NLRP3 inhibitor compounds and their manufacturing methods and applications

Abstract

The present invention provides compounds as NLRP3 inhibitors, which have a novel bicyclic fused ring core. The present invention further relates to methods for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of NLRP3-mediated diseases and disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Chinese patent application CN202310139999.7 filed on February 14, 2023, Chinese patent application CN202310644402.4 filed on May 31, 2023, Chinese patent application CN202310705888.8 filed on June 14, 2023, and Chinese patent application CN202410056683.6 filed on January 12, 2024, the entire contents of which are incorporated herein by reference and for all purposes. [Technical Field]

[0002] The present invention relates to compounds that inhibit NLRP3, as well as methods for producing and applications thereof. [Background technology]

[0003] The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and procaspase-1 (Procaspase-1). NLRP3 inflammasome activation requires two steps: priming (the first signal) and activation (the second signal). The first signal activates the nuclear transcription factor NF-κB, which then upregulates the transcription of inactive NLRP3 and inflammasome-associated components, including the IL-1β precursor. The second signal promotes the conversion of inactive NLRP3 to active NLRP3. After activation, NLRP3 recruits ASC and procaspase-1, and the three components form the inflammasome. The inflammasome promotes the self-cleavage of pro-caspase-1 to produce active caspase-1, which then induces the cleavage of Gasdermin D (GSDMD), forming pores in the cell membrane and causing cell death, i.e., pyroptosis. Caspase-1 induces pyroptosis and simultaneously promotes the secretion of IL-1β and IL-18, thereby regulating the body's inflammatory response.

[0004] Research has revealed that abnormal activation of the NLRP3 inflammasome causes the development of many diseases, such as cryopyrin-associated periodic fever syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID), which are genetic disorders caused by NLRP3 gain-of-function mutations. The NLRP3 inflammasome is also involved in the development of many complex diseases, such as central nervous system diseases (Alzheimer's disease, brain infections, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease), lung diseases (asthma and idiopathic pulmonary fibrosis), metabolic disorders (type II diabetes and related complications, atherosclerosis, obesity, and gout), liver diseases (chronic liver disease, nonalcoholic steatohepatitis, viral hepatitis, and cirrhosis), kidney diseases (acute and chronic kidney injury), inflammatory bowel disease (IBD), other autoimmune diseases (rheumatoid arthritis, hidradenitis suppurativa, and systemic lupus erythematosus), and tumors (colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis). Therefore, the NLRP3 inflammasome is an important potential target with significant therapeutic value for many diseases.

[0005] Currently, no drug molecules targeting the NLRP3 inflammasome have been released, leaving a clear unmet market demand. Compounds developed and entering clinical trials include Dapansutrile (Olatec), IFM-2427 (IFM / Novartis), ZYIL-1 (Zydus Lifesciences), and VTX-2735 (Zomagen Biosciences / Ventyx Biosciences). Many of these compounds are derivatives of the sulfonylurea small molecule NLRP3 inhibitor MCC950, which has drawbacks such as a single structure, short half-life, and poor blood-brain barrier penetration. Therefore, there is a strong need for the development of next-generation small molecule NLRP3 inflammasome inhibitors with high activity and better drug formability. Summary of the Invention

[0006] In order to solve one of the above technical problems in the prior art, the present invention provides compounds with a bicyclic fused ring core as NLRP3 inhibitors, and the compounds according to the present invention have better drug formability.

[0007] In one aspect, the present invention provides a compound according to formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof, [ka] where: [ka] is connected to ring A, [ka] is connected to ring B, Ring A and ring B are each independently selected from a 5- to 6-membered heteroaryl group, a 5- to 6-membered heterocyclic group, and a phenyl group; Ring C is selected from a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a phenyl-fused 4- to 7-membered cycloalkyl group, a phenyl-fused 4- to 7-membered heterocyclic group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered heterocyclic group, a 4- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; Each R c are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, R c1 S(O)2-, -(CH2) s-N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a phenyl group substituted with one or more halogens or a phenyl group substituted with one or more hydroxy groups, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R c can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Each R a and R b are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, oxo, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, C 1-6 Haloalkoxy group, hydroxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(=O)-(C 1-6 alkyl), a 3- to 6-membered heterocyclic group optionally substituted with a hydroxy group; L 1 is a bond, C 3-6 Cycloalkylene group, -NR 2-、-O-、-S-、-C(=O)-、-(CR 3 R 4 ) a -、-NR 2 -(CR 3 R 4 ) a -、-(CR 3 R 4 ) a -NR 2 -、-O-(CR 3 R 4 ) a -、-(CR 3 R 4 ) a -O-、-S-(CR 3 R 4 ) a -、-(CR 3 R 4 ) a -S-、-C(=O)-(CR 3 R 4 ) a -、-(CR 3 R 4 ) a -C(=O)-、-(CR 3 R 4 ) a -(CR 9 =CR 10 )-、-(CR 9 =CR 10 )-(CR 3 R 4 ) a -、-C(=O)-O-、-O-C(=O)-、-C(=O)-NR 2 -、-(CR 3 R 4 ) a -C(=O)-NR 2 -、-NR 2 -C(=O)-、-(CR 3 R 4 ) a -NR 2 -C(=O)-、-S(=O)2-NR 2 -、-NR 2 -S(=O)2-、-NR 2 -(CR 3 R 4 ) a -C(=O)-、-C(=O)-(CR 3R 4 ) a -NR 2 -, -NR 2 -(CR 3 R 4 ) a -C(=O)-NR 5 -, -NR 2 -C(=O)-(CR 3 R 4 ) a -NR 5 -, -C(=S)-NR 2 -, -NR 2 -C(=S)-, L 2 is the bond, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -S- is selected from Each R 2 , R 5 , R 6 , R 9 and R 10 are independently hydrogen, deuterium, and C 1-6 alkyl groups, Each R 3 , R 4 , R 7 and R 8 are independently hydrogen, deuterium, halogen, oxo, hydroxy group, amino group, C 1-6 alkyl groups, R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, C 1-6 Alkyl group, C1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 alkyl-OC(═O)—, a 3- to 10-membered cycloalkyl group (preferably a 3- to 6-membered cycloalkyl group), a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 The alkyl-OC(=O)-, 3- to 10-membered cycloalkyl group (preferably 3- to 6-membered cycloalkyl group), 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered bicyclic heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered heteroaryl groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -CH2-C(=O)OR c4 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -CH2-C(=O)-N(R c4 )(R c4 ), -N(R c4 )-C(=O)-N(R c6 )(Rc5 ), -P(=O)R c5 R c6 , -CR c7 R c8 -CN, -(CH2) s -R c9 is further substituted with 1, 2, 3 substituents selected from Each R c1 and R c2 are independently hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkoxy group, C 3-6 selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group, R c3 are hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 cycloalkyl groups, wherein C 1-6 Alkyl groups and C 3-6 The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), R c4 are hydrogen, deuterium, and C 1-6 alkyl groups, R c5 and R c6 are hydrogen, deuterium, and C 1-6 Alkyl group, C 3-6 cycloalkyl groups, or R c5 and R c6 form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, and 1-6 Alkyl group, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally be substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), R c7 and R c8 are hydrogen, deuterium, and C 1-6 alkyl group, or R c7 and R c8 form a 3- to 6-membered cycloalkyl group together with the C atom to which they are attached, R c9 is selected from a 3- to 6-membered heterocyclic group, and the heterocyclic group optionally contains hydrogen, deuterium, C 1-6 substituted with one, two or three alkyl groups; R 11 are hydrogen, deuterium, and C 1-6 selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group; each a and b is independently 1, 2, 3, or 4; each s, n, m, and p is independently selected from 0, 1, 2, 3, or 4; As a condition, [ka] is hydrogen, C 1-6 It is not an alkyl group.

[0008] In some embodiments, the groups associated with ring A and ring B [ka] teeth, [ka] is selected from the group Each M 1 , M 2 , M 3 , M 4 , U 1 , U 2 are each independently selected from CH and N; Each U 3 , U 4 , U 5 , U 6 are each independently selected from CH, NH, O, and S.

[0009] In some embodiments, the groups associated with ring A and ring B [ka] teeth, [ka] is selected from the group Each M 1 , M 2 , M 3 , M 4 , U 1 , U 2 are each independently selected from CH and N; Each U 3 , U 4 , U 5 , U 6 are each independently selected from CH, NH, O, and S.

[0010] In some embodiments, the groups associated with ring A and ring B [ka] teeth, [ka] [ka] [ka] is selected from the group Each M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , U 2 are each independently selected from CH and N; Each U 3 , U 4 , U 5 , U 6 are each independently selected from CH, NH, O, and S.

[0011] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-3 or VIII-4: [ka] where R 1 is a hydroxyl group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 alkyl-OC(═O)—, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 The alkyl-OC(=O)-, 3 to 10-membered cycloalkyl group, 3 to 6-membered monocyclic heterocyclic group, 6 to 11-membered bicyclic heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered heteroaryl groups, -CR c7 R c8 -CN, -(CH2) s -R c9 and R cn is the above R c as defined in The conditions are to simultaneously satisfy the following 1) to 45), 1) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 2) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1is -NH-CH2- and R 1 but, [ka] It is not based on 3) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is a bond and R 1 but, [ka] It is not based on 4) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 5) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is a bond and R 1 but, [ka] It is not based on 6) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH-CH2- and R 1 but, [ka] It is not based on 7) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -CH2- and R 1 but, [ka] It is not based on 8) [ka] but [ka] and L 2 is the bond, [ka] but [ka] and L 1 is -NH- and R 1 but, [ka] It is not based on 9) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 10) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 11) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 12) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 13) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 14) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 15) [ka] but [ka] and L 2is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 16) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 17) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 18) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 19) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 20) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on twenty one) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on twenty two) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on twenty three) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on twenty four) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on twenty five) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 26) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 27) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 28) [ka] but [ka] and L 2 is the bond, [ka] but [ka] and L 1 is -NH- and R 1 but, [ka] It is not based on 29) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 30) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 31) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 32) [ka] but [ka] and [ka] but [ka] and L 1 is -NH- and R 1 but, [ka] It is not based on 33) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 34) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 35) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 36) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 37) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 38) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1is -NH- and R 1 but, [ka] It is not based on 39) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is -NH- and R 1 but, [ka] It is not based on 40) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is a bond and R 1 but, [ka] It is not based on 41) [ka] but [ka] and L 2 is the bond, [ka] but [ka] and L 1 is a bond and R 1 but, [ka] It is not based on 42) [ka] but [ka] and L 2 is a bond and L 1 is -NH- and R 1 but [ka] At the same time, [ka] but, [ka] It is not based on 43) [ka] but [ka] and L 2 is a bond and L 1 is -NH- and R 1 but [ka] At the same time, [ka] but, [ka] It is not based on 44) [ka] but [ka] and L 2 is a bond, m=p=0 or R a =R b = H, and L 1 is a bond and R 1 but, [ka] It is not based on 45) [ka] isn't it.

