Polycyclic derivative inhibitors, their preparation methods and applications

Abstract

This invention relates to polycyclic derivative inhibitors, their preparation methods, and applications. In particular, it relates to compounds represented by formula (I′), their preparation methods, pharmaceutical compositions containing such compounds, and their use as kinase inhibitors in the treatment of autoimmune diseases, wherein the substituents in formula (I′) are as defined in the specification.

Description

Polycyclic derivative inhibitor, preparation method and application thereof Technical Field

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

[0002] KIT (CD117), encoded by the c-Kit proto-oncogene, is a Type III receptor tyrosine kinase. Its structure primarily comprises an extracellular domain resembling five immunoglobulins, a transmembrane region, and an intracellular kinase domain. KIT is highly expressed in immune cells, hematopoietic stem cells, germ cells, and melanocytes. When SCF binds to KIT on the cell surface, it activates KIT phosphorylation, promoting the activation of downstream signaling pathways including MAPK, JAK-STAT, and PI3K, thereby promoting their proliferation, survival, and function. Furthermore, while other immune cells may lose KIT during differentiation, mast cell differentiation, survival, and activation are all dependent on KIT expression. Therefore, inhibiting the KIT pathway may simultaneously inhibit mast cell degranulation and proliferation.

[0003] Results from mouse genetic models, in vitro and ex vivo human mast cells, human skin tissue, and human clinical trials have demonstrated that mast cells play a key role in inflammation and urticaria. Targeting mast cells has become an important therapeutic approach for these diseases. KIT inhibitors hold promise for treating urticaria patients who have a poor response to existing therapies.

[0004] Introduction to currently available clinical drugs:

[0005] Celldex's wild-type KIT monoclonal antibody CDX-0159 (Barzolvolimab) is in Phase II clinical trials for urticaria. Preliminary clinical trial results indicate that CDX-0159 has good efficacy in urticaria patients, is well tolerated, has minimal hematologic side effects, and has reversible reproductive side effects. Other indications, including eosinophilic esophagitis and prurigo nodularis, are in Phase I clinical trials. Third Harmonic's KIT inhibitor THB001 entered Phase 1b for urticaria but was discontinued in December 2022 due to hepatotoxicity. The next-generation inhibitor, THB335, is expected to enter the IND phase and initiate clinical trials in the first half of 2024.

[0006] Other KIT small molecule inhibitors include BLU-808 introduced by Blueprint Medicines and MOD-B developed by PeptiDream / Modulus, both of which are in the early preclinical stage.

[0007] Currently published patent applications for KIT inhibitors include: WO2013033070 A1, WO2013033167 A1, WO2013033116A1, etc.

[0008] KIT inhibitors have good application prospects in the pharmaceutical industry as drugs.

[0009] First: KIT inhibitors are expected to provide safer and more effective treatments for patients with urticaria who have relapsed, are refractory, or have poor responses to existing therapies.

[0010] Second: KIT inhibitors block multiple downstream signaling pathways by inhibiting SCF-KIT binding, thereby achieving mast cell depletion, which can theoretically be expanded to other mast cell-related indications.

[0011] Third: As small molecule inhibitors, KIT inhibitors have the advantages of oral administration and good patient compliance compared to large molecule drugs such as IgE monoclonal antibodies and IL-4R monoclonal antibodies. Summary of the Invention

[0012] The object of the present invention is to provide a compound represented by formula (I') or a pharmaceutically acceptable salt thereof:

[0013] in:

[0014] R f Selected from substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 4-14 membered heterocyclic group, substituted or unsubstituted C3-C 14 Cycloalkyl, The substitution mentioned herein refers to the substitution of 1-4 R r replace;

[0015] Ring C is selected from 5-10 membered heterocyclic group, C5-C 10 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0016] Ring D is selected from 5-10 membered heterocyclic group, C5-C 10 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0017] Ring E is selected from phenyl, 5-6 membered heteroaryl, 5-10 membered heterocyclic group or C5-C 10 Cycloalkyl;

[0018] R c 、R d and R eand each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R 11 、-(CH2) p OR 11 、(CH2) p NR 11 R 12 、(CH2) p COR 13 、(CH2) p COOR 11 、(CH2) p CONR 11 R 12 、(CH2) p NR 11 COR 13 、(CH2) p NR 11 COOR 12 、(CH2) p SOR 13 、(CH2) p SONR 11 R 12 、(CH2) p SO2R 13 or (CH2) p SO2NR 11 R 12 ; wherein the substitution refers to 1-4 R 111 replace;

[0019] R 11 、R 12 and R 13and each independently selected from hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to 1-4 R 1111 replace;

[0020] R 111 and R 1111 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0021] R r independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2) q OR 21 、(CH2) q NR21 R 22 、(CH2) q COR 23 、(CH2) q COOR 21 、(CH2) q CONR 21 R 22 、(CH2) q NR 21 COR 23 、(CH2) q NR 21 COOR 22 、(CH2) q SOR 23 、(CH2) q SONR 21 R 22 、(CH2) q SO2R 21 、(CH2) q SO2NR 21 R 22 ; wherein the substitution refers to 1-4 R fff replace;

[0022] R 21 、R 22 and R 23 Each is independently selected from the group consisting of hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to 1-4 R ffff replace;

[0023] R fff and R ffff Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0024] Ring A is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkyl, phenyl and 5-6 membered heterocyclyl, phenyl and C5-C6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and C5-C6 cycloalkyl;

[0025] R a and each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, NHC1-C6 alkyl, N(C1-C6 alkyl)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution refers to substitution by 1-4 groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy or C1-C6 hydroxyalkyl;

[0026] L1 is selected from a bond, (CH2) m1 , C2-C4 alkenylene, C2-C4 alkynylene, (CH2) m2 -O-(CH2) m3 、(CH2) m2 -S-(CH2) m3 、(CH2) m2 -NR h -(CH2) m3 、(CH2) m2 -CO-(CH2)m3 、(CH2) m2 -COO-(CH2) m3 、(CH2) m2 -CONR h -(CH2) m3 、(CH2) m2 -NR h COO-(CH2) m3 、(CH2) m2 -R l NCONR h -(CH2) m3 、(CH2) m2 -SO2-(CH2) m3 、(CH2) m2 -SO2NR h -(CH2) m3 、(CH2) m2 -R l NSO2NR h -(CH2) m3 、(CH2) m2 -SO-(CH2) m3 、(CH2) m2 -SONR h -(CH2) m3 、(CH2) m2 -R l NSONR h -(CH2) m3 or (CH2) m2 -R l NC(=NH)NR h -(CH2) m3 ;

[0027] Ring B is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkyl, phenyl and 5-6 membered heterocyclyl, phenyl and C5-C6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl or 5-6 membered heteroaryl and C5-C6 cycloalkyl;

[0028] R beach independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, (CH2) k OR B-1 、(CH2) k NR B-1 R B-2 、(CH2) k COR B-3 , =NHOR B-1 、=CR B-1 R B-2 、(CH2) k C(=NH)OR B- 1. (CH2) k CONR B-1 R B-2 、(CH2) k NR B-1 COR B-3 、(CH2) k COOR B-3 、(CH2) k NR B-1 COOR B-3 、(CH2) k C(=NH)NR B-1 R B-2 、(CH2) k NR B-1 C(=NH)R B-3 、(CH2) k SOR B-1 、(CH2) k SONR B-1 R B-2 、(CH2) k NR B-1 SOR B-3 、(CH2) k SO2R B-1 、(CH2) k SO2NR B-1 R B-2 or (CH2) k NR B-1SO2R B-3 ; wherein the substitution refers to 1-4 R bb replace;

[0029] R bb Selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl, 5-10 membered halogenated heteroaryl, (CH2) j OR b-1 、(CH2) j NR b-1 R b-2 、(CH2) j COR b-3 , =NHOR b-1 、=CR b-1 R b-2 、(CH2) j C(=NH)OR b- 1. (CH2) j CONR b-1 R b-2 、(CH2) j NR b-1 COR b-3 、(CH2) j NR b-1 COOR b-3 、(CH2) j COOR b-3 、(CH2) j C(=NH)NR b-1 R b-2 、(CH2) j NR b-1 C(=NH)R b-3 、(CH2) j SOR b-1 、(CH2) j SONR b-1 R b-2 、(CH2) j NR b-1 SOR b-3 、(CH2) j SO2R b-1、(CH2) j SO2NR b-1 R b-2 or (CH2) j NR b-1 SO2R b-3 wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with 1-4 R bbb replace;

[0030] R bbb Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0031] R B-1 、R B-2 、R B-3 、R b-1 、R b-2 and R b-3 each independently selected from H, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 haloalkyl, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10Halogenated aryl, 5-10 membered halogenated heteroaryl; wherein the substitution refers to 1-4 R bbbb replace;

[0032] R bbbb Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0033] The H in the above CH2 may be optionally substituted by a substituent selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl;

[0034] R h and R l Each is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0035] m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0036] x is selected from 0, 1, 2, 3, 4, 5, 6; y is selected from 0, 1, 2, 3, 4, 5, 6;

[0037] p, q, j, k, z, e and f are each independently selected from 0, 1, 2, 3, 4, 5, 6.

[0038] In certain embodiments of the present invention, when Ring A is phenyl, R f Not substituted or unsubstituted

[0039] In certain embodiments of the present invention, R f Selected from substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted C3-C 12 Cycloalkyl, preferably, R f Selected from substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 8-10 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocyclyl, substituted or unsubstituted C3-C 12 Cycloalkyl, preferably, R f is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 9-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl, substituted or unsubstituted C5-C 10 Cycloalkyl, more preferably, R f is selected from substituted or unsubstituted 9-10 membered heteroaryl containing 1, 2, 3, 4, 5 or 6 N atoms, wherein the substitution refers to the substitution of 1-4 R r Replacement, R r The definition of is as above.

[0040] In certain embodiments of the present invention, R r is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 , OR 21 NR 21 R 22 、COR 23 、COOR 21 、CONR 21 R 22 NR 21 COR 23 NR 21 COOR 22 、SOR 23 ,SONR 21 R 22 、SO2R 21 、SO2NR 21 R 22 , wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further optionally substituted with deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C The alkyl radicals may be substituted by one or more of C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6 membered haloheterocyclyl, halophenyl or 5-6 membered haloheteroaryl.

[0041] In certain embodiments of the present invention, R r is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further optionally substituted with deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C The alkyl radicals may be substituted by one or more of C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6 membered haloheterocyclyl, halophenyl or 5-6 membered haloheteroaryl.

[0042] In certain embodiments of the present invention, R r is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C3 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR21 R 22 ; wherein the C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl may optionally be further substituted with one or more of deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl and C1-C6 haloalkoxy.

[0043] In certain embodiments of the present invention, R f for

[0044] Wherein: Ring C is selected from phenyl, naphthyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl;

[0045] or Ring D is selected from a 5-6 membered heterocyclyl or a C5-C6 cycloalkyl;

[0046] Preferably, ring C is selected from phenyl, naphthyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, pyrrolopyridinyl, imidazopyridinyl, imidazopyrimidinyl, triazolopyrimidinyl, triazolopyridinyl;

[0047] Preferably, ring D is a 5-6 membered heterocyclic group containing 1, 2 or 3 N atoms;

[0048] Further optimization More preferably Among them, R c1 、R c2 and R c3 The definition is the same as R c , R d1 、R d2 and R d3 The definition is the same as R d ;

[0049] Preferably, R c1 、R c2 and R c3and each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R c11 , OR c11 NR c11 R c12 、COR c13 、CONR c11 R c12 NR c11 COR c13 NR c11 COOR c12 、SOR c13 ,SONR c11 R c12 、SO2R c13 、SO2NR c11 R c12 ; Among them, R c1 、R c2 and R c3 The substitution mentioned in the above is 1-4 R cc replace;

[0050] R c11 、R c12 and R c13 and each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, R c11 、R c12 and R c13 The substitution in the formula is 1-4 Rccc replace;

[0051] R d1 、R d2 and R d3 and each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R d11 , OR d11 NR d11 R d12 、COR d13 、CONR d11 R d12 NR d11 COR d13 NR d11 COOR d12 、SOR d13 ,SONR d11 R d12 、SO2R d13 、SO2NR d11 R d12 ; Among them, R d1 、R d2 and R d3 The substitution mentioned in the above is 1-4 R dd Replacement, R dd Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl; R d11 、Rd12 and R d13 and each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, R d11 、R d12 and R d13 The substitution in the formula is 1-4 R ddd replace;

[0052] R cc 、R ccc 、R dd and R ddd Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0053] Preferably, R c1 Selected from C1-C6 alkylene-R c11 , OR c11 NR c11 R c12 More preferably, R c1 Selected from amino, NHCH3, N(CH3)2, R c2 and R c3 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, preferably hydrogen, methyl, ethyl;

[0054] Preferably, R d1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, more preferably, R d1is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl; R d2 and R d3 Each is independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen, methyl, ethyl.

[0055] In certain embodiments of the present invention, R f for Wherein: Ring C is selected from 5-6 membered heterocyclic group or C5-C6 cycloalkyl;

[0056] Alternatively, ring D is selected from phenyl, naphthyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl; preferably, ring D is selected from pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, pyrrolopyridinyl, imidazopyridinyl, imidazopyrimidinyl, triazolopyrimidinyl, triazolopyridinyl.

[0057] In certain embodiments of the present invention, the compound has a structure shown in formula (I'-A) or (I'-B)

[0058] in,

[0059] Ring Cy is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5-C6 cycloalkyl; wherein the phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5-C6 cycloalkyl is optionally further substituted by 1-4 R r replace;

[0060] X 2 Select N or CR 2 r ;X 4 Select N or CR 4 r ;X 7 Select N or CR 7 r ;X 8 Selected from N or C;

[0061] R 2 r 、R 4 r and R 7 r The definition is the same as R r Preferably, R 2 r 、R 4 r and R 7 rEach is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 , OR 21 NR 21 R 22 、COR 23 、COOR 21 、CONR 21 R 22 NR 21 COR 23 NR 21 COOR 22 、SOR 23 ,SONR 21 R 22 、SO2R 21 、SO2NR 21 R 22wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further optionally substituted with deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C The alkyl radicals may be substituted by one or more of C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6 membered haloheterocyclyl, halophenyl or 5-6 membered haloheteroaryl.

[0062] In certain embodiments of the present invention, the compound has a structure shown in formula (I") or formula (I'):

[0063] in, Each is independently a substituted or unsubstituted 8-9 membered heteroaryl group;

[0064] Ar is selected from 5-6 membered heteroaryl, wherein said heteroaryl is optionally further substituted with 1-4 R r replace;

[0065] X 2 Select N or CR 2 r ;X 4 Select N or CR 4 r ;X 7 Select N or CR 7 r ;X 8 Selected from N or C;

[0066] R 2 r 、R 4 r and R 7 r The definition is the same as R r ;

[0067] Preferably, R 2 r 、R 4 r and R 7 rEach is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further optionally substituted with deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C The alkyl radicals may be substituted by one or more of C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6 membered haloheterocyclyl, halophenyl or 5-6 membered haloheteroaryl.

[0068] In certain embodiments of the present invention, R 2 r 、R 4 r and R 7 rEach is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 , OR 21 NR 21 R 22 、COR 23 、COOR 21 、CONR 21 R 22 NR 21 COR 23 NR 21 COOR 22 、SOR 23 ,SONR 21 R 22 、SO2R 21 、SO2NR 21 R 22wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further optionally substituted with deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C The alkyl radicals may be substituted by one or more of C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6 membered haloheterocyclyl, halophenyl or 5-6 membered haloheteroaryl.

[0069] In certain embodiments of the present invention, R f for

[0070] In certain embodiments of the present invention, the compound has a structure shown in formula (I'-1), formula (I"-1) or formula (I"'-1):

[0071] in, is a substituted or unsubstituted 9-membered heteroaryl group; Each is independently a substituted or unsubstituted 8-membered heteroaryl group;

[0072] X 1 Select N or CR 1 r ;X 2 Select N or CR 2 r ;X 3 Select N or CR 3 r ;X 4 Select N or CR 4 r ;

[0073] X 5 Select N or CR 5 r ;X 6 Select N or CR 6 r ;X 7 Select N or CR 7 r ;X 8 Selected from N or C;

[0074] Y 1Selected from N, O, S or CR 8 r ; Y 2 Selected from N, O, S or CR 9 r ;

[0075] Y 3 Selected from N, O, S or CR 10 r ; R 1 r 、R 2 r 、R 3 r 、R 4 r 、R 5 r 、R 6 r 、R 7 r 、R 8 r 、R 9 r and R 10 r The definition is the same as R r .

[0076] In certain embodiments of the present invention, R 1 r 、R 2 r 、R 3 r 、R 4 r 、R 5 r 、R 6 r 、R 7 r 、R 8 r 、R 9 r and R 10 r Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further optionally substituted with deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C The alkyl radicals may be substituted by one or more of C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6 membered haloheterocyclyl, halophenyl or 5-6 membered haloheteroaryl.

[0077] In certain embodiments of the present invention, It is a 5-membered heteroaromatic ring.

[0078] In certain embodiments of the present invention, ring A is phenyl, 5-6 membered heteroaryl, 5-10 membered heterocyclyl, C5-C 10 Cycloalkyl, preferably ring A is phenyl or 5-6 membered heteroaryl, preferably phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridonyl, thienyl, furyl, thiazolyl, imidazolyl.

[0079] In certain embodiments of the present invention, the compound has a structure represented by Formula (I'-2), Formula (I'-3), or Formula (I'-A'-1):

[0080] Among them, R a1 、R a2 、R a3 、R a4 、R a5 and R a6 The definition is the same as R a ;

[0081] Preferably, R a1 、R a2 、R a3 、R a4 、R a5 and R a6 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy.

