'-pyrrolo[2,3-b]pyridine]-5'-yl)urea (25 mg, yield 90.6%). MS m / z (ESI): 623 [M+H].

[0332] Step 8: At room temperature, trifluoromethanesulfonic acid (0.1 mL) was added to a solution of compound 83-8 (25 mg, 40.2 μmol) in 1.0 mL of trifluoroacetic acid, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated, and the crude product was separated by high performance liquid chromatography to obtain Example 83 (5 mg). MS m / z (ESI): 473 [M+H].

[0333] Example 84

[0334] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(4,4-dioxo-1,2,3,5-tetrahydropyrido[2,3-e][1,4]thiamethoxam-7-yl)urea

[0335] Step 1: At room temperature, m-chloroperoxybenzoic acid (818 mg, 3.8 mmol, 80% purity) was added to a dichloromethane (10 mL) solution of compound 83-4 (600 mg, 1.5 mmol) under nitrogen protection and stirred at 25 °C for 2 hours. The reaction solution was diluted with dichloromethane and washed successively with saturated sodium bicarbonate aqueous solution, saturated sodium bisulfite aqueous solution, and saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 7-bromo-1-(3,4-dimethoxybenzyl)-1,2,3,5-tetrahydropyridine[2,3-e][1,4]tiazepine 4,4-dioxide (380 mg, yield 58.6%). MS m / z (ESI): 427 [M+H].

[0336] Step 2: At room temperature, tris(dibenzylacetone)dipalladium (61 mg, 66.7 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (154 mg, 266.8 μmol) were added to a solution of compound 84-1 (380 mg, 889.3 μmol), cesium carbonate (724 mg, 2.2 mmol), and benzophenone imine (242 mg, 1.3 mmol) in dioxane (8 mL). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give 1-(3,4-dimethoxybenzyl)-7-((diphenylmethylene)amino)-1,2,3,5-tetrahydropyridine[2,3-e][1,4]tiazepine 4,4-dioxide (100 mg, yield 19.9%). MS m / z (ESI): 528 [M+H].

[0337] Step 3: At room temperature, a solution of dichloromethane (4 mL) containing 330 mg (625.4 μmol) of compound 84-2 was added to a solution of dioxane (4 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 7-amino-1-(3,4-dimethoxybenzyl)-1,2,3,5-tetrahydropyridine[2,3-e][1,4]tiazepine 4,4-dioxide (15 mg, yield 32.0%). MS m / z (ESI): 364 [M+H].

[0338] Step 4: At room temperature, phenyl chloroformate (111 mg, 550.3 μmol) was added to a 2 mL solution of compound 84-3 (200 mg, 550.3 μmol) in tetrahydrofuran, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to obtain 4-nitrophenyl (1-(3,4-dimethoxybenzyl)-4,4-dioxide-1,2,3,5-tetrahydropyridine[2,3-e][1,4]thiazepine-7-yl)carbamate (290 mg, crude product). MS m / z (ESI): 529 [M+H].

[0339] Step 5: At room temperature, intermediate A (145 mg, 548.7 μmol) was added to a pyridine (5 mL) solution of compound 84-4 (290 mg, 548.7 μmol), and the mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1-(3,4-dimethoxybenzyl)-4,4-dioxide-1,2,3,5-tetrahydropyridine[2,3-e][1,4]thiazepine-7-yl)urea (120 mg, yield 33.4%). MS m / z (ESI): 655 [M+H].

[0340] Step 6: At room temperature, trifluoromethanesulfonic acid (0.5 mL) was added to a 5 mL solution of compound 84-5 (120 mg, 183.3 μmol) in trifluoroacetic acid, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated, and the crude product was separated by high performance liquid chromatography to obtain Example 84 (53 mg). MS m / z (ESI): 505 [M+H].

[0341] The following embodiments can also be synthesized using the following methods:

[0342] Example 88

[0343] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(3'-oxospiro[cyclopropane-1,1'-isoindolyl]-6'-yl)urea

[0344] Step 1: At room temperature, tris(dibenzylacetone)dipalladium (63 mg, 69.3 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (160 mg, 277.2 μmol) were added to a solution of 6'-bromospiro[cyclopropane-1,1'-isoindoline]-3'-one (220 mg, 924.1 μmol), cesium carbonate (753 mg, 2.3 mmol), and benzophenone imine (251 mg, 1.4 mmol) in dioxane (5 mL). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain 6'-((diphenylmethylene)amino)spiro[cyclopropane-1,1'-isoindoline]-3'-one (220 mg, yield 70.4%). MS m / z (ESI): 339 [M+H].

[0345] Step 2: At room temperature, a solution of compound 88-2 (220 mg, 650.1 μmol) in dichloromethane (4 mL) was added to a solution of dioxane hydrochloride (2 mL, 4 M), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 6'-aminospiro[cyclopropane-1,1'-isoindoline]-3'-one (90 mg, yield 79.4%). MS m / z (ESI): 174 [M+H].

[0346] Step 3: At room temperature, p-nitrophenyl chloroformate (58 mg, 287.0 μmol) was added to a 2 mL solution of compound 88-3 (50 mg, 287.0 μmol) in tetrahydrofuran, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give 4-nitrophenyl (3'-oxospirocyclopropane-1,1'-isoindoline]-6'-yl)carbamate (97 mg, crude product). MS m / z (ESI): 340 [M+H].

[0347] Step 4: At room temperature, intermediate A (76 mg, 285.9 μmol) was added to a pyridine (3 mL) solution of compound 88-4 (97 mg, 285.9 μmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain Example 88 (35 mg). MS m / z (ESI): 466 [M+H].

[0348] 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.48(s,1H),7.85(d,J=9.4Hz,1H),7.55(d,J=8.2Hz,1H),7.47–7.36(m,3H ),7.26(dd,J=8.2,1.8Hz,1H),6.06(p,J=8.2Hz,1H),2.31(s,3H),1.43(q,J=5.0Hz,2H),1.32(q,J=5.0Hz,2H).

[0349] Example 99

[0350] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(1,1-dioxo-3,4-dihydro-2H-[1,4]oxothione[2,3-b]pyridin-8-yl)urea

[0351] Step 1: 2-Chloro-3-fluoro-5-bromopyridine (200 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (20 mL). 3-Mercapto-1-propanol (93 mg, 1.0 mmol) and sodium tert-butoxide (192 mg, 2.0 mmol) were added at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction solution was poured into water, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give 8-bromo-3,4-dihydro-2H-[1,4]oxathiono[2,3-b]pyridine (292 mg, yield 80.0%). MS m / z (ESI): 245 [M+H].

[0352] Step 2: Compound 99-2 (292 mg, 0.8 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (324 mg, 1.6 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was extracted with water and ethyl acetate, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography to give 8-bromo-3,4-dihydro-2H-[1,4]oxathiazo[2,3-b]pyridine 1,1-dioxide (222 mg, 100% yield). MS m / z (ESI): 278 [M+H].

[0353] Step 3: Compound 99-3 (222 mg, 0.8 mmol) was dissolved in 1,4-dioxane (10 mL), and benzophenone imine (217 mg, 1.2 mmol), tris(dibenzylacetone)dipalladium (146 mg, 159.6 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (92 mg, 159.6 μmol), and cesium carbonate (780 mg, 2.4 mmol) were added. Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give 8-((diphenylmethylene)amino)-3,4-dihydro-2H-[1,4]oxathiopheno[2,3-b]pyridine-1,1-dioxide (200 mg, yield 66.0%). MS m / z (ESI): 379 [M+H].

[0354] Step 4: Compound 99-4 (200 mg, 0.5 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Extraction was performed with water and ethyl acetate, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography to give 8-amino-3,4-dihydro-2H-[1,4]oxathiophene[2,3-b]pyridine-1,1-dioxide (113 mg, 100% yield). MS m / z (ESI): 215 [M+H].

[0355] Step 5: Compound 99-5 (100 mg, 0.5 mmol) was dissolved in tetrahydrofuran (10 mL), and phenyl p-nitrochlorocarbamate (101 mg, 0.5 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The filtrate was concentrated to give 4-nitrophenyl (1,1-dioxide-3,4-dihydro-2H-[1,4]oxathiopheno[2,3-b]pyridin-8-yl)carbamate (200 mg, crude product). MS m / z (ESI): 380 [M+H].

[0356] Step 6: Compound 99-6 (200 mg, 0.5 mmol) was dissolved in pyridine (10 mL), and intermediate A (124 mg, 0.5 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated, and the crude product was separated by high performance liquid chromatography to obtain Example 99 (18 mg). MS m / z (ESI): 506 [M+H].

[0357] 1H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.56(d,J=2.5Hz,1H),8.36(d,J=2.5Hz,1H),8.05(m,1H),7.4 7–7.40(m,2H),6.13–6.09(m,1H),4.25–4.22(m,2H),3.62–3.59(m,2H),2.32(s,3H),2.28(s,2H).

[0358] Example 106

[0359] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-5'-yl)urea

[0360] Step 1: 5'-Bromospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (3.0 g, 12.6 mmol) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (602 mg, 25.1 mmol, 60% purity) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Then, 2-(trimethylsilyl)ethoxymethyl chloride (3.1 g, 18.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the product 5'-bromo-1'-(2-trimethylsilylethoxymethyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'-one (3.5 g, 75.5% yield). MS m / z(ESI): 370 [M+H].

[0361] Step 2: Compound 106-2 (3.5 g, 9.5 mmol) was dissolved in 1,4-dioxane (60 mL). Diphenylmethylimine (2.6 g, 14.2 mmol), palladium acetate (213 mg, 947.7 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.1 g, 1.9 mmol), and cesium carbonate (6.2 g, 19.0 mmol) were added sequentially at room temperature. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction solution was extracted with water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 5'-(diphenylmethylimino)-1'-(2-trimethylsilylethoxymethyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'-one (2.0 g, yield 44.9%). MS m / z(ESI): 470 [M+H].

[0362] Step 3: Compound 106-3 (1.9 g, 4.0 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL). Dioxane hydrochloride solution (15 mL, 4 M) was added at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction solution was extracted with water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5'-amino-1'-(2-trimethylsilylethoxymethyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'-one (1.2 g, crude). MS m / z (ESI): 306 [M+H].

[0363] Step 4: Dissolve intermediate A (1.0 g, 3.8 mmol) in tetrahydrofuran (20 mL), add triethylamine (572 mg, 5.7 mmol) at 0 °C, then add triphosgene (895 mg, 3.1 mmol), and stir at 0 °C for 1 hour. Filter the reaction solution, and adjust the pH of the filtrate to 8 with N,N-diisopropylethylamine to obtain a crude solution of compound 106-5. Dissolve compound 106-4 (689 mg, 2.6 mmol) in tetrahydrofuran (12 mL), slowly add the crude solution of 106-5 (12 mL), then add N,N-diisopropylethylamine (338 mg, 2.6 mmol), and stir the reaction solution at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 1-[1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl]-3-[2'-oxo-1'-(2-trimethylsilylethoxymethyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-5'-yl]urea (1.0 g, yield 64.0%). MS m / z (ESI): 597 [M+H].

[0364] Step 5: Compound 106-6 (500 mg, 838.0 μmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (96 mg, 838.0 μmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and methanol (8 mL) and ammonia (0.8 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain Example 106 (120 mg). MS m / z (ESI): 467 [M+H].

[0365] 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.57(s,1H),7.97(d,J=2.3Hz,1H),7.82(d,J=9.4Hz,1H),7.48(d,J=2.3Hz ,1H),7.44–7.37(m,2H),6.04(p,J=8.3Hz,1H),2.31–2.28(m,3H),1.64–1.58(m,2H),1.51(q,J=4.2,3.7Hz,2H).