[0012] In some embodiments, the groups associated with ring A and ring B [ka] is selected from the group [ka] represents rings A and B from left to right, or rings A and B from right to left; where R ab are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl; Each k is independently selected from 0, 1, 2, 3, or 4.

[0013] In some embodiments, the groups associated with ring A and ring B [ka] is selected from the group [ka] represents rings A and B from left to right, or rings A and B from right to left; where R ab are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl; Each k is independently selected from 0, 1, 2, 3, or 4.

[0014] In some embodiments, the groups associated with ring A and ring B [ka] is selected from the group [ka] The bicyclic group represents rings A and B from left to right, or rings A and B from right to left.

[0015] In some embodiments, the groups associated with ring A and ring B [ka] is selected from the group [ka] The bicyclic group represents rings A and B from left to right, or rings A and B from right to left.

[0016] In some embodiments, Ring C is selected from a 6- to 10-membered aryl group, a 5- to 6-membered heteroaryl group, a phenyl-fused 5- to 6-membered heteroaryl group, a phenyl-fused 4- to 6-membered cycloalkyl group, a phenyl-fused 4- to 6-membered heterocyclic group, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-fused 4- to 6-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 4- to 6-membered heterocyclic group, a 5- to 6-membered cycloalkyl group, and a 5- to 6-membered heterocyclic group.

[0017] In some embodiments, Ring C is selected from a 6- to 10-membered aryl group, a 5- to 6-membered heteroaryl group, a phenyl-fused 5- to 6-membered heteroaryl group, a phenyl-fused 4- to 6-membered cycloalkyl group, a phenyl-fused 4- to 6-membered heterocyclic group, a nitrogen-containing 6-membered heteroaryl-fused 5- to 6-membered heteroaryl group, a nitrogen-containing 6-membered heteroaryl-fused 4- to 6-membered cycloalkyl group, a nitrogen-containing 6-membered heteroaryl-fused 4- to 6-membered heterocyclic group, a 5- to 6-membered cycloalkyl group, and a 5- to 6-membered heterocyclic group.

[0018] In some embodiments, the group associated with ring C [ka] teeth, [ka] is selected from the group wherein rings C1 and C2 are each independently selected from a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, and a 6-membered cycloalkyl group; preferably, rings C1 and C2 are each independently selected from a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, a 2,3-dihydrofuranyl group, a 2,3-dihydrothienyl group, a 2,3-dihydropyrrolyl group, a 2,3-dihydrodioxinyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; E 1 , E 2 , E 3 , E 4 and E 5 are each independently selected from CH2, O, S, and NH, with the proviso that E 1 , E 2 , E 3 , E 4 and E 5 At least one of them is NH, and together they form a stable ring.

[0019] In some embodiments, the group associated with ring C [ka] teeth, [ka] is selected from the group:

[0020] where R c , n has the definition described in the present invention.

[0021] In some embodiments, the group associated with ring C [ka] teeth, [ka] [ka] is selected from the group:

[0022] In some embodiments, each R a and R b are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, amino, cyano, oxo, methyl, ethyl, trifluoromethyl, methoxy, n-propyl, isopropyl, dimethylamino, and acetyl.

[0023] In some embodiments, each R c are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, C 1-4 Alkyl group, C 1-4 Haloalkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Alkoxy-C 1-2 Alkyl group, R c1 S(O)2-, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, and a phenyl group, and the phenyl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, or a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R ccan form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; In some embodiments, each R c are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Alkoxy-C 1-2 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a phenyl group substituted with one or more halogens, or a phenyl group substituted with one or more hydroxy groups, or two R c can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; In some embodiments, each R care independently fluorine, chlorine, bromine, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, cyclohexenyl, oxetanyl, phenyl, 4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, pyridyl, cyclobutylamino, [ka] methylsulfonyl group, or two R c together with the C atoms to which they are attached form a cyclopentenyl group, a 2,3-dihydrofuranyl group, a cyclobutenyl group, a thienyl group, a 1,4-dioxanyl group, a pyridyl group, a cyclopenta-1,3-dienyl group, a phenyl group, or a dioxinyl group.

[0024] In some embodiments, Each R 2 , R 5 and R 6 are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, and an isopropyl group; Each R 3 , R 4 , R 7 and R 8 are each independently selected from hydrogen, deuterium, oxo, hydroxy, amino, methyl, ethyl, propyl, and isopropyl; Each a and b is independently 1 or 2.

[0025] In some embodiments, L 1 is the bond, -NR 2 -, -O-, -S-, -C(=O)-, -NR 2 -(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -NR 2 -, -O-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -O-, -S-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -S-, where a is 1 or 2; L 2 is the bond, -NR 6 -, -NR 6 -(CR 7 R 8 ) b -, -O-, and -S-.

[0026] In some embodiments, each s, n, m, and p is independently selected from 0, 1, 2, or 3.

[0027] In some embodiments, R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, C 1-4 Alkyl group, C 1-4 Alkoxy group, NHR 11 -C(=O)-, C 1-4 Alkyl-C(=O)-O-, C 1-4 alkyl-OC(═O)—, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered spiro bicyclic heterocyclic group, a 6- to 11-membered bridged bicyclic heterocyclic group, a 6- to 11-membered fused bicyclic heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C 1-4 Alkyl group, C1-4 Alkoxy group, NHR 11 -C(=O)-, C 1-4 Alkyl-C(=O)-O-, C 1-4 Alkyl-OC(=O)-, 3- to 6-membered cycloalkyl group, 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered spiro bicyclic heterocyclic group, 6- to 11-membered bridged bicyclic heterocyclic group, 6- to 11-membered fused bicyclic heterocyclic group, phenyl group, naphthyl group, and 5- to 10-membered heteroaryl group each independently optionally represent hydrogen, deuterium, halogen, hydroxy group, amino group, oxo, C 1-4 Alkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -CH2-C(=O)OR c4 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -CH2-C(=O)-N(R c4 )(R c4 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)R c5 R c6 , -CR c7 R c8 -CN, -(CH2) s -R c9 further substituted with 1, 2, 3 substituents selected from: 11 are hydrogen, deuterium, and C 1-4 It is selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group.

[0028] In some embodiments, R 1represents hydrogen, hydroxy group, amino group, carboxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, NH2-C(=O)-, CH3NH-C(=O)-, CH3CH2NH-C(=O)-, CH3-C(=O)-O-, CH3CH2-C(=O)-O-, CH3-OC(=O)-, CH3CH2-OC(=O)-, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, selected from oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, tetrahydro-2H-pyranyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, quinolyl, isoquinolyl, or [ka] is selected from the group Here, the above-mentioned methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, NH2-C(=O)-, CH3NH-C(=O)-, CH3CH2NH-C(=O)-, CH3-C(=O)-O-, CH3CH2-C(=O)-O-, CH3-OC(=O)-, CH3CH2-OC(=O)-, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetane group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a 1,4-dioxanyl group, a tetrahydro-2H-pyranyl group, a phenyl group, a naphthyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a triazolyl group, a quinolyl group, an isoquinolyl group, [ka] are each independently any of hydrogen, deuterium, halogen, a hydroxy group, an amino group, oxo, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a 3- to 6-membered monocyclic heterocyclic group, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)R c5 R c6 , -CR c7 R c8 It is further substituted with 1, 2, 3 substituents selected from -CN.

[0029] In some embodiments, where R 1 is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, or a 6- to 11-membered bicyclic heterocyclic group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is selected from the group consisting of -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c6 R c5 , -P(=O)R c5 R c6 and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, a hydroxy group, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group (preferably C 1-6 Alkoxy-C 1-4alkyl group), -(CH2) s -N(R c1 )(R c2 ), C 3-6 is further substituted by 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; R c3 is C 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein C 1-6 Alkyl groups and C 3-6 The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), R c5 and R c6 are H, deuterium, and C 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein C 1-6 Alkyl groups and C 3-6 The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl).

[0030] In some embodiments, where R 1represents a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] is -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c5 R c6 , -P(=O)R c5 R c6 and wherein the cyclopentane group, the cyclohexane group, the azetidinyl group, the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, the piperazinyl group, [ka] is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group (preferably C 1-6 Alkoxy-C 1-4 alkyl group), -(CH2) s -N(R c1 )(R c2 ), C 3-6 It is further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group.

[0031] In some embodiments, where R 1 represents a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] is -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c5 R c6 , -P(=O)R c5 R c6 and the tetrahydropyrrolyl, piperidinyl, morpholinyl or piperazinyl group is optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, hydroxy, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, C 1-6 Alkoxy-C 1-6 Alkyl group (preferably C 1-6 Alkoxy-C 1-4 It is further substituted with 1, 2, or 3 substituents selected from alkyl groups, 3- to 6-membered monocyclic heterocyclic groups.

[0032] In some embodiments, where R 1 is selected from a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, or a piperazinyl group, and the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, or the piperazinyl group is selected from a —C(═O)—R c3 , -S(=O)2-R c3 , -P(=O)R c5 R c6 and the tetrahydropyrrolyl, piperidinyl, morpholinyl or piperazinyl group is optionally substituted with one substituent selected from deuterium, halogen, hydroxyl group, C 1-6Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group (preferably C 1-6 Alkoxy-C 1-4 alkyl groups).

[0033] In some embodiments, where R 1 teeth, [ka] is selected from.

[0034] In some embodiments, the compounds of the present invention have the structure shown in Formula II: [ka] Here, ring B, ring C, L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M 3 , M 4 has the definition set forth in the present invention.

[0035] In some embodiments, the compounds of the present invention have the structure shown in Formula III: [ka] Here, rings B and L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M 3 , M 4 has the definition set forth in the present invention.

[0036] In some embodiments, the compounds of the present invention have the structure shown in formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10: [ka] Here, rings C and L 1 , L 2 , R a , R b , R c ,n,m,p,R 1、 , M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0037] In some embodiments, the compounds of the present invention have the structure shown in formula IV-1.

[0038] In some embodiments, the compounds of the present invention have the structure shown in formula IV-2.

[0039] In some embodiments, the compounds of the present invention have the structure shown in formula IV-3.

[0040] In some embodiments, the compounds of the present invention have the structure shown in formula IV-4.

[0041] In some embodiments, the compounds of the present invention have the structure shown in formula IV-5.