[0082] In certain embodiments of the present invention, ring B is a 5-6 membered heteroaryl group, preferably, ring B is oxazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxadiazolyl; preferably, ring B is More preferably, Ring B is

[0083] In certain embodiments of the present invention, the compound has a structure shown in formula (I'-4), formula (I'-5), formula (I'-A-1) or formula (I'-A-2):

[0084] Among them, R b’ The definition is the same as R b ,

[0085] R b’ It is preferably selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy.

[0086] In certain embodiments of the present invention, the compound has a structure shown in formula (I'-6)-(I'-9), formula (I'-A-3) or formula (I'-A-4).

[0087] In certain embodiments of the present invention, R f Selected from Or thiazolyl, wherein Cy1 is a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group, wherein the thiazolyl, the 5-6 membered heteroaryl group, the 5-6 membered heterocyclic group is optionally further substituted by 1-4 R r Substituted; preferably R f Selected from the following groups: substituted or unsubstituted Preferably R f Selected from the following groups: substituted or unsubstituted Preferably R fSelected from the following groups: substituted or unsubstituted The substitution mentioned herein refers to the substitution of 1-4 R r replace.

[0088] In certain embodiments of the present invention, R f Selected from

[0089] In certain embodiments of the present invention, the compound has a structure represented by formula (I'-10), formula (I'-11), formula (I'-10'), formula (I'-11'), (I"-10) or formula (I"-11)

[0090] In certain embodiments of the present invention, the compound has a structure shown in (I'-12), formula (I'-13), formula (I'-12'), formula (I'-13'), (I"-12), formula (I"-13), formula (I'-A'-6) or formula (I'-A'-7).

[0091] In certain embodiments of the present invention, the compound has a structure shown in formula (I'-14) or formula (I'-15):

[0092] In certain embodiments of the present invention, the compound has a structure shown in Formula (I'-16), Formula (I'-17), Formula (I'-16') or Formula (I'-17'):

[0093] In certain embodiments of the present invention, R f Selected from -Ar3-L2-R p ,in,

[0094] Ar3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution refers to substitution by 1-3 groups selected from the following groups: hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to 1-4 Rfff replace;

[0095] L2 is selected from a bond, C1-C6 alkylene, O, NR p1 、CO、COO、CONR p2 NR p3 COO, SO, SONR p4 、SO2、SO2NR p5 ;

[0096] R p1 、R p2 、R p3 、R p4 and R p5 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl;

[0097] R p is selected from hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to 1-4 R ffff replace.

[0098] In certain embodiments of the present invention, R f for Preferred R f for More preferably R f for X 2 Selected from O, S, N, NR 11 r or CR 2 r Preferably, X 2 Select N or CR 2 r ;

[0099] X 3 Select N or CR3 r ;X 4 Selected from O, S, N, NR 11 r or CR 4 r Preferably, X 4 Select N or CR 4 r ;X 5 Select N or CR 5 r ;X 6 Select N or CR 6 r ;X 7 Select N or CR 7 r ;X 8 Selected from N or C; Y 1 Selected from N, O, S or CR 8 r ; Y 2 Selected from N, O, S or CR 9 r ; Y 3 Selected from N, O, S or CR 10 r ; R 1 r 、R 2 r 、R 3 r 、R 4 r 、R 5 r 、R 6 r 、R 7 r 、R 8 r 、R 9 r 、R 10 r and R 11 r The definition is the same as R r .

[0100] In certain embodiments of the present invention, ring Cy is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5-C6 cycloalkyl; wherein the phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5-C6 cycloalkyl is optionally further substituted by 1-4 R r replace.

[0101] In certain embodiments of the present invention, Each is independently a substituted or unsubstituted 8-9 membered heteroaryl. In certain embodiments of the present invention, Each is independently a substituted or unsubstituted 8-membered heteroaryl. In certain embodiments of the present invention, R f Selected from Wherein, Cy1 is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group or the 5-6 membered heterocyclic group is optionally further substituted with 1-4 R r substituted; preferably, R f is selected from the following substituted or unsubstituted groups: The substitution refers to the substitution of 1-4 R r Replacement; R fff 、R ffff and R r The definition of is as above.

[0102] In certain embodiments of the present invention, Ring B is selected from the group consisting of substituted or unsubstituted C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkyl, phenyl and 5-6 membered heterocyclic group, phenyl and C5-C6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclic group or 5-6 membered heteroaryl and C5-C6 cycloalkyl; wherein, the substitution refers to 1-4 R b 'replace;

[0103] Preferably, ring B is a substituted or unsubstituted 5-6 membered heteroaryl or a substituted or unsubstituted 5-6 membered heteroaryl and 5-6 membered heterocyclyl. Preferably, ring B is a substituted or unsubstituted 5-6 membered heteroaryl, a substituted or unsubstituted 5 membered heteroaryl and 5 membered heterocyclyl, a substituted or unsubstituted 5 membered heteroaryl and 6 membered heterocyclyl, a substituted or unsubstituted 6 membered heteroaryl and 5 membered heterocyclyl, a substituted or unsubstituted 6 membered heteroaryl and 6 membered heterocyclyl; Preferably, ring B is a substituted or unsubstituted The following groups: oxazolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, triazinyl; More preferably, ring B is substituted or unsubstituted: oxazolyl, isoxazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxadiazolyl; wherein the substitution refers to the substitution of 1-4 R b 'replace;

[0104] Among them, R b'are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thioxo, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl or 5-10 membered halogenated heteroaryl;

[0105] Preferably, ring B is selected from Preferably selected from

[0106] Cy3 is a 5-membered heteroaryl group; Cy2 is a 5-6-membered heterocyclic group; y" is 0, 1 or 2; y"' is 0, 1, 2 or 3; R b ' - 6 、R b ' -7 and R b ' -8 The definition is the same as R b ';

[0107] Preferably, R b ' -6 、R b ' -7 and R b ' -8 Each is independently selected from H, deuterium, halogen, amino, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0108] In certain embodiments of the present invention, R b 'are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thioxo, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10halogenated aryl or 5-10 membered halogenated heteroaryl.

[0109] In certain embodiments of the present invention, for wherein ring G is selected from C3-C8 cycloalkyl or 4-8 membered heterocyclic group, f1 is 1, 2, 3 or 4; y' is 0, 1, 2 or 3; R b ' and R bb The definition of is as above,

[0110] More preferably Selected from

[0111] wherein Ar1 is a 5-membered heteroaryl group; Ar2 is a 6-membered heteroaryl group; Z2 is selected from C or N; Z3 is selected from O, S, N, NR b ' -4 , CR b ' -2 ; Z4 is selected from O, S, N, NR b ' -4 , CR b ' -3 ; Z5 is selected from C or N; Z6 is selected from O, S, N, NR b ' - 4 , CR b ' -1 ; W1 is selected from CR b ' -1 or N; W2 is selected from CR b ' -2 or N; W3 is selected from CR b ' -3 or N; W4 is selected from CR b ' -5 or N;

[0112] Preferably, Selected from Among them, R b ' -1 、R b ' -2 、R b ' -3 、R b ' -4 and R b ' -5 The definition is the same as R b '; Preferably, R b ' -1 、R b ' -2 、R b '-3 and R b ' -5 R is selected from the group consisting of H, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; b ' -4 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl.

[0113] In certain embodiments of the present invention, R b and each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, (CH2) k OR B-1 、(CH2) k NR B-1 R B-2 、(CH2) k COR B-3 、(CH2) k COOR B-3 、(CH2) k OCOR B-3 , =NHOR B-1 、=CR B-1 R B-2 、(CH2) k C(=NH)OR B-1 、(CH2) k CONR B-1 R B-2 、(CH2) k NR B-1 COR B-3 、(CH2) k NR B-1 COOR B-3 、(CH2) k C(=NH)NR B-1 R B-2 、(CH2) k NR B-1 C(=NH)RB-3 、(CH2) k SOR B-1 、(CH2) k SONR B-1 R B-2 、(CH2) k NR B-1 SOR B-3 、(CH2) k SO2R B-1 、(CH2) k SO2NR B-1 R B-2 or (CH2) k NR B- 1SO2R B-3 ; wherein the substitution refers to 1-4 R bb replace;

[0114] R bb Selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 halogenated aryl, 5-10 membered halogenated heteroaryl, (CH2) j OR b-1 、(CH2) j NR b-1 R b-2 、(CH2) j COR b-3 、(CH2) j COOR b-3 、(CH2) j OCOR b-3 , =NHOR b-1 、=CR b-1 R b-2 、(CH2) j C(=NH)OR b-1 、(CH2) j CONR b-1 R b-2 、(CH2) j NR b-1 COR b-3 、(CH2) j NRb- 1COOR b-3 、(CH2) j C(=NH)NR b-1 R b-2 、(CH2) j NR b-1 C(=NH)R b-3 、(CH2) j SOR b-1 、(CH2) j SONR b- 1R b-2 、(CH2) j NR b-1 SOR b-3 、(CH2) j SO2R b-1 、(CH2) j SO2NR b-1 R b-2 or (CH2) j NR b-1 SO2R b-3 wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with 1-4 R bbb In certain embodiments of the present invention, R b and each is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, oxo, thioxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, OR B-1 NR B-1 R B-2 、COR B-3 、COOR B-3 , OCOR B-3 , =NHOR B-1 、CONR B-1 R B-2 NRB-1 COR B-3 NR B-1 COOR B-3 、C(=NH)NR B-1 R B-2 、=CR B-1 R B-2 NR B- 1C(=NH)R B-3 、SOR B-1 ,SONR B-1 R B-2 NR B-1 SOR B-3 、SO2R B-1 、SO2NR B-1 R B-2 or NR B-1 SO2R B- 3; among them, R b The substitution mentioned herein refers to substitution by 1 to 4 R bb Substitute, where R bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halophenyl, 5-6 membered halogenated heteroaryl, OR b-1 NR b-1 R b-2 、COR b-1 、COOR b-1 , OCOR b-1 、CONR b- 1R b-2 NR b-1 COR b-1 , =NHOR b-1 NR b-1 COOR b-3 、C(=NH)NR b-1 R b-2 NR b-1 C(=NH)R b-3 、=CR b-1 R b-2 、SOR b-1 ,SONR b-1 R b-2 NR b-1 SOR b-3 、SO2R b-1 、SO2NRb-1 R b-2 or NR b-1 SO2R b-3 , preferably, R b each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, OR B-1 NR B-1 R B-2 、COR B-3 , =NHOR B-1 、CONR B-1 R B-2 NR B-1 COR B-3 、COOR B-3 NR B- 1COOR B-3 、C(=NH)NR B-1 R B-2 、=CR B-1 R B-2 NR B-1 C(=NH)R B-3 、SOR B-1 ,SONR B-1 R B-2 NR B- 1SOR B-3 、SO2R B-1 、SO2NR B-1 R B-2 or NR B-1 SO2R B-3 ; Among them, R b The substitution mentioned herein refers to substitution by 1 to 4 R bb Substitute, where R bbis selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halophenyl, 5-6 membered halogenated heteroaryl, OR b-1 NR b-1 R b-2 、COR b-1 、CONR b-1 R b-2 NR b-1 COR b-1 , =NHOR b-1 、COOR b-3 NR b-1 COOR b-3 、C(=NH)NR b-1 R b-2 NR b-1 C(=NH)R b-3 、=CR b-1 R b-2 、SOR b-1 ,SONR b-1 R b-2 NR b-1 SOR b-3 、SO2R b- 1. SO2NR b-1 R b-2 or NR b-1 SO2R b-3 , where R bb The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may be further replaced by 1-4 R bbb Replacement, R bbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halophenyl, 5-6 membered halogenated heteroaryl; wherein R B-1 、R B-2、R B-3 、R b-1 、R b-2 and R b-3 Each is independently selected from hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halophenyl, 5-6 membered halogenated heteroaryl; wherein, R B-1 、R B-2 、R B-3 、R b-1 、R b-2 and R b-3 The substitution in the formula is 1-4 R bbbb Substitute, where R bbbb Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thioxo, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halophenyl, 5-6 membered halogenated heteroaryl.

[0115] In certain embodiments of the present invention, R b Each independently C1-C3 alkylene OC1-C3 alkyl, C1-C3 alkylene OC1-C3 haloalkyl, wherein ring G is selected from C3-C6 cycloalkyl or 4-6 membered heterocyclic group, and f1 is 1, 2, 3 or 4.

[0116] In certain embodiments of the present invention, R bC1-C3 alkylene OC1-C3 alkyl, C1-C3 alkylene OC1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C3 alkylene C3-C6 cycloalkyl, C1-C3 alkylene 4-6 membered heterocyclic group, C1-C3 alkylene C3-C6 halocycloalkyl, C1-C3 alkylene 4-6 membered haloheterocyclic group, C1-C3 alkoxy substituted C3-C6 cycloalkyl, C1-C3 haloalkoxy substituted C3-C6 cycloalkyl, C1-C3 alkylCOO substituted C3-C6 cycloalkyl, C1-C3 alkylOCO substituted C3-C6 cycloalkyl, C1-C3 alkylCO NH-substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1-C3 alkylNHCO, C3-C6 cycloalkyl substituted by C1-C3 alkylNHCOO, 4-6-membered heterocyclyl, 4-6-membered halogenated heterocyclyl, 4-6-membered heterocyclyl substituted by C1-C3 alkoxy, 4-6-membered heterocyclyl substituted by C1-C3 haloalkoxy, 4-6-membered heterocyclyl substituted by C1-C3 alkylCOO, 4-6-membered heterocyclyl substituted by C1-C3 alkylOCO, 4-6-membered heterocyclyl substituted by C1-C3 alkylCONH, 4-6-membered heterocyclyl substituted by C1-C3 alkylNHCO or 4-6-membered heterocyclyl substituted by C1-C3 alkylNHCOO.

[0117] In certain embodiments of the present invention, R f Selected from

[0118] In certain embodiments of the present invention, R f Selected from Preferably, R f Selected from Preferred R f Selected from In certain embodiments of the present invention, R f Selected from In certain embodiments of the present invention, R f Selected from

[0119] In certain embodiments of the present invention, for More preferably for Among them, R a1、R a2 、R a3 and R a4 The definition of is as above.

[0120] In certain embodiments of the present invention, R a1 Selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, preferably methyl.

[0121] In certain embodiments of the present invention, R a2 It is selected from hydrogen or halogen (such as fluorine, chlorine or bromine), preferably hydrogen or fluorine.

[0122] In certain embodiments of the present invention, R a3 It is selected from hydrogen or halogen (such as fluorine, chlorine or bromine), preferably hydrogen or fluorine.

[0123] In certain embodiments of the present invention, R a4 Selected from hydrogen.

[0124] In certain embodiments of the present invention, for Among them, R a5 and R a6 The definition of is as above.

[0125] In certain embodiments of the present invention, Ring A is Preferably, ring A is Preferably, ring A is

[0126] In certain embodiments of the present invention, Ring A is

[0127] In certain embodiments of the present invention, R a are each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, preferably, R a Each is independently selected from hydrogen, deuterium, halogen, and C1-C3 alkyl.

[0128] In certain embodiments of the present invention, R b Each is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, COC1-C3 alkyl, CH=NOH, CH=NOC1-C3 alkyl, Preferred R bEach independently selected from More preferably R b for

[0129] In certain embodiments of the present invention, Ring B is selected from the group consisting of substituted or unsubstituted: Wherein, the substitution refers to 1, 2 or 3 R b 'replace.

[0130] In certain embodiments of the present invention, R b ' is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy.

[0131] In certain embodiments of the present invention, ring G is selected from C3-C6 cycloalkyl or 4-6 membered heterocyclic group, preferably

[0132] In certain embodiments of the present invention, R bb Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylCOO, C1-C3 alkylOCO, C1-C3 alkylCONH, C1-C3 alkylNHCO, C1-C3 alkylNHCOO, C1-C3 haloalkylCOO, C1-C3 haloalkylOCO, C1-C3 haloalkylCONH, C1-C3 haloalkylNHCO, C1-C3 haloalkylNHCOO.

[0133] In certain embodiments of the present invention, L2 is selected from NH or NHCOO.

[0134] In certain embodiments of the present invention, Ar3 is selected from substituted or unsubstituted 5-6 membered heteroaryl, preferably substituted or unsubstituted: thiazolyl, thiadiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl; more preferably substituted or unsubstituted: The substitution refers to hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0135] In certain embodiments of the present invention, Ar and Cy1 are each independently selected from the group consisting of substituted or unsubstituted oxazolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, triazinyl; wherein the substitution refers to hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C1-C2 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0136] In certain embodiments of the present invention, R p C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl, 5-6 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl, 5-6 membered heteroaryl are optionally further substituted by one or more of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy; preferably, R p Selected from methyl, ethyl, propyl, cyclopropyl,

[0137] In certain embodiments of the present invention, L1 is selected from a bond, NH, O, CO, CONH, and L1 is preferably a bond.

[0138] In certain embodiments of the present invention, X 1 In certain embodiments of the present invention, X 2 is N.

[0139] In certain embodiments of the present invention, X 5 In certain embodiments of the present invention, X 7 is N.

[0140] In certain embodiments of the present invention, X 2 and X 7 is N. In certain embodiments of the present invention, X 1 、X 2 and X 7 In certain embodiments of the present invention, X 2 、X 5 and X 7 In certain embodiments of the present invention, X 3 CR 3 r In certain embodiments of the present invention, X 4 CR 4 r In certain embodiments of the present invention, X 6 CR 6 r In certain embodiments of the present invention, Y 1 is selected from S or O. In certain embodiments of the present invention, Y 2 Selected from CR 9 r In certain embodiments of the present invention, Y 3 Selected from CR 10 r In certain embodiments of the present invention, X 7 is N or C. In certain embodiments of the present invention, X 8 is N.