[0366] Examples 107-125 were prepared using the same method as in Example 106:

[0367] Example 126

[0368] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(5'-oxo-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0369] Step 1: Under ice bath conditions, sodium hydride (187 mg, 4.7 mmol, 60% purity) and p-methoxybenzyl chloride (732 mg, 4.7 mmol) were added sequentially to N,N-dimethylformamide (20 mL) containing 1.0 g, 4.7 mmol of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, filtered, and dried to obtain 1.3 g, 83.1% yield of 3-bromo-6-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. MS m / z (ESI): 334 [M+H].

[0370] Step 2: Compound 126-2 (1.3 g, 3.9 mmol) was dissolved in N,N-dimethylformamide (50 mL) under ice bath conditions. Sodium hydride (312 mg, 7.8 mmol, 60% purity) and 1,3-dibromopropane (1.2 g, 5.8 mmol) were added sequentially, and the mixture was stirred under ice bath conditions for 2 hours. The reaction was quenched with ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the product 3'-bromo-6'-(4-methoxybenzyl)spiro[cyclobutane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (700 mg, yield 48.0%). MS m / z (ESI): 374 [M+H].

[0371] Step 3: Compound 126-3 (700 mg, 1.9 mmol) was dissolved in 1,4-dioxane (20 mL), and diphenylmethylimine (339 mg, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (171 mg, 187.6 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (233 mg, 375.1 μmol), and cesium carbonate (1.2 g, 3.8 mmol) were added sequentially. Under nitrogen protection, the mixture was stirred at 100 °C for 10 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 3'-((diphenylmethylene)amino)-6'-(4-methoxybenzyl)spiro[cyclobutane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (400 mg, yield 45.0%). MS m / z(ESI): 474 [M+H].

[0372] Step 4: Compound 126-4 (300 mg, 633.5 μmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride solution (791 μL, 4 M) was added. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filter cake was dried to give 3'-amino-6'-(4-methoxybenzyl)spiro[cyclobutane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (100 mg, yield 51.1%). MS m / z (ESI): 310 [M+H].

[0373] Step 5: Compound 126-5 (62 mg, 200.4 μmol) was dissolved in dichloromethane (5 mL), and p-nitrochlorophenyl ester (40 mg, 200.4 μmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated to obtain 4-nitrophenyl (6'-(4-methoxybenzyl)-5'-oxo-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)carbamate (95 mg, crude product).

[0374] Step 6: Compound 126-6 (95 mg, crude) was dissolved in pyridine (5 mL), and intermediate A (53 mg, 200.2 μmol) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to obtain 1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(4-methoxybenzyl)-5'-oxo-5',6'-dihydrospirocyclic[cyclobutane-1,7'-pyrrolo[3,4-b]pyridin]-3'-yl)urea (120 mg, crude). MS m / z (ESI): 601 [M+H].

[0375] Step 7: Compound 126-7 (120 mg, 199.8 μmol) was dissolved in trifluoroacetic acid (10.0 mL) and stirred at 70 °C for 1 hour. The reaction solution was concentrated, and the crude product was separated by high performance liquid chromatography to obtain Example 126 (28 mg). MS m / z (ESI): 481 [M+H].

[0376] Example 127

[0377] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0378] Step 1: 5-Bromo-2-methylnicotinic acid methyl ester (25.0 g, 108.7 mmol) was dissolved in trifluorotoluene (250 mL), and azobisisobutyronitrile (3.3 g, 20.0 mmol) and N-bromosuccinimide (21.9 g, 122.8 mmol) were added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 5-bromo-2-(bromomethyl)nicotinic acid methyl ester (23.1 g, yield 68.8%). MS m / z (ESI): 308 [M+H].

[0379] Step 2: Compound 127-2 (18.9 g, 61.2 mmol) was dissolved in ethanol (200 mL), and 2,4-dimethoxybenzylamine (45.9 g, 274.6 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated, slurry was added with diethyl ether, and the solid was collected by filtration to give 3-bromo-6-(3,4-dimethylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (16.8 g, yield 75.8%). MS m / z (ESI): 331 [M+H].

[0380] Step 3: Compound 127-3 (1.0 g, 2.7 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (330 mg, 8.3 mmol, 60% purity) and 1,2-dibromoethane (1.0 g, 5.5 mmol) were added under ice bath conditions. The mixture was stirred at room temperature for 1 hour, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3-bromo-6-(3,4-dimethylbenzyl)spiro[cyclopropane-1,7-pyrrolo[3,4-b]pyridine]-5(6H)-one (140 mg, yield 13.1%). MS m / z (ESI): 390 [M+H].

[0381] Step 4: Compound 127-4 (140 mg, 0.4 mmol) was dissolved in 1,4-dioxane (5 mL), and diphenylmethylimine (163 mg, 1.0 mmol), tris(dibenzylidene indacetone)dipalladium(0) (66 mg, 71.9 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (208 mg, 359.7 μmol), and cesium carbonate (352 mg, 1.1 mmol) were added. The mixture was stirred at 100 °C for 10 hours under nitrogen protection. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain 6'-(3,4-dimethylbenzyl)-3'-(diphenylmethylene)amino)spiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (140 mg, yield 79.5%). MS m / z(ESI): 490 [M+H].

[0382] Step 5: Compound 127-5 (140 mg, 286.0 μmol) was dissolved in dichloromethane (2 mL), and dioxane hydrochloride solution (791 μL, 4 M) was added. The mixture was stirred at room temperature for 1 hour, and filtered to obtain 3'-amino-6'-(3,4-dimethylbenzyl)spiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (50 mg, crude product). MS m / z (ESI): 326 [M+H].

[0383] Step 6: Compound 127-6 (50 mg, 153.7 μmol) was dissolved in tetrahydrofuran (5 mL), and phenyl p-nitrochlorocarbamate (34 mg, 169.0 μmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain 4-nitrophenyl (6'-(3,4-dimethylbenzyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)carbamate (75 mg, crude product).

[0384] Step 7: Dissolve compound 127-7 (75 mg, 152.9 μmol) in pyridine (5.0 mL), add intermediate A (61 mg, 230.5 μmol), stir at 80 °C for 2 hours, concentrate the reaction solution to obtain (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(3,4-dimethylbenzyl)-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea (50 mg, crude product).

[0385] Step 8: Compound 127-8 (50 mg, 81.1 μmol) was dissolved in trifluoroacetic acid (10.0 mL), stirred at 70 °C for 1 hour, the reaction solution was concentrated, and the crude product was separated by high performance liquid chromatography to obtain Example 127 (12 mg). MS m / z (ESI): 467 [M+H].

[0386] 1 H NMR (400MHz, CDCl3) δ9.38(s,1H),8.84(s,1H),7.95(s,1H),7.38(d,J=9.2Hz,1H),7.00(d,J=7.6H z,1H),6.87(t,J=9.6Hz,1H),6.67(s,1H),6.00–5.83(m,1H),2.29(s,3H),1.71(d,J=70.6Hz,4H).

[0387] Alternatively, Example 129 can be synthesized using the following method:

[0388] Example 129

[0389] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-methyl-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0390] Step 1: At room temperature, 1,2-dibromoethane (5.0 g, 26.8 mmol) and sodium hydride (2.1 g, 52.8 mmol, 60% purity) were added sequentially to a tetrahydrofuran (30 mL) solution of compound 126-2 (4.4 g, 13.2 mmol). The mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3'-bromo-6'-(4-methoxybenzyl)spirocyclic [cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (2.3 g, 49.0% yield). MS m / z (ESI): 360 [M+H].

[0391] Step 2: At room temperature, trifluoroacetic acid (5.0 mL) was added to a solution of compound 129-1 (2.3 g, 6.5 mmol) in dichloromethane (30 mL), and the mixture was stirred at 50 °C for 16 hours under nitrogen protection. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3'-bromospirocyclic [cyclopropane-1,7'-pyrrole[3,4-b]pyridine]-5'(6'H)-one (1.3 g, yield 85.0%). MS m / z (ESI): 240 [M+H].

[0392] Step 3: At room temperature, iodomethane (852 mg, 6.0 mmol) and sodium hydride (320 mg, 8.0 mmol, 60% purity) were added sequentially to a tetrahydrofuran (30 mL) solution of compound 129-2 (1.3 g, 5.5 mmol). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3'-bromo-6'-methylspiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (1.3 g, 94.0% yield). MS m / z (ESI): 254 [M+H].

[0393] Step 4: At room temperature, compound 129-3 (1.3 g, 5.1 mmol), cesium carbonate (5.0 g, 15.3 mmol), benzophenone imine (2.7 g, 15.3 mmol), tris(dibenzylacetone)dipalladium (70 mg, 77.1 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (178 mg, 308.3 μmol) were mixed in dioxane (10 mL), and stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 3'-((diphenylmethylene)amino)-6'-methylspirocyclic [cyclopropane-1,7'-pyrrole[3,4-b]pyridine]-5'(6'H)-one (903 mg, yield 50.0%). MS m / z (ESI): 354 [M+H].

[0394] Step 5: At room temperature, a solution of dioxane hydrochloride (1 mL, 4 M) was added to a solution of compound 129-4 (903 mg, 2.6 mmol) in dichloromethane (4 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3'-amino-6'-methylspiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-5'(6'H)-one (395 mg, 80% yield). MS m / z (ESI): 190 [M+H].

[0395] Step 6: At room temperature, phenyl chloroformate (160 mg, 1.0 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 129-5 (395 mg, 2.1 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give phenyl(6'-methyl-5'-oxo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)carbamate (570 mg, crude product). MS m / z (ESI): 310 [M+H].

[0396] Step 7: At room temperature, intermediate A (480 mg, 1.8 mmol) was added to a pyridine (5 mL) solution of compound 129-6 (570 mg, 1.8 mmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain Example 129 (120 mg). MS m / z (ESI): 481 [M+H].

[0397] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.57(d,J=2.4Hz,1H),8.28(d,J=2.4Hz,1H),7.99(d,J=9.4Hz,1H),7. 58–7.29(m,2H),6.24–5.87(m,1H),2.83(s,3H),2.33(s,3H),1.67(q,J=5.2Hz,2H),1.41(q,J=5.2Hz,2H).

[0398] Example 139

[0399] (R)-1-(1-(6,8-difluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroethyl)-3-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-3-yl)urea

[0400] Step 1: 2-Pyrrolidone (1.2 g, 14.1 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (0.8 g, 19.5 mmol, 60% purity) was added. The mixture was stirred at 25°C for half an hour under nitrogen protection. Compound 139-1 (3.1 g, 14.1 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1-(5-bromo-3-nitro-2-pyridyl)pyrrolidone-2-one (560 mg, yield 13.8%). MS m / z (ESI): 286 [M+H].

[0401] Step 2: Compound 139-2 (560 mg, 2.0 mmol) was dissolved in ethanol (10 mL) and water (10 mL), and reduced iron powder (328 mg, 5.9 mmol) and ammonium chloride (315 mg, 5.9 mmol) were added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 1-(3-amino-5-bromo-2-pyridyl)pyrrolidine-2-one (490 mg, yield 97.7%). MS m / z (ESI): 256 [M+H].

[0402] Step 3: Compound 139-3 (490 mg, 1.9 mmol) was dissolved in toluene (10 mL), and acetic acid (1.7 g, 28.7 mmol) was added. The reaction mixture was reacted at 110 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give 3-bromo-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine (162 mg, yield 35.5%). MS m / z (ESI): 238 [M+H].

[0403] Step 4: Compound 139-4 (162 mg, 0.7 mmol) was dissolved in 1,4-dioxane (5 mL), and benzophenone imine (148 mg, 0.8 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II) (54 mg, 0.1 mmol), and cesium carbonate (443 mg, 1.4 mmol) were added. The mixture was stirred at 95 °C for 5 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give N-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-3-yl)-1,1-diphenylmethylimine (133 mg, yield 57.7%). MS m / z (ESI): 339 [M+H].