[0042] In some embodiments, the compounds of the present invention have the structure shown in formula IV-6.

[0043] In some embodiments, the compounds of the present invention have the structure shown in formula IV-7.

[0044] In some embodiments, the compounds of the present invention have the structure shown in formula IV-8.

[0045] In some embodiments, the compounds of the present invention have the structure shown in formula IV-9.

[0046] In some embodiments, the compounds of the present invention have the structure shown in formula IV-10.

[0047] In some embodiments, the compounds of the invention have the structure shown in Formula V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, V-9, or V-10: [ka] where L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0048] In some embodiments, the compounds of the present invention have the structure shown in Formula V-1.

[0049] In some embodiments, the compounds of the present invention have the structure shown in Formula V-2.

[0050] In some embodiments, the compounds of the present invention have the structure shown in Formula V-3.

[0051] In some embodiments, the compounds of the present invention have the structure shown in Formula V-4.

[0052] In some embodiments, the compounds of the present invention have the structure shown in formula V-5.

[0053] In some embodiments, the compounds of the present invention have the structure shown in Formula V-6.

[0054] In some embodiments, the compounds of the present invention have the structure shown in Formula V-7.

[0055] In some embodiments, the compounds of the present invention have the structure shown in formula V-8.

[0056] In some embodiments, the compounds of the present invention have the structure shown in formula V-9.

[0057] In some embodiments, the compounds of the present invention have the structure shown in formula V-10.

[0058] In some embodiments, the compounds of the invention have the structure shown in Formula VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VI-9, or VI-10: [ka] where n1 is 0, 1, 2 or 3, and L 1 , L 2 , R a , R b , R c , m, p, R 1 , M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0059] In some embodiments, the compounds of the present invention have the structure shown in formula VI-1.

[0060] In some embodiments, the compounds of the present invention have the structure shown in formula VI-2.

[0061] In some embodiments, the compounds of the present invention have the structure shown in formula VI-3.

[0062] In some embodiments, the compounds of the present invention have the structure shown in formula VI-4.

[0063] In some embodiments, the compounds of the present invention have the structure shown in formula VI-5.

[0064] In some embodiments, the compounds of the present invention have the structure shown in formula VI-6.

[0065] In some embodiments, the compounds of the present invention have the structure shown in formula VI-7.

[0066] In some embodiments, the compounds of the present invention have the structure shown in formula VI-8.

[0067] In some embodiments, the compounds of the present invention have the structure shown in formula VI-9.

[0068] In some embodiments, the compounds of the present invention have the structure shown in formula VI-10.

[0069] In some embodiments, the compounds of the invention have the structure shown in Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VII-9, or VII-10: [ka] where n2 is 0, 1 or 2, and L 1 , L 2 , R a , R b , R c , m, p, R 1 , M 1 , M2 , M 3 , M 4 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0070] In some embodiments, the compounds of the present invention have the structure shown in formula VII-1.

[0071] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-2.

[0072] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-3.

[0073] In some embodiments, the compounds of the present invention have the structure shown in formula VII-4.

[0074] In some embodiments, the compounds of the present invention have the structure shown in formula VII-5.

[0075] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-6.

[0076] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-7.

[0077] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-8.

[0078] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-9.

[0079] In some embodiments, the compounds of the present invention have the structure shown in Formula VII-10.

[0080] In some embodiments, the compounds of the invention have the structure shown in Formula VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, VIII-9, VIII-10, VIII-11, or VIII-12. [ka]

[0081] where R a , R b , R c , m, n, p, L 1 , L 2 , R 1 has the definition set forth in the present invention.

[0082] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-1.

[0083] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-2.

[0084] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-3.

[0085] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-4.

[0086] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-5.

[0087] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-6.

[0088] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-7.

[0089] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-8.

[0090] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-9.

[0091] In some embodiments, the compounds of the present invention have the structure shown in formula VIII-10.

[0092] In some embodiments, the compounds of the present invention have the structure shown in formula VIII-11.

[0093] In some embodiments, the compounds of the present invention have the structure shown in formula VIII-12.

[0094] In some embodiments, compounds of the invention have the structure shown in formula IX-1, IX-2, IX-3, IX-4, IX-5, or IX-6. [ka]

[0095] where R a , R b , L 1 , L 2 , R 1 , m, p have the definitions described in the present invention.

[0096] In some embodiments, the compounds of the present invention have the structure shown in formula IX-1.

[0097] In some embodiments, the compounds of the present invention have the structure shown in formula IX-2.

[0098] In some embodiments, the compounds of the present invention have the structure shown in formula IX-3.

[0099] In some embodiments, the compounds of the present invention have the structure shown in formula IX-4.

[0100] In some embodiments, the compounds of the present invention have the structure shown in formula IX-5.

[0101] In some embodiments, the compounds of the present invention have the structure shown in formula IX-6.

[0102] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-1 or VIII-2: [ka] Each R cn are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, or a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R cn can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Preferably, each R cnare independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a phenyl group substituted with one or more halogens, or a phenyl group substituted with one or more hydroxy groups; Or two R cn can form a 3- to 6-membered cycloalkyl group or a 4- to 7-membered heterocyclic group together with the C atom to which they are attached, Each R a and R b are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, C 1-6 Haloalkoxy group, hydroxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(=O)-(C 1-6 alkyl), a 3- to 6-membered heterocyclic group optionally substituted with a hydroxy group; Preferably, each R a and R b are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(=O)-(C1-6 alkyl), L 1 is a bond, C 3-6 Cycloalkylene group, -NR 2 -, -O-, -S-, -C(=O)-, -(CR 3 R 4 ) a -, -NR 2 -(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -NR 2 -, -O-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -O-, -S-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -S-, -C(=O)-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -C(=O)-, -(CR 3 R 4 ) a -(CR 9 =CR 10 )-, -(CR 9 =CR 10 )-(CR 3 R 4 ) a -, -C(=O)-O-, -OC(=O)-, -C(=O)-NR 2 -,-(CR 3 R 4 ) a -C(=O)-NR 2 -, -NR 2 -C(=O)-, -(CR 3 R 4 ) a -NR 2 -C(=O)-, -S(=O)2-NR 2 -, -NR 2-S(=O)2-, -NR 2 -(CR 3 R 4 ) a -C(=O)-, -C(=O)-(CR 3 R 4 ) a -NR 2 -, -NR 2 -(CR 3 R 4 ) a -C(=O)-NR 5 -, -NR 2 -C(=O)-(CR 3 R 4 ) a -NR 5 -, -C(=S)-NR 2 -, -NR 2 -C(=S)-, L 2 is the bond, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -S- is selected from Each R 2 , R 5 , R 6 , R 9 and R 10 are independently hydrogen, deuterium, and C 1-6 alkyl groups, Each R 3 , R 4 , R 7 and R 8are independently hydrogen, deuterium, halogen, oxo, hydroxy group, amino group, C 1-6 alkyl groups, R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 alkyl-OC(═O)—, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 The alkyl-OC(=O)-, 3 to 10-membered cycloalkyl group, 3 to 6-membered monocyclic heterocyclic group, 6 to 11-membered bicyclic heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered heteroaryl groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -C(O)-N(R c6 )(R c5 ), -CH2-C(=O)-N(R c4 )(R c4 ), -N(R c4)-C(=O)-N(R c6 )(R c5 ) further substituted with 1, 2, 3 substituents selected from Each R c1 and R c2 are independently hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkoxy group, C 3-6 selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group, R c3 are hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl group may optionally contain deuterium, hydroxyl, halogen, C 1-6 further substituted with 1, 2, 3 substituents selected from alkyl groups; R c4 are hydrogen, deuterium, and C 1-6 alkyl groups, R c5 and R c6 are hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 cycloalkyl groups, or R c5 and R c6 form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, and 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally contain deuterium, a hydroxy group, a halogen, C 1-6 further substituted with 1, 2, 3 substituents selected from alkyl groups; R 11 are hydrogen, deuterium, and C 1-6 selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group; each a and b is independently 1, 2, 3, or 4; each m is 0 or 1; each p is 0, 1, or 2; each s and n is independently selected from 0, 1, 2, 3, or 4; The conditions are to simultaneously satisfy the following 1) and 2) 1) [ka] is not H, methyl group, ethyl group, CHF2, Boc, 2) [ka] [ka] isn't it.

[0103] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-1: [ka]

[0104] In some embodiments, where L 2 is a bond.

[0105] In some embodiments, where R a and R b are each independently selected from hydrogen, deuterium, F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, dimethylamino, and acetyl groups, and preferably R a and R b are each independently selected from hydrogen, deuterium, F, Cl, Br, a methyl group, and an ethyl group, and more preferably, R a and R b are each independently selected from hydrogen, deuterium, and a methyl group.

[0106] In some embodiments, wherein each R cn are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, C 1-4 Alkyl group, C1-4 Haloalkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Alkoxy-C 1-2 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, and a phenyl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, and the phenyl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 alkoxy groups, or two R cn can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, In some embodiments, wherein each R cn are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Alkoxy-C 1-2 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a phenyl group substituted with one or more halogens, or a phenyl group substituted with one or more hydroxy groups, or two R cn can form a 3- to 6-membered cycloalkyl group or a 4- to 7-membered heterocyclic group together with the C atom to which they are attached, In some embodiments, wherein each R cnare independently fluorine, chlorine, bromine, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, phenyl, 4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-hydroxyphenyl, cyclobutylamino, [ka] or two R cn form together with the C atom to which they are attached a cyclopentyl or tetrahydrofuranyl group, In some embodiments, wherein each R cn are independently selected from fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy groups.

[0107] In some embodiments, wherein: [ka] teeth, [ka] is selected from.

[0108] In some embodiments, wherein: [ka] teeth, [ka] is selected from.

[0109] In some embodiments, where L 1 is a bond, C 3-6 Cycloalkylene group, -NR 2 -, -O-, -S-, -C(=O)-, -(CR 3 R 4 ) a -, -NR 2 -(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -NR 2 -, -O-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -O-, -S-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -S-, -C(=O)-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -C(=O)-, -(CR 3 R 4 ) a -(CR 9 =CR 10 )-, -(CR 9 =CR 10 )-(CR 3 R 4 ) a -, -C(=O)-O-, -OC(=O)-, -C(=O)-NR 2 -,-(CR 3 R 4 ) a -C(=O)-NR 2 -, -NR 2 -C(=O)-, -(CR 3 R4 ) a -NR 2 -C(=O)-, -S(=O)2-NR 2 -, -NR 2 -S(=O)2-, -NR 2 -(CR 3 R 4 ) a -C(=O)-, -C(=O)-(CR 3 R 4 ) a -NR 2 - is selected from.