[0141] In certain embodiments of the present invention, R 1 r 、R 2 r 、R 3 r 、R 4 r 、R 5 r 、R 6 r 、R 7 r 、R 8 r 、R9 r and R 10 r Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C3 alkylene-R 21 、(CH2)OR 21 、(CH2)NR 21 R 22 、(CH2)COR 23 、(CH2)COOR 21 、(CH2)CONR 21 R 22 、(CH2)NR 21 COR 23 、(CH2)NR 21 COOR 22 、(CH2)SOR 23 、(CH2)SONR 21 R 22 、(CH2)SO2R 21 、(CH2)SO2NR 21 R 22 ; wherein the C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl may optionally be further substituted with one or more of deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl and C1-C6 haloalkoxy.

[0142] In certain embodiments of the present invention, m1 is 0, 1, 2 or 3.

[0143] In certain embodiments of the present invention, m2 and m3 are each independently 0 or 1, preferably 0.

[0144] The present invention also provides a compound shown below

[0145] Among them, R Nis selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0146] R a1 、R a2 、R a4 , L1, Ring B, y and R b The definition of is as above.

[0147] The present invention also provides a method for preparing a compound of formula (I"-10), formula (I"-14), formula (I"-15) or formula (I'-A'-1) or a pharmaceutically acceptable salt thereof:

[0148] Method 1: React the compounds represented by formula (INT-3) and formula (INT-2) to prepare the compound represented by formula (I"-10).

[0149] Method 2: React the compounds represented by formula (INT-3) and formula (INT'-2) to prepare the compound represented by formula (I"-14).

[0150] Method 3: React the compounds represented by formula (INT-3) and formula (INT"-2) to prepare the compound represented by formula (I"-15).

[0151] Method 4: reacting the compound represented by formula (INT-4) and formula (INT"'-2) to prepare the compound represented by formula (I'-A'-4).

[0152] Preferably, the reaction of methods 1 to 4 is carried out in the presence of a base and a catalyst, the base is an organic base, and the catalyst is an amide condensation agent; wherein R O Selected from OH or C1-C6 alkoxy;

[0153] R N is selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0154] R4 r 、R 9 r 、R 10 r 、R a 、R b , L1, Ring A, Ring B, x, y, R f 、R a1 、R a2 、R a4 , L1, R b’ and R b The definition of is as above.

[0155] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the above compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0156] In certain embodiments of the present invention, the weight percentage of the compound or a pharmaceutically acceptable salt thereof in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0157] The present invention further relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a medicament for preparing a kinase inhibitor, preferably an FMS (CSF1R), PDGFRβ, PDGFRα, FLT3, or c-KIT kinase inhibitor, more preferably a c-KIT kinase inhibitor, and more preferably an inhibitor that exhibits good selectivity for c-KIT.

[0158] The present invention further relates to the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a drug for treating c-KIT kinase-related diseases.

[0159] In a preferred embodiment of the present invention, the disease is selected from the group consisting of: mast cell-related diseases, respiratory diseases, inflammatory disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH);

[0160] Preferably, the disease is selected from the group consisting of asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, chronic urticaria, spontaneous chronic urticaria, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mastocytoma, mastocytosis, allergic reaction syndrome, type I diabetes or type II diabetes, more preferably urticaria or chronic urticaria.

[0161] The present invention further relates to a method for preparing a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating mast cell-related diseases, respiratory diseases, inflammatory conditions, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH).

[0162] The present invention also relates to a method for treating, preventing and / or treating mast cell-related diseases, respiratory diseases, inflammatory disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH), which comprises administering to a patient a therapeutically effective dose of a compound as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0163] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with FMS (CSF1R), PDGFRβ, PDGFRα, FLT3, c-KIT kinase inhibitors, more preferably c-KIT kinase dysfunction, and showing good selectivity for c-KIT.

[0164] The present invention also relates to a method of treating mast cell-related diseases, respiratory diseases, inflammatory disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH) in a mammal, 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.

[0165] In some embodiments, the present method relates to the treatment of conditions such as asthma, eosinophilic esophagitis, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, chronic urticaria, spontaneous chronic urticaria, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mastocytoma, mastocytosis, allergic reaction syndrome, type I diabetes or type II diabetes, more preferably urticaria or chronic urticaria.

[0166] In some embodiments, urticaria or chronic urticaria includes acute urticaria, chronic spontaneous urticaria (type I IgE mediated / type II IgG mediated), and chronic inducible urticaria.

[0167] Detailed Description of the Invention

[0168] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0169] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

[0170] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C1-C 20 ), 1 to 15 (C1-C 15 ), 1 to 12 (C1-C 12 ), 1 to 10 (C1-C 10 ), a straight-chain saturated hydrocarbon group having 1 to 8 (C1-C8), 1 to 6 (C1-C6) or 1 to 3 (C1-C3) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C3-C 20 ), 3 to 15 (C3-C 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C 10 ), 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms with a branched saturated hydrocarbon group. The straight chain C 1- -C6 alkyl and branched C 3- -C6 alkyl groups are also called "lower alkyl". For example, C 1--C6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1- -C6 alkyl 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 chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0171] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0172] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be located at any position within the alkenyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkenyl group is a group having 2 to 20 (C2-C 20 ), 2 to 15 (C2-C 15 ), 2 to 12 (C2-C 12 ), 2 to 10 (C2-C 10), a straight-chain unsaturated hydrocarbon group having 2 to 8 (C2-C8), 2 to 6 (C2-C6) or 2 to 4 (C2-C4) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C3-C 20 ), 3 to 15 (C3-C 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C 10 ), 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. Unless otherwise indicated, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C2-C6 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 C2-C6 alkenyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0173] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 2 to 20 (C2-C 20 ), 2 to 15 (C2-C 15 ), 2 to 12 (C2-C 12 ), 2 to 10 (C2-C 10 ), a straight-chain unsaturated hydrocarbon group having 2 to 8 (C2-C8), 2 to 6 (C2-C6) or 2 to 4 (C2-C4) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C3-C 20 ), 3 to 15 (C3-C 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C 10 ), 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, a C2-C6 alkynyl group 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 C2-C6 alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0174] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a particular embodiment, the cycloalkyl ring contains 3 to 20 (C3-C 20 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C 10 ), 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0175] The term "spiroalkyl" refers to an aliphatic hydrocarbon polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroalkyl group contains 5 to 20 (C5-C 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 ) (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl is divided into mono-, di-, or poly-spirocycloalkyl according to the number of shared spiro atoms between the rings, and in one embodiment, is mono- and di-spirocycloalkyl. In one embodiment, it is a 4-, 3-, 5-, 4-, 5-, 4-, 6-, 5-, or 5-membered mono-spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

[0176] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the fused cycloalkyl group comprises 5 to 20 (C5-C20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, and in one embodiment, it is bicyclic or tricyclic, and further in one embodiment, it is a 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. In one embodiment, the fused cycloalkyl group is an optionally substituted fused cycloalkyl group described elsewhere herein or a fused cycloalkyl group optionally fused with a heterocyclic group, an aryl group or a heteroaryl group. Non-limiting examples of fused cycloalkyl groups include:

[0177] The term "bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the bridged cycloalkyl group comprises 5 to 20 (C5-C 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 ) (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of constituent rings, the bridged cycloalkyl group may be bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl group is an optionally substituted bridged cycloalkyl group described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include:

[0178] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxygen, but excluding the ring portion of -OO- or -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl group contains 3 to 20, 3 to 12, 3 to 10, 3 to 8, 4 to 10, 4 to 8, 3 to 6 or 4 to 6 ring atoms, of which 1 to 4 are heteroatoms, such as nitrogen, oxygen, sulfur; in one embodiment, the heterocyclyl group contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10 or 7 to 11 ring atoms; in one embodiment, the heterocyclyl group contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.In one embodiment, described heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0179] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl according to the number of spirohetero atoms shared between the rings; monospiroheterocyclyl and bispiroheterocyclyl are preferred; in one embodiment, the spiroheterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:

[0180] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclyl is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl is an optionally substituted or fused heterocyclyl described elsewhere herein, or a cycloalkyl, heterocyclyl, aryl or heteroaryl group; non-limiting examples of fused heterocyclyls include:

[0181] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In specific embodiments, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups; preferably bicyclic, tricyclic or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0182] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted with one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is aromatic and the other rings may be saturated, partially unsaturated, or contain one or more heteroatoms independently selected from O, S, and N. In one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl group, a benzo 3-10 membered cycloalkyl group, or a benzo 3-10 membered heterocyclyl group. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl group, a benzo 3-6 (e.g., 5-6) membered cycloalkyl group, or a benzo 3-6 (e.g., 5-6) membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

[0183] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

[0184] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, the heteroaryl group contains 5 to 20, 5 to 15 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in particular embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from a heteroaryl group with 6-10 members, a heteroaryl group with 3-10 members, or a heteroaryl group with 3-10 members, and a heterocyclyl group with 3-10 members. In another embodiment, the heteroaryl group is selected from a 5- or 6-membered heteroaryl group with 6-10 members, a 5- or 6-membered heteroaryl group with 3-6 members, and a 5- or 6-membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothienyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0185] The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

[0186] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0187] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

[0188] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0189] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH2CF3,

[0190] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0191] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0192] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.

[0193] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0194] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

[0195] The term "aminocarbonyl" refers to NH2-C(O)-.

[0196] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0197] The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0198] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0199] The term "hydroxy" refers to an -OH group.

[0200] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0201] The term "amino" refers to -NH2.

[0202] The term "cyano" refers to -CN.

[0203] The term "nitro" refers to -NO2.

[0204] The term "carboxy" refers to -C(O)OH.

[0205] The term "acetyl" refers to -C(O)CH3.

[0206] The term "oxo" or "oxo" refers to =0.

[0207] The term "mercapto" refers to -SH.

[0208] The term "hydrogen" includes protons ( 1 H), deuterium ( 2H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

[0209] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Isotopically labeled compounds can be prepared in the usual manner by substituting a readily available isotopically labeled reagent for a non-isotopic reagent using the disclosed exemplified schemes.

[0210] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituents are selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

[0211] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0212] Unless otherwise indicated, when describing a substituent by writing a conventional chemical formula from left to right, the substituent also includes chemically equivalent substituents obtained when writing the formula from right to left. For example, -CH2O- is equivalent to -OCH2-, and -CONH- is equivalent to -NHCO-.

[0213] In this application The position of the group is indicated by the bond extending into the ring. This means attachment at any available ring vertex, e.g., the group Middle key It can be connected to any connectable position of the ring, and its substituent R c and / or R d Any hydrogen atom on the ring may be substituted, including any hydrogen on a carbon atom and any hydrogen on a nitrogen atom.

[0214] In certain embodiments of the present invention, represents a ring system in which ring C, ring D and ring E are fused in pairs, for example

[0215] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0216] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0217] " substituted " refers to that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment in one embodiment. When a substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" refers to that it may be substituted or not, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical achievable. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0218] In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

[0219] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0220] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0221] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0222] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0223] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

[0224] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0225] "Optically active" and "enantiomeric active" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.

[0226] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of the optical rotations (+) and (-) have nothing to do with the absolute configuration, R or S, of the molecule. DETAILED DESCRIPTION

[0227] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0228] Example

[0229] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0230] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0231] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0232] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0233] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0234] Preparation of intermediate 2-(5-cyclopropylisoxazol-3-yl)-5-methyl-pyridin-4-amine

[0235] Step 1: Preparation of 5-methyl-4-nitro-pyridine-2-carbaldehyde oxime

[0236] 5-Methyl-4-nitro-pyridine-2-carbaldehyde (12 g, 72.23 mmol) was dissolved in ethanol (80 mL), and a 50% aqueous hydroxylamine solution (5 mL) was added. The reaction mixture was heated and stirred at 80°C for 1 hour. The solvent was removed under reduced pressure to obtain the crude compound 5-methyl-4-nitro-pyridine-2-carbaldehyde oxime (12.5 g, 95.5%), which was used directly in the next step. MS m / z (ESI): 182.0 [M+H] + .

[0237] Step 2: Preparation of 5-cyclopropyl-3-(5-methyl-4-nitro-2-pyridyl)isoxazole

[0238] Under ice, 5-methyl-4-nitro-pyridine-2-carbaldehyde oxime (12.5 g, 69.00 mmol) and cyclopropylacetylene (9.12 g, 138.01 mmol) were dissolved in methanol (100 mL) / water (20 mL). [Bis(trifluoroacetoxy)iodo]benzene (44.51 g, 103.51 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (10.6 g, 62.6%). MS m / z (ESI): 246.1 [M+H] + .

[0239] Step 3: Preparation of 2-(5-cyclopropylisoxazol-3-yl)-5-methyl-pyridin-4-amine

[0240] Dissolve 5-cyclopropyl-3-(5-methyl-4-nitro-2-pyridyl)isoxazole (8.4 g, 34.25 mmol) in ethanol (100 mL), add zinc powder (11.20 g, 171.27 mmol) and acetic acid (10 mL), and heat the reaction mixture at 80°C with stirring for 6 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (3.3 g, 44.8%). MS m / z (ESI): 216.1 [M+H] + .

[0241] 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.15(s,1H),6.55(s,1H),6.03(s,2H),2.20-2.11(m,1H),2.04(s,3H),1.13-1.02(m,2H),1.00-0.87(m,2H).

[0242] Preparation of intermediate 3-(3-(4-amino-5-methylpyridin-2-yl)isoxazol-5-yl)azetidine-1-carboxylic acid methyl ester

[0243] Step 1: Preparation of tert-butyl (2-formyl-5-methylpyridin-4-yl)carbamate

[0244] At room temperature, tert-butyl (2-bromo-5-methylpyridin-4-yl)carbamate (600.8 mg, 2.1 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to -78°C. n-Butyl lithium (3.3 mL, 5.3 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes. Then, dimethylformamide (766.5 mg, 10.5 mmol) was added dropwise and stirred at -78°C for 30 minutes. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude tert-butyl (2-formyl-5-methylpyridin-4-yl)carbamate (495.6 mg, 100%), which was used directly in the next step. MS m / z (ESI): 237.1 [M+H] + .

[0245] Step 2: Preparation of tert-butyl (2-((oximino)methyl)-5-methylpyridin-4-yl)carbamate

[0246] At room temperature, tert-butyl (2-formyl-5-methylpyridin-4-yl)carbamate (495.6 mg, 2.1 mmol) was dissolved in ethanol (8 mL), and a 50% aqueous hydroxylamine solution (693.0 mg, 10.5 mmol) was added. The mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated to give crude tert-butyl (2-((oximino)methyl)-5-methylpyridin-4-yl)carbamate (527.1 mg, 100%), which was used directly in the next reaction. MS m / z (ESI): 252.1 [M+H] + .

[0247] Step 3: Preparation of tert-butyl 3-(3-(4-((tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoxazol-5-yl)azetidine-1-carboxylate

[0248] At room temperature, tert-butyl (2-((hydroxyimino)methyl)-5-methylpyridin-4-yl)carbamate (527.1 mg, 2.1 mmol) was dissolved in tetrahydrofuran / methanol / water (5 mL / 5 mL / 2 mL). tert-butyl 3-ethynylazetidine-1-carboxylate (760.2 g, 4.2 mmol) and [bis(trifluoroacetoxy)iodo]benzene (2.7 g, 6.3 mmol) were added. The mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (284.1 mg, 31%). MS m / z (ESI): 431.2 [M+H] + .

[0249] Step 4: Preparation of 2-(5-(azetidin-3-yl)isoxazol-3-yl)-5-methylpyridin-4-amine

[0250] At room temperature, tert-butyl 3-(3-(4-((tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoxazol-5-yl)azetidine-1-carboxylate (284.1 mg, 0.66 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude 2-(5-(azetidine-3-yl)isoxazol-3-yl)-5-methylpyridin-4-amine (151.8 mg, 100%), which was used directly in the next reaction. MS m / z (ESI): 231.1 [M+H] + .

[0251] Step 5: Preparation of methyl 3-(3-(4-amino-5-methylpyridin-2-yl)isoxazol-5-yl)azetidine-1-carboxylate

[0252] 2-(5-(azetidin-3-yl)isoxazol-3-yl)-5-methylpyridin-4-amine (151.8 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL) at room temperature and cooled to 0°C. Triethylamine (333.3 mg, 3.3 mmol) was added, followed by the dropwise addition of dimethyl dicarbonate (176.9 mg, 1.32 mmol). The mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to obtain the title compound (169.6 mg, 89%), which was used directly in the next step. MS m / z (ESI): 289.1 [M+H] + .

[0253] Preparation of intermediate 3-[3-(5-amino-2-fluoro-4-methyl-phenyl)isoxazol-5-yl]azetidine-1-carboxylic acid methyl ester

[0254] Step 1: Preparation of 2-fluoro-4-methyl-5-nitrobenzaldehyde oxime

[0255] 2-Fluoro-4-methyl-5-nitrobenzaldehyde (5 g, 27.30 mmol) was dissolved in ethanol (50 mL), and a 50% aqueous hydroxylamine solution (5 mL) was added. The reaction mixture was heated and stirred at 80°C for 1 hour. The solvent was removed under reduced pressure to obtain the crude compound 2-fluoro-4-methyl-5-nitrobenzaldehyde oxime (5.1 g, 94.3%), which was used directly in the next step. MS m / z (ESI): 199.0 [M+H] + .

[0256] Step 2: Preparation of tert-butyl 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoxazol-5-yl]azetidine-1-carboxylate

[0257] Under ice, 2-fluoro-4-methyl-5-nitrobenzaldehyde oxime (5.10 g, 25.74 mmol) and tert-butyl 3-alkynyl-1-azetidinecarboxylate (5.60 g, 30.89 mmol) were dissolved in methanol (50 mL) / water (10 mL). [Bis(trifluoroacetoxy)iodo]benzene (16.60 g, 38.61 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (4.89 g, 50.4%). MS m / z (ESI): 378.1 [M+H] + .