[0404] Step 5: Compound 139-5 (133 mg, 39 μmol) was dissolved in tetrahydrofuran (5 mL), and concentrated hydrochloric acid (0.5 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was slurried in ethyl acetate (10 mL), filtered, and 7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-3-amine hydrochloride (82 mg, yield 99.0%) was obtained. MS m / z (ESI): 175 [M+H].

[0405] Step 6: At room temperature, intermediate B (76 mg, 285.9 μmol) was added to a pyridine (3 mL) solution of compound 139-6 (97 mg, 285.9 μmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain Example 139 (30 mg). MS m / z (ESI): 466 [M+H].

[0406] The preparation of Examples 128-138, 155-160, 163-178, 182-185, 219-250, 255, 266-271, 274-308, 310-323, 330, 331, 336, and 337 was carried out according to the synthesis method of Example 127; the preparation of Examples 140-150, 161, 162, 186-218, and 262-265 was carried out according to the synthesis method of Example 139; Examples 151-154 were prepared according to the synthesis method of Example 126; Examples 179-181 were prepared according to the synthesis method of Example 106; Examples 251-254, 256-261, 272, 273, and 309 were prepared according to the synthesis method of Example 1; Examples 324 and 325 were prepared according to the synthesis method of Example 88; Examples 326-329 and 332-335 were prepared according to the synthesis method of Example 77.

[0407] The following embodiments can also be synthesized using the following methods:

[0408] Example 171

[0409] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2'-methyl-3'-oxospiro[cyclopropane-1,1'-isoindolidin]-5'-yl)urea

[0410] Step 1: At room temperature, azobisisobutyronitrile (300 mg, 1.8 mmol) was added to a solution of methyl 5-bromo-2-methylbenzoate (8.0 g, 29.8 mmol) and N-bromosuccinimide (5.2 g, 29.8 mmol) in 100 mL of trifluorotoluene. The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was cooled, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give methyl 5-bromo-2-(bromomethyl)benzoate (5.8 g, yield 62.4%). MS m / z (ESI): 309 [M+H].

[0411] Step 2: At room temperature, compound 171-2 (5.8 g, 18.8 mmol), 4-methoxybenzylamine (5.5 g, 40.0 mmol), and triethylamine (4.0 g, 40.0 mmol) were dissolved in ethanol (50 mL). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 6-bromo-2-(4-methoxybenzyl)indololin-1-one (4.4 g, yield 70.0%). MS m / z (ESI): 333 [M+H].

[0412] Step 3: At room temperature, 1,2-dibromoethane (5.0 g, 26.8 mmol) and sodium hydride (2.1 g, 52.8 mmol, 60% purity) were added sequentially to a tetrahydrofuran (30 mL) solution of compound 171-3 (4.4 g, 13.2 mmol). The mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5'-bromo-2'-(4-methoxybenzyl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (2.3 g, yield 49.0%). MS m / z (ESI): 359 [M+H].

[0413] Step 4: At room temperature, trifluoroacetic acid (5.0 g, 43.9 mmol) was added to a solution of compound 171-4 (2.3 g, 6.5 mmol) in dichloromethane (30 mL), and the mixture was stirred at 50 °C for 16 hours under nitrogen protection. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5'-bromospirocyclic [cyclopropane-1,1'-isoindoline]-3'-one (1.3 g, yield 85.0%). MS m / z (ESI): 239 [M+H].

[0414] Step 5: At room temperature, iodomethane (852 mg, 6.0 mmol) and sodium hydride (320 mg, 8.0 mmol, 60% purity) were added sequentially to a tetrahydrofuran (30 mL) solution of compound 171-5 (1.3 g, 5.5 mmol). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5'-bromo-2'-methylspiro[cyclopropane-1,1'-isoindolin]-3'-one (1.3 g, 94.0% yield). MS m / z (ESI): 253 [M+H].

[0415] Step 6: At room temperature, tris(dibenzylacetone)dipalladium (70 mg, 77.1 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (178 mg, 308.3 μmol) were added to a solution of compound 171-6 (1.3 g, 5.1 mmol), cesium carbonate (5.0 g, 15.3 mmol), and benzophenone imine (2.7 g, 15.3 mmol) in dioxane (10 mL). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 5'-((diphenylmethylene)amino)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (950 mg, yield 55.0%). MS m / z (ESI): 353 [M+H].

[0416] Step 7: At room temperature, add 1 mL of dioxane hydrochloride solution (4 M) to a solution of compound 171-7 (900 mg, 2.6 mmol) in dichloromethane (4 mL), and stir at 25 °C for 1 hour. Pour the reaction mixture into a saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, collect the organic phase, dry to anhydrous sodium sulfate, filter and concentrate. Purify the crude product by silica gel column chromatography to give 5'-amino-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (400 mg, yield 81%). MS m / z (ESI): 189 [M+H].

[0417] Step 8: At room temperature, phenyl chloroformate (170 mg, 1.1 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 171-8 (400 mg, 2.1 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give phenyl (2'-methyl-3'-oxospiro[cyclopropane-1,1'-isobenzopiperidine]-5'-yl)carbamate (600 mg, crude product). MS m / z (ESI): 309 [M+H].

[0418] Step 9: At room temperature, intermediate A (500 mg, 1.9 mmol) was added to a pyridine (5 mL) solution of compound 171-9 (600 mg, 1.9 mmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography to obtain Example 171 (100 mg). MS m / z (ESI): 480 [M+H].

[0419] 1 H NMR (400MHz, CDCl3) δ9.40(s,1H),8.49(dd,J=8.4,2.0Hz,1H),7.86(d,J=9.8Hz,1H),7.72(d,J=2.0Hz,1H),7.08(d,J=8.4Hz,1H),6.98(dd,J=7 .8,2.4Hz,1H),6.82(ddd,J=11.2,9.4,2.4Hz,1H),6.09(dq,J=9.6,7.8 Hz,1H),3.10(s,3H),2.32(s,3H),1.73–1.58(m,2H),1.50–1.32(m,2H).

[0420] Example 174

[0421] (R)-1-(6'-acetyl-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0422] Step 1: At room temperature, a tetrahydrofuran solution (100 mL) of compound 127-4 (10.0 g, 42.0 mmol) was added to a diisobutylaluminum hydride n-hexane solution (252 mL, 1 M). The mixture was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was then poured into methanol and stirred. The mixture was filtered and the filtrate was concentrated to obtain 3'-bromo-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine] (8.0 g, crude product). MS m / z (ESI): 225 [M+H].

[0423] Step 2: At room temperature, N,N-diisopropylethylamine (12.9 g, 100.0 mmol) and di-tert-butyl dicarbonate (7.8 g, 35.6 mmol) were added sequentially to a solution of compound 174-1 (8.0 g, 35.6 mmol) in dichloromethane (30 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3'-bromospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-6'(5'H)-carboxylic acid tert-butyl ester (9.2 g, yield 80.0%). MS m / z (ESI): 325 [M+H].

[0424] Step 3: At room temperature, tris(dibenzylacetone)dipalladium (2.6 g, 2.8 mmol), cesium carbonate (27.8 g, 85.3 mmol), and benzophenone imine (5.2 g, 28.4 mmol) in a dioxane (10 mL) solution were added. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 3'-((diphenylmethylene)amino)spiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-6'(5'H)-tert-butyl carboxylate (6.0 g, yield 50.0%). MS m / z (ESI): 426 [M+H].

[0425] Step 4: At room temperature, a solution of dichloromethane (40 mL) containing 6.0 g (14.2 mmol) of compound 174-3 was added to a solution of dioxane (40 mL) containing 20 mL (4 M) of dioxane, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3'-aminospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-6'(5'H)-carboxylic acid tert-butyl ester (3.7 g, 80% yield). MS m / z (ESI): 262 [M+H].

[0426] Step 5: At room temperature, phenyl chloroformate (77 mg, 0.4 mmol) was added to a 5 mL solution of compound 174-4 (100 mg, 0.4 mmol) in tetrahydrofuran, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give tert-butyl 3'-((4-nitrophenoxy)carbonyl)amino)spiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-6'(5'H)-carboxylic acid (150 mg, crude product). MS m / z (ESI): 427 [M+H].

[0427] Step 6: At room temperature, intermediate A (93 mg, 0.4 mmol) was added to a pyridine (5 mL) solution of compound 174-5 (150 mg, 0.4 mmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give (R)-3'-(3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)ureido)spiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-6'(5'H)-carboxylic acid tert-butyl ester (100 mg, yield 51%). MS m / z (ESI): 553 [M+H].

[0428] Step 7: Compound 174-6 (100 mg, 76.9 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea (100 mg, crude product). MS m / z (ESI): 453 [M+H].

[0429] Step 8: Compound 174-7 (100 mg, 0.2 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol) were dissolved in dichloromethane (2 mL). Acetyl chloride (16 mg, 0.2 mmol) was slowly added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain Example 174 (42 mg, yield 50.5%). MS m / z (ESI): 495 [M+H].

[0430] 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 8.32 (d, J = 2.3Hz, 1H), 8.07–7.71 (m, 2H), 7.55–7.29 (m, 2H), 6. 29–5.87(m,1H),4.94(s,2H),2.32(s,3H),2.18(q,J=3.6Hz,2H),2.02(s,3H),0.89(q,J=3.7Hz,2H).

[0431] The preparation of Examples 338–711 follows the synthesis method of Example 1 or Example 174:

[0432] The following embodiments can also be synthesized using the following methods:

[0433] Example 176

[0434] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(methylsulfonyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0435] Example 176 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 531 [M+H].

[0436] 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.32(d,J=2.3Hz,1H),7.94(d,J=2.3Hz,1H),7.93–7.86(m,1H),7.46–7.40 (m,2H),6.13–6.04(m,1H),4.82(s,2H),2.96(s,3H),2.31(s,3H),1.66(q,J=3.6Hz,2H),1.05(q,J=3.7Hz,2H)..

[0437] Example 187

[0438] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(5-oxo-8,9-dihydro-5H,7H-pyrazolo[1',2':1,2]pyrazolo[3,4-b]pyridin-3-yl)urea

[0439] Step 1: At room temperature, triethylamine (2.0 g, 20 mmol) was added to an ethanol (30 mL) solution of methyl 5-bromo-2-chloronicotinamide (3.3 g, 13.2 mmol) and hydrazine hydrate (2.6 g, 65.9 mmol, 80% purity). The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was cooled, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 5-bromo-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (2.3 g, yield 81.6%). MS m / z (ESI): 215 [M+H].

[0440] Step 2: At room temperature, compound 187-2 (500 mg, 2.3 mmol), potassium carbonate (967 mg, 7.0 mmol), and 1-bromo-3-chloropropane (735 mg, 4.7 mmol) were added to dioxane (10 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3-bromo-8,9-dihydro-5H,7H-pyrazolo[1',2':1,2]pyrazolo[3,4-b]pyridin-5-one (300 mg, yield 51.0%). MS m / z (ESI): 255 [M+H].

[0441] Step 3: At room temperature, tris(benzylacetone)dipalladium (70 mg, 77.1 μmol), cesium carbonate (770 mg, 2.4 mmol), and benzophenone imine (357 mg, 2.0 mmol) in a dioxane (10 mL) solution were added to a mixture of tris(benzylacetone)dipalladium (70 mg, 77.1 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (178 mg, 308.3 μmol). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 3-((benzylacetone)amino)-8,9-dihydro-5H,7H-pyrazolo[1',2':1,2]pyrazolo[3,4-b]pyridin-5-one (140 mg, yield 50.2%). MS m / z (ESI): 355 [M+H].

[0442] Step 4: At room temperature, a solution of dioxane (4 mL) containing 140 mg (395.0 μmol) of compound 187-4 was added to a solution of dichloromethane (4 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3-amino-8,9-dihydro-5H,7H-pyrazolopyrazolo[1,2-b]pyridin-5-one (32 mg, yield 42.5%). MS m / z (ESI): 191 [M+H].