[0110] In some embodiments, where L 1 is a bond, C 3-6 Cycloalkylene group, -C(=O)-, -(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -(CR 9 =CR 10 )-, -(CR 3 R 4 ) a -C(=O)-NR 2 -,-(CR 3 R 4 ) a -NR 2 -C(=O)-.

[0111] In some embodiments, wherein each R 2 are independently hydrogen, deuterium, and C 1-4 alkyl groups, and each R 3 , R 4 are independently hydrogen, deuterium, halogen, hydroxyl group, C 1-4 The alkyl group is selected from the group consisting of:

[0112] In some embodiments, where L 1 represents a bond, a methylene group, -C(=O)-, a cyclopropylene group, [ka] n-propylene group, n-butylene group, ethylene group, [ka] is selected from.

[0113] In some embodiments, where L 1 is selected from a bond, a methylene group, —C(═O)—, and a cyclopropylene group.

[0114] In some embodiments, where R 1 is C 1-6 Alkyl group, C 1-6 Alkoxy group, NHR 11 -C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 alkyl-OC(═O)—, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkyl-C(=O)-O-, C 1-6 The alkyl-OC(=O)-, 3 to 10-membered cycloalkyl group, 3 to 6-membered monocyclic heterocyclic group, 6 to 11-membered bicyclic heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3, -C(O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ) is further substituted with 1, 2, or 3 substituents selected from

[0115] In some embodiments, where R 1 is C 1-3 Alkyl group, NHR 11 -C(=O)-, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1-3 The alkyl group, the 3- to 10-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the 6- to 11-membered bicyclic heterocyclic group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group each independently optionally include deuterium, halogen, a hydroxy group, an oxo group, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -C(O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ) is further substituted with 1, 2, or 3 substituents selected from

[0116] In some embodiments, where R 1is a methyl group, an ethyl group, an isopropyl group, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a tetrahydropyranyl group, a thietanyl group, an oxetanyl group, an azetidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a cyclobutane group, a cyclopentane group, a cyclohexane group, an n-heptane group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrazolyl group, a furyl group, a triazolyl group, -C(=O)-NH2, [ka] wherein said methyl group, ethyl group, isopropyl group, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, tetrahydropyranyl group, thietanyl group, oxetanyl group, azetidinyl group, piperidinyl group, morpholinyl group, piperazinyl group, cyclobutane group, cyclopentane group, cyclohexane group, n-heptane group, phenyl group, pyridinyl group, pyrimidinyl group, pyrrolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group, furyl group, triazolyl group, [ka] are each independently optionally selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -C(O)-N(R c6 )(Rc5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ) is further substituted with 1, 2, or 3 substituents selected from

[0117] In some embodiments, where R 1 is selected from a methyl group, an isopropyl group, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a tetrahydropyranyl group, a thietanyl group, an oxetanyl group, an azetidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a cyclobutane group, a cyclopentane group, a cyclohexane group, an n-heptane group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrazolyl group, a furyl group, and a triazolyl group, wherein the methyl group, the isopropyl group , pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, tetrahydropyranyl group, thietanyl group, oxetanyl group, azetidinyl group, piperidinyl group, morpholinyl group, piperazinyl group, cyclobutane group, cyclopentane group, cyclohexane group, n-heptane group, phenyl group, pyridinyl group, pyrimidinyl group, pyrrolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group, furyl group, and triazolyl group each independently optionally contain deuterium, halogen, hydroxy group, oxo, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -O(R c1 ), -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -C(O)-N(R c6 )(R c5 ), -N(Rc4 )-C(=O)-N(R c6 )(R c5 ) is further substituted with 1, 2, or 3 substituents selected from

[0118] In some embodiments, where -L 1 -R 1 teeth, [ka] [ka] is selected from.

[0119] In some embodiments, where -L 1 -R 1 teeth, [ka] is selected from.

[0120] In some embodiments, where -L 1 -R 1 teeth, [ka] is selected from.

[0121] In some embodiments, the compounds of the present invention have the structure shown in formula X-1 or X-2: [ka] Ring C is selected from a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a phenyl-fused 4- to 7-membered cycloalkyl group, a phenyl-fused 4- to 7-membered heterocyclic group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered heterocyclic group, a 4- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; Each Rcn are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, R c1 S(O)2-, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, or a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R cn can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Each R a and R b are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, C 1-6 Haloalkoxy group, hydroxy-C 1-6 Alkyl group, -NH(C1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(=O)-(C 1-6 alkyl), a 3- to 6-membered heterocycloalkyl group optionally substituted with a hydroxy group; L 1 is a bond, C 3-6 Cycloalkylene group, -NR 2 -, -O-, -S-, -C(=O)-, -(CR 3 R 4 ) a -, -NR 2 -(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -NR 2 -, -O-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -O-, -S-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -S-, -C(=O)-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -C(=O)-, -(CR 3 R 4 ) a -(CR 9 =CR 10 )-, -(CR 9 =CR 10 )-(CR 3 R 4 ) a -, -C(=O)-O-, -OC(=O)-, -C(=O)-NR 2 -,-(CR 3 R 4 ) a -C(=O)-NR 2 -, -NR 2 -C(=O)-, -(CR3 R 4 ) a -NR 2 -C(=O)-, -S(=O)2-NR 2 -, -NR 2 -S(=O)2-, -NR 2 -(CR 3 R 4 ) a -C(=O)-, -C(=O)-(CR 3 R 4 ) a -NR 2 -, -NR 2 -(CR 3 R 4 ) a -C(=O)-NR 5 -, -NR 2 -C(=O)-(CR 3 R 4 ) a -NR 5 -, -C(=S)-NR 2 -, -NR 2 -C(=S)-, L 2 is the bond, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -,-(CR 7 R 8 ) b -S- is selected from Each R 2 , R 5 , R 6 , R 9 and R 10 are independently hydrogen, deuterium, and C 1-6 alkyl groups, Each R 3 , R 4 , R 7 and R 8 are independently hydrogen, deuterium, halogen, oxo, hydroxy group, amino group, C 1-6 alkyl groups, R 1 is selected from a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, and the 3- to 10-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the 6- to 11-membered bicyclic heterocyclic group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently selected from the group consisting of -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c5 R c6 , -P(=O)R c5 R c6 and the 3- to 10-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the 6- to 11-membered bicyclic heterocyclic group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), C 3-6 is further substituted by 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; Each R c1 and R c2 are independently hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkoxy group, C 3-6 selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group, R c3 is C 1-6 Alkyl group, C3-6 cycloalkyl groups, wherein C 1-6 Alkyl groups and C 3-6 The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), R c5 and R c6 are H, deuterium, and C 1-6 Alkyl group, C 3-6 cycloalkyl groups, or R c5 and R c6 form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, and 1-6 Alkyl group, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally be substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), each a and b is independently 1, 2, 3, or 4; each m is 0 or 1; each p is 0, 1, or 2; each s and n is independently selected from 0, 1, 2, 3, or 4; As a condition, [ka] isn't it.

[0122] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-3 or VIII-4: [ka] Each R cn are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, R c1 -S(O)2-, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, or a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R cn can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Each R a and Rb are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, C 1-6 Haloalkoxy group, hydroxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(=O)-(C 1-6 alkyl), a 3- to 6-membered heterocycloalkyl group optionally substituted with a hydroxy group; L 1 is a bond, C 3-6 Cycloalkylene group, -NR 2 -, -O-, -S-, -C(=O)-, -(CR 3 R 4 ) a -, -NR 2 -(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -NR 2 -, -O-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -O-, -S-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -S-, -C(=O)-(CR 3 R 4 ) a -,-(CR 3 R 4 ) a -C(=O)-, -(CR 3 R 4 ) a -(CR 9 =CR 10 )-, -(CR 9 =CR10 )-(CR 3 R 4 ) a -、-C(=O)-O-、-OC(=O)-、-C(=O)-NR 2 -、-(CR 3 R 4 ) a -C(=O)-NR 2 -、-NR 2 -C(=O)-、-(CR 3 R 4 ) a -NR 2 -C(=O)-、-S(=O)2-NR 2 -、-NR 2 -S(=O)2-、-NR 2 -(CR 3 R 4 ) a -C(=O)-、-C(=O)-(CR 3 R 4 ) a -NR 2 -、-NR 2 -(CR 3 R 4 ) a -C(=O)-NR 5 -、-NR 2 -C(=O)-(CR 3 R 4 ) a -NR 5 -、-C(=S)-NR 2 -、-NR 2 -C(=S)- from L 2 -NR 6 -、-O-、-S-、-NR 6 -(CR 7 R 8 ) b -、-(CR 7 R 8 ) b -NR 6 -、-O-(CR 7 R 8 ) b -、-(CR 7 R 8 ) b -O-、-S-(CR 7 R 8 )b -,-(CR 7 R 8 ) b -S- is selected from Each R 2 , R 5 , R 6 , R 9 and R 10 are independently hydrogen, deuterium, and C 1-6 alkyl groups, Each R 3 , R 4 , R 7 and R 8 are independently hydrogen, deuterium, halogen, oxo, hydroxy group, amino group, C 1-6 alkyl groups, R 1 is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, or a 6- to 11-membered bicyclic heterocyclic group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is selected from the group consisting of -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c5 R c6 , -P(=O)R c5 R c6 and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), C 3-6 is further substituted by 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; Each R c1 and R c2 are independently hydrogen, C 1-6 Alkyl group, C 1-6Haloalkoxy group, C 3-6 selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group, R c3 is C 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein C 1-6 Alkyl groups and C 3-6 The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), R c5 and R c6 are H, deuterium, and C 1-6 Alkyl group, C 3-6 cycloalkyl groups, or R c5 and R c6 form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, and 1-6 Alkyl group, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally be substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), R 11 are hydrogen, deuterium, and C 1-6 selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group; each a and b is independently 1, 2, 3, or 4; each m is 0 or 1; each p is 0, 1, or 2; Each s and n is independently selected from 0, 1, 2, 3, or 4.

[0123] In some embodiments, wherein the compound has the structure shown in Formula VIII-3: [ka]

[0124] In some embodiments, where L 2 is a bond.

[0125] In some embodiments, where R a and R b are each independently selected from hydrogen, deuterium, F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, 1-hydroxyethyl-1-yl, methylamino, dimethylamino, acetyl, and 3-hydroxyazetidinyl, and preferably R a and R b are each independently selected from hydrogen, deuterium, F, Cl, Br, a methyl group, and an ethyl group, and more preferably, R a and R b are each independently selected from hydrogen, deuterium, and a methyl group.