[0258] Step 3: Preparation of methyl 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoxazol-5-yl]azetidine-1-carboxylate

[0259] tert-Butyl 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoxazol-5-yl]azetidine-1-carboxylate (4.89 g, 12.96 mmol) was dissolved in DCM (20 mL) / 4M HCl dioxane (5 mL) and stirred at room temperature for 30 minutes. The solvent was removed from the reaction mixture under reduced pressure, and the residue was dissolved in DCM (20 mL). Triethylamine (8.01 g, 79.11 mmol, 11.03 mL) was added, and dimethyl dicarbonate (2.55 g, 18.99 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride solution and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (3.83 g, 88.2%). MS m / z (ESI): 336.1 [M+H] + .

[0260] Step 4: Preparation of 3-[3-(5-amino-2-fluoro-4-methyl-phenyl)isoxazol-5-yl]azetidine-1-carboxylic acid methyl ester

[0261] Methyl 3-[3-(2-fluoro-4-methyl-5-nitrophenyl)isoxazol-5-yl]azetidine-1-carboxylate (3.83 g, 11.42 mmol) was dissolved in ethanol (80 mL). Zinc powder (3.73 g, 57.12 mmol) and acetic acid (10 mL) were added. The reaction mixture was stirred at 80°C for 6 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (2.75 g, 78.9%). MS m / z (ESI): 306.1 [M+H] + .

[0262] Preparation of intermediate 3-(5-(4-amino-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylic acid methyl ester

[0263] Step 1: Preparation of tert-butyl 3-((oxime)methyl)azetidine-1-carboxylate

[0264] At room temperature, tert-butyl 3-formylazetidine-1-carboxylate (5.0 g, 27.0 mmol) was dissolved in ethanol (50 mL), and a 50% aqueous hydroxylamine solution (8.9 g, 135.0 mmol) was added. The mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain crude tert-butyl 3-((oximino)methyl)azetidine-1-carboxylate (5.4 g, 100%), which was used directly in the next reaction. MS m / z (ESI): 201.1 [M+H] + .

[0265] Step 2: Preparation of tert-butyl N-(2-bromo-5-methyl-4-pyridyl)-N-tert-butoxycarbonylcarbamate

[0266] Dissolve 2-bromo-5-methylpyridin-4-amine (10 g, 53.47 mmol) in THF (200 mL), add DMAP (1.31 g, 10.69 mmol) and triethylamine (16.23 g, 160.40 mmol, 22.37 mL), and slowly add di-tert-butyl dicarbonate (29.17 g, 133.66 mmol) under ice-cooling. Stir at room temperature for 12 hours. The reaction mixture is diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent is concentrated under reduced pressure. The resulting residue is isolated by column chromatography to obtain the title compound (16.6 g, 80.2%). MS m / z (ESI): 387.1 [M+H] + .

[0267] Step 3: Preparation of tert-butyl N-tert-butyloxycarbonyl-N-[5-methyl-2-(2-trimethylsilylethynyl)-4-pyridyl]carbamate

[0268] Dissolve tert-butyl N-(2-bromo-5-methyl-4-pyridyl)-N-tert-butoxycarbonylcarbamate (16.6 g, 42.86 mmol) and trimethylsilylacetylene (12.63 g, 128.59 mmol) in THF (200 mL). Add CuI (816.35 mg, 4.29 mmol), Pd(PPh3)2Cl2 (3.01 g, 4.29 mmol), and triethylamine (21.69 g, 214.32 mmol, 29.89 mL). Heat and stir at 50°C for 2 h. The reaction mixture is diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent is concentrated under reduced pressure. The resulting residue is isolated by column chromatography to obtain the title compound (12.8 g, 73.8%). MS m / z (ESI): 405.2 [M+H] +

[0269] Step 4: Preparation of tert-butyl N-tert-butyloxycarbonyl-N-(2-ethynyl-5-methyl-4-pyridyl)carbamate

[0270] Under ice, tert-butyl N-tert-butoxycarbonyl-N-[5-methyl-2-(2-trimethylsilylethynyl)-4-pyridyl]carbamate (12.8 g, 31.64 mmol) was dissolved in THF (200 mL). A 1 M solution of TBAF in tetrahydrofuran (34.8 mL, 34.80 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (8.4 g, 81.1%). MS m / z (ESI): 333.2 [M+H] + .

[0271] Step 5: Preparation of tert-butyl 3-(5-(4-(di(tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylate

[0272] At room temperature, tert-butyl N-tert-butoxycarbonyl-N-(2-ethynyl-5-methyl-4-pyridyl)carbamate (2.5 g, 7.5 mmol) was dissolved in tetrahydrofuran / methanol / water (20 mL / 20 mL / 8 mL). tert-butyl 3-((oximino)methyl)azetidine-1-carboxylate (4.5 g, 22.5 mmol) and [bis(trifluoroacetoxy)iodo]benzene (9.7 g, 22.5 mmol) were added. The mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was isolated by column chromatography to obtain the title compound (3.3 g, 83%). MS m / z (ESI): 531.3 [M+H] + .

[0273] Step 6: Preparation of 2-(3-(azetidin-3-yl)isoxazol-5-yl)-5-methylpyridin-4-amine

[0274] At room temperature, tert-butyl 3-(5-(4-(di(tert-butoxycarbonyl)amino)-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylate (1.0 g, 1.9 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude 2-(3-(azetidine-3-yl)isoxazol-5-yl)-5-methylpyridin-4-amine (437.0 mg, 100%), which was used directly in the next reaction. MS m / z (ESI): 231.1 [M+H] + .

[0275] Step 7: Preparation of methyl 3-(5-(4-amino-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylate

[0276] 2-(3-(azetidin-3-yl)isoxazol-5-yl)-5-methylpyridin-4-amine (437.0 mg, 1.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature and cooled to 0°C. Triethylamine (959.5 mg, 9.5 mmol) was added, followed by the dropwise addition of dimethyl dicarbonate (388.6 mg, 2.9 mmol). The mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to obtain the title compound (366.1 mg, 67%). MS m / z (ESI): 289.1 [M+H] + .

[0277] 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.09(s,1H),6.98(s,1H),6.14(s,2H),4.35-4.22(m,2H),4.16 -3.94(m,3H),3.35(s,3H),2.06(s,3H).

[0278] Preparation of intermediate 2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-amine

[0279] Step 1: Preparation of tert-butyl N-tert-butyloxycarbonyl-N-[2-(3-cyclopropylisoxazol-5-yl)-5-methyl-4-pyridyl]carbamate

[0280] Under ice, tert-butyl N-tert-butoxycarbonyl-N-(2-ethynyl-5-methyl-4-pyridyl)carbamate (4.1 g, 12.33 mmol) and cyclopropanecarbaldehyde oxime (2.10 g, 24.67 mmol) were dissolved in MeOH (60 mL) / water (10 mL). [Bis(trifluoroacetoxy)iodo]benzene (15.91 g, 37.00 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (3.3 g, 64.39%). MS m / z (ESI): 416.2 [M+H] + .

[0281] Step 2: Preparation of 2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-amine

[0282] Dissolve tert-butyl N-tert-butoxycarbonyl-N-[2-(3-cyclopropylisoxazol-5-yl)-5-methyl-4-pyridyl]carbamate (3.3 g, 7.94 mmol) in DCM (60 mL), add trifluoroacetic acid (9.06 g, 79.43 mmol), and stir at room temperature for 2 hours. The reaction mixture is diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent is concentrated under reduced pressure. The resulting residue is isolated by column chromatography to obtain the title compound (1.56 g, 91.25%). MS m / z (ESI): 216.1 [M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.03(s,1H),6.59(s,1H),6.11(s,2H),2.04(s,3H),2.03-1.96(m,1H),1.05-0.98(m,2H),0.86-0.80(m,2H).

[0284] Example 1

[0285] 6-Cyclopropyl-N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyrazine-3-carboxamide

[0286] Step 1: Synthesis of ethyl 6-bromoimidazo[1,2-a]pyrazine-3-carboxylate

[0287] 5-Bromopyrazin-2-amine (1.74 g, 10 mmol) and ethyl 2-chloro-3-oxopropionate (4.52 g, 30 mmol) were mixed in NMP (30 mL). Acetic acid (1 mL) was added and the mixture was allowed to react at room temperature for 12 hours, then heated to 140°C for 1 hour. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (1 g, 37%). MS m / z (ESI): 270.0 [M+H] + .

[0288] Step 2: Synthesis of 6-bromoimidazo[1,2-a]pyrazine-3-carboxylic acid

[0289] Ethyl 6-bromoimidazo[1,2-a]pyrazine-3-carboxylate (1 g, 3.70 mmol) was dissolved in a mixture of THF (16 mL), MeOH (2 mL), and water (2 mL). Lithium hydroxide (106.3 mg, 4.44 mmol) was added, and the reaction mixture was stirred at 55°C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, the organic solvent was concentrated, and water (20 mL) was added. The pH was adjusted to 3-4 with 1N aqueous HCl. The resulting mixture was freeze-dried to obtain the crude title compound (890 mg). MS m / z (ESI): 242.0 [M+H] + .

[0290] Step 3: Synthesis of 6-bromo-N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyrazine-3-carboxamide

[0291] 6-Bromoimidazo[1,2-a]pyrazine-3-carboxylic acid (242 mg, 1 mmol), 5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (233.2 mg, 1 mmol), and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 45°C for 2 hours. After completion of the reaction, the organic solvent was concentrated under reduced pressure and the title compound was isolated by column chromatography to obtain 180 mg, 39% yield. MS m / z (ESI): 457.0 [M+H] + .

[0292] Step 4: Synthesis of 6-cyclopropyl-N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyrazine-3-carboxamide

[0293] 6-Bromo-N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyrazine-3-carboxamide (91.5 mg, 0.2 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.4 mg, 0.3 mmol) were mixed in dioxane (2.5 mL) and water (0.5 mL). Potassium carbonate (55.3 mg, 0.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (16.2 mg, 0.02 mmol) were added. After nitrogen substitution, the temperature was raised to 100°C and the reaction was allowed to react for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the title compound (42 mg, 50%) was isolated by column chromatography.

[0294] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.35(s,1H),9.23(s,1H),8.73(s,1H),8.12(s,1H),7.88(d,J=7.0Hz,1H),7.58(d,J=8.0Hz,1H),5.45- 5.25(m,1H),3.18-3.09(m,1H),2.44(s,3H),2.36-2.30(m,1H),2.09-2 .04(m,1H),1.71-1.62(m,1H),1.35-1.28(m,2H),1.05-1.01(m,2H); MS m / z(ESI):419.2[M+H] + .

[0295] For the synthesis methods of Examples 2 to 538, refer to Example 1.

[0296] Some compounds 1 The H NMR data are as follows

[0297] Example 5 3-(3-(6-cyclopropylimidazo[1,2-a]pyrazine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylic acid methyl ester can also be prepared according to the following method

[0298] Step 1: Preparation of ethyl 6-cyclopropylimidazo[1,2-a]pyrazine-3-carboxylate

[0299] Ethyl 6-bromoimidazo[1,2-a]pyrazine-3-carboxylate (270.1 mg, 1.0 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (252 mg, 1.5 mmol) were mixed in dioxane (4 mL) / water (0.5 mL). Potassium carbonate (276.4 mg, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (81.7 mg, 0.1 mmol) were added. The reaction mixture was heated and stirred at 100°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (185 mg, 80%). MS m / z (ESI): 232.1 [M+H] + .

[0300] Step 2: Preparation of 6-cyclopropylimidazo[1,2-a]pyrazine-3-carboxylic acid

[0301] Ethyl 6-cyclopropylimidazo[1,2-a]pyrazine-3-carboxylate (185 mg, 0.8 mmol) was dissolved in a mixture of THF (4 mL) / MeOH (1 mL) / water (1 mL). Lithium hydroxide (28.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 55°C for 1 hour. The reaction mixture was cooled to room temperature, the organic solvent was concentrated, and water (5 mL) was added. The pH was adjusted to 3-4 with 1N aqueous HCl. The resulting mixture was freeze-dried to obtain the crude title compound (162 mg). MS m / z (ESI): 204.1 [M+H] + .

[0302] Step 3: Preparation of methyl 3-(3-(6-cyclopropylimidazo[1,2-a]pyrazine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate

[0303] 6-Cyclopropylimidazo[1,2-a]pyrazine-3-carboxylic acid (101.6 mg, 0.5 mmol), methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (144.2 mg, 0.5 mmol), and N-methylimidazole (131.4 mg, 1.6 mmol) were mixed in acetonitrile (3 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (168.3 mg, 0.6 mmol) was added, and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (106.5 mg, 45%). MS m / z (ESI): 474.2 [M+H] + .

[0304] 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.29(d,J=1.2Hz,1H),9.16(d,J=1.2Hz,1H),8.66(s,1H),8.12(s,1H),7.86(dd,J=8.0,1.2Hz,1H),7. 52(d,J=8.0Hz,1H),4.42-4.33(m,2H),4.32-4.24(m,1H),4.23-4.14( m,2H),3.60(s,3H),2.38(s,3H),2.30-2.23(m,1H),0.91-0.99(m,4H).

[0305] Example 173 N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-2-methylimidazo[2,1-b]thiazole-5-carboxamide can also be prepared as follows

[0306] 2-Methylimidazo[2,1-b]thiazole-5-carboxylic acid (182.2 mg, 1 mmol), 5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (233.2 mg, 1 mmol), and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (151 mg, 38%). MS m / z (ESI): 398.1 [M+H] + .

[0307] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),8.16(s,1H),8.12(s,1H),8.00(s,1H),7.79-7.73(m,1H),7.47(d,J=8.0 Hz,1H),5.39-5.18(m,1H),3.11-3.01(m,1H),2.48(s,3H),2.33(s,3H),2.01-1.88(m,1H),1.63-1.54(m,1H).

[0308] Example 177 3-(3-(4-methyl-3-(2-methylimidazo[2,1-b]thiazole-5-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate can also be prepared as follows:

[0309] 2-Methylimidazo[2,1-b]thiazole-5-carboxylic acid (182.2 mg, 1 mmol), methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (288.3 mg, 1 mmol), and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (162.9 mg, 36%). MS m / z (ESI): 453.1 [M+H] + .

[0310] 1 H NMR(400MHz, DMSO-d6)δ9.93(s,1H),8.18-8.12(m,2H),8.08(d,J=1.6Hz,1H),7.83(dd,J=8.0,1.6Hz,1H),7.49( d,J=8.0Hz,1H),4.41-4.32(m,2H),4.30-4.23(m,1H),4.22-4.15(m,2H),3.60(s,3H),2.48(s,3H),2.34(s,3H).

[0311] Example 194 3-(3-(3-fluoro-4-methyl-5-(2-methylimidazo[2,1-b]thiazole-5-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylic acid methyl ester can also be prepared as follows

[0312] 2-Methylimidazo[2,1-b]thiazole-5-carboxylic acid (182.2 mg, 1 mmol), methyl 3-(3-(3-amino-5-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (306.3 mg, 1 mmol), and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (150.6 mg, 32%). MS m / z (ESI): 471.1 [M+H]+ .

[0313] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.18(s,1H),8.14(d,J=1.6Hz,1H),7.97(s,1H),7.66(dd,J=9.7,1. 7Hz,1H),4.42-4.33(m,2H),4.32-4.24(m,1H),4.23-4.15(m,2H),3.60(s,3H),2.48(s,3H),2.23(s,3H).

[0314] Example 245 3-(3-(3-fluoro-5-(2-fluoroimidazo[2,1-b]thiazole-5-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylic acid methyl ester can also be prepared as follows

[0315] Step 1: Preparation of ethyl 2-fluoroimidazo[2,1-b]thiazole-5-carboxylate

[0316] 5-Fluorothiazol-2-amine (1.18 g, 10 mmol) and ethyl 2-chloro-3-oxopropionate (4.52 g, 30 mmol) were mixed in NMP (30 mL). Acetic acid (1 mL) was added and the mixture was allowed to react at room temperature for 12 hours, then heated to 130°C for 1 hour. The reaction solution was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (749.7 mg, 35%). MS m / z (ESI): 215.0 [M+H] + .

[0317] Step 2: Preparation of 2-fluoroimidazo[2,1-b]thiazole-5-carboxylic acid

[0318] Ethyl 2-fluoroimidazo[2,1-b]thiazole-5-carboxylate (749.7 mg, 3.5 mmol) was dissolved in a mixture of THF (8 mL), MeOH (2 mL), and water (2 mL). Lithium hydroxide (100.6 mg, 4.2 mmol) was added, and the reaction mixture was stirred at 55°C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, the organic solvent was concentrated, and water (20 mL) was added. The pH was adjusted to 3-4 with 1N aqueous HCl. The resulting mixture was freeze-dried to obtain the crude title compound (651 mg). MS m / z (ESI): 187.0 [M+H] + .

[0319] Step 3: Preparation of methyl 3-(3-(3-fluoro-5-(2-fluoroimidazo[2,1-b]thiazole-5-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate

[0320] 2-Fluoroimidazolo[2,1-b]thiazole-5-carboxylic acid (186.2 mg, 1 mmol), methyl 3-(3-(3-amino-5-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (306.3 mg, 1 mmol), and N-methylimidazole (262.7 mg, 3.2 mmol) were mixed in acetonitrile (5 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (156.6 mg, 33%). MS m / z (ESI): 475.1 [M+H] + .

[0321] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.46(s,1H),8.23(s,1H),7.96(s,1H),7.67(d,J=9.6 Hz,1H),4.41-4.33(m,2H),4.32-4.25(m,1H),4.22-4.15(m,2H),3.60(s,3H),2.33(s,3H).