[0443] Step 5: At room temperature, phenyl chloroformate (85 mg, 550 μmol) was added to a 5 mL solution of tetrahydrofuran containing compound 187-5 (32 mg, 168.2 μmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give 100 mg of crude 3-amino-8,9-dihydro-5H,7H-pyrazolopyrazolo[1,2-b]pyridin-5-one. MS m / z (ESI): 311 [M+H].

[0444] Step 6: At room temperature, intermediate A (100 mg, 380 μmol) was added to a pyridine (5 mL) solution of compound 187-6 (100 mg, 320 μmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain Example 187 (7 mg). MS m / z (ESI): 482 [M+H].

[0445] 1 H NMR (400MHz, DMSO-d6) δ8.92(d,J=2.8Hz,1H),8.47(d,J=2.4Hz,1H),8.17(d,J=2.4Hz,1H),7.96(d,J=9.4Hz,1H),7.4 7–7.37(m,2H),6.10(t,J=8.4Hz,1H),3.81(t,J=7.2Hz,2H),3.65(t,J=6.8Hz,2H),2.56(p,J=6.8Hz,2H),2.32(s,3H).

[0446] Example 192

[0447] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(8-methylene-5-oxo-8,9-dihydro-5H,7H-pyrazolo[1',2':1,2]pyrazolo[3,4-b]pyridin-3-yl)urea

[0448] Example 192 was prepared according to the synthesis method of Example 187. MS m / z (ESI): 494 [M+H].

[0449] 1 H NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.49(d,J=2.4Hz,1H),8.22(d,J=2.4Hz,1H),7.97(d,J=9.4Hz,1H),7.50–7.31( m,2H),6.09(q,J=8.4Hz,1H),5.34(dq,J=10.0,2.4Hz,2H),4.47(t,J=2.0Hz,2H),4.29(t,J=2.0Hz,2H),2.32(s,3H).

[0450] Example 193

[0451] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(5'-oxo-5'H,7'H,9'H-spiro[cyclopropane-1,8'-imidazo[1',2':1,2]pyrazolo[3,4-b]pyridin]-3'-yl)urea

[0452] Example 193 was prepared according to the synthesis method of Example 187. MS m / z (ESI): 508 [M+H].

[0453] 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.47(d,J=2.4Hz,1H),8.20(d,J=2.4Hz,1H),7.93(d,J=9.4Hz ,1H),7.48–7.37(m,2H),6.10(p,J=8.4Hz,1H),3.77(s,2H),3.60(s,2H),2.32(s,3H),0.83(s,4H).

[0454] Example 211

[0455] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(7H,9H-furano[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0456] Step 1: At room temperature, hydrazine hydrate (2.6 g, 45.0 mmol, 85% purity) was added to an ethanol (60 mL) solution of 4-oxotetrahydrofuran-3-carboxynitrile (5.0 g, 45.0 mmol) and acetic acid (3.5 g, 58.5 mmol). The reaction mixture was stirred at 90 °C for 2 hours under nitrogen protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2,6-dihydro-4H-furano[3,4-c]pyrazol-3-amine (5.0 g, yield 88.8%). MS m / z (ESI): 126 [M+H].

[0457] Step 2: At room temperature, 2-bromomalondialdehyde (6.0 g, 39.9 mmol) was added to a solution of compound 211-2 (5.0 g, 39.9 mmol) in ethanol (60 mL) and acetic acid (12 mL). The reaction mixture was stirred at 90 °C for 3 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3-bromo-7H,9H-furano[3',4':3,4]pyrazolo[1,5-a]pyrimidine (1.0 g, yield 10.4%). MS m / z (ESI): 240 [M+H].

[0458] Step 3: At room temperature, tris(dibenzylacetone)dipalladium (381 mg, 416.5 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (964 mg, 1.7 mmol) were added to a solution of compound 211-3 (1.0 g, 4.2 mmol), cesium carbonate (3.4 g, 10.4 mmol), and benzophenone imine (981 mg, 5.4 mmol) in dioxane (15 mL). The reaction mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give N-(7H,9H-furano[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)-1,1-diphenylmethane imine (800 mg, yield 56.4%). MS m / z (ESI): 341 [M+H].

[0459] Step 4: At room temperature, a solution of dioxane (10 mL) containing 800 mg (2.3 mmol) of compound 211-4 was added to a solution of dichloromethane (10 mL) and dioxane hydrochloride (10 mL, 4 M). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction mixture was then poured into a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 7H,9H-furano[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-amine (80 mg, yield 19.3%). MS m / z (ESI): 177 [M+H].

[0460] Step 5: At room temperature, p-nitrophenyl chlorocarbamate (91 mg, 454.1 μmol) was added to a tetrahydrofuran (4 mL) solution of compound 211-5 (80 mg, 454.1 μmol). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction mixture was concentrated under reduced pressure to give 4-nitrophenyl (7H,9H-furano[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)carbamate (154 mg, yield 99.9%). MS m / z (ESI): 342 [M+H].

[0461] Step 6: At room temperature, (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-amine (120 mg, 453.9 μmol) was added to a pyridine (4 mL) solution of compound 211-6 (154 mg, 453.9 μmol). The reaction solution was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain Example 211 (28 mg, yield 13.2%). MS m / z (ESI): 468 [M+H].

[0462] 1 H NMR (400MHz, DMSO-d6) δ9.23(d,J=2.4Hz,1H),8.87(s,1H),8.42(d,J=2.4Hz,1H),8.14(d,J=9.2Hz,1H ),7.49–7.37(m,2H),6.11(p,J=8.0Hz,1H),5.05(t,J=2.0Hz,2H),4.96(t,J=2.0Hz,2H),2.32(s,3H).

[0463] Example 213

[0464] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(8-methyl-8,9-dihydro-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0465] Example 213 was prepared using the same synthesis method as in Example 211. MS m / z (ESI): 481 [M+H].

[0466] 1 H NMR (400MHz, DMSO-d6) δ9.49(d,J=2.4Hz,1H),8.58(s,1H),8.52(d,J=2.4Hz,1H),7.91(d,J=9.2Hz,1H),7.4 9–7.37(m,2H),5.65(p,J=8.0Hz,1H),4.45(t,J=2.0Hz,2H),3.96(t,J=2.0Hz,2H),2.45(s,3H),2.32(s,3H).

[0467] Example 214

[0468] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(8,8-dioxa-7H,9H-thieno[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0469] Example 214 was prepared using the same synthesis method as in Example 211. MS m / z (ESI): 516 [M+H].

[0470] 1 H NMR (400MHz, DMSO-d6) δ9.32(d,J=2.4Hz,1H),8.96(s,1H),8.53(d,J=2.4Hz,1H),8.19(d,J =9.3Hz,1H),7.49–7.29(m,2H),6.11(q,J=8.4Hz,1H),4.65(s,2H),4.58(s,2H),2.32(s,3H) .

[0471] Example 227

[0472] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(2-methoxyethyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)urea

[0473] Step 1: At room temperature, sodium hexamethyldisilamide (128 mL, 1 M) was added to a tetrahydrofuran (150 mL) solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (17.0 g, 85.8 mmol) under nitrogen protection. Ethyl bromoacetate (43.0 g, 257.5 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give ethyl 2-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)acetate (9.0 g, yield 35.1%). MS m / z (ESI): 284 [M+H].

[0474] Step 2: At room temperature, compound 227-2 (0.6 g, 2.1 mmol) was dissolved in ethanol (15 mL), and sodium borohydride (239 mg, 6.3 mmol) was added. The reaction mixture was stirred at 40 °C for 1 hour under nitrogen protection. Water and ethyl acetate were added for extraction, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)ethanol-1-ol (0.3 g, yield 55.1%). MS m / z (ESI): 242 [M+H].

[0475] Step 3: At room temperature, iodomethane (351 mg, 2.5 mmol) and sodium hydride (248 mg, 6.2 mmol, 60% purity) were added sequentially to a solution of compound 227-3 (0.3 g, 1.2 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5-bromo-2-(2-methoxyethyl)-2H-pyrazolo[3,4-b]pyridine (200 mg, yield 61.7%). MS m / z (ESI): 256 [M+H].

[0476] Step 4: At room temperature, tris(dibenzylacetone)dipalladium (71 mg, 78.1 μmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (45 mg, 78.1 μmol) were added to a solution of compound 227-4 (200 mg, 0.8 mmol), cesium carbonate (508 mg, 1.6 mmol), and benzophenone imine (212 mg, 1.2 mmol) in dioxane (10 mL). The mixture was stirred at 110 °C for 10 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give N-(2-(2-methoxyethyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,1-diphenylmethylimine (230 mg, yield 82.6%). MS m / z (ESI): 357 [M+H].

[0477] Step 5: At room temperature, hydroxylamine hydrochloride (98 mg, 1.4 mmol) and sodium acetate (173 mg, 2.1 mmol) were added to a methanol (10 mL) solution of compound 227-5 (230 mg, 640.2 μmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2-(2-methoxyethyl)-2H-pyrazolo[3,4-b]pyridine-5-amine (130 mg, yield 93.1%). MS m / z (ESI): 193 [M+H].

[0478] Step 6: At room temperature, phenyl chloroformate (36 mg, 234.3 μmol) was added to a 2 mL solution of tetrahydrofuran containing compound 227-6 (45 mg, 234.3 μmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give phenyl (2-(2-methoxyethyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)carbamate (80 mg, crude product). MS m / z (ESI): 313 [M+H].

[0479] Step 7: At room temperature, intermediate A (67 mg, 255.6 μmol) was added to a pyridine (3 mL) solution of compound 227-7 (80 mg, 255.6 μmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(2-methoxyethyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)urea (20 mg, yield 16.5%). MS m / z (ESI): 484 [M+H].

[0480] 1H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.41(d,J=2.6Hz,1H),8.33–8.25(m,2H),7.84(d,J=9.4Hz,1H),7.45(dd,J=5.6,2.6 Hz,1H),7.45–7.35(m,1H),6.10(p,J=8.2Hz,1H),4.56(t,J=5.2Hz,2H),3.83(t,J=5.2Hz,2H),3.23(s,3H),2.33(s,3H).

[0481] Example 228

[0482] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(2-(methylsulfonyl(ethyl)-2H-pyrazolo[3,4-b]pyridin-5-yl)urea)

[0483] Example 228 was prepared according to the synthesis method of Example 227. MS m / z (ESI): 532 [M+H].

[0484] 1 H NMR (400MHz, CDCl3) δ8.35(d,J=2.3Hz,1H),8.27(d,J=2.4Hz,1H),7.88(d,J=2.4Hz,1H),7.61(s,1H),6.97(dd,J=7.7,2.5Hz,1H),6.84(ddd,J= 11.2,9.1,2.4Hz,1H),6.63(d,J=9.5Hz,1H),6.00–5.87(m,1H),5.03(t, J=6.3Hz,2H),3.83(t,J=6.3Hz,2H),2.89(d,J=2.3Hz,3H),2.28(s,3H).

[0485] Example 230

[0486] (R)-2-(5-(3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)ureoyl)-2H-pyrazolo[3,4-b]pyridin-2-yl)-

[0487] N-Methylacetamide

[0488] Example 230 was prepared according to the synthesis method of Example 227. MS m / z (ESI): 497 [M+H].

[0489] 1H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.42(d,J=2.6Hz,1H),8.29(d,J=2.2Hz,1H),7.90(d,J=9.4Hz,1H),7.47–7. 37(m,2H),7.20(s,1H),6.14–6.05(m,1H),5.33(t,J=4.8Hz,1H),5.07(s,2H),2.64(d,J=4.6Hz,3H),2.32(s,3H).