[0126] In some embodiments, wherein each R cn are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, C 1-4 Alkyl group, C 1-4 Haloalkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Alkoxy-C 1-2 Alkyl group, R c1 -S(O)2-, -(CH2) s-N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, or a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 alkoxy groups, or two R cn can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 may be substituted with 1 to 3 substituents selected from haloalkyl groups; In some embodiments, wherein each R cn are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C 1-4 Alkoxy group, C 1-4 Haloalkoxy group, C 1-4 Alkyl group, C 1-4 Haloalkyl group, hydroxy C 1-4 Alkyl group, C 1-4 Alkoxy-C 1-2 Alkyl group, R c1 -S(O)2-, -(CH2) s -N(R c1 )(R c2 ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, a phenyl group substituted with one or more halogens, or a phenyl group substituted with one or more hydroxy groups, or two R cncan form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 It may be substituted with 1 to 3 substituents selected from haloalkyl groups.

[0127] In some embodiments, wherein each R cn are independently fluorine, chlorine, bromine, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, cyclohexenyl, oxetanyl, phenyl, 4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, pyridyl, cyclobutylamino, [ka] or two R cn form, together with the C atoms to which they are attached, a cyclopentenyl group, a 2,3-dihydrofuranyl group, a cyclobutenyl group, a thienyl group, a 1,4-dioxanyl group, a pyridyl group, a cyclopenta-1,3-dienyl group, a phenyl group, or a 1,4-dioxa-2-hexenyl group.

[0128] In some embodiments, wherein each Rcn are independently selected from fluorine, chlorine, bromine, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy groups.

[0129] In some embodiments, wherein: [ka] teeth, [ka] [ka] is selected from.

[0130] In some embodiments, wherein: [ka] teeth, [ka] is selected from.

[0131] In some embodiments, where L 2 is the bond, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b1 -,-(CR 7 R 8 ) b1 -NR 6 -, -O-(CR 7 R 8 ) b1 -,-(CR 7 R 8 ) b1 -O-, -S-(CR 7 R 8 )b1 -,-(CR 7 R 8 ) b1 -S-, where b1 is 1 or 2.

[0132] In some embodiments, where L 2 is the bond, -NR 6 -, -NR 6 -(CR 7 R 8 ) b1 -,-(CR 7 R 8 ) b1 -NR 6 -, where b1 is 1 or 2.

[0133] In some embodiments, where L 2 is -NR 6 -, -NR 6 -(CR 7 R 8 ) b1 -,-(CR 7 R 8 ) b1 -NR 6 -, where b1 is 1.

[0134] In some embodiments, where L 2 -NH-, -NH-(CR 7 R 8 )- is selected from.

[0135] In some embodiments, where L 2 is selected from -NH-, -NH-CH2-.

[0136] In some embodiments, where R 1 represents a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] is -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c5 R c6 , -P(=O)R c5 R c6 and wherein the cyclopentane group, the cyclohexane group, the azetidinyl group, the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, the piperazinyl group, [ka] is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, -(CH2) s -N(R c1 )(R c2 ), C 3-6 It is further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group.

[0137] In some embodiments, R 1 represents a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] is -C(=O)-R c3 , -S(=O)-R c3 , -S(=O)2-R c3 , -C(=O)-NR c5 R c6 , -P(=O)R c5 R c6 and wherein the tetrahydropyrrolyl group, piperidinyl group, morpholinyl group, piperazinyl group, [ka] is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, C 1-6 Alkoxy-C 1-6 It is further substituted with 1, 2, or 3 substituents selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group.

[0138] In some embodiments, R 1 represents a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, [ka] is -C(=O)-R c3 , -S(=O)2-R c3 , -P(=O)R c5 R c6 and wherein the tetrahydropyrrolyl group, piperidinyl group, morpholinyl group, piperazinyl group, [ka] is optionally deuterium, halogen, hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C 1-6 It is further substituted with one or two substituents selected from alkyl groups.

[0139] In some embodiments, R 1 teeth, [ka] [ka] is selected from.

[0140] In some embodiments, R 1 teeth, [ka] is selected from.

[0141] In some embodiments, wherein the compound has the structure shown in formula VIII-8 or VIII-12: [ka] where R 1 , L 1 , R a , R b , R c , L 2 , m, n, and p are defined as above.

[0142] In some embodiments, each R c are independently hydrogen, deuterium, halogen, hydroxy group, cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6Haloalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy-C 1-6 Alkyl group, R c1 S(O)2-, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, or a C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R c can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are linked, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; L 2 is the bond, -NR 6 -, -O-, -S-; R a , R b , R c , R c1 , R 6 , R 1 , L 1 , n, m, and p are as defined above.

[0143] In some embodiments, wherein the compound has the structure shown in formula VIII-8: [ka] where R 1 , L 1 , R a , R b, R c , L 2 , m, n, and p are defined as above.

[0144] In some embodiments, where R 1 is a 3- to 6-membered monocyclic heterocyclic group, and the 3- to 6-membered monocyclic heterocyclic group may optionally contain deuterium, halogen, a hydroxy group, an oxo group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) S -O(R c1 ), -(CH2) S -N(R c1 )(R c2 ), C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered heteroaryl groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)R c5 R c6 is further substituted with 1, 2, 3 substituents selected from In some embodiments, the R 1 is selected from a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, and a 1,4-oxathiyl group, and each of the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, the piperazinyl group, and the 1,4-oxathiyl group independently optionally contains deuterium, halogen, hydroxyl group, amino group, oxo, C 1-4 Alkyl group, C 1-4 Haloalkyl group, hydroxy C 1-4Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)R c5 R c6 and preferably, the R 1 is selected from a morpholinyl group, and the morpholinyl group is optionally selected from a group including deuterium, halogen, hydroxyl, amino, oxo, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)R c5 R c6 is further substituted with 1, 2, or 3 substituents selected from:

[0145] In some embodiments, where R 1 teeth, [ka] is selected from.

[0146] In some embodiments, the compounds of the present invention have the structure shown in Formula VIII-9: [ka] where R 1 , L 1 , R a , R b , R c , L 2 The definitions of m, n, and p are as described above, and the conditions are as follows: [ka] isn't it.

[0147] In some embodiments, the R 1 is a 3- to 6-membered monocyclic heterocyclic group, and the 3- to 6-membered monocyclic heterocyclic group may optionally contain deuterium, halogen, a hydroxy group, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy group, -(CH2) s -N(R c1 )(R c2 )-, C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)Rc5 R c6 is further substituted with 1, 2, or 3 substituents selected from:

[0148] In some embodiments, the R 1 is selected from a morpholinyl group and a piperidinyl group, and the morpholinyl group and the piperidinyl group each independently optionally contain deuterium, halogen, a hydroxy group, an amino group, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, 3- to 6-membered monocyclic heterocyclic groups, -C(=O)-R c3 , -S(O)-R c3 , -S(O)2-R c3 , -C(=O)OR c3 , -N(R c4 )-C(=O)-R c3 , -CH2-N(R c4 )-C(=O)-R c4 , -C(=O)-N(R c6 )(R c5 ), -N(R c4 )-C(=O)-N(R c6 )(R c5 ), -P(=O)R c5 R c6 is further substituted with 1, 2, or 3 substituents selected from:

[0149] In some embodiments, the R 1 teeth, [ka] is selected from.

[0150] In some embodiments, the compounds of the present invention have the following structure: [ka] [ka] [ka] [ka] [ka]

[0151] In some embodiments, the compounds of the invention have the following structure: [ka] [ka] [ka] [ka]

[0152] In some embodiments, the compounds of the invention have the following structure: [ka] [ka] [ka] [ka] [ka] [ka]

[0153] In some embodiments, the compounds of the invention have the following structure: [ka] [ka] [ka] [ka] [ka]

[0154] In some embodiments, the compounds of the invention have the following structure: [ka] [ka] [ka] [ka]

[0155] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the present invention, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof.

[0156] In another aspect, the present invention provides a combination, said combination comprising a therapeutically effective amount of a compound according to the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, and one or more therapeutic agents.

[0157] In some embodiments of the combinations of the invention, wherein the one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists, steatosis inhibitors, antifibrotic agents, JAK inhibitors, checkpoint inhibitors, chemotherapy, radiation therapy and surgery, uric acid lowering therapy, anabolic agents and cartilage regeneration therapy, blockers of IL-17, complement inhibitors, Bruton's tyrosine kinase inhibitors (BTK inhibitors), Toll-like receptor inhibitors (TLR7 / 8 inhibitors), CAR-T therapy, antihypertensive agents, cholesterol lowering agents, leukotriene A4 hydrolase (LTAH4) inhibitors, SGLT2 inhibitors, beta2-agonists, anti-inflammatory agents, nonsteroidal anti-inflammatory drugs ("NSAIDs"), acetylsalicylic acid drugs (ASA), regenerative therapy treatment, treatment of cystic fibrosis, and treatment of atherosclerosis.

[0158] In another aspect, the present invention provides the application of a compound according to the present invention, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, or a combination according to the present invention, as a drug.

[0159] In another aspect, the present invention provides the application of the compounds according to the present invention, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitroxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated) or prodrugs thereof, in the treatment of the following diseases or disorders in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of said disease or disorder: In another aspect, the present invention provides a method of treating a disease or disorder described below, in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder, the method comprising administering a therapeutically effective amount of a compound of the present invention, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope, or prodrug thereof.

[0160] In another aspect, the present invention provides the use of a compound according to the present invention, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, in the manufacture of a medicament for use in the treatment of the following diseases or disorders in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of said disease or disorder:

[0161] In another aspect, the present invention relates to a compound for use according to the present invention or a method of treatment according to the present invention, wherein the disease or disorder is an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, such as autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic fever syndrome), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute and chronic arthropathy), a kidney-related disease (e.g., hyperoxaluria, leukemia, rheumatoid arthritis ... and inflammatory skin diseases / disorders (e.g., hidradenitis suppurativa, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0162] In another aspect, the present invention provides a method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope, or prodrug thereof.

[0163] Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds of formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6.

[0164] Any one embodiment of any one aspect of the present invention may be combined with other embodiments unless a contradiction arises, and any one technical feature of any one embodiment of any one aspect of the present invention may be applied to the same technical feature of other embodiments unless a contradiction arises.

[0165] The foregoing merely outlines some aspects of the present invention, but is not intended to be limiting. These and other aspects are more particularly and completely described below. All references herein are hereby incorporated by reference in their entirety. DETAILED DESCRIPTION OF THE INVENTION

[0166] In order to clarify the objectives, technical solutions, and advantages of the present invention, the present invention will be described in more detail below in conjunction with examples. The specific examples described herein are merely for the purpose of illustrating the present invention and are not intended to limit the present invention in any way. In the following description, descriptions of known structures and techniques will be omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and techniques have also been described in many publications.