[0322] Example 290 3-(3-(5-methyl-4-(2-methylimidazo[2,1-b]thiazole-5-carboxamido)pyridin-2-yl)isoxazol-5-yl)azetidine-1-carboxylic acid methyl ester can also be prepared as follows:

[0323] Methyl 3-(3-(4-amino-5-methylpyridin-2-yl)isoxazol-5-yl)azetidine-1-carboxylate (95.0 mg, 0.33 mmol) and 2-methylimidazo[2,1-b]thiazole-5-carboxylic acid (90.1 mg, 0.49 mmol) were dissolved in dimethylformamide (4 mL) at room temperature. Methylimidazole (81.3 mg, 0.99 mmol) and tetramethylchlorouronium hexafluorophosphate (137.5 mg, 0.49 mmol) were added. The mixture was stirred at 90°C for 5 hours. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (20.1 mg, 13%). MS m / z (ESI): 453.1 [M+H] + .

[0324] Example 293 3-(3-(2-fluoro-5-(imidazo[2,1-b]thiazole-5-carboxamido)-4-methylphenyl)isoxazol-5-yl)azetidine-1-carboxylate can also be prepared as follows:

[0325] Methyl 3-[3-(5-amino-2-fluoro-4-methyl-phenyl)isoxazol-5-yl]azetidine-1-carboxylate (50 mg, 163.77 μmol) and ethyl imidazo[2,1-B]thiazole-5-carboxylate (34.4 mg, 175.51 μmol) were dissolved in tetrahydrofuran (5 mL). 1M LiHMDS solution in tetrahydrofuran (1 mmol, 1 mL) was added, and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (10.1 mg, 13.5%). MS m / z (ESI): 456.1 [M+H] + .

[0326] 1 H NMR(400MHz, DMSO-d6)δ9.98(s,1H),8.29-8.25(m,1H),8.21(s,1H),7.86(d,J=6.8Hz,1H),7.51-7.47(m,1H),7.42-7.36( d,J=10.4Hz,1H),7.01(d,J=2.8Hz,1H),4.37-4.29(m,2H),4.19-4.12(m,1H),4.11-4.03(m,2H),3.59(s,3H),2.32(s,3H).

[0327] Example 373 3-(5-(4-(imidazo[1,2-a]pyridine-3-carboxamido)-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylic acid methyl ester can also be prepared as follows

[0328] At room temperature, ethyl imidazo[1,2-a]pyridine-3-carboxylate (32.9 mg, 173.43 μmol) and methyl 3-(5-(4-amino-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylate (50 mg, 173.43 μmol) were dissolved in tetrahydrofuran (2 mL). 1M LiHMDS solution in tetrahydrofuran (0.68 mL, 0.68 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford the crude product, which was purified by column chromatography to yield the title compound (34.3 mg, 45.7%). MS m / z (ESI): 433.2 [M+H] + .

[0329] 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.48-9.44(m,1H),8.67(s,1H),8.59(s,1H),8.30(s,1H),7.84-7.80(m,1H),7.6 1-7.54(m,1H),7.25-7.22(m,2H),4.38-4.27(m,2H),4.12-4.04(m,2H),4.03-3.97(m,1H),3.59(s,3H),2.40(s,3H).

[0330] Example 490 N-(2-(5-cyclopropylisoxazol-3-yl)-5-methylpyridin-4-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxamide can also be prepared as follows

[0331] Step 1: Preparation of N'-(5-bromothiazol-2-yl)-N,N-dimethylformamidine

[0332] At room temperature, 5-bromothiazol-2-amine (5.0 g, 28.0 mmol) was dissolved in toluene (60 mL). Triethylamine (8.5 g, 84.0 mmol) was added and stirred for 10 minutes. N,N-dimethylformamide dimethyl acetal (16.7 g, 140.0 mmol) was added and the temperature was raised to 110°C and stirred for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (6.5 g, 100%). MS m / z (ESI): 234.0 [M+H] + .

[0333] Step 2: Preparation of ethyl 2-bromoimidazo[2,1-b]thiazole-5-carboxylate

[0334] At room temperature, N'-(5-bromothiazol-2-yl)-N,N-dimethylformamidine (1.5 g, 6.4 mmol) was dissolved in ethyl bromoacetate (8 mL) and stirred at room temperature for 10 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (4.9 g, 32.0 mmol) was then added dropwise and stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (650.5 mg, 37%). MS m / z (ESI): 274.9 [M+H] + .

[0335] 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.01 (s, 1H), 4.34 (q, J = 7.1Hz, 2H), 1.33 (t, J = 7.1Hz, 3H).

[0336] Step 3: Preparation of ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate

[0337] At room temperature, ethyl 2-bromoimidazo[2,1-b]thiazole-5-carboxylate (650.5 g, 2.37 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (807.8 mg, 3.56 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (173.2 mg, 0.237 mmol), and cesium carbonate (2.3 g, 7.11 mmol) were dissolved in dioxane / water (10 mL / 2 mL). The mixture was heated to 125°C and stirred in a microwave oven for 2 hours. Saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (450.2 mg, 50%). MS m / z (ESI): 378.1 [M+H]. + .

[0338] Step 4: Preparation of ethyl 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate

[0339] At room temperature, ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate (450.2 mg, 1.2 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude ethyl 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate (332.4 mg, 100%), which was used directly in the next reaction. MS m / z (ESI): 278.1 [M+H] + .

[0340] Step 5: Ethyl 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate

[0341] At room temperature, ethyl 2-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate (332.4 mg, 1.2 mmol) was dissolved in methanol (6 mL). Formaldehyde (972.9 mg, 12.0 mmol) and 2 drops of acetic acid were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (226.1 mg, 3.6 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (265.7 mg, 76%). MS m / z (ESI): 292.1 [M+H] + .

[0342] Step 6: Preparation of N-(2-(5-cyclopropylisoxazol-3-yl)-5-methylpyridin-4-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxamide

[0343] At room temperature, ethyl 2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[2,1-b]thiazole-5-carboxylate (81.2 mg, 0.28 mmol) and 2-(5-cyclopropylisoxazol-3-yl)-5-methylpyridin-4-amine (50.0 mg, 0.23 mmol) were dissolved in tetrahydrofuran (4 mL). 1M LiHMDS solution in tetrahydrofuran (0.92 mL, 0.92 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (38.6 mg, 36%). MS m / z (ESI): 461.2 [M+H] + .

[0344] 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.54(s,1H),8.29(s,1H),8.26(s,1H),8.18(s,1H),6.70(s,1H),6.13-6.08(m,1H),3.07-3.0 0(m,2H),2.61-2.52(m,3H),2.36(s,3H),2.28(s,3H),2.24-2.16(m,1H),2.04-1.95(m,1H),1.14-1.08(m,2H),1.00-0.94(m,2H).

[0345] Example 494 N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-2-methylimidazo[2,1-b]thiazole-5-carboxamide can also be prepared as follows

[0346] At room temperature, 2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-amine (45 mg, 209.06 μmol) and ethyl 2-methylimidazo[2,1-B]thiazole-5-carboxylate (43.96 mg, 209.06 μmol) were dissolved in tetrahydrofuran (2 mL). 1M LiHMDS solution in tetrahydrofuran (1 mmol, 1 mL) was added, and the reaction mixture was heated and stirred at 60°C for 2 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (21.8 mg, 27.48%). MS m / z (ESI): 380.1 [M+H] + .

[0347] 1 H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.54(s,1H),8.25(s,1H),8.21(s,1H),8.21-8.16(m,1H), 6.81(s,1H),2.43(s,3H),2.36(s,3H),2.10-2.04(m,1H),1.08-1.03(m,2H),0.89-0.85(m,2H).

[0348] Example 500 4-[3-[[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]carbamoyl]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylic acid methyl ester can also be prepared as follows

[0349] Step 1: Preparation of ethyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0350] Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (1.1 g, 4.8 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (270.5 g, 0.37 mmol), and sodium carbonate (1.2 g, 11.1 mmol) were dissolved in dioxane / water (12 mL / 2 mL) at room temperature and stirred at 100°C for 5 hours. Saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (1.1 g, 80%). MS m / z (ESI): 372.2 [M+H] + .

[0351] Step 2: Preparation of ethyl 5-(1-tert-butoxycarbonyl-4-piperidinyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0352] Ethyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 269.23 μmol) was dissolved in THF (5 mL) / MeOH (1 mL). 10% Pd / C (50 mg) and 10% Pd(OH)2 / C (50 mg) were added. The hydrogen atmosphere was replaced three times, and the reaction solution was heated and stirred at 60°C for 2 h. The reaction solution was filtered through celite to remove insoluble solids. The filtrate was then stripped of solvent under reduced pressure to yield ethyl 5-(1-tert-butoxycarbonyl-4-piperidinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 79.6%), which was used directly in the next step. MS m / z (ESI): 374.2 [M+H] + .

[0353] Step 3: Preparation of tert-butyl 4-[3-[[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]carbamoyl]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylate

[0354] Ethyl 5-(1-tert-butoxycarbonyl-4-piperidinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 214.22 μmol) and 2-(5-cyclopropylisoxazol-3-yl)-5-methyl-pyridin-4-amine (46.1 mg, 214.22 μmol) were dissolved in tetrahydrofuran (5 mL). 1M LiHMDS solution in tetrahydrofuran (1 mmol, 1 mL) was added, and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (56 mg, 48.2%). MS m / z (ESI): 543.3 [M+H] + .

[0355] Step 4: Preparation of methyl 4-[3-[[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]carbamoyl]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylate

[0356] Tert-butyl 4-[3-[[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]carbamoyl]pyrazolo[1,5-a]pyridin-5-yl]piperidine-1-carboxylate (56 mg, 103.20 μmol) was dissolved in DCM (5 mL) / 4M HCl dioxane (5 mL) and stirred at room temperature for 30 min. The solvent was removed from the reaction mixture under reduced pressure, and the residue was dissolved in DCM (5 mL). Triethylamine (52.21 mg, 516.01 μmol, 71.97 μL) was added. Dimethyl dicarbonate (16.61 mg, 123.84 μmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride solution and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. The resulting residue was separated by column chromatography to obtain the title compound (28.9 mg, 55.9%). MS m / z (ESI): 501.2 [M+H] + .

[0357] 1 H NMR (400MHz, DMSO-d6) δ9.62(s,1H),8.82(d,J=7.1Hz,1H),8.80(s,1H),8.52(s,1H),8.40(s,1H),8.18(d,J=1.8Hz,1H),7.13(dd,J=7.1,1.8 Hz,1H),6.70(s,1H),3.70(s,3H),2.58-2.53(m,4H),2.38(s,3H),2.27 -2.16(m,1H),2.05-1.93(m,4H),1.15-1.07(m,2H),1.01-0.96(m,2H).

[0358] Example 511 N-[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]-5-(3-oxa-9-azaspiro[5.5]undec-9-yl)pyrazolo[1,5-a]pyridine-3-carboxamide can also be prepared as follows

[0359] Step 1: Preparation of ethyl 5-(3-oxa-9-azaspiro[5.5]undec-9-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0360] Ethyl 5-bromopyrazolo[1,5-A]pyridine-3-carboxylate (433 mg, 1.61 mmol), 3-oxa-9-azaspiro[5.5]undecane (250 mg, 1.61 mmol), XantPhos Pd G4 (154.99 mg, 161.04 μmol), and cesium carbonate (1.05 g, 3.22 mmol) were dissolved in dioxane (20 mL). The reaction mixture was heated and stirred at 100°C for 12 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (410 mg, 74.1%). MS m / z (ESI): 344.2 [M+H] + .

[0361] Step 2: Preparation of N-[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]-5-(3-oxa-9-azaspiro[5.5]undec-9-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0362] Ethyl 5-(3-oxa-9-azaspiro[5.5]undec-9-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 145.59 μmol) and 2-(5-cyclopropylisoxazol-3-yl)-5-methyl-pyridin-4-amine (31.3 mg, 145.59 μmol) were dissolved in tetrahydrofuran (5 mL). 1M LiHMDS solution in tetrahydrofuran (1 mmol, 1 mL) was added, and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (15.4 mg, 20.6%). MS m / z (ESI): 513.3 [M+H] + .

[0363] 1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 8.60 (s, 1H), 8.56 (d, J = 7.8Hz, 1H), 8.48 (s, 1H),8.45(s,1H),7.36(d,J=2.7Hz,1H),7.00(dd,J=7.8,2.8Hz,1H),6.68(s,1H) ,3.58(t,J=5.3Hz,4H),3.38(t,J=5.9Hz,4H),2.37(s,3H),2.24-2.17(m,1H),1. 62(t,J=5.9Hz,4H),1.48(t,J=5.3Hz,4H),1.14-1.07(m,2H),0.99-0.94(m,2H).

[0364] Example 512 N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide can also be prepared as follows

[0365] Step 1: Preparation of 1-(4-boronic acid pinacol ester-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-boronic acid pinacol ester-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0366] 3-Methylpyrazole-4-boronic acid pinacol ester (6.4 g, 30.76 mmol) was dissolved in DMF (100 mL), and 1,2-epoxy-2-methylpropane (4.44 g, 61.52 mmol) and potassium carbonate (12.75 g, 92.28 mmol) were added. The mixture was heated at 110°C with stirring for 12 h. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to yield a mixture of 1-(4-boronic acid pinacol ester-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-boronic acid pinacol ester-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (5.63 g, 20.09 mmol, 65.33%). MS m / z (ESI): 281.2 [M+H] + .

[0367] Step 2: Preparation of 5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester and 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester

[0368] A mixture of 1-(4-boronic acid pinacol ester-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-boronic acid pinacol ester-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (5.63 g, 20.09 mmol) was dissolved in 1'4-Dioxane (100 mL) / water (20 mL), and ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (5.41 g, 20.09 mmol), Pd(dppf)Cl2 (1.47 g, 2.01 mmol) and potassium carbonate (5.55 g, 40.19 mmol) were added and heated at 100°C with stirring for 6 h. The reaction mixture was added with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative chromatography to give ethyl 5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.95 g, 5.70 mmol) and ethyl 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (2.93 g, 8.55 mmol). MS m / z (ESI): 343.2 [M+H]. + .

[0369] Step 3: N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0370] Ethyl 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 233.65 μmol) and 2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-amine (50.3 mg, 233.65 μmol) were dissolved in THF (5 mL) and 1M LiHMDS in THF (1 mL). The mixture was stirred at 60°C for 2 h. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative chromatography to obtain the title compound (36.8 mg, 71.93 μmol, 30.8%). MS m / z (ESI): 512.2 [M+H]. + .

[0371] 1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.86(d,J=7.2Hz,1H),8.81(s,1H),8 .52(s,1H),8.32(s,1H),8.22(d,J=2.0Hz,1H),7.89(s,1H),7.30(dd,J=7. 2,2.0Hz,1H),6.81(s,1H),4.72(s,1H),4.06(s,2H),2.54(s,3H),2.39(s, 3H),2.11-2.03(m,1H),1.15(s,6H),1.08-1.01(m,2H),0.89-0.80(m,2H).

[0372] Example 514 N-(2-(5-cyclopropylisoxazol-3-yl)-5-methylpyridin-4-yl)-6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide can also be prepared as follows

[0373] Step 1: Preparation of ethyl 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate

[0374] At room temperature, ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.24 g, 5.55 mmol), 1,1'-bis(diphenylphosphinoferrocenedichlorid)palladium(II) (270.5 g, 0.37 mmol), and sodium carbonate (1.2 g, 11.1 mmol) were dissolved in dioxane / water (15 mL / 2 mL). The mixture was heated to 100°C and stirred for 5 hours. Saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (1.0 g, 95%). MS m / z (ESI): 286.1 [M+H] + .

[0375] Step 2: Preparation of ethyl 6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate

[0376] At room temperature, ethyl 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (285 mg, 1.0 mmol) was dissolved in tetrahydrofuran / methanol (5 mL / 5 mL). Palladium on carbon (150 mg) and palladium hydroxide (150 mg) were added. The atmosphere was replaced with hydrogen three times, and the temperature was raised to 60°C and stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to obtain crude ethyl 6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (215.3 mg, 75%), which was used directly in the next reaction. MS m / z (ESI): 288.2 [M+H] + .

[0377] Step 3: N-(2-(5-cyclopropylisoxazol-3-yl)-5-methylpyridin-4-yl)-6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

[0378] At room temperature, ethyl 6-(1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (65.6 mg, 0.23 mmol) and 2-(5-cyclopropylisoxazol-3-yl)-5-methylpyridin-4-amine (50.0 mg, 0.23 mmol) were dissolved in tetrahydrofuran (4 mL). 1M LiHMDS solution in tetrahydrofuran (0.92 mL, 0.92 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (59.1 mg, 56%). MS m / z (ESI): 457.2 [M+H] + .

[0379] 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.30(s,1H),8.60(s,1H),8.55(s,1H) ,8.31(s,1H),7.75(d,J=9.2Hz,1H),7.57-7.52(m,1H),6.71(s,1H),2.92-2 .84(m,2H),2.66-2.57(m,1H),2.38(s,3H),2.21(s,3H),2.05-1.96(m,3H), 1.87-1.79(m,2H),1.74-1.63(m,2H),1.13-1.09(m,2H),1.01-0.95(m,2H).

[0380] Example 515 3-(5-(4-(6-cyclopropylimidazo[1,2-a]pyridine-3-carboxamido)-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylic acid methyl ester can also be prepared as follows

[0381] Step 1: Preparation of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate

[0382] Ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (1.5 g, 5.6 mmol), cyclopropylboronic acid (952 mg, 11.2 mmol), potassium phosphate (4.8 g, 22.4 mmol), palladium acetate (125.4 mg, 0.56 mmol), and tricyclohexylphosphine (156.8 mg, 0.56 mmol) were dissolved in toluene / water (15 mL / 2 mL) at room temperature, heated to 100°C, and stirred for 5 hours. The reaction mixture was added with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give ethyl 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate (1.0 g, 78%). MS m / z (ESI): 231.1 [M+H] + .