[0490] Example 258

[0491] (R)-1-(6'-acetyl-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(6,8-difluoro-3-methylindoleazin-2-yl)-2,2,2-trifluoroethyl)urea

[0492] Example 258 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 494 [M+H].

[0493] 1 H NMR(400MHz, DMSO-d6)δ8.70(s,1H),8.31(d,J=2.0Hz,1H),8.24–8.21(m,1H),7.91(d,J=2.0Hz,1H),7.55(d,J=8.0Hz,1H),7.0 0–6.92(m,1H),6.74(s,1H),5.77(p,J=8.4Hz,1H),4.93(s,2H),2.49(s,3H),2.19–2.15(m,2H),2.01(s,3H),0.92–0.81(m,2H).

[0494] Example 260

[0495] (R)-1-(6'-acetyl-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(8-chloro-6-fluoro-3-methylindoleazin-2-yl)-2,2,2-trifluoroethyl)urea

[0496] Example 260 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 510 [M+H].

[0497] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.37–8.33(m,1H),8.32(d,J=4.0Hz,1H),7.94–7.89(m,1H),7.61(d,J=8.0Hz,1H),7.22(dd,J=8. 0,4.0Hz,1H),6.73(s,1H),5.77(p,J=8.4Hz,1H),4.93(s,2H),2.50(s,3H),2.18(q,J=3.6Hz,2H),2.01(s,3H),0.89(q,J=3.6Hz,2H).

[0498] Example 264

[0499] (R)-1-(1-(8-chloro-6-fluoro-3-methylindenindene-2-yl)-2,2,2-trifluoroethyl)-3-(7H,9H-furano[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0500] Example 264 was prepared according to the synthesis method of Example 211. MS m / z (ESI): 483 [M+H].

[0501] 1 H NMR (400MHz, DMSO-d6) δ9.22(d,J=2.4Hz,1H),8.67(s,1H),8.44(d,J=2.4Hz,1H),8.36–8.32(m,1H),7.88(d,J=8.0Hz ,1H),7.24–7.21(m,1H),6.77(s,1H),5.80(p,J=8.4Hz,1H),5.05(t,J=2.0Hz,2H),4.96(t,J=2.0Hz,2H),2.50(s,3H).

[0502] Example 301

[0503] (R)-1-(6'-acetyl-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0504] Step 1: At room temperature, phenyl chloroformate (500 mg, 2.7 mmol) was added to a 5 mL solution of intermediate E (500 mg, 1.8 mmol) in tetrahydrofuran, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give phenyl(R)-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)carbamate (1.0 g, crude product). MS m / z (ESI): 402 [M+H].

[0505] Step 2: At room temperature, intermediate 174-4 (1.0 g, 3.8 mmol) was added to a pyridine (5 mL) solution of compound 301-1 (1.0 g, 2.5 mmol), and the mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give tert-butyl(R)-3'-(3-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)ureoyl)spiro[cyclopropane-1,7'-pyrrole[3,4-b]pyridine]-6'(5'H)-carboxylic acid ester (639 mg, yield 45.0%). MS m / z (ESI): 569 [M+H].

[0506] Step 3: At room temperature, dioxane hydrochloride solution (1 mL, 4 M) was added to a 4 mL solution of compound 301-2 (639 mg, 1.1 mmol) in dichloromethane, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give (R)-1-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(5',6'-dihydrospirocyclic[cyclopropane-1,7'-pyrrolo[3,4-b]pyridin]-3'-yl)urea (500 mg, crude product). MS m / z (ESI): 469 [M+H].

[0507] Step 4: At room temperature, triethylamine (500 mg, 5.0 mmol) and acetyl chloride (157 mg, 2.0 mmol) were added to a dichloromethane (5 mL) solution of compound 301-3 (500 mg, 1.1 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and separated by high performance liquid chromatography to obtain Example 301 (326 mg). MS m / z (ESI): 511 [M+H].

[0508] 1H NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.32(d,J=2.2Hz,1H),7.92(d,J=2.4Hz,1H),7.82(d,J=9.2Hz,1H),7.57(ddd,J=11.8, 8.8, 2.4Hz, 2H), 6.09 (p, J = 8.4Hz, 1H), 4.94 (s, 2H), 2.32 (s, 3H), 2.18 (q, J = 3.6Hz, 2H), 2.02 (s, 3H), 0.90 (t, J = 3.4Hz, 2H).

[0509] Example 303

[0510] (S)-1-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)-3-(6'-methyl-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0511] Example 303 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 511 [M+H].

[0512] 1 H NMR(400MHz, CDCl3)δ8.13(s,1H),8.09(s,1H),7.90(m,2H),7.77(m,1H),7.67(m,1H),6 .26–6.18(m,1H),4.93(s,2H),2.47(s,3H),2.01(s,3H),1.38–1.21(m,2H),0.89(m,2H).

[0513] Example 306

[0514] (S)-1-(1-(7-chloro-5-fluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(methanesulfonyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0515] Example 306 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 563 [M+H].

[0516] 1H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.33(d,J=2.3Hz,1H),7.94(dd,J=2.3,1.2Hz,1H),7.89(d,J=9.0Hz,1H),7.76(dd,J=9.5,2.3H z,1H),7.67(dd,J=8.9,2.3Hz,1H),6.28–6.14(m,1H),4.81(s,2H),2.95(s,3H),2.47(s,3H),1.67–1.58(m,2H),1.08–1.02(m,2H).

[0517] Example 307

[0518] (S)-1-(6'-acetyl-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(7-chloro-5-fluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)urea

[0519] Example 307 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 527 [M+H].

[0520] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.32(d,J=2.2Hz,1H),7.90(d,J=6.7Hz,2H),7.77(dd,J=9.4,2.3Hz,1H),7.6 7(dd,J=8.8,2.3Hz,1H),6.26–6.18(m,1H),4.93(s,2H),2.47(s,3H),2.01(s,3H),1.38–1.21(m,2H),0.89(m,2H).

[0521] Example 326

[0522] (R)-1-(6-acetyl-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0523] Step 1: Compound 127-3 (4.8 g, 13.2 mmol), methyl iodoform (7.5 g, 52.9 mmol), and sodium hydride (3.2 g, 79.3 mmol, 60% purity) were mixed in N,N-dimethylformamide (60 mL) and stirred at 0 °C for 1 hour under nitrogen protection. The reaction mixture was quenched in a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-bromo-6-[(2,4-dimethoxyphenyl)methyl]-7,7-dimethylpyrrolo[3,4-b]pyridin-5-one (5.0 g, 96.7% yield). MS m / z (ESI): 391 [M+H].

[0524] Step 2: At room temperature, compound 326-1 (5.0 g, 12.8 mmol) was dissolved in tetrahydrofuran (60 mL), and a tetrahydrofuran solution of diisobutylaluminum hydride (63.9 mL, 1 M) was added dropwise. The mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction solution, and the mixture was filtered. The filter cake was washed with ethyl acetate, and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3-bromo-6-[(2,4-dimethoxyphenyl)methyl]-7,7-dimethyl-5H-pyrrolo[3,4-b]pyridine (3.6 g, yield 74.6%). MS m / z (ESI): 377 [M+H].

[0525] Step 3: At room temperature, compound 326-2 (3.6 g, 9.5 mmol) was added to trifluoroacetic acid (40 mL), and the mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give 3-bromo-7,7-dimethyl-5,6-dihydropyrrolo[3,4-b]pyridine (2.1 g, yield 96.9%). MS m / z (ESI): 227 [M+H].

[0526] Step 4: At room temperature, compound 326-3 (310 mg, 1.4 mmol) and N,N-diisopropylethylamine (705 mg, 5.4 mmol) were dissolved in dichloromethane (10 mL), and acetyl chloride (160 mg, 2.0 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 1-(3-bromo-7,7-dimethyl-5H-pyrrolo[3,4-b]pyridin-6-yl)acetone (300 mg, yield 81.6%). MS m / z (ESI): 269 [M+H].

[0527] Step 5: At room temperature, compound 326-4 (300 mg, 1.1 mmol), cesium carbonate (908 mg, 2.8 mmol), 2,4-dimethoxybenzylamine (208 mg, 1.7 mmol), tris(dibenzylacetone)dipalladium (102 mg, 111.4 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (65 mg, 111.4 μmol) were mixed with dioxane (10 mL) and stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 1-[3-[(2,4-dimethoxyphenyl)methylamino]-7,7-dimethyl-5H-pyrrolo[3,4-b]pyridin-6-yl]acetone (390 mg, yield 98.4%). MS m / z (ESI): 356 [M+H].

[0528] Step 6: At room temperature, compound 326-5 (390 mg, 1.1 mmol) was added to 10 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give 1-(3-amino-7,7-dimethyl-5H-pyrrolo[3,4-b]pyridin-6-yl)acetone (220 mg, yield 97.6%). MS m / z (ESI): 206 [M+H].

[0529] Step 7: At room temperature, 4-nitrobenzoyl chloride (50 mg, 271.0 μmol) was added to a tetrahydrofuran (6 mL) solution of compound 326-6 (46 mg, 224.5 μmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to give 4-nitrophenyl (6-acetyl-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)carbamate (83 mg, 100% yield). MS m / z (ESI): 371 [M+H].

[0530] Step 8: At room temperature, intermediate A (93 mg, 224.5 μmol) was added to a pyridine (6 mL) solution of compound 326-7 (83 mg, 224.5 μmol), and the mixture was stirred at 80 °C for 1 hour. The reaction solution was cooled, concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain Example 326 (10 mg). MS m / z (ESI): 497 [M+H].

[0531] 1H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.40 (d, J = 2.3Hz, 1H), 8.00–7.86 (m, 2H), 7.48–7. 38(m,2H),6.16–5.98(m,1H),4.76(s,2H),2.32(s,3H),2.03(s,3H),1.61–1.53(m,6H).

[0532] Example 338

[0533] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(8-(methanesulfonyl)-8,9-dihydro-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0534] Example 338 was prepared according to the synthesis method of Example 211. MS m / z (ESI): 545 [M+H].

[0535] 1 H NMR (400MHz, DMSO-d6) δ9.20(d,J=2.4Hz,1H),8.93(s,1H),8.39(d,J=2.4Hz,1H),8.15(d,J= 9.2Hz,1H),7.41–7.31(m,2H),6.05(p,J=8.4Hz,1H),4.60(s,4H),2.98(s,3H),2.25(s,3H).

[0536] Example 339

[0537] (R)-1-(8-acetyl-8,9-dihydro-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0538] Example 339 was prepared according to the synthesis method of Example 211. MS m / z (ESI): 509 [M+H].

[0539] 1H NMR(400MHz,DMSO-d6)δ9.25(d,J=2.4Hz,1H),8.88(s,1H),8.45–8.43(m,1H),8.15–8.11(m,1H ),7.48–7.37(m,2H),6.11(p,J=8.4Hz,1H),4.85(s,2H),4.60(s,2H),2.32(s,3H),2.09(s,3H).

[0540] Example 340

[0541] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(8-propionyl-8,9-dihydro-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0542] Example 340 was prepared according to the synthesis method of Example 211. MS m / z (ESI): 523 [M+H].

[0543] 1 H NMR(400MHz,DMSO-d6)δ9.26(d,J=2.4Hz,1H),8.94(s,1H),8.45(s,1H),8.16–8.12(m,1H),7.49–7.37(m,2 H),6.12(p,J=8.4Hz,1H),4.84(s,2H),4.62(s,2H),2.45–2.38(m,2H),2.33(s,3H),1.05(t,J=7.2Hz,3H).

[0544] Example 341

[0545] (R)-3-(3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)ureo)7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-8(9H)-carboxylic acid methyl ester

[0546] Example 341 was prepared according to the synthesis method of Example 211. MS m / z (ESI): 525 [M+H].