[0167] definition Some embodiments of the present invention are described in detail below, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to encompass all alternatives, modifications, and equivalent technical solutions, all of which are within the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the cited documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terms, application of terms, described techniques, etc.), this application shall control.

[0168] It should be further appreciated that some features of the invention, which are, for clarity, described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in a single embodiment, may also be provided alone or in any suitable subcombination.

[0169] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0170] Unless otherwise stated, the following definitions shall apply as used herein. For purposes of the present invention, the chemical elements shall conform to the CAS version of the Periodic Table of the Elements and the "Science and Physics Manual," 75th Edition, 1994. For general principles of organic chemistry, reference may be made to "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0171] Unless otherwise stated or clearly contradicted by context, the articles "a," "an," "one," and "said," as used herein, are intended to include "at least one" or "one or more." As such, as used herein, these articles refer to one or more (i.e., at least one) of the object article. For example, "a component" refers to one or more components, i.e., it is conceivable that more than one component may be employed or used in practicing the embodiment.

[0172] The term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0173] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

[0174] The term "comprises" is an open expression and includes the content explicitly meant by the present invention, but does not exclude the content of other aspects.

[0175] When a substituent is written in a conventional chemical formula written left to right, it also includes the chemically equivalent substituent obtained when the structural formula is written right to left. For example, -CH2O- is equivalent to -OCH2-.

[0176] The term "enantiomers" refers to two isomers of a compound that are non-superimposable mirror images of one another.

[0177] The term "diastereomer" refers to two or more stereoisomers that contain chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0178] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0179] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. When tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions achieved by rearrangement of some bond electrons. A specific example of keto-enol tautomerism is the tautomerism of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. One specific example of phenol-keto tautomerism is the tautomerization of pyridin-4-ol and pyridin-4(1H)-one. Further, for example, the hydrogen on the nitrogen atom at position 1 of the imidazole ring can be transferred to the nitrogen atom at position 3, and the two forms of the imidazole ring are tautomers, i.e., groups containing an imidazole ring as used herein have tautomers, e.g., [ka] is a tautomer, [ka] Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0180] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc.

[0181] The term "geometric isomers", also called "cis-trans isomers", are isomers resulting from the inability to freely rotate about double bonds (including olefinic double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms.

[0182] The definitions and rules of stereochemistry used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of one or more chiral centers of the molecule. The prefixes d and l or (+) and (-) are symbols used to designate the rotation of plane-polarized light in a compound, where (-) or l indicates that the compound is levorotatory. A compound with the prefix (+) or d is levorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0183] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may be present in racemic or enantiomerically enriched form, for example, in the (R)-, (S)-, or (R,S)-configuration. In some embodiments, each asymmetric atom is in the (R)- or (S)-configuration in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0184] Depending on the selection of starting materials and processes, the compounds of the present invention can exist in the form of one of the possible isomers or in a mixture thereof, for example, a mixture of racemates and diastereomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthesizers or chiral reagents or resolved by conventional techniques. When the compounds contain one double bond, the substituents can be in the E- or Z-configuration, and when the compounds contain a disubstituted cycloalkyl group, the cycloalkyl group substituents can have a cis- or trans-configuration.

[0185] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0186] In known manner, any resulting racemic final products or intermediates can be resolved into their optical enantiomers by methods well known to those skilled in the art, for example, by separating the diastereomeric salts obtained therefrom. Racemic products can also be separated by chiral chromatography, for example, by high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be produced by asymmetric synthesis, and reference can be made to, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012), Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972), and Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0187] The term "nitrogen oxide" means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or the N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amines can be treated with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages 1977). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), which involves reacting an amino compound with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0188] The term "metabolite" refers to a product obtained by metabolism in the body from a specific compound or salt thereof. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by testing methods as described herein. Such products can be obtained by treating the administered compound with methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including those produced by sufficient contact of a compound of the present invention with a mammal for a period of time.

[0189] The term "pharmaceutically acceptable" refers to a substance or composition that must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith. Preferably, "pharmaceutically acceptable" according to the present invention means approved by a federal regulatory agency or national government or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0190] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts include salts formed with a compound and an acid, including, but not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, phosphate, sulfate, nitrate, perchlorate) and organic acid salts (e.g., acetate, hydroxyacetate, oxalate, maleate, tartrate, citrate, succinate, fumarate, mandelate, sulfosalicylate), or obtained by other methods, such as ion exchange methods, as described in the literature. Many pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, boronate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, glucarate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, and hydroiodide. Pharmaceutically acceptable salts include salts formed by compounds with bases, such as 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts further include salts formed by compounds with bases, including, but not limited to, inorganic base salts (e.g., alkali metal salts, alkaline earth metal salts, ammonium salts, and N(C1-4 alkyl)4 salts). Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts of compounds containing an N group. Water- or oil-soluble or dispersible products can be obtained by quaternary ammonium conversion.Pharmaceutically acceptable salts further include suitable non-toxic ammonium and quaternary ammonium salts and amine cations consisting of anti-equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates, and aromatic sulfonates. For organic base salts (e.g., primary, secondary, and tertiary amines, substituted amines (naturally occurring substituted amines, cyclic amines, and basic ion exchange resins)), some organic amine salts include, for example, isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine salts.

[0191] Pharmaceutically acceptable acid addition salts can be formed by the reaction of the compounds of the present invention with an inorganic or organic acid, and pharmaceutically acceptable base addition salts can be formed by the reaction of the compounds of the present invention with an inorganic or organic base. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometrically appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc., of Na, Ca, Mg, or K), or by reacting these free base forms with a stoichiometrically appropriate acid. Such reactions are generally carried out in water or an organic solvent, or a mixture of both. Generally, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, must be used where appropriate. Lists of some other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th Edition, Mack Publishing Company, Easton, Pa., (1985), and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0192] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvent may be water, acetic acid, ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol, sec The solvent may be, for example, n-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene, or a mixture thereof.

[0193] The term "hydrate" refers to an association formed by one or more water molecules and a compound of the present invention.

[0194] In addition, the compounds disclosed in the present invention and salts containing them may be obtained in the form of their hydrates or in the form containing a solvent (e.g., ethanol, DMSO, etc.), which is used for their crystallization. The compounds disclosed in the present invention can naturally or artificially form solvates with pharmaceutically acceptable solvents (including water), and therefore, the present invention is intended to encompass both solvated and unsolvated forms.

[0195] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, where R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group according to the present invention.

[0196] The term "isotopically labeled compound" refers to a compound of the present invention that is isotopically labeled, which is identical to those compounds described in the present invention except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the naturally occurring atomic mass or mass number. Also, exemplary isotopes that can be introduced into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 16 O. 17 O. 31 P, 32 P, 36 S, 18 F and 37 Contains Cl.

[0197] All compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are included within the scope of the present invention. Isotopically labeled compounds of the present invention, such as compounds containing radioactive isotopes, e.g. 3 H and 14 The compounds of the present invention incorporating C can be used in drug and / or substrate tissue distribution analysis. Because of their ease of preparation and detection, tritium, i.e. 3 H, and carbon-14, i.e. 14 C is a particularly preferred isotope. Note that isotopes with higher mass numbers, such as deuterium, i.e. 2 Substitution with H may offer some therapeutic advantages, such as greater metabolic stability, increased in vivo half-life or reduced dose requirements, and therefore may be preferred in some cases.

[0198] It should be noted that substitution with heavy isotopes, particularly deuterium (i.e., 2H or D), can provide several therapeutic advantages, such as increased metabolic stability, reduced dosage requirements, or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compounds of formulas (I) to (IV). The concentration of such heavy isotopes, particularly deuterium, can be defined using an isotopic enrichment factor. The term "isotopic enrichment factor," as used in the present invention, refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. When a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom position), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the solvent of crystallization may be isotopically substituted, eg, D2O, acetone-d6, DMSO-d6.

[0199] The term "prodrug" as used herein means that a compound is converted in the body to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compounds of the present invention may be esters, and those useful as prodrugs in prior inventions include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonate esters, carbamates, and amino acid esters. For example, if a compound of the present invention contains a hydroxy group, acylation of this group can yield a prodrug form of the compound. Other prodrug forms include phosphate esters; for example, these phosphate ester compounds can be obtained by phosphorylating the parent hydroxy group. For a complete discussion of prodrugs, see Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270; and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0200] Unless otherwise clearly indicated, the descriptive methods employed in the present invention, "each...independently", "...respectively independently" and "...independently", are interchangeable and should all be understood in a broad sense, which may mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other.

[0201] The terms "optionally," "optionally," or "optional," "optionally," and "optionally" mean that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both instances where the described event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with" indicates that the substitution may or may not be present.

[0202] The terms "unsaturated" or "unsaturated" refer to partially containing one or more degrees of unsaturation.

[0203] In each section of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is particularly noted that the present invention is a combination of each of the independent subgroups of each member including the type and range of these groups. For example, the term "C1-6 alkyl group" specifically refers to the independently disclosed methyl group, ethyl group, C3 alkyl group, C4 alkyl group, C5 alkyl group, and C6 alkyl group.

[0204] In each section 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 as the linking group. For example, when the structure requires a linking group and an "alkyl group" or an "aryl group" is listed for the definition of the Markush group for that variable, the "alkyl group" or "aryl group" should be understood to represent the linked alkylene group or arylene group, respectively.

[0205] The term "heteroatom" refers to O, S, N, P, and Si, and includes any oxidation state of S, N, and P, primary, secondary, and tertiary amine and quaternary ammonium salt forms, or forms in which hydrogen on a nitrogen atom in a heterocycle is substituted, such as N (N in a 3,4-dihydro-2H-pyrrolyl group), NH (NH in a pyrrolidinyl group), or NRT (NRT in an N-substituted pyrrolidinyl group, where RT is a substituent on N). When a compound according to the present invention contains multiple heteroatoms, the compound comprising such atoms complies with the valence and composition rules of organic compounds; that is, a compound containing multiple heteroatoms excludes compounds that do not comply with the valence and composition rules of organic compounds.