[0383] Step 2: Preparation of methyl 3-(5-(4-(6-cyclopropylimidazo[1,2-a]pyridine-3-carboxamido)-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylate

[0384] At room temperature, 6-cyclopropylimidazo[1,2-a]pyridine-3-carboxylate (39.1 mg, 0.17 mmol) and methyl 3-(5-(4-amino-5-methylpyridin-2-yl)isoxazol-3-yl)azetidine-1-carboxylic acid ethyl ester (48.9 mg, 0.17 mmol) were dissolved in tetrahydrofuran (2 mL). 1M LiHMDS solution in tetrahydrofuran (0.68 mL, 0.68 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (32.5 mg, 41%). MS m / z (ESI): 473.2 [M+H] + .

[0385] 1H NMR(400MHz, DMSO-d6)δ9.86(s,1H),9.30(d,J=7.2Hz,1H),8.58(d,J=5.0Hz,2H),8.30(s,1H),7.53(s,1H),7.23(s,1H),6.96-6.9 1(m,1H),4.37-4.28(m,2H),4.13-3.99(m,3H),3.59(s,3H),2.39(s,3H),2.14-2.05(m,1H),1.12-1.07(m,2H),0.91-0.83(m,2H).

[0386] Example 516 N-[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]-5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-carboxamide can also be prepared as follows

[0387] Step 1: Preparation of tert-butyl 9-(3-ethoxycarbonylpyrazolo[1,5-a]pyridin-5-yl)-3-azaspiro[5.5]undec-9-ene-3-carboxylate

[0388] Tert-butyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (250 mg, 662.56 μmol), ethyl 5-bromopyrazolo[1,5-A]pyridine-3-carboxylate (178.3 mg, 662.56 μmol), Pd(dppf)Cl2 (48.5 mg, 66.26 μmol) and potassium carbonate (183.1 mg, 1.33 mmol) were dissolved in dioxane (20 mL) / water (4 mL) and heated with stirring at 100 °C for 6 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride solution and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. The resulting residue was separated by column chromatography to obtain tert-butyl 9-(3-ethoxycarbonylpyrazolo[1,5-a]pyridin-5-yl)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (180 mg, 61.8%). MS m / z (ESI): 440.2 [M+H] + .

[0389] Step 2: Preparation of ethyl 5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-carboxylate

[0390] Tert-butyl 9-(3-ethoxycarbonylpyrazolo[1,5-a]pyridin-5-yl)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (300 mg, 682.52 μmol) was dissolved in dichloromethane (5 mL) / 4M HCl in dioxane (5 mL) and stirred at room temperature for 30 minutes. The solvent was removed from the reaction mixture under reduced pressure, and the residue was dissolved in acetonitrile (10 mL). Potassium carbonate (282.99 mg, 2.05 mmol) and 1-fluoro-2-iodoethane (237.4 mg, 1.37 mmol) were added, and the reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride solution and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (160 mg, 60.8%). MS m / z(ESI):386.2[M+H] + .

[0391] Step 3: Preparation of N-[2-(5-cyclopropylisoxazol-3-yl)-5-methyl-4-pyridinyl]-5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-carboxamide

[0392] Ethyl 5-[3-(2-fluoroethyl)-3-azaspiro[5.5]undec-9-en-9-yl]pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 207.54 μmol) and 2-(5-cyclopropylisoxazol-3-yl)-5-methyl-pyridin-4-amine (44.7 mg, 207.54 μmol) were dissolved in tetrahydrofuran (5 mL). 1M LiHMDS solution in tetrahydrofuran (1 mmol, 1 mL) was added, and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The resulting residue was isolated by column chromatography to obtain the title compound (8.1 mg, 7.1%). MS m / z (ESI): 555.3 [M+H] + .

[0393] 1H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 8.74-8.60 (m, 2H), 8.44 (s, 1H), 8.33 (s, 1H), 8.07 (d, J = 1.5 Hz,1H),7.27(dd,J=7.5,1.5Hz,1H),6.62(s,1H),6.43(s,1H),4.51(t,J=4.9Hz,1H),4.39(t,J=4 .9Hz,1H),2.60-2.51(m,2H),2.40-2.33(m,4H),2.31(s,3H),2.17-2.09(m,2H),2.08-2.04(m,2H ),1.95-1.87(m,1H),1.59-1.52(m,2H),1.40-1.32(m,4H),1.08-0.99(m,2H),0.94-0.85(m,2H).

[0394] Example 520 N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide can also be prepared as follows:

[0395] Step 1: Preparation of ethyl 5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0396] 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid pinacol ester (250 mg, 1.07 mmol) and ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (287.4 mg, 1.07 mmol) were dissolved in 1'4-Dioxane (40 mL) / water (8 mL). Pd(dppf)Cl2 (78.14 mg, 106.79 μmol) and potassium carbonate (295.18 mg, 2.14 mmol) were added, and the mixture was heated and stirred at 100°C for 4 h. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative chromatography to obtain the title compound (263 mg, 887.54 μmol, 83.1%). MS m / z (ESI): 297.1 [M+H] + .

[0397] Step 2: Preparation of N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0398] Ethyl 5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (55 mg, 185.6 μmol) and 2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-amine (39.9 mg, 185.61 μmol) were dissolved in THF (5 mL). 1M LiHMDS in THF (0.74 mL) was added and stirred at 60°C for 2 h. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative chromatography to yield the title compound (28.8 mg, 61.9 μmol, 33.3%). MS m / z (ESI): 466.2 [M+H]. + .

[0399] 1 H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.84(dd,J=7.2,0.9Hz,1H),8.79(s,1H),8 .52(s,1H),8.34(s,1H),8.24(dd,J=2.0,0.9Hz,1H),8.11(s,1H),7.36(dd,J=7. 2,2.0Hz,1H),6.81(s,1H),4.14(t,J=7.3Hz,2H),3.17(t,J=7.3Hz,2H),2.70-2. 65(m,2H),2.40(s,3H),2.12-2.03(m,1H),1.11-1.01(m,2H),0.92-0.84(m,2H).

[0400] Example 521 N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide can also be prepared as follows

[0401] Step 1: Preparation of ethyl 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0402] 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (250 mg, 905.6 μmol) and ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (243.7 mg, 905.6 μmol) were dissolved in 1'4-Dioxane (40 mL) / water (8 mL). Pd(dppf)Cl2 (662.6 mg, 905.59 μmol) and potassium carbonate (125.16 mg, 905.59 μmol) were added, and the mixture was heated and stirred at 100°C for 4 h. Saturated ammonium chloride solution was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative chromatography to obtain the title compound (195 mg, 576.44 μmol, 63.65%). MS m / z(ESI):339.1[M+H] + .

[0403] Step 2: Preparation of N-(2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-yl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0404] Ethyl 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 236.49 μmol) and 2-(3-cyclopropylisoxazol-5-yl)-5-methylpyridin-4-amine (50.9 mg, 236.49 μmol) were dissolved in THF (2 mL) / 1M LiHMDS THF (840.00 μL) and stirred at 100°C for 4 h. The reaction mixture was added with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase preparative chromatography to obtain the title compound (36.6 mg, 72.12 μmol, 30.50%). MS m / z(ESI):508.2[M+H] + .

[0405] 1H NMR (400MHz, DMSO-d6) δ9.64(s,1H),8.88(d,J=7.2Hz,1H),8.81(s,1H),8.46(s,1H),8.22(s,1H),8.18(d,J=2.0 Hz,1H),7.90(s,1H),7.09(dd,J=7.2,2.0Hz,1H),6.73(s,1H),4.02(s,3H),2.32(s,3H),2.04-1.96(m,1H),1.01 -0.95(m,2H),0.83-0.77(m,2H).

[0406] Some compounds can also be prepared by referring to the above-mentioned compound preparation method. 1 The H NMR data are as follows

[0407] Biological test evaluation

[0408] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0409] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on enzymes (KIT, FMS (CSF1R), PDGFRβ, PDGFRα, FLT3)

[0410] 1. Experimental purpose: The purpose of this test is to measure the inhibitory ability of compounds on enzymes (KIT, FMS (CSF1R), PDGFRβ, PDGFRα, FLT3).

[0411] 2. Experimental instruments and reagents:

[0412] 2.1 Instruments:

[0413] 3. Experimental methods:

[0414] Incubate 1 nM KIT and serially diluted compounds in 1× enzyme reaction buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20) for 0.5 h. Add 100 nM ULight-poly GT and 20 μM ATP and incubate at room temperature for 0.5 h. Add an equal volume of detection and stop mix (containing 20 mM EDTA and 4 nM Eu-W1024 Anti-phosphor tyrosine (PT66) was added to the plate in 1× LANCE detection buffer, mixed thoroughly, and centrifuged. The plate was sealed with film and incubated at room temperature for 1 hour. The plate was read using the TR-FRET program on the EnVision instrument, and the fluorescence values ​​of each well were measured at 665 nm and 615 nm.

[0415] 4. Experimental Data Processing Method: Calculate the inhibition rate using the following formula from the raw data (665nm / 615nm reading ratio): 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 reaction wells without compound or enzyme, and negative control wells are reaction wells without enzyme.

[0416] Use the log(inhibitor) vs. response--Variable slope (four parameters) in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0417] 5. Experimental results:

[0418] Among them: "A" represents IC 50 ≤0.05μM, "B" represents 0.05μM≤IC 50 ≤0.5μM, "C" represents 0.5μM≤IC 50 ≤5μM, "D" represents 5μM≤IC 50 ≤25μM, “E” represents IC 50 ≥25μM.

[0419] 6. Experimental results and conclusions:

[0420] The above data demonstrate that the compounds of the present invention have strong inhibitory activity against KIT. Furthermore, the compounds of the present invention exhibit varying degrees of selectivity for FMS (CSF1R). Among them, the compounds of the present invention exhibit selectivity for FMS (CSF1R) of greater than 50-fold, preferably greater than 100-fold, and more preferably greater than 500-fold.

[0421] Test Example 2: Inhibitory effect of the compounds of the present invention on cell proliferation in cell lines (Ba / F3-ETV6-cKIT, Ba / F3-ETV6-Ckit and Ba / F3-TEL-CSF1R, Ba / F3-TEL-PDGFRβ, Ba / F3-TEL-PDGFRα and Ba / F3-TEL-FLT3)

[0422] 1. Purpose: The purpose of this test is to measure the inhibitory effect of compounds on the proliferation of Ba / F3-ETV6-cKIT, Ba / F3-ETV6-Ckit, Ba / F3-TEL-CSF1R, Ba / F3-TEL-PDGFRβ, Ba / F3-TEL-PDGFRα, and Ba / F3-TEL-FLT3 cells.

[0423] 2. Experimental instruments and reagents:

[0424] 2.1 Instruments:

[0425] 2.2 Reagents:

[0426] 3. Experimental methods:

[0427] 3.1 Cell culture:

[0428] 3.2 Cell proliferation assay:

[0429] a) All cell lines were cultured in complete medium at 37°C and 5% CO2.

[0430] b) Harvest cells in the logarithmic growth phase and count the cells using a platelet counter. Detect cell viability using the trypan blue exclusion method to ensure that the cell viability is above 90%.

[0431] c) Complete culture medium was used to adjust the cell density, and then 3000 cells were seeded into a 96-well cell culture plate at 90 μL per well.

[0432] d) The cells in the 96-well plate were cultured at 37°C and 5% CO2.

[0433] e) Prepare 10x drug solutions with the highest working concentration of the positive compound being 10 μM, using 9 concentrations and 3.16-fold dilutions; then transfer 10 μL of each serially diluted compound to the corresponding experimental wells of a 96-well cell plate, with two replicates for each drug concentration.

[0434] f) The cells in the 96-well plate were cultured at 37°C and 5% CO2 for 72 hours. 2.0 Analysis.

[0435] g) Thaw the CellCounting-Lite 2.0 Luminescent Cell Viability Assay reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0436] h) Add an equal volume of CellCounting-Lite 2.0 Luminescent Cell Viability Assay solution to each well.

[0437] i) Lyse the cells by shaking on an orbital shaker for 5 minutes.

[0438] j) Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal.

[0439] k) Read the luminescence value and collect the data.

[0440] 3.3 Data Analysis: GraphPad Prism 7.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC was calculated from it. 50 Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照 -Lum 培养液对照 )×100%.

[0441] 4. Experimental results and conclusions:

[0442] Experimental conclusion: The compounds of the present invention exhibit varying degrees of selectivity for the target PDGFRα at the cellular level, with the compounds of the present invention exhibiting over 1000-fold selectivity for the target PDGFRα at the cellular level.

[0443] Test Example 3: Selective inhibition of phosphorylation of stable cell lines by the compounds of the present invention

[0444] 1. Inhibitory effect of the compounds of the present invention on phosphorylation of the stably transfected cell line HEK293-KIT

[0445] 1. Experimental purpose: The purpose of this test example is to detect the ability of the compound of the present invention to inhibit phosphorylation of the stably transfected cell line HEK293-KIT.

[0446] 2. Experimental instruments and reagents:

[0447] 2.1 Instruments:

[0448] 2.2 Reagents

[0449] 3. Experimental methods:

[0450] Cell preparation: Hek293-KIT cells were adjusted to a cell density of 15k cells / well and plated in a 96-well plate with 100 μL per well for overnight culture.

[0451] Compound preparation and incubation: HEK293-KIT cells: The stock solution concentration was 10 mM. The highest concentration tested in HEK293-KIT cells was 1000 nM. The compound stock solution was first diluted with DMSO to a 1000x (1 mM) intermediate dilution solution (the highest concentration). This intermediate dilution was then serially diluted to 31.55x the intermediate dilution solution, for a total of three concentrations. Compounds were then dispensed into a 96-well plate using an IDOT non-contact microdispensing system, with a total volume of 100 nL (containing 0.1% DMSO) per well, for a total of nine doses. 100 nL of DMSO was added to the Max well, and 100 nL of 10 mM cation was added to the Min well. The plate was incubated in a CO2 incubator for 2 hours.

[0452] Cytokine stimulation: Remove the 96-well plate and add 100 ng / ml human SCF for 10 minutes.

[0453] Lyse cells: Dilute 10X Cell Lysis Buffer to 1X with ddH2O. Keep the 1X buffer on ice and add the appropriate amount of protease inhibitors and phosphatase inhibitors at a standard concentration of 1 tablet / mL before use. Remove the 96-well plate and add 120µl of cells to each well. Lyse the cells for 15 minutes.

[0454] MSD detection: Coat the MSD plate one day in advance: dilute the coating antibody with PBS, add 30ul to each well for coating, and incubate at 24℃ overnight.

[0455] Blocking: Wash the MSD detection plate, add 300 μl of blocking solution, and block at room temperature for 1 hour;

[0456] Sample incubation: Wash the blocked test plate four times, adding 300 μL to each well, remove all liquid, take 40 μL of the lysed cell supernatant and add it to the corresponding wells, incubate at 24°C for 2 hours;

[0457] Detection antibody incubation: Wash the plate and incubate with 25 μL of detection antibody per well at 24°C for 1 hour;

[0458] Reading: Wash the plate, add 150 μl of 2x read buffer and detect on MSD.

[0459] Data processing: The compound signal was converted into inhibition rate, and nonlinear regression fitting was performed on the compound concentration and the corresponding inhibition rate using log(inhibitor) vs.response--Variable slope (four parameters) in Graphpad. The fitting curve was used to obtain IC 50 value.

[0460] II. Inhibitory effect of the compounds of the present invention on phosphorylation of transiently transfected cell lines HEK293-PDGFRα and HEK293-PDGFRβ

[0461] 1. Experimental Purpose: The purpose of this test example is to detect the ability of the compounds of the present invention to inhibit the phosphorylation of stably transfected cell lines HEK293-PDGFRα and HEK293-PDGFRβ.

[0462] 2. Experimental instruments and reagents:

[0463] 2.1 Instruments:

[0464] 3. Experimental methods:

[0465] Cell Preparation: Plate cells in a 6-well plate and culture overnight. Mix the PDGFRα plasmid with FuGENE transfection reagent, incubate at room temperature for 10 minutes, add the mixture to the cells, and culture for 24 hours. Hek293-PDGFRα cells were plated at a density of 15k cells / well in a 96-well plate, with 100 μL per well, and cultured overnight.

[0466] Plate cells in 6-well plates and culture overnight. Mix the PDGFRβ plasmid with FuGENE transfection reagent, incubate at room temperature for 10 minutes, add the mixture to the cells, and culture for 24 hours. Adjust the cell density of HEK293-PDGFRβ cells to 15 kcells / well and plate them in 96-well plates, using 100 μL per well, and culture overnight.

[0467] Compound Preparation and Incubation: HEK293-PDGFRα Cells: The stock solution concentration was 10 mM. The highest concentration tested in HEK293-PDGFRα cells was 30,000 nM. The stock solution was diluted with DMSO to a concentration of 31.55x the intermediate dilution for a total of three concentrations. The compound was then dispensed into a 96-well plate using an IDOT non-contact microdispensing system, with a total volume of 300 nL (containing 0.3% DMSO) per well, for a total of nine doses. The stock solution was first diluted with DMSO to a maximum concentration of 1000x (2 mM) of the intermediate dilution solution, and then diluted to a concentration of 31.55x the intermediate dilution for a total of three concentrations. The compound was then dispensed into a 96-well plate using an IDOT non-contact microdispensing system at a total volume of 300 nL (containing 0.3% DMSO) per well, for a total of 9 doses. 300 nL / well DMSO was added to the Max and Min wells, and the plate was incubated in a CO2 incubator for 2 hours.