[0547] 1H NMR (400MHz, DMSO-d6) δ9.25(d,J=2.4Hz,1H),8.91(s,1H),8.44(d,J=2.4Hz,1H),8.14(d,J=9.2Hz ,1H),7.49–7.38(m,2H),6.12(t,J=8.4Hz,1H),4.66(s,2H),4.63(s,2H),3.69(s,3H),2.32(s,3H).

[0548] Example 342

[0549] (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(8-(2-methoxyacetyl)-8,9-dihydro-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-3-yl)urea

[0550] Example 342 was prepared according to the synthesis method of Example 211. MS m / z (ESI): 539 [M+H].

[0551] 1 H NMR(400MHz, DMSO-d6)δ9.26(dd,J=2.4,1.2Hz,1H),8.90(s,1H),8.45(dd,J=2.4,1.2Hz,1H),8.16–8.10(m,1 H),7.49–7.37(m,2H),6.12(p,J=8.4Hz,1H),4.80(s,2H),4.66(s,2H),4.19(s,2H),3.36(s,3H),2.32(s,3H).

[0552] Example 445

[0553] (R)-1-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(2-hydroxyacetyl)-5',6'-dihydrospirocyclic[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0554] Example 445 was prepared according to the synthesis method of Example 301. MS m / z (ESI): 527 [M+H].

[0555] 1H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.33(d,J=2.4Hz,1H),7.90(d,J=2.4Hz,1H),7.80(d,J=9.4Hz,1H),7.57(ddd,J=11.6,8.8,2.4Hz,2H) ,6.07(d,J=8.4Hz,1H),4.87(s,2H),4.58(t,J=5.6Hz,1H),4.05(d,J=5.6Hz,2H),2.31(s,3H),2.21(q,J=3.8Hz,2H),0.95(q,J=3.8Hz,2H).

[0556] Example 447

[0557] (R)-1-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(2-hydroxy-2-methylpropionyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0558] Example 447 was prepared according to the synthesis method of Example 301. MS m / z (ESI): 555 [M+H].

[0559] 1 H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.34(d,J=2.3Hz,1H),7.88–7.83(m,1H),7.78(d,J=9.4Hz,1H),7.57(ddd,J=11.8,8.7,2.5 Hz,2H),6.08(p,J=8.2Hz,1H),5.38(s,1H),5.29(s,2H),2.31(s,3H),2.25(t,J=3.2Hz,2H),1.32(s,6H),0.87(d,J=2.9Hz,2H).

[0560] Example 551

[0561] (R)-1-(1-(6,8-difluoro-3-methyl-inden-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(2-hydroxyacetyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0562] Example 551 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 510 [M+H].

[0563] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.33(d,J=2.4Hz,1H),8.25–8.19(m,1H),7.90(d,J=2.4Hz,1H),7.56(d,J=9.2Hz,1H),6.99–6.93(m,1H),6.73 (s,1H),5.77(p,J=8.4Hz,1H),4.86(s,2H),4.58(t,J=5.6Hz,1H),4.05(d ,J=5.6Hz,2H),2.49(s,3H),2.21(q,J=3.6Hz,2H),0.94(q,J=3.6Hz,2H).

[0564] Example 604

[0565] (R)-1-(6'-(acetyl-d3)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0566] Example 604 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 498 [M+H].

[0567] 1 H NMR(400MHz, DMSO-d6)δ8.89(s,1H),8.32(d,J=2.3Hz,1H),8.07–7.71(m,2H),7.55–7.29(m,2 H),6.29–5.87(m,1H),4.94(s,2H),2.32(s,3H),2.18(q,J=3.6Hz,2H),0.89(q,J=3.7Hz,2H).

[0568] Example 631

[0569] (R)-1-(6'-(acetyl-d3)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)-3-(1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0570] Example 631 was prepared according to the synthesis method of Example 301. MS m / z (ESI): 514 [M+H].

[0571] 1H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.31(d,J=2.2Hz,1H),7.91(d,J=2.2Hz,1H),7.80(d,J=9.4Hz,1H),7.57(ddd, J=11.6,8.8,2.4Hz,2H),6.20–6.03(m,1H),4.94(s,2H),2.31(s,3H),2.18(q,J=3.6Hz,2H),0.89(t,J=3.4Hz,2H).

[0572] Example 634

[0573] 1-((R)-1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(R)-2-hydroxypropionyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0574] Example 634 was prepared according to the synthesis method of Example 301. MS m / z (ESI): 541 [M+H].

[0575] 1 H NMR (400MHz, DMSO-d6) δ8.93 (s, 1H), 8.32 (d, J = 2.3Hz, 1H), 7.91 (d, J = 2.3Hz, 1H),7.80(dd,J=9.4,3.4Hz,1H),7.56(ddd,J=11.7,8.7,2.4Hz,2H),6.08(p,J =8.3Hz,1H),5.14(d,J=15.3Hz,1H),5.06–4.95(m,2H),4.30(p,J=6.6Hz,1H) ,2.31(s,3H),2.28–2.12(m,2H),1.20(d,J=6.4Hz,3H),0.92(d,J=3.0Hz,2H).

[0576] Example 635

[0577] 1-((R)-1-(7-chloro-5-fluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(6'-(S)-2-hydroxypropanoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0578] Example 635 was prepared according to the synthesis method of Example 301. MS m / z (ESI): 541 [M+H].

[0579] 1 H NMR (400MHz, DMSO-d6) δ8.97(d,J=10.7Hz,1H),8.32(d,J=2.3Hz,1H),7.91(d,J= 2.2Hz,1H),7.82(dd,J=9.4,4.3Hz,1H),7.57(ddd,J=11.7,8.7,2.4Hz,2H),6.08( p,J=8.3Hz,1H),5.13(d,J=15.1Hz,1H),5.00(q,J=8.6Hz,2H),4.30(p,J=6.6Hz, 1H), 2.31 (s, 3H), 2.28–2.08 (m, 2H), 1.20 (d, J = 6.4Hz, 3H), 0.92 (d, J = 4.1Hz, 2H).

[0580] Example 661

[0581] 1-(1-(6,8-difluoro-3-methylindenhydride-2-yl)-2,2,2-trifluoroethyl)-3-(6'-((R)-2-hydroxypropanoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0582] Example 661 was prepared according to the synthesis method of Example 551. MS m / z (ESI): 524 [M+H].

[0583] 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.32(d,J=2.4Hz,1H),8.25–8.19(m,1H) ,7.91(d,J=2.4Hz,1H),7.55(d,J=9.2Hz,1H),7.00–6.93(m,1H),6.73(s,1H), 5.77(p,J=8.4Hz,1H),5.16–5.09(m,1H),5.03–4.94(m,2H),4.30(p,J=6.4Hz, 1H), 2.49 (s, 3H), 2.27–2.14 (m, 2H), 1.20 (d, J = 6.4Hz, 3H), 0.95–0.88 (m, 2H).

[0584] Example 662

[0585] 1-(1-(6,8-difluoro-3-methylindenhydride-2-yl)-2,2,2-trifluoroethyl)-3-(6'-((S)-2-hydroxypropanoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0586] Example 662 was prepared according to the synthesis method of Example 551. MS m / z (ESI): 524 [M+H].

[0587] 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.32(d,J=2.4Hz,1H),8.25–8.19(m,1H) ,7.91(d,J=2.4Hz,1H),7.55(d,J=9.2Hz,1H),7.01–6.92(m,1H),6.73(s,1H), 5.77(p,J=8.4Hz,1H),5.16–5.09(m,1H),5.06–4.94(m,2H),4.30(p,J=6.4Hz, 1H), 2.49 (s, 3H), 2.29–2.12 (m, 2H), 1.20 (d, J = 6.4Hz, 3H), 0.95–0.88 (m, 2H).

[0588] Example 679

[0589] 1-(1-(8-chloro-6-fluoro-3-methylindenhydride-2-yl)-2,2,2-trifluoroethyl)-3-(6'-((R)-2-hydroxypropanoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0590] Example 679 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 540 [M+H].

[0591] 1 H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.38–8.30(m,2H),7.91(d,J=2.3Hz,1H ),7.62(d,J=9.4Hz,1H),7.22(dd,J=8.3,1.9Hz,1H),6.73(s,1H),5.77(p,J =8.4Hz,1H),5.14(d,J=15.2Hz,1H),5.07–4.95(m,2H),4.31(p,J=6.5Hz,1H ),2.50(s,3H),2.29–2.11(m,2H),1.20(d,J=6.5Hz,3H),1.01–0.82(m,2H).

[0592] Example 680

[0593] 1-(1-(8-chloro-6-fluoro-3-methylindenhydride-2-yl)-2,2,2-trifluoroethyl)-3-(6'-((S)-2-hydroxypropanoyl)-5',6'-dihydrospiro[cyclopropane-1,7'-pyrrolo[3,4-b]pyridine]-3'-yl)urea

[0594] Example 680 was prepared according to the synthesis method of Example 174. MS m / z (ESI): 540 [M+H].

[0595] 1 H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.38–8.30(m,2H),7.91(d,J=2.3Hz,1H ),7.62(d,J=9.4Hz,1H),7.22(dd,J=8.3,1.9Hz,1H),6.73(s,1H),5.77(p,J =8.4Hz,1H),5.14(d,J=15.2Hz,1H),5.07–4.95(m,2H),4.31(p,J=6.5Hz,1H ),2.50(s,3H),2.29–2.11(m,2H),1.20(d,J=6.5Hz,3H),1.01–0.82(m,2H).

[0596] Biological testing evaluation

[0597] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0598] Test Example 1: Inhibitory activity experiment of the compounds of the present invention against PI3Kα mutant and wild-type kinases.

[0599] Experimental objective: The purpose of this test case is to test the inhibitory activity of the compound on PI3Kα mutant and wild-type kinases.

[0600] Experimental instruments: Centrifuge (5810R) purchased from Eppendorf, pipettes purchased from Eppendorf or Rainin, and microplate reader purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[0601] Experimental Methods: This experiment used the ADP-Glo ​​lipid kinase assay (Promega#V9102) from Promega. The lipid kinase PI3Kα undergoes a catalytic reaction in the presence of the substrate PIP2:3PS and ATP, converting ATP to ADP. The activity of the lipid kinase was characterized by measuring the ADP content in the reaction, and the half-maximal inhibitory concentration (IC50) of the compound on the PI3Kα kinase activity was determined. 50.

[0602] The specific experimental procedure is as follows:

[0603] The kinase reaction was performed in white 384-well plates (Perkin Elmer #6007299). 2 μL of different concentrations of the compound diluted with ddH2O containing 1% DMSO was added to each well. For the positive control wells, 2 μL of ddH2O containing 1% DMSO was added. Then, 2 μL of 0.01–1 μg / mL PI3Kα mutant (H1047R, E545K, E542K) and wild-type kinase solutions diluted with 5× kinase buffer (HEPES 250mM, MgCl2 15mM, NaCl 250mM, BSA 0.05%) was added to each well. For the negative control wells, 2 μL of 5× kinase buffer was added. 4 μL of 50 μM substrate PIP2:3PS (Promega #V1701) prepared with 10× dilution buffer and ddH2O was added to all wells. Finally, 2 μL of 50–100 μM kinase diluted with water was added. The reaction was started with ATP solution. After reacting at room temperature for 90–120 minutes, 10 μL of ADP-Glo ​​Reagent (containing 10 mM MgCl2) was added to each well and reacted at room temperature for 60 minutes to remove excess ATP. Then, 20 μL of Kinase Detection Reagent was added to each well and reacted at room temperature in the dark for 20 minutes. The chemiluminescence value was then detected using a BioTek Synergy H1 microplate reader.

[0604] Experimental data processing methods:

[0605] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no kinase added) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[0606] Experimental results:

[0607] Experimental conclusion:

[0608] The above methods show that the compound of this invention exhibits good inhibitory activity in the PI3Kα mutant kinase activity assay, but has weak inhibitory activity against PI3Kα wild-type and has a certain degree of selectivity.