[0206] The term "heterocyclic group" or "heterocycle" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing carbon atoms and heteroatoms, wherein the heteroatoms have the meanings described herein. The bicyclic or tricyclic ring system may be a spirocyclic, bridged, or fused ring system, e.g., bicyclic systems include spiro-bicyclic, bridged, and fused bicyclic rings. A saturated or partially unsaturated heterocyclic group may be fully saturated or may contain one or more unsaturated bonds, but must not contain any aromatic rings. In one embodiment, the heterocyclic group is a 3- to 6-membered ring, e.g., a 3- to 6-membered saturated or partially unsaturated heterocyclic group (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, where S or P are optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2). In one embodiment, the saturated or partially unsaturated heterocyclic group is selected from saturated monocyclic heterocyclic groups, saturated bicyclic heterocyclic groups, saturated tricyclic heterocyclic groups, partially unsaturated monocyclic heterocyclic groups, partially unsaturated bicyclic heterocyclic groups, and partially unsaturated tricyclic heterocyclic groups. Bicyclic heterocyclic groups refer to bicyclic heterocyclic groups, for example, bicyclic heterocyclic groups include spiro bicyclic heterocycles, bridged bicyclic heterocycles, and fused bicyclic heterocycles. Monocyclic heterocyclic groups refer to monocyclic heterocyclic groups. Five- to six-membered heterocyclic groups refer to heterocyclic groups having five to six ring atoms. Four- to seven-membered heterocyclic groups refer to heterocyclic groups having four to seven ring atoms. Three- to six-membered heterocyclic groups refer to heterocyclic groups having three to six ring atoms.

[0207] The term "cycloalkyl group" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing carbon atoms. A saturated or partially unsaturated cycloalkyl group may be fully saturated or may contain one or more unsaturated bonds, but may not contain any aromatic rings. In one embodiment, a cycloalkyl group contains 3 to 6 carbon atoms, e.g., a C3-C6 saturated or partially unsaturated cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl group is selected from a saturated monocyclic cycloalkyl group, a saturated bicyclic cycloalkyl group, a saturated tricyclic cycloalkyl group, a partially unsaturated monocyclic cycloalkyl group, a partially unsaturated bicyclic cycloalkyl group, and a partially unsaturated tricyclic cycloalkyl group. Bicyclic cycloalkyl groups refer to cycloalkyl groups of bicyclic ring systems, for example, bicyclic cycloalkyl groups include spiro bicyclic cycloalkyl groups, bridged bicyclic cycloalkyl groups, and fused bicyclic cycloalkyl groups. Monocyclic cycloalkyl groups refer to cycloalkyl groups of monocyclic ring systems. 4- to 7-membered cycloalkyl groups refer to cycloalkyl groups having 4 to 7 ring atoms. 3- to 6-membered cycloalkyl groups refer to cycloalkyl groups having 3 to 6 ring atoms.

[0208] The term "heteroaryl group" refers to monocyclic, bicyclic, and tricyclic aromatic systems containing 5 to 10 ring atoms, and the term "heteroaryl group" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, a heteroaryl group is a heteroaryl group of 5 to 10 atoms, i.e., a 5-10 membered heteroaryl group, containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; a heteroaryl group is a heteroaryl group of 5 to 8 atoms, i.e., a 5-8 membered heteroaryl group, containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, a heteroaryl group is a heteroaryl group of 5 to 7 atoms, i.e., a 5-7 membered heteroaryl group, containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; In some embodiments, the heteroaryl group is a heteroaryl group of 5 to 6 atoms, i.e., a 5- to 6-membered heteroaryl group, containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a heteroaryl group of 5 atoms, i.e., a 5-membered heteroaryl group, containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a heteroaryl group of 6 atoms, i.e., a 6-membered heteroaryl group, containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0209] The term "aryl group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system. The term "aryl group" may be used interchangeably with the term "aromatic ring" or "aromatic ring." A 6- to 10-membered aryl group refers to an aryl group containing 6 to 10 ring atoms. Examples include, but are not limited to, phenyl, naphthyl, and the like.

[0210] The term "hydrogen" 1 H, and "deuterium" refers to 2 Point to H.

[0211] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0212] The term "amino group" refers to -NH2.

[0213] The term "hydroxy" refers to -OH.

[0214] The term "cyano" refers to -CN.

[0215] The term "nitro group" refers to -NO2.

[0216] The term "carboxyl group" refers to HO(C=O)-.

[0217] The term "O=" refers to oxo, i.e., when a substituent is O=, the O is linked to the group it replaces via a double bond.

[0218] The term "alkyl" or "alkyl group" refers to a saturated, straight- or branched-chain hydrocarbon group containing carbon atoms. In one embodiment, an alkyl group contains 1 to 6 carbon atoms, i.e., a C1-C6 alkyl group; in another embodiment, an alkyl group contains 1 to 4 carbon atoms, i.e., a C1-C4 alkyl group; and in yet another embodiment, an alkyl group contains 1 to 3 carbon atoms, i.e., a C1-C3 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0219] The term "alkoxy group" refers to an alkyl group linked to the remainder of the molecule via an oxygen atom, wherein alkyl group has the meaning described herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., a C1-C6 alkoxy group, in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, i.e., a C1-C4 alkoxy group, and in one embodiment, the alkoxy group contains 1 to 3 carbon atoms, i.e., a C1-C3 alkoxy group.

[0220] The term "alkylamino group" refers to an alkyl group linked to the remainder of the molecule via a carbon atom, wherein alkyl group has the meaning described herein. In one embodiment, the alkylamino group is a monoalkylamino group, designated as "alkyl-NH-". In one embodiment, the alkylamino group is a dialkylamino group, designated as "(alkyl)N-". In one embodiment, the alkylamino group contains 1 to 6 carbon atoms, i.e., a C1-C6 alkylamino group; in another embodiment, the alkylamino group contains 1 to 4 carbon atoms, i.e., a C1-C4 alkylamino group; and in another embodiment, the alkylamino group contains 1 to 3 carbon atoms, i.e., a C1-C3 alkylamino group. The term "haloalkyl group" refers to an alkyl group in which a hydrogen is replaced with one or more halogens (F, Cl, Br), the term "hydroxyalkyl group" refers to an alkyl group in which a hydrogen is replaced with one or more hydroxy groups (OH), and the term "aminoalkyl group" refers to an alkyl group in which a hydrogen is replaced with one or more amino (NH).

[0221] Halophenyl groups (one or more) refer to phenyl groups with one, two, three, four, or five halogen substitutions, where halogen has the definition provided herein. Halophenyl groups (one or more) also refer to phenyl groups substituted with one or more halogens.

[0222] A phenyl group substituted with one or more hydroxy groups refers to a phenyl group having 1, 2, 3, 4 or 5 hydroxy group substitutions, said hydroxy group having the definition given herein.

[0223] When "fused" is used to link two ring systems, it means that the two ring systems are in a fused relationship, and the two corresponding rings each have the definitions described herein. For example, a phenyl-fused 4- to 7-membered cycloalkyl group represents a group in which a phenyl group is fused with a cycloalkyl group having 4 to 7 ring atoms as described in the present invention, and a 5- to 6-membered heteroaryl-fused 4- to 7-membered cycloalkyl group represents a group in which a heteroaryl group having 5 to 6 ring atoms as described in the present invention is fused with a cycloalkyl group having 4 to 7 ring atoms as described in the present invention.

[0224] When two groups are used in combination, it indicates that the first group is linked to the rest of the molecule via the second group, e.g., C 1-6 Alkoxy-C 1-6 The alkyl group is C 1-6 The alkoxy group is C 1-6 represents a link to the rest of the molecule via an alkyl group; 1-6 The alkyl group has a hydroxy group of C 1-6 It represents being linked to the rest of the molecule via an alkylene group.

[0225] As described in the present invention, the ring system formed by the substituent R being connected to the center of the ring via a single bond (as shown in the diagram below) indicates that the substitution of the substituent R is limited to any substitutable position or any reasonable position on the A ring. For example, the formula f represents any substitutable position on the A ring, such as the formula f 1 -f 4 As shown in the figure. [ka]

[0226] As described in the present invention, the ring system structure formed by directly connecting the substituent R to the polycyclic ring via a single bond (as shown in the diagram below) indicates that the substituent R can be substituted at any substitutable position or any reasonable position on the A and B rings. For example, formula e represents any substitutable position on the A and B rings, such as formula e 1 -e 7 As shown in the figure. [ka]

[0227] As described herein, ring systems formed by connecting substituents to the center of the ring through a single bond, such as (R x ) n is n substituents R x can be substituted at any substitutable position on the ring where it is located. For example, formula a represents a benzene ring having n R x It means that it can be replaced by. [ka]

[0228] The term "substituted" refers to the replacement of one or more hydrogen atoms in a specific group with a specific substituent. Specific substituents are those described above or in each example. Unless otherwise specified, a substituted group may have one substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position, i.e., each substitution is independent of the others. Those skilled in the art should understand that the combinations of substituents anticipated by the present invention are those that are stable or chemically feasible.

[0229] In the present invention, the groups relating to ring A and ring B [ka] is a fused structure formed by ring A and ring B sharing a ring edge (i.e., ring A and ring B form a fused bicyclic ring), for example [ka] Refers to...

[0230] In the present invention, the definitions of the substituents are meant to be linked to the corresponding groups from left to right, for example, in the formula I [ka] In the structure of c C 1-6 Alkoxy-C 1-6 When selected from alkyl groups, C 1-6 The alkoxy group is C 1-6 linked to an alkyl group, C 1-6 This means that the alkyl group is further linked to Ring C.

[0231] Description of the Compounds of the Invention The present invention provides a compound having the structure shown in Formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof, [ka] where: [ka] is connected to ring A, [ka] is connected to ring B, Here, ring A, ring B, ring C, L 1 , L 2 , R a , R b, R c ,n,m,p,R 1 has the definition set forth in the present invention.

[0232] In some embodiments, the present invention provides a compound having the structure shown in Formula II: [ka] Here, ring B, ring C, L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M 3 , M 4 has the definition set forth in the present invention.

[0233] In some embodiments, the present invention provides a compound having the structure shown in Formula III: [ka] Here, rings B and L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M 3 , M 4 has the definition set forth in the present invention.

[0234] In some embodiments, the present invention provides a compound having the structure shown in formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or IV-8: [ka] Here, rings C and L 1 , L 2 , R a , R b , Rc ,n,m,p,R 1、 , M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0235] In some embodiments, the present invention provides a compound having a structure shown in Formula V-1, V-2, V-3, V-4, V-5, V-6, V-7, or V-8: [ka] where L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0236] In some embodiments, the present invention provides a compound having the structure shown in Formula VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, or VI-8: [ka] where n1 is 0, 1, 2 or 3, and L 1 , L 2 , R a , R b , R c ,n,m,p,R 1 , M 1 , M 2 , M3 , M 4 , M 5 , M 6 , U 1 , U 3 , U 4 , U 5 has the definition set forth in the present invention.