[0468] HEK293-PDGFRβ cells: The stock solution concentration was 10 mM. The highest concentration tested in HEK293-PDGFRβ cells was 30,000 nM. The compound stock solution was serially diluted with DMSO to a concentration of 31.55x the intermediate dilution, for a total of three concentrations. Compounds were then dispensed into a 96-well plate using an IDOT non-contact microdispensing system, with a total volume of 300 nL (containing 0.3% DMSO) per well, for a total of nine doses. The compound stock solution was first diluted with DMSO to a maximum concentration of 1000x (2 mM) of the intermediate dilution, and then serially diluted to a concentration of 31.55x the intermediate dilution, for a total of three concentrations. Compounds were then dispensed into a 96-well plate using an IDOT non-contact microdispensing system, with a total volume of 300 nL (containing 0.3% DMSO) per well, for a total of nine doses. 300 nL / well of DMSO was added to the Max and Min wells, and the plates were incubated in a CO2 incubator for 2 hours.

[0469] Cytokine stimulation: Take out the 96-well plate, add cytokine PDGFRAA or cytokine PDGFRBB to a final concentration of 50 ng / ml, and stimulate for 10 minutes.

[0470] Lyse cells: Dilute 10X Cell Lysis Buffer to 1X with ddH2O. Keep the 1X buffer on ice and add the appropriate amount of protease inhibitors and phosphatase inhibitors at a standard volume of 1 tablet / ml just before use. Remove the 96-well plate and add 120 μl of cells to each well. Lyse the cells for 15 minutes.

[0471] ELISA Assay: Dilute the coating antibody in PBS one day in advance, add 100.0 μl to each well for coating, and incubate at room temperature overnight. On the day of the ELISA assay, remove the cell supernatant and thaw at room temperature before use. Blocking: Wash the assay plate, add 300 μl of blocking buffer, and block at room temperature for 1 hour. Wash the blocked assay plate four times, adding 300 μl per well. Remove all liquid, add 100 μl of the diluted cell supernatant after centrifugation to the corresponding well, and incubate at 24°C for 2 hours. Incubate with the detection antibody: Wash the plate, incubate 100 μl of HRP-conjugated detection antibody per well at 24°C for 1.5-2 hours. Color development and termination: Wash the plate, add 100 μl of color developer, and incubate in the dark for approximately 5-10 minutes. Add 50 μl of stop buffer to terminate color development and detect using Envision at 450 / 570 nm.

[0472] 4. Data processing: OD (450-570nm) was used to convert the inhibition rate of each compound concentration. The compound concentration and the corresponding inhibition rate were fitted by nonlinear regression using log (inhibitor) vs. response--Variable slope (four parameters) in Graphpad. The fitting curve was used to obtain IC 50 value.

[0473] 3. Experimental results and conclusions of the selective inhibition of phosphorylation of stable cell lines by the compounds of the present invention

[0474] 1. Experimental Results

[0475] 2. Experimental Conclusions: The compounds of the present invention exhibit varying degrees of selectivity for the target PDGFRα at the cellular level, with some compounds exhibiting selectivity for PDGFRα exceeding 100-fold, preferably exceeding 500-fold, and more preferably exceeding 1000-fold.

Claims

1. A compound of formula (I”) or a pharmaceutically acceptable salt thereof: Among them, is a substituted or unsubstituted 8- to 9-membered heteroaryl; Ar is selected from 5- to 6-membered heteroaryl, wherein said heteroaryl is optionally further substituted by 1 to 4 Rs r substituted; X 2 Selected from N or CR 2 r ; X 4 selected from N or CR 4 r ; X 7 selected from N or CR 7 r ; R 2 r , R 4 r and R 7 r are defined the same as R r ; R r independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R 21 , (CH2) q OR 21 , (CH2) q NR 21 R 22 , (CH2) q COR 23 , (CH2) q COOR 21 , (CH2) q CONR 21 R 22 , (CH2) q NR 21 COR 23 , (CH2) q NR 21 COOR 22 , (CH2) q SOR 23 , (CH2) q SONR 21 R 22 , (CH2) q SO2R 21 , (CH2) q SO2NR 21 R 22 ; wherein the substitution means being substituted by 1-4 R fff substituents; R 21 、R 22 and R 23 are each independently selected from: hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the said substitution means being substituted by 1-4 R ffff substituents; R fff and R ffff each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thioxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl; Ring A is selected from C6-C 10 aryl, 5-10-membered heteroaryl, 4-10-membered heterocyclic group, C3-C 10 cycloalkyl, phenyl-fused 5-6-membered heterocyclic group, phenyl-fused C5-C6 cycloalkyl, 5-6-membered heteroaryl-fused 5-6-membered heterocyclic group, 5-6-membered heteroaryl-fused C5-C6 cycloalkyl; R a Each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, NHC1-C6 alkyl, N(C1-C6 alkyl)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted 5-10 membered heteroaryl, wherein said substitution means being substituted with 1-4 groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy or C1-C6 hydroxyalkyl; L1 is selected from a bond, (CH2) m1 , a C2-C4 alkenylene, a C2-C4 alkynylene, (CH2) m2 -O-(CH2) m3 , (CH2) m2 -S-(CH2) m3 , (CH2) m2 -NR h -(CH2) m3 , (CH2) m2 -CO-(CH2) m3 , (CH2) m2 -COO-(CH2) m3 , (CH2) m2 -CONR h -(CH2) m3 , (CH2) m2 -NR h COO-(CH2) m3 , (CH2) m2 -R l NCONR h -(CH2) m3 , (CH2) m2 -SO2-(CH2) m3 , (CH2) m2 -SO2NR h -(CH2) m3 , (CH2) m2 -R l NSO2NR h -(CH2) m3 , (CH2) m2 -SO-(CH2) m3 , (CH2) m2 -SONR h -(CH2) m3 , (CH2) m2 -R l NSONR h -(CH2) m3 or (CH2) m2 -R l NC(=NH)NR h -(CH2) m3 ; Ring B is selected from C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, C3-C 10 cycloalkyl, phenyl-fused 5- to 6-membered heterocyclic group, phenyl-fused C5-C6 cycloalkyl, 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl-fused C5-C6 cycloalkyl; R b Each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, (CH2) k OR B-1 、(CH2) k NR B-1 R B-2 、(CH2) k COR B-3 、=NHOR B-1 、=CR B-1 R B-2 、(CH2) k C(=NH)OR B- 1、(CH2) k CONR B-1 R B-2 、(CH2) k NR B-1 COR B-3 、(CH2) k COOR B-3 、(CH2) k NR B-1 COOR B-3 、(CH2) k C(=NH)NR B-1 R B-2 、(CH2) k NR B-1 C(=NH)R B-3 、(CH2) k SOR B-1 、(CH2) k SONR B-1 R B-2 、(CH2) k NR B-1 SOR B-3 、(CH2) k SO2R B-1 、(CH2) k SO2NR B-1 R B-2 or (CH2) k NR B-1 SO2R B-3 ; wherein the substitution means being substituted by 1 to 4 R bb substitutions; R bb Selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thioxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl, 5-10 membered halogenated heteroaryl, (CH2) j OR b-1 、(CH2) j NR b-1 R b-2 、(CH2) j COR b-3 、=NHOR b-1 、=CR b-1 R b-2 、(CH2) j C(=NH)OR b- 1、(CH2) j CONR b-1 R b-2 、(CH2) j NR b-1 COR b-3 、(CH2) j NR b-1 COOR b-3 、(CH2) j COOR b-3 、(CH2) j C(=NH)NR b-1 R b-2 、(CH2) j NR b-1 C(=NH)R b-3 、(CH2) j SOR b-1 、(CH2) j SONR b-1 R b-2 、(CH2) j NR b-1 SOR b-3 、(CH2) j SO2R b-1 、(CH2) j SO2NR b-1 R b-2 or (CH2) j NR b-1 SO2R b-3 wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl may optionally be further substituted by 1-4 R bbb substituents; R bbb selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halocyclic group, C6-C 10 haloaryl or 5-10 membered haloheteroaryl; R B-1 、R B-2 、R B-3 、R b-1 、R b-2 and R b-3 are each independently selected from H, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 haloalkyl, C3-C 10 halocycloalkyl, 4-10 membered halocyclic group, C6-C 10 haloaryl, 5-10 membered haloheteroaryl; wherein the substitution means being substituted by 1-4 R bbbb substituents; R bbbb selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 halocycloalkyl, 4- to 10-membered haloheterocyclic group, C6-C 10 haloaryl or 5- to 10-membered haloheteroaryl; The H in the above CH2 may optionally be substituted by a substituent selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl; R h and R l each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl; m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6; x is selected from 0, 1, 2, 3, 4, 5, 6; y is selected from 0, 1, 2, 3, 4, 5, 6; q, j and k are each independently selected from 0, 1, 2, 3, 4, 5, 6.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is phenyl, 5- or 6-membered heteroaryl, 5- to 10-membered heterocyclic group, C5-C 10 cycloalkyl; preferably Ring A is phenyl or 5- or 6-membered heteroaryl, preferably phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridonyl, thienyl, furyl, thiazolyl or imidazolyl.

3. A compound of formula (I'-A'-1) or a pharmaceutically acceptable salt thereof, Among them, R a1 , R a2 and R a4 are defined in the same way as R a ; Preferably, R a1 , R a2 and R a4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy; R a Each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, NHC1-C6 alkyl, N(C1-C6 alkyl)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution means being substituted by 1-4 groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy or C1-C6 hydroxyalkyl; L1 is selected from a bond, (CH2) m1 , a C2-C4 alkenylene, a C2-C4 alkynylene, (CH2) m2 -O-(CH2) m3 , (CH2) m2 -S-(CH2) m3 , (CH2) m2 -NR h -(CH2) m3 , (CH2) m2 -CO-(CH2) m3 , (CH2) m2 -COO-(CH2) m3 , (CH2) m2 -CONR h -(CH2) m3 , (CH2) m2 -NR h COO-(CH2) m3 , (CH2) m2 -R l NCONR h -(CH2) m3 , (CH2) m2 -SO2-(CH2) m3 , (CH2) m2 -SO2NR h -(CH2) m3 , (CH2) m2 -R l NSO2NR h -(CH2) m3 , (CH2) m2 -SO-(CH2) m3 , (CH2) m2 -SONR h -(CH2) m3 , (CH2) m2 -R l NSONR h -(CH2) m3 or (CH2) m2 -R l NC(=NH)NR h -(CH2) m3 ; R f selected from substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5- to 14-membered heteroaryl, substituted or unsubstituted 4- to 14-membered heterocyclic group, substituted or unsubstituted C3-C 14 cycloalkyl, wherein the substitution means being substituted by 1 to 4 Rs r substituted; Ring C is selected from a 5- to 10-membered heteroaryl group, a C5-C 10 cycloalkyl group, a C6-C 10 aryl group or a 5- to 10-membered heteroaryl group; Ring D is selected from a 5- to 10-membered heterocyclic group, a C5-C 10 cycloalkyl group, a C6-C 10 aryl group or a 5- to 10-membered heteroaryl group; Ring E is selected from phenyl, 5-6 membered heteroaryl, 5-10 membered heterocyclic or C5-C 10 cycloalkyl; R c , R d and R e and each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R 11 、-(CH2) p OR 11 、(CH2) p NR 11 R 12 、(CH2) p COR 13 、(CH2) p COOR 11 、(CH2) p CONR 11 R 12 、(CH2) p NR 11 COR 13 、(CH2) p NR 11 COOR 12 、(CH2) p SOR 13 、(CH2) p SONR 11 R 12 、(CH2) p S02R 13 or (CH2) p SO2NR 11 R 12 ; wherein the substitution refers to 1-4 R 111 replace; R 11 , R 12 and R 13 Each is independently selected from hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to 1-4 R 1111 replace; R 111 and R 1111 each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thioxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl; R r independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R 21 , (CH2) q OR 21 , (CH2) q NR 21 R 22 , (CH2) q COR 23 , (CH2) q COOR 21 , (CH2) q CONR 21 R 22 , (CH2) q NR 21 COR 23 , (CH2) q NR 21 COOR 22 , (CH2) q SOR 23 , (CH2) q SONR 21 R 22 , (CH2) q SO2R 21 , (CH2) q SO2NR 21 R 22 ; wherein the substitution means being substituted by 1-4 R fff substituents; R 21 , R 22 and R 23 Each is independently selected from: hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to 1-4 R ffff replace; R fff and R ffff each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thioxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl; Ring B is selected from C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C3-C 10 cycloalkyl, phenyl-fused 5- to 6-membered heterocycloalkyl, phenyl-fused C5-C6 cycloalkyl, 5- to 6-membered heteroaryl-fused 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl-fused C5-C6 cycloalkyl; R b Each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, (CH2) k OR B-1 、(CH2) k NR B-1 R B-2 、(CH2) k COR B-3 、=NHOR B-1 、=CR B-1 R B-2 、(CH2) k C(=NH)OR B- 1、(CH2) k CONR B-1 R B-2 、(CH2) k NR B-1 COR B-3 、(CH2) k COOR B-3 、(CH2) k NR B-1 COOR B-3 、(CH2) k C(=NH)NR B-1 R B-2 、(CH2) k NR B-1 C(=NH)R B-3 、(CH2) k SOR B-1 、(CH2) k SONR B-1 R B-2 、(CH2) k NR B-1 SOR B-3 、(CH2) k SO2R B-1 、(CH2) k SO2NR B-1 R B-2 or (CH2) k NR B-1 SO2R B-3 ; wherein the substitution means being substituted by 1 to 4 R bb substitutions; R bb Selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thioxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4- to 10-membered halogenated heterocyclic group, C6-C 10 haloaryl, 5- to 10-membered halogenated heteroaryl, (CH2) j OR b-1 、(CH2) j NR b-1 R b-2 、(CH2) j COR b-3 、(CH2) j COOR b-3 、(CH2) j OCOR b-3 、=NHOR b-1 、=CR b-1 R b-2 、(CH2) j C(=NH)OR b-1 、(CH2) j CONR b-1 R b-2 、(CH2) j NR b-1 COR b-3 、(CH2) j NR b- 1COOR b-3 、(CH2) j C(=NH)NR b-1 R b-2 、(CH2) j NR b-1 C(=NH)R b-3 、(CH2) j SOR b-1 、(CH2) j SONR b- 1R b-2 、(CH2) j NR b-1 SOR b-3 、(CH2) j SO2R b-1 、(CH2) j SO2NR b-1 R b-2 or (CH2) j NR b-1 SO2R b-3 , wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl may optionally be further substituted by 1 to 4 R bbb substituents; R bbb selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10-membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10-membered halogenated heteroaryl; R B-1 、R B-2 、R B-3 、R b-1 、R b-2 and R b-3 are each independently selected from H, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 haloalkyl, C3-C 10 halocycloalkyl, 4-10 membered halocyclic group, C6-C 10 haloaryl, 5-10 membered haloheteroaryl; wherein the substitution means being substituted by 1-4 R bbbb substituents; R bbbb selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 halocycloalkyl, 4-10-membered halocyclic group, C6-C 10 haloaryl or 5-10-membered haloheteroaryl; The H in the above CH2 may optionally be substituted by a substituent selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, nitro, oxo, thio, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl; R h and R l each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl; m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6; y is selected from 0, 1, 2, 3, 4, 5, 6; p, q, j, k, z, e and f are each independently selected from 0, 1, 2, 3, 4, 5, 6.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, It has the structure shown in formula (I'-A'-4). Among them, R b’ is defined in the same way as R b , R b’ Preferably hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy.

5. The compound or its pharmaceutically acceptable salt according to any one of claims 3-4, characterized in that, R f Selected from or thiazolyl, wherein Cy1 is a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group, and the thiazolyl, 5- or 6-membered heteroaryl group, and 5- or 6-membered heterocyclic group are optionally further substituted by 1 to 4 R r Preferably, R f is selected from the following groups which may be substituted or unsubstituted Preferably, R f is selected from the following groups which may be substituted or unsubstituted Preferably, R f is selected from the following groups which may be substituted or unsubstituted wherein the substitution means being substituted by 1 to 4 R r substituted; or R f selected from -Ar3-L2-R p , wherein, Ar3 is selected from substituted or unsubstituted 5- to 10-membered heteroaryl groups, where said substitution means substitution with 1 to 3 groups selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4- to 10-membered heterocyclic groups, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; where said substitution means substitution with 1 to 4 R fff substituents; L2 is selected from a bond, C1-C6 alkylene, O, NR p1 , CO, COO, CONR p2 , NR p3 COO, SO, SONR p4 , SO2, SO2NR p5 ; R p1 、R p2 、R p3 、R p4 and R p5 each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl; R p Selected from hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution means being substituted by 1-4 R ffff substitutions; Or R f is Preferably R f is More preferably R f is X 2 selected from O, S, N, NR 11 r or CR 2 r ; Preferably, X 2 is selected from N or CR 2 r ; X 3 selected from N or CR 3 r ; X 4 Selected from O, S, N, NR 11 r or CR 4 r ; Preferably, X 4 is selected from N or CR 4 r ; X 5 selected from N or CR 5 r ; X 6 selected from N or CR 6 r ; X 7 selected from N or CR 7 r ; X 8 selected from N or C; Y 1 selected from N, O, S or CR 8 r ; Y 2 selected from N, O, S or CR 9 r ; Y 3 selected from N, O, S or CR 10 r ; R 1 r 、R 2 r 、R 3 r 、R 4 r 、R 5 r 、R 6 r 、R 7 r 、R 8 r 、R 9 r 、R 10 r and R 11 r are defined the same as R r ; or R f selected from Among them, Cy1 is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the 5-6 membered heteroaryl group and the 5-6 membered heterocyclic group are optionally further substituted by 1-4 Rs r ; preferably, R f is selected from the following groups which are substituted or unsubstituted: wherein the substitution means being substituted by 1 to 4 Rs r substituted; R r independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C1-C6 alkylene-R 21 , (CH2) q OR 21 , (CH2) q NR 21 R 22 , (CH2) q COR 23 , (CH2) q COOR 21 , (CH2) q CONR 21 R 22 , (CH2) q NR 21 COR 23 , (CH2) q NR 21 COOR 22 , (CH2) q SOR 23 , (CH2) q SONR 21 R 22 , (CH2) q SO2R 21 , (CH2) q SO2NR 21 R 22 ; wherein the substitution means being substituted by 1-4 R fff substituents; R 21 , R 22 and R 23 Each is independently selected from: hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to 1-4 R ffff replace; R fff and R ffff each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thioxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl.

6. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, characterized in that, (I”-10), the structure represented by formula (I”-11), formula (I”-14) or formula (I”-15) Wherein: R b'-1 is defined in the same way as R b' ; R b ' are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halide heterocyclic group, C6-C 10 haloaryl or 5-10 membered haloheteroaryl; Preferably, R b'-1 is selected from H, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; R 4 r , R 9 r and R 10 r are defined the same as R r ; Preferably, R 4 r , R 9 r and R 10 r are each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6-membered heterocyclic group, phenyl, 5-6-membered heteroaryl, C1-C6 alkylene-R 21 , (CH2)OR 21 , (CH2)NR 21 R 22 , (CH2)COR 23 , (CH2)COOR 21 , (CH2)CONR 21 R 22 , (CH2)NR 21 COR 23 , (CH2)NR 21 COOR 22 , (CH2)SOR 23 , (CH2)SONR 21 R 22 , (CH2)SO2R 21 , (CH2)SO2NR 21 R 22 ; wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6-membered heterocyclic group, phenyl, 5-6-membered heteroaryl may optionally be further substituted by one or more of deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6-membered heterocyclic group, phenyl, 5-6-membered heteroaryl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, 4-6-membered haloheterocyclic group, halophenyl or 5-6-haloheteroaryl.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 or 6, characterized in that, It has a structure represented by formula (I”-12), formula (I”-13), formula (I’-A’-6), formula (I’-A’-7), formula (I”-16), formula (I”-17), formula (I’-A’-8) or formula (I’-A’-9). Among them, R a1 , R a2 , R a3 and R a4 are defined in the same way as R a ; Preferably, R a1 , R a2 , R a3 and R a4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 - 4 or 5, characterized in that, Ring B is a 5- or 6-membered heteroaryl group. Preferably, ring B is an oxazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, or oxadiazolyl group; more preferably, ring B is even more preferably ring B is Or ring B is selected from the group consisting of substituted or unsubstituted: C6-C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 cycloalkyl, phenyl-fused 5-6 membered heterocyclic group, phenyl-fused C5-C6 cycloalkyl, 5-6 membered heteroaryl-fused 5-6 membered heterocyclic group or 5-6 membered heteroaryl-fused C5-C6 cycloalkyl; wherein said substitution means being substituted by 1-4 R b' substituents; Preferably, ring B is a substituted or unsubstituted 5- or 6-membered heteroaryl group or a substituted or unsubstituted 5- or 6-membered heteroaryl group fused to a 5- or 6-membered heterocyclic group. Preferably, ring B is a substituted or unsubstituted 5- or 6-membered heteroaryl group, a substituted or unsubstituted 5-membered heteroaryl group fused to a 5-membered heterocyclic group, a substituted or unsubstituted 5-membered heteroaryl group fused to a 6-membered heterocyclic group, a substituted or unsubstituted 6-membered heteroaryl group fused to a 5-membered heterocyclic group, or a substituted or unsubstituted 6-membered heteroaryl group fused to a 6-membered heterocyclic group. Preferably, ring B is a substituted or unsubstituted group selected from the following: oxazolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxadiazolyl, isoxazolyl, tetrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridone, pyridazinyl, triazinyl. More preferably, ring B is a substituted or unsubstituted group selected from the following: oxazolyl, isoxazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxadiazolyl; wherein the substitution means being substituted by 1-4 R b' substitutions; Wherein, R b' each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, hydroxy, oxo, thio, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl or 5-10 membered halogenated heteroaryl; Preferably, ring B is selected from Preferably selected from Cy3 is a 5-membered heteroaryl; Cy2 is a 5- to 6-membered heterocyclic group; y” is 0, 1 or 2; y”' is 0, 1, 2 or 3; R b'-6 , R b'-7 and R b'-8 Same definition as R b' ; Preferably, R b'-6 , R b'-7 and R b'-8 are each independently selected from H, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; or For Among them, ring G is selected from C3-C8 cycloalkyl or 4-8 membered heterocyclic group, f1 is 1, 2, 3 or 4; y' is 0, 1, 2 or 3; R b' and R bb are defined as described above, Further preferably Selected from Wherein, Ar1 is a 5-membered heteroaryl; Ar2 is a 6-membered heteroaryl; Z2 is selected from C or N; Z3 is selected from O, S, N, NR b'-4 , CR b'-2 ; Z4 is selected from O, S, N, NR b'-4 , CR b'-3 ; Z5 is selected from C or N; Z6 is selected from O, S, N, NR b'-4 , CR b'-1 ; W1 is selected from CR b'-1 or N; W2 is selected from CR b'-2 or N; W3 is selected from CR b'-3 or N; W4 is selected from CR b'-5 or N; Preferably, Selected from Among them, R b'-1 , R b'-2 , R b'-3 , R b'-4 and R b'-5 are defined in the same way as R b' ; Preferably, R b'-1 , R b'-2 , R b'-3 and R b'-5 are selected from H, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; R b'-4 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl.

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, characterized in that, R b Each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, (CH2) k OR B-1 、(CH2) k NR B-1 R B-2 、(CH2) k COR B-3 、(CH2) k COOR B-3 、(CH2) k OCOR B-3 、=NHOR B-1 、=CR B-1 R B-2 、(CH2) k C(=NH)OR B-1 、(CH2) k CONR B-1 R B-2 、(CH2) k NR B-1 COR B-3 、(CH2) k NR B-1 COOR B-3 、(CH2) k C(=NH)NR B-1 R B-2 、(CH2) k NR B-1 C(=NH)R B-3 、(CH2) k SOR B-1 、(CH2) k SONR B-1 R B-2 、(CH2) k NR B-1 SOR B-3 、(CH2) k SO2R B-1 、(CH2) k SO2NR B-1 R B-2 or (CH2) k NR B-1 SO2R B-3 ; wherein the substitution means being substituted by 1-4 R bb substituted; R bb Selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thioxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C 10 halocycloalkyl, 4-10 membered halogenated heterocyclic group, C6-C 10 haloaryl, 5-10 membered halogenated heteroaryl, (CH2) j OR b-1 、(CH2) j NR b-1 R b-2 、(CH2) j COR b-3 、(CH2) j COOR b-3 、(CH2) j OCOR b-3 、=NHOR b-1 、=CR b-1 R b-2 、(CH2) j C(=NH)OR b-1 、(CH2) j CONR b-1 R b-2 、(CH2) j NR b-1 COR b-3 、(CH2) j NR b- 1COOR b-3 、(CH2) j C(=NH)NR b-1 R b-2 、(CH2) j NR b-1 C(=NH)R b-3 、(CH2) j SOR b-1 、(CH2) j SONR b- 1R b-2 、(CH2) j NR b-1 SOR b-3 、(CH2) j SO2R b-1 、(CH2) j SO2NR b-1 R b-2 or (CH2) j NR b-1 SO2R b-3 , wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl may optionally be further substituted by 1-4 R bbb substituents; Preferably, R b is independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, oxo, thio, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, OR B-1 、NR B-1 R B-2 、COR B-3 、COOR B-3 、OCOR B-3 、=NHOR B-1 、CONR B-1 R B-2 、NR B-1 COR B-3 、NR B-1 COOR B-3 、C(=NH)NR B-1 R B-2 、=CR B-1 R B-2 、NR B-1 C(=NH)R B-3 、SOR B-1 、SONR B-1 R B-2 、NR B-1 SOR B-3 、SO2R B-1 、SO2NR B-1 R B-2 or NR B-1 SO2R B-3 ; wherein, the substitution in R b means being substituted by 1-4 R bb s, wherein, R bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halocyclic group, halophenyl, 5-6 membered haloheteroaryl, OR b-1 、NR b-1 R b-2 ,COLOR b-1 COOR b-1 、OCOR b-1 CONR b-1 R b-2 、NR b-1 COLOR b-1 、=LORD b-1 、NR b-1 COOR b-3 、C(=NH)NR b-1 R b-2 、NR b-1 C(=NH)R b-3 、=CR b-1 R b-2 、SOR b-1 、SONR b-1 R b-2 、NR b-1 SOR b-3 SO2R b- 1、SO2NR b-1 R b-2 或NR b-1 SO2R b-3 ; Preferably, R b is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, OR B-1 、NR B-1 R B-2 、COR B-3 、=NHOR B-1 、CONR B-1 R B-2 、NR B-1 COR B-3 、COOR B- 3、NR B-1 COOR B-3 、C(=NH)NR B-1 R B-2 、=CR B-1 R B-2 、NR B-1 C(=NH)R B-3 、SOR B-1 、SONR B- 1R B-2 、NR B-1 SOR B-3 、SO2R B-1 、SO2NR B-1 R B-2 or NR B-1 SO2R B-3 ; wherein, R b the substitution described therein means being substituted by 1-4 R bb s, wherein, R bb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halocyclic group, halophenyl, 5-6 membered haloheteroaryl, OR b-1 、NR b-1 R b-2 , COR b-1 , CONR b-1 R b-2 , NR b-1 COR b-1 , =NHOR b-1 , COOR b-3 , NR b-1 COOR b-3 , C(=NH)NR b-1 R b-2 , NR b-1 C(=NH)R b-3 , =CR b-1 R b-2 , SOR b-1 , SONR b-1 R b-2 , NR b-1 SOR b-3 , SO2R b-1 , SO2NR b-1 R b-2 or NR b-1 SO2R b-3 , wherein, R bb The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl in can be further substituted by 1-4 R bbb R bbb is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halocyclic group, halophenyl, 5-6 membered haloheteroaryl; wherein, R B-1 , R B-2 , R B-3 , R b-1 , R b- 2 and R b-3 Each is independently selected from hydrogen, COOC1-C6 alkyl, SO2C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 haloalkoxy, substituted or unsubstituted C1-C6 deuterated alkyl, substituted or unsubstituted C1-C6 deuterated alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halogenated phenyl, 5-6 membered halogenated heteroaryl; wherein, R B-1 , R B-2 , R B-3 , R b-1 , R b-2 and R b-3 The substitution in the formula is 1 to 4 R bbbb Replacement, where R bbbb Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, hydroxyl, oxo, thioxo, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, 4-8 membered halogenated heterocyclyl, halophenyl, 5-6 membered halogenated heteroaryl; Preferably, R b each independently is C1-C3 alkylene OC1-C3 alkyl, C1-C3 alkylene OC1-C3 haloalkyl, wherein the ring G is selected from C3-C6 cycloalkyl or 4- to 6-membered heterocyclic group, and f1 is 1, 2, 3 or 4; Preferably, R b is independently selected from C1-C3 alkylene OC1-C3 alkyl, C1-C3 alkylene OC1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C3 alkylene C3-C6 cycloalkyl, C1-C3 alkylene 4-6-membered heterocyclic group, C1-C3 alkylene C3-C6 halocycloalkyl, C1-C3 alkylene 4-6-membered haloheterocyclic group, C1-C3 alkoxy-substituted C3-C6 cycloalkyl, C1-C3 haloalkoxy-substituted C3-C6 cycloalkyl, C1-C3 alkyl COO-substituted C3-C6 cycloalkyl, C1-C3 alkyl OCO-substituted C3-C6 cycloalkyl, C1-C3 alkyl CONH-substituted C3-C6 cycloalkyl, C1-C3 alkyl NHCO-substituted C3-C6 cycloalkyl, C1-C3 alkyl NHCOO-substituted C3-C6 cycloalkyl, 4-6-membered heterocyclic group, 4-6-membered haloheterocyclic group, C1-C3 alkoxy-substituted 4-6-membered heterocyclic group, C1-C3 haloalkoxy-substituted 4-6-membered heterocyclic group, C1-C3 alkyl COO-substituted 4-6-membered heterocyclic group, C1-C3 alkyl OCO-substituted 4-6-membered heterocyclic group, C1-C3 alkyl CONH-substituted 4-6-membered heterocyclic group, C1-C3 alkyl NHCO-substituted 4-6-membered heterocyclic group or C1-C3 alkyl NHCOO-substituted 4-6-membered heterocyclic group.

10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, characterized in that, R f selected from R f selected from Preferably, R f is selected from Preferably R f selected from More preferably R f selected from and / or For Further preferably For Among them, R a1 , R a2 , R a3 and R a4 are defined as described above; and / or, R a1 selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, preferably methyl; and / or, R a2 selected from hydrogen or a halogen (such as fluorine, chlorine or bromine), preferably hydrogen, fluorine; and / or, R a3 selected from hydrogen or a halogen (such as fluorine, chlorine or bromine), preferably hydrogen, fluorine; and / or, R a4 selected from hydrogen; and / or, ring A is and / or, R a each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy; preferably, R a each independently selected from hydrogen, deuterium, halogen, C1-C3 alkyl; and / or, R b each independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, COC1-C3 alkyl, CH=NOH, CH=NOC1-C3 alkyl, Preferably R b each independently selected from More preferably R b is and / or, ring B is selected from the group consisting of substituted or unsubstituted groups: Wherein, the substitution means being substituted by 1, 2 or 3 Rs b ' substitutions; and / or, R b 'is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy; and / or, ring G is selected from C3-C6 cycloalkyl or 4-6 membered heterocyclic group, preferably and / or, R bb selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thioxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl COO, C1-C3 alkyl OCO, C1-C3 alkyl CONH, C1-C3 alkyl NHCO, C1-C3 alkyl NHCOO, C1-C3 haloalkyl COO, C1-C3 haloalkyl OCO, C1-C3 haloalkyl CONH, C1-C3 haloalkyl NHCO, C1-C3 haloalkyl NHCOO; and / or, L2 is selected from NH or NHCOO; and / or, R p selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 aryl, 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 aryl, 5-6 membered heteroaryl are optionally further substituted by one or more of hydrogen, deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy; preferably, R p is selected from methyl, ethyl, propyl, cyclopropyl, and / or, L1 is selected from a bond, NH, O, CO, CONH, and L1 is preferably a bond; and / or, X 1 is N; and / or, X 2 is N; and / or, X 5 is N; and / or, X 7 is N; and / or, X 2 and X 7 is N; and / or, X 1 , X 2 and X 7 is N; and / or, X 2 , X 5 and X 7 is N; and / or, X 3 is CR 3 r ; and / or, X 4 is CR 4 r ; and / or, X 6 is CR 6 r ; and / or, Y 1 is selected from S or O; and / or, Y 2 is selected from CR 9 r ; and / or, Y 3 is selected from CR 10 r ; and / or, X 8 is N; and / or, R 1 r , R 2 r , R 3 r , R 4 r , R 5 r , R 6 r , R 7 r , R 8 r , R 9 r and R 10 r each independently is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C3 alkylene-R 21 , (CH2)OR 21 , (CH2)NR 21 R 22 , (CH2)COR 23 , (CH2)COOR 21 , (CH2)CONR 21 R 22 , (CH2)NR 21 COR 23 , (CH2)NR 21 COOR 22 , (CH2)SOR 23 , (CH2)SONR 21 R 22 , (CH2)SO2R 21 , (CH2)SO2NR 21 R 22 ; wherein, the C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkyl, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl may optionally be further substituted by one or more of deuterium, halogen, amino, cyano, hydroxy, nitro, oxo, thio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 hydroxyalkyl and C1-C6 haloalkoxy; and / or, m1 is 0, 1, 2 or 3; and / or, m2 and m3 are each independently 0 or 1, preferably 0.

11. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the following compounds:

12. A compound as shown below Wherein, R N selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; R a1 、R a2 、R a4 、L1, ring B, y, and R b are defined as described in claim 3; Preferably, the compound is selected from the following compounds 13. A method for preparing a compound of formula (I”-10), formula (I”-14), formula (I”-15) as described in claim 6 or a compound of formula (I’-A’-1) as described in claim 3 or a pharmaceutically acceptable salt thereof: Method 1: React the compounds represented by formula (INT-3) and formula (INT-2) to prepare the compound represented by formula (I”-10). Method 2: React the compounds represented by formula (INT-3) and formula (INT'-2) to prepare the compound represented by formula (I”-14). Method 3: React the compounds represented by formula (INT-3) and formula (INT”-2) to prepare the compound represented by formula (I”-15). Method 4: React the compounds represented by formula (INT-4) and formula (INT”'-2) to prepare the compound represented by formula (I’-A’-4). Preferably, the reactions described in Methods 1 to 4 are carried out in the presence of a base and a catalyst, the base is an organic base, and the catalyst is an amide condensing agent; wherein, R O selected from OH or C1-C6 alkoxy; R N selected from H or an amino protecting group; wherein the amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; R 4 r , R 9 r , R 10 r , R a , R b , R b’-1 , L1, the definition of ring A and x is as described in claim 6; R f 、R a1 、R a2 、R a4 、L1, ring B, y, and R b are defined as described in claim 3.

14. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a medicament for the treatment of the following related diseases; wherein the diseases are selected from mast cell-related diseases, respiratory diseases, inflammatory disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), autoimmune diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH); Preferably, the diseases are selected from asthma, eosinophilic esophagitis, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, chronic urticaria, spontaneous chronic urticaria, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, gastrointestinal stromal tumor, mast cell tumor, mastocytosis, anaphylactic reaction syndrome, type I diabetes or type II diabetes, more preferably urticaria or chronic urticaria.