[0609] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention against PI3Kβ / γ / δ kinases.

[0610] Experimental objective: The purpose of this test case is to test the inhibitory activity of the compound on PI3Kβ / γ / δ kinases.

[0611] Experimental instruments: Centrifuge (5810R) purchased from Eppendorf, pipettes purchased from Eppendorf or Rainin, and microplate reader purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[0612] Experimental Methods: This experiment employed the ADP-Glo ​​lipid kinase assay method from Promega (Promega#V9102). The lipid kinase PI3Kβ / γ / δ undergoes a catalytic reaction in the presence of the substrate PIP2:3PS and ATP, converting ATP to ADP. The activity of the lipid kinase was characterized by measuring the ADP content in the reaction, and the half-maximal inhibitory concentration (IC50) of the compound on the PI3Kβ / γ / δ kinase activity was determined. 50 .

[0613] The specific experimental procedure is as follows:

[0614] The kinase reaction was performed in white 384-well plates (Perkin Elmer #6007299). 2 μL of different concentrations of the compound diluted with ddH2O containing 1% DMSO was added to each well. For the positive control wells, 2 μL of ddH2O containing 1% DMSO was added. Then, 2 μL of 0.25–1 μg / mL PI3K kinase solution diluted with 5× kinase buffer (HEPES 250 mM, MgCl2 15 mM, NaCl 250 mM, BSA 0.05%) was added to each well. For the negative control wells, 2 μL of 5× kinase buffer was added. 4 μL of 50 μM substrate PIP2:3PS (Promega #V1701) prepared with 10× dilution buffer and ddH2O was added to all wells. Finally, 2 μL of 50–100 μM ATP solution diluted with water was added to initiate the reaction. After reacting at room temperature for 90–120 minutes, 10 μL of ADP-Glo ​​was added to each well. Reagent (containing 10mM MgCl2) was reacted at room temperature for 60 minutes to remove excess ATP from the reaction. Then, 20μL of Kinase Detection Reagent was added to each well, and the reaction was carried out at room temperature in the dark for 20 minutes. The chemiluminescence value was then detected using a BioTek Synergy H1 microplate reader.

[0615] Experimental data processing methods:

[0616] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no kinase added) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[0617] Experimental results:

[0618] Experimental conclusion:

[0619] The above methods show that the compound of this invention has weak inhibitory activity against PI3Kβ / γ / δ kinases.

[0620] Test Example 3: Determination of the inhibitory effect of the compound of the present invention on the proliferation of PI3Kα mutant cancer cells.

[0621] Experimental objective: The purpose of this test case is to test the inhibitory activity of the compound on the proliferation of PI3Kα mutant cancer cells HCC1954 (PIK3CA H1047R), T47D (PIK3CA H1047R), HGC-27 (PIK3CA E542K), and MKN1 (PIK3CA E545K).

[0622] Experimental instruments: Centrifuge (5702R) purchased from Eppendorf, CO2 incubator purchased from Thermo, biosafety cabinet purchased from Shanghai Boxun Company, pipettes purchased from Eppendorf or Rainin, and ELISA reader purchased from BioTek, USA, model SynergyH1 full-function ELISA reader.

[0623] Experimental methods: The inhibitory effects of the compounds on the proliferation of PI3Kα mutant cancer cell lines HCC1954, T47D, HGC-27, and MKN1 were detected using the Cell Titer-Glo method. Cell lines were cultured in RPMI 1640 medium (Gibco#22400089) containing 10% FBS (Gibco#10091148) and 1% P / S (Hyclone#SV30010) at 37°C and 5% CO2. Cells were collected when they reached a certain degree of confluence. After counting, the cell density was adjusted, and cells were seeded at a density of 1000-10000 cells / well in white 96-well plates (Corning#3610). The plates were incubated overnight at 37°C with 5% CO2. Different concentrations of prepared compound solutions were added, and corresponding solvent controls were set up. The plates were incubated at 37°C with 5% CO2 for 72-144 hours. The cell plates and their contents were equilibrated to room temperature. 20-100 μL of Cell Titer-Glo solution (Promega#G7573) was added to each well. The plates were shaken to mix and then incubated at room temperature in the dark for 10 minutes. The chemiluminescence value was detected using a BioTek SynergyH1 microplate reader.

[0624] Experimental data processing methods:

[0625] The percentage inhibition rate (% inhibition rate) of the wells treated with the compound was calculated using the solvent control wells on the plate {% inhibition rate = 100 - (test compound value / solvent control value) × 100}. The IC50 was calculated by fitting different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula using GraphPad Prism. 50 value.

[0626] Experimental results:

[0627] Experimental conclusion:

[0628] The above methods showed that the compounds of this invention exhibited good inhibitory activity against the proliferation of PI3Kα mutant cancer cells HCC1954 (PIK3CA H1047R), T47D (PIK3CA H1047R), HGC-27 (PIK3CA E542K), and MKN1 (PIK3CA E545K).

[0629] Test Example 4: Determination of the inhibitory activity of the compounds of the present invention on AKT phosphorylation levels in PI3Kα mutant and wild-type tumor cells.

[0630] Experimental objective: The purpose of this test case is to measure the inhibitory activity of the compound on AKT phosphorylation levels in PI3Kα mutant and wild-type tumor cells.

[0631] Experimental apparatus:

[0632] Centrifuge (5810R) purchased from Eppendorf; pipettes purchased from Eppendorf or Rainin; microplate reader purchased from BioTek (Synergy H1 full-function microplate reader); cell counter purchased from Life Sciences (Countess II); nanoliter dispensing system purchased from Dispendix.

[0633] Laboratory reagents and consumables:

[0634] HCC1954 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.; SK-BR-3 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd.; HTRF Phospho-AKT (SER473) Detection Kits were purchased from CisBio, catalog number 64AKSPEG; McCoy's... 5a medium was purchased from Gibco (catalog number 12330-031); RPMI 1640 medium was purchased from Gibco (catalog number 22400-089); FBS was purchased from Gibco (catalog number 10091-148); trypsin was purchased from Gibco (catalog number 25200-056); PBS was purchased from Gibco (catalog number 10010-023); DMSO was purchased from Sigma (catalog number D8418-250ml); cell culture plates were purchased from Corning (catalog number 3610); counting plates were purchased from Invitrogen (catalog number C10283); and white 384-well plates were purchased from PE (catalog number 6007299).

[0635] Experimental methods:

[0636] This experiment used HTRF to detect the intracellular phosphorylated AKT (SER473) levels in PI3Kα mutant cells HCC1954 (PIK3CA H1047R) and PI3Kα wild-type cells SK-BR-3. Different cell lines were cultured in RPMI 1640 or McCoy's 5a complete medium containing 10% FBS at 37°C and 5% CO2. Cells were collected when they reached a certain confluence, counted, and adjusted to a suitable cell density using complete medium. The cell suspension was then seeded into 96-well plates (50 μL per well) and incubated overnight at 37°C with 5% CO2. Different concentrations of compound solutions were prepared using DMSO, and a solvent control was set up. The compound solutions were added to 96-well plates at 150–300 nL per well and incubated at 37°C in a 5% CO2 incubator for 2 hours. After incubation, the supernatant was discarded, and 50 μL of cell lysis buffer containing blocking solution was added. The plates were shaken at room temperature for 30 minutes to 1 hour to allow the cells to fully lyse. 16 μL of the supernatant was transferred to a 384-well plate, and 4 μL of premixed detection reagents (phospho-AKT Eu Cryptate antibody and phospho-AKT d2 antibody) were added. After thorough mixing, the plates were incubated at room temperature in the dark for 4 hours or overnight. The readings were then taken using a BioTek Synergy H1 microplate reader.

[0637] Experimental data processing methods:

[0638] The inhibition rate was calculated using the fluorescence ratio, which was (665nm signal value / 620nm signal value) * 10. 4 Inhibition rate % = [(Average value of positive control wells - Value of sample wells) / (Average value of positive control wells - Average value of negative control wells)] * 100, where positive control wells are those containing cell lysis buffer and negative control wells are those containing lysis buffer. The concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC50. 50 value.

[0639] Experimental results:

[0640] Experimental conclusion:

[0641] The above methods demonstrate that the compound of this invention exhibits excellent inhibitory effects on AKT phosphorylation levels in the PI3Kα mutant tumor cell line HCC1954 (PIK3CAH1047R).

[0642] Test Example 5: Determination of the inhibitory activity of the compound of the present invention on hERG potassium ion channels

[0643] Experimental objective: The purpose of this test case is to evaluate the inhibitory effect of the compound on the hERG potassium ion channel.

[0644] Experimental reagents:

[0645] Reagents and formulations for extracellular fluid used in experiments:

[0646] Reagents and formulations for intracellular fluid used in experiments:

[0647] Experimental methods:

[0648] 1) Cell Culture

[0649] The CHO cells stably expressing the hERG potassium channel used in the experiment (CHO-hERG) were obtained from Sophion Biosciences (Barrerup, Denmark) and passaged and cryopreserved at WuXi AppTec in Shanghai. CHO-hERG cells were passaged in Ham's F-12 medium containing 1x GlutaMAX, 10% fetal bovine serum, 100 μg / mL G418, and 100 μg / mL hygromycin B at 37°C with 5% CO2.

[0650] 2) Preparation of intracellular and extracellular fluids

[0651] Extracellular fluid was prepared monthly and aliquoted into 1L storage bottles. Intracellular fluid was prepared every three months, aliquoted, and frozen at -20°C. Intracellular fluid was thawed in a 37°C water bath before the start of the experiment and then placed in an ice bath for later use.

[0652] 3) Preparation of compounds

[0653] The compounds were prepared as 10 mM or 30 mM stock solutions in 100% DMSO (Sigma-Aldrich, D2650). Before the experiment, the stock solutions of the test compounds were diluted with DMSO to 1000-fold or 333-fold co...

Claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof: M1 is selected from N and NR. a CR a or CR a R a1 Preferred from N and NR a or CR a ; M2 is selected from N and NR. b CR b or CR a R a1 Preferred from N and NR b or CR b ; M3 is selected from N and NR. c CR c or CR a R a1 Preferred from N and NR b or CR c ; L1 is selected from key, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; L2 is selected from bond, -O-, -C(O)-, -C(O)O-, -C(S-), -C(NR) d3 )-、-C(=CR d3 R d4 )-、-NR d2 -, -S-, -S(O)-, -S(O)2-, -C(O)NR d2 -、-C(S)NR d2 -、-C(NR d3 )NR d2 -、-C(=CR d3 R d4 )NR d2 -、C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; L3 is selected from bond, -O-, -C(O)-, -C(S)-, -NR d5 -, -S-, -S(O)-, -S(O)2-, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Alternatively, L2 and L3 form C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene and 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1- 6-Hydroalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Alternatively, atoms on L3 and ring A can link to form C. 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene and 5-14 heteroarylene, optionally further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R1 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R2 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R3 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6- 14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Alternatively, any two R3 atoms can form C with adjacent atoms. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R a Or R a1 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R b Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R c Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, R a R b and R c Any two substituents in the group can be linked to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents are replaced in C; preferably, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted, unsubstituted 5-14 membered heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents are substituted in the C; more preferably, the C is preferred. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted, unsubstituted 5-14 membered heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents in it are replaced; R d1 R d2 R d3 R d4 and R d5 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R aa and R bb Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, R aa With R bb Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R cc and R dd Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, R cc With R dd Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R ee and R ff Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, R ee With R ff Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; n1 is selected from 0, 1, 2, 3, 4 or 5; n2 is selected from 0, 1, 2, 3, 4 or 5; n3 is selected from 0, 1, 2, 3, 4 or 5; a is selected from 0, 1, 2, 3, 4, 5 or 6; b is selected from 0, 1, 2, 3, 4, 5 or 6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, is characterized in that, Further, as shown in general formula (II): M4 is selected from O and NR. e , S or CR e1 R e2 ; Preferred O; Alternatively, M4 and L3 may link to form a 3-12-membered heterocyclic group or a 5-14-membered heterocyclic group, wherein the 3-12-membered heterocyclic group and the 5-14-membered heterocyclic group may optionally be further modified by hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R e1 R e2 and R e3 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -S(R) ee 5. -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff Or -CH=CH(CH2) n3 NR ff C(O)R ee The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted by one or more substituents in the aryl group and substituted or unsubstituted 5-14 heteroaryl groups. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 is characterized in that, Selected from Preferred Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1- 6-alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R 2c Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff 、 -(CH2) n3 NR ff C(O)R ee 、 -(CH2) n3 NR ff S(O)2R ee 、 -NR ff (CH2) n3 R ee 、 -CH=CH(CH2) n3 R ee 、 -CH=CH(CH2) n3 NR ee R ff 、 -CH=CH(CH2) n3 NR ff C(O)R ee 、 =N-OR ee 或 =CR ee R ff ; Or, any two R 2c Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents are replaced in C; preferably, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff One or more substituents in it are replaced; c is selected from 0, 1, 2, 3, 4 or 5; More preferably, Selected from M5 is selected from -(CR f1 R f2 ). n4 -, -CR f1 -, -CR f1 =CR f2 -, -C(O)-, -O-, -S-, -S(O)2-, =S(R f1 )(O)-, -N- or -NR f1 -; preferably selected from -(CR f1 R f2 ). n4 -, -CR f1 -, -CR f1 =CR f2 -, -C(O)-, -O-, -S-, -N- or -NR f1 -; M6 is selected from -(CR) f1 R f2 ) n5 -、-CR f1 -、-CR f1 =CR f2 -, -C(O)-, -O-, -S-, -S(O)2-, =S(R f1 (O)-, -N-, or -NR f1 -; Preferred from -(CR) f3 R f4 ) n5 -、-CR f3 -、-CR f3 =CR f4 -、-C(O)-、-O-、-S-、-N- or -NR f3 -; M7 is selected from -(CR) f1 R f2 ) n6 -、-CR f1 -、-CR f1 =CR f2 -, -C(O)-, -O-, -S-, -S(O)2-, =S(R f1 (O)-, -N-, or -NR f1 -; Preferred from -(CR) f5 R f6 ) n6 -、-CR f5 -、-CR f5 =CR f6 -、-C(O)-、-O-、-S-、-N- or -NR f5 -; Ring C is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; Ring D is selected from C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; R 2d Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff More preferably, C is derived from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee , -S(R ee )5, -(CH2) n3 S(O)2R ee , -(CH2) n3 NR ee R ff , -(CH2) n3 C(O)NR ee R ff , -(CH2) n3 NR ff C(O)R ee , -(CH2) n3 NR ff S(O)2R ee , -NR ff (CH2) n3 R ee , -CH=CH(CH2) n3 R ee , -CH=CH(CH2) n3 NR ee R ff , -CH=CH(CH2) n3 NR ff C(O)R ee , =N-OR ee ; or =CR ee [ R ff ; Or, any two R 2d Forming C with adjacent atoms 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; R f1 R f2 R f3 R f4 R f5 Or R f6 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6- 14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 C(O)C(O)R ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -S(O)2(CH2) n3 OR ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 C(O)C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff Preferred from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C 1- 6-alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -C(O)(CH2) n3 OR ee -(CH2) n3 S(O)R ee -(CH2) n3 S(O)(R ee ) = NR ff -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff More preferably, C is derived from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl and substituted or unsubstituted 5-14 membered heteroaryl groups, -(CH2) n3 R ee -(CH2) n3 OR ee -O(CH2) n3 R ee -(CH2) n3 SR ee -(CH2) n3 C(O)R ee -(CH2) n3 C(O)OR ee -(CH2) n3 S(O)R ee -S(R) ee 5. -(CH2) n3 S(O)2R ee -(CH2) n3 NR ee R ff -(CH2) n3 C(O)NR ee R ff -(CH2) n3 NR ff C(O)R ee -(CH2) n3 NR ff S(O)2R ee -NR ff (CH2) n3 R ee -CH=CH(CH2) n3 R ee -CH=CH(CH2) n3 NR ee R ff -CH=CH(CH2) n3 NR ff C(O)R ee =N-OR ee or = CR ee R ff More preferably, it is derived from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 6-alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; n4 is selected from 0, 1, 2 or 3; n5 is selected from 0, 1, 2 or 3; n6 is selected from 0, 1, 2 or 3; d is selected from 0, 1, 2, 3, 4 or 5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 is characterized in that, Further, as shown in general formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), or (III-7): Preferably, general formula (III-1) is further shown as general formula (III-7): M8 is selected from key, -CR h1 =CR h2 -、-O-、-S-、-NR h3 -、-C(O)NR h3 -、-NR h3 C(O)-、-S(O)2NR h3 -、-NR h3 S(O)2- or -S(O)(=NR h3 )-; M9 is selected from key, -CR h1 =CR h2 -、-O-、-S-、-NR h3 -、-C(O)NR h3 -、-NR h3 C(O)-、-S(O)2NR h3 -、-NR h3 S(O)2- or -S(O)(=NR h3 )-; R h1 R h2 and R h3 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; n7 is selected from 0, 1, 2 or 3; n8 is selected from 0, 1, 2 or 3; n9 is selected from 0, 1, 2 or 3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 is characterized in that, Ring A is selected from C 3-8 Monocyclic cycloalkyl, C 7-11 Spirocycloalkyl, C 7-10 Fused cycloalkyl groups, 3-8 membered monocyclic heterocyclic groups, 7-11 membered spirocyclic groups, 7-10 membered fused heterocyclic groups, C 6-10 Aryl, 5-6 membered monocyclic heteroaryl or 7-14 membered polycyclic heteroaryl; Preferably, ring A is selected from More preferably, ring A is selected from The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 is characterized in that, Selected from X1 and X2 are each independently selected from O, S, Se, N, C(O), NR g1 CR g1 or CR g1 R g2 Preferred from O, S, N, C(O), NR g1 CR g1 or CR g1 R g2 ; X3 is selected from N and NR. g3 CR g3 or C(R) g3 )2; N or CR g3 ; X4 is selected from N or CR g4 X5 is selected from N or CR g5 X6 is selected from N or CR g6 X7 is selected from N or C; X8 is selected from N or C; R g1 R g2 R g3 R g4 R g5 and R g6 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, R g1 With R g3 R g4 R g5 Or R g6 Any substituent in the chain forms C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, R g3 R g4 R g5 and R g6 Any substituent in the chain forms C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, Selected from Preferred from The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 is characterized in that, L1 is selected from key, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, wherein the C 1-3 Alkylene, C 1- 3-ene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Preferred key or C 1-3 Alkylene, wherein the C 1-3 Alkylene, optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; More preferably -CH2-, wherein the -CH2- is optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Alternatively, L3 is selected from key, -O-, -C(O)-, -C(S)-, -NR d1 -, -S-, -S(O)-, -S(O)2-, C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, wherein the C 1-3 Alkylene, C 1-3 imidene group, C 1-3 Ethyne group, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene or 5-10 heteroarylene, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Preferred key or C 1-3 Alkylene, wherein the C 1-3 Alkylene, optionally further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; More preferably, the bond -CH2-, wherein the -CH2- is optionally further converted by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 is characterized in that, Further examples are shown in general formulas (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), or (V-8): R6 and R7 are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Or R6 and X1 are linked to form C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene, wherein the C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene and 5-14 heteroarylene, optionally further converted by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 8 is characterized in that, R2, R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 R aa -(CH2) n1 OR aa -O(CH2) n1 R aa -(CH2) n1 SR aa -S(R) aa 5. -(CH2) n1 C(O)R aa -(CH2) n1 C(O)OR aa -(CH2) n1 S(O)R aa -(CH2) n1 S(O)2R aa -(CH2) n1 NR aa R bb -(CH2) n1 C(O)NR aa R bb -(CH2) n1 NR bb C(O)R aa -(CH2) n1 NR bb S(O)2R aa -NR bb (CH2) n1 R aa -CH=CH(CH2) n1 R aa -CH=CH(CH2) n1 NR aa R bb Or -CH=CH(CH2) n1 NR bb C(O)R aa The C mentioned therein 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents selected from aryl and 5-14 heteroaryl groups; preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl. Or, R3, R 3a R 3b R 3c R 3d and R 3e Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n2 R cc -(CH2) n2 OR cc -O(CH2) n2 R cc -(CH2) n2 SR cc -S(R) cc 5. -(CH2) n2 C(O)R cc -(CH2) n2 C(O)OR cc -(CH2) n2 S(O)R cc -(CH2) n2 S(O)2R cc -(CH2) n2 NR cc R dd -(CH2) n2 C(O)NR cc R dd -(CH2) n2 NR dd C(O)R cc -(CH2) n2 NR dd S(O)2R cc -NR dd (CH2) n2 R cc -CH=CH(CH2) n2 R cc -CH=CH(CH2) n2 NR cc R dd -CH=CH(CH2) n2 NR dd C(O)R cc =N-OR cc or = CR cc R dd The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents selected from aryl and 5-14 heteroaryl groups; preferably hydrogen, fluorine, chlorine, bromine, amino, cyano, mercapto, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl. Or, any two R3, R 3a Or R 3b It can form carbon with adjacent atoms. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Alternatively, R1 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents selected from aryl and 5-14 heteroaryl groups; preferably hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl. Alternatively, R4 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted with one or more substituents from aryl and 5-14 heteroaryl groups; preferably hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, halomethyl, haloethyl, halopropyl, haloisopropyl, methoxy, ethoxy, halomethoxy, haloethoxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl or cyclopropyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 is characterized in that, Selected from the following compounds: A compound of general formula (III-4-1) or a pharmaceutically acceptable salt thereof: Preferably, compounds of the general formula (V-2-1) or their pharmaceutically acceptable salts are preferred: R L1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Hydroxyalkyl; R1 and L1 as defined in claim 1; rings D, M6, M7, R 2a R 2b R 2d And d as defined in claim 3. The compound according to claim 11 or a pharmaceutically acceptable salt thereof is characterized in that, The structure of the compound is as follows: A method for preparing compounds of general formula (III-4) or pharmaceutically acceptable salts thereof, characterized in that: The compound of general formula (III-4-1) or its pharmaceutically acceptable salt reacts with the compound of general formula (III-4-2) or its pharmaceutically acceptable salt in the presence of a base to give the compound of general formula (III-4) or its pharmaceutically acceptable salt. Preferably, the method is a method for preparing a compound of general formula (V-2) or a pharmaceutically acceptable salt thereof: The compound of general formula (V-2-1) or its pharmaceutically acceptable salt reacts with the compound of general formula (V-2-2) or its pharmaceutically acceptable salt in the presence of a base to give the compound of general formula (V-2) or its pharmaceutically acceptable salt. R L1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 1-6 Hydroxyalkyl; R L2 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Rings A, R1, R3, L1, L3 and b as defined in claim 1; R4 as defined in claim 2; rings D, M6, M7, R 2a R 2b R 2d and d as defined in claim 3; X1, R g1 ~R g6 As defined in claim 6; R6 and R7 as defined in claim 8. A pharmaceutical composition comprising a therapeutically effective dose of a compound of the general formula shown in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The use of the compound of any of the general formulas shown in claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14, in the preparation of a medicament for treating diseases associated with PI3Kα kinase dysfunction. The use of the compound of any one of the general formulas shown in claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition of claim 14 in the preparation of a treatment for cancer, PROS, immune disorders, or inflammatory disorders; preferably, the PROS is selected from vascular malformations, lymphatic malformations, and megalencephalopathy, and the cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer, and multiple myeloma; preferably, clear cell ovarian cancer or breast cancer.

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