[0237] In some embodiments, the compounds of the invention have the structure shown in Formula VII-1, VII-2, VII-3, VII-4, VII-5, or VII-6: [ka] where L 1 , L 2 , R a , R b , m, p, R 1 , M 1 , M 2 , M 3 , M 4 , M 5 , U 1 has the definition set forth in the present invention.

[0238] In some embodiments, the compounds of the invention have the structure shown in Formula VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, or VIII-8: [ka] where R c , n, L 1 , L 2 , R 1 , R a , R b , m, n have the definitions set forth in the present invention.

[0239] In some embodiments, compounds of the invention have the structure shown in formula IX-1, IX-2, IX-3, IX-4, IX-5, or IX-6: [ka] where L 1 , L 2 , R 1 has the definition according to the present invention, R ab are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl; Each k is independently selected from 0, 1, 2, or 3.

[0240] Pharmaceutical compositions and methods of administration The present invention relates to pharmaceutical compositions, which comprise a compound according to the present invention or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs thereof, and a pharmaceutically acceptable carrier or diluent.

[0241] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers, diluents, and may further include excipients such as vehicles, adhesives, fillers, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a living body.

[0242] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, adhesive, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or composition thereof, all of which are known to those skilled in the art (e.g., as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any common carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0243] The present invention further relates to a pharmaceutical composition comprising a compound having formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6 as an active ingredient or a pharmaceutically acceptable salt thereof, which can be used in particular for the treatment of neoplastic diseases, especially cancer, as described herein. The compositions can be prepared for non-parenteral administration, such as nasal, oral, peroral, pulmonary, vaginal, sublingual, topical, transdermal, ocular, or especially oral administration (e.g. in the form of oral solid preparations, such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (appropriately coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions), or for parenteral administration to mammals, especially humans, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration (e.g. in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles). These compositions may comprise the active ingredient alone or, preferably, also comprise a pharmaceutically acceptable carrier.

[0244] Formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII Compounds having the amino acid sequence VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, or IX-6, or pharmaceutically acceptable salts thereof, can be processed with pharmaceutically inert inorganic or organic excipients to produce oral solid formulations such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard or HPMC capsules, or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch, or derivatives thereof, adhesives such as cellulose, starch, polyvinylpyrrolidone, or derivatives thereof, flow agents such as talc, stearic acid, or salts thereof, and flow agents such as fumed silica can be used as such excipients to prepare and manufacture oral solid formulations such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard or HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

[0245] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0246] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0247] The pharmaceutical preparation may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparation may further contain other therapeutically valuable substances.

[0248] The dosage can vary within a wide range and, of course, will meet the individual needs in each particular case. In general, for oral administration, a daily dosage of about 1 to 1000 mg of a compound having general formula (I) per person is appropriate, although the above lower or upper limits may be exceeded if necessary.

[0249] Compounds of formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6 can also be used in combination with one or more other pharmacologically active compounds, and these other compounds can also be used in combination with one or more other pharmacologically active compounds. and preferably employs a different mode of action or reduces or prevents possible undesirable side effects of compounds having formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6. The combination partners can be administered simultaneously in such treatment, for example by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms, each dosage form containing one or more combination partners.

[0250] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used in the manufacture or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, pharmaceutical stabilizers, adhesives, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, such as those known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, 2013, pp. 1049-1070).

[0251] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that elicits a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, remission of disease symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting example, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject, (1) at least partially ameliorates, inhibits, prevents, and / or improves a disease, disorder, or condition that (i) is mediated by NLRP3, or (ii) is associated with NLRP3 activity, or (iii) is characterized by NLRP3 activity (normal or abnormal), or (2) reduces or inhibits NLRP3 activity, or (3) reduces or inhibits NLRP3 expression. In another non-limiting example, the term "therapeutically effective amount" of a compound of the invention refers to an amount that, when administered to a cell, or tissue, or non-cellular biomaterial or medium, effectively at least partially reduces or inhibits the activity of NLRP3 or at least partially reduces or inhibits the expression of NLRP3.

[0252] The term "treatment" as used herein in the context of treating a disease or disorder generally refers to human or animal (e.g., veterinary) treatment and therapy, where some desired therapeutic effect is achieved, such as inhibiting the progression of the disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, ameliorating the symptoms of the disease or disorder, improving the disease or disorder, and curing the disease or disorder. Treatment as a preventative measure (i.e., prophylaxis) is also included. For example, use in patients who have not yet developed the disease or disorder but are at risk of developing the disease or disorder is covered by the term "treatment." For example, treatment includes preventing cancer, reducing the incidence of cancer, ameliorating the symptoms of cancer, etc.

[0253] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to alleviating or inhibiting a given disease, symptom, disorder, or condition, or significantly reducing the baseline activity of a biological activity or process. Specifically, inhibition of NLRP3 or inhibition of the NLRP3 inflammasome pathway includes reducing the ability of NLRP3 or the NLRP3 inflammasome pathway to induce the production of IL-1β and / or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, destabilizing, and / or altering the distribution of NLRP3.

[0254] As used herein, the terms "prevent, preventing or prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder or the delay in the onset or progression of the disease or disorder.

[0255] As used herein, the term "NLRP3" refers to nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof, including, but not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0256] Synthesis method Compounds having formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6 can be synthesized by the methods given below, the methods given in the experimental section below, or by analogous methods. The schemes described herein are not intended to represent an exhaustive list of methods for preparing compounds having formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6; on the contrary, other techniques known to the skilled chemist may be used to synthesize the compounds.

[0257] The structure of the compound was determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or / and 19This is confirmed by F-NMR. 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and a Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, using deuterated chloroform (CDCl), deuterated methanol (CD3OD or MeOH-d4), or deuterated dimethyl sulfoxide (DMSO-d6) as the measurement solvent. TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks occur, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiple), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broadened singlet). The coupling constant J is expressed in units of hertz (Hz).

[0258] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC measurements were performed using an Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm chromatography column).

[0259] Thin-layer chromatography silica gel plates are Qingdao GF254 silica gel plates, with a 0.15-0.20 mm mesh for TLC and a 0.4-0.5 mm mesh for preparative thin-layer chromatography. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as the carrier.

[0260] The starting materials in the examples of the present invention are either known and commercially available or are synthesized using literature sources already reported in the art.

[0261] Unless otherwise stated, all reactions of the present invention are carried out under dry inert gas (e.g., nitrogen or argon) protection with continuous magnetic stirring, and all reaction temperatures are in degrees Celsius.

[0262] Those skilled in the art of organic synthesis should understand that optimal reaction conditions may vary depending on the particular reactants or solvents used, but these conditions can be determined by routine optimization processes. In some cases, the following reaction schemes and / or the order in which reaction steps are carried out can be modified to facilitate the reaction or avoid the formation of unwanted by-products. It should be noted that the functional groups present at each position on the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods must then be used. It should be noted that in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compounds, and it is assumed that such protecting groups (PG) are in appropriate positions, as necessary. Common protecting groups can be used practically according to standards well known in the art (see, for an explanation, Greene TW, Wuts PGM, Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014). The protecting groups may be removed at any convenient stage in the synthesis or may be removed in a subsequent reaction step or work-up using conventional techniques well known in the art.

[0263] The following abbreviations are used throughout the present invention:

[0264] ℃: Celsius h, hr: time MW: Microwave TEA: Triethylamine TFA: Trifluoroacetic acid DCM: dichloromethane MeOH: Methanol EtOH: ethanol DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine THF: tetrahydrofuran ACN: acetonitrile BrCN: cyanogen bromide A mixed solution of dichloromethane and trifluoroacetic acid in a volume ratio of DCM / TFA = 1:1:1:1 K3PO4: Potassium phosphate NaIO4: Sodium periodate NHOAc: Ammonium acetate TsCl: 4-toluenesulfonyl chloride Cs2CO3: Cesium carbonate K2CO3: Potassium carbonate NH3H2O: Ammonia water Pd(dppf)Cl2: 1,1'-bisdiphenylphosphinoferrocene palladium dichloride XPhos Pd G3: (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate NaBH3CN: sodium cyanoborohydride -OMOM: methoxymethoxy group Boc-: tert-butoxycarbonyl group Boc2O: di-tert-butyl dicarbonate LHMDS: lithium bistrimethylsilylamide CDI: N,N'-carbonyldiimidazole POCl3: Phosphorus oxychloride NMP: N-methylpyrrolidone DMAP: 4-dimethylaminopyridine

[0265] General synthesis method Typical synthetic steps for preparing the compounds disclosed in this invention are as shown in the synthetic scheme below.

[0266] Scheme 1 The compound of formula I-1 is synthesized by the following method: [ka] Formula I-1-1 is subjected to a ring-binding reaction to obtain compound I-1-2, and Formula I-1-2 is subjected to a coupling reaction to obtain compound I-1, where X is a halogen and M1, M2, M3, R a , R c , L1, R1, m, and n are defined as described in the above examples. [Brief explanation of the drawings]

[0267] [Figure 1] 1 shows the efficacy of Compound 111 of the present application and a positive control compound in an iodoacetic acid-induced SD rat knee osteoarthritis model. [Figure 2] 1 shows the efficacy of Compound 111 of the present application and a positive control compound in an iodoacetic acid-induced SD rat knee osteoarthritis model.

[0268] Examples and drawings are provided below to help understand the present invention. However, it should be understood that these examples and drawings are only for explaining the present invention and do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. Any modifications and variations can be made without departing from the spirit of the present invention.

[0269] Production of Intermediate M-1

Chemical formula

[0270] Example 1: Production of Compound 12

Chemical formula

[0271] Step 2): At room temperature, compound 12-2 (600 mg, 2.50 mmol) and N,N-dimethylformamide (6 mL) were sequentially added to a 40 mL IKA flask. Then, triethylamine (1.04 mL, 7.49 mmol) and 1-ethylpiperidin-3-amine hydrochloride (534.16 mg, 3.24 mmol, Rakuken) were added to the reaction flask. The reaction mixture was stirred at 60 °C for 5 hours. The reaction mixture was monitored for completion by LCMS. 10 mL of saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted twice with 10 mL of tetrahydrofuran. The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate / aqueous ammonia = 1:1:0.1) to give compound 12-3. LC-MS: m / z: 332.1 [M+H] + .

[0272] Step 3): At room temperature, compound 12-3 (400 mg, 2.50 mmol) and dimethyl sulfoxide (4 mL) were sequentially added to a 40 mL IKA flask, and DIPEA (0.60 mL, 3.61 mmol) was added to the reaction flask. The reaction mixture was stirred at 130 °C for 3 hours. Completion of the reaction mixture was monitored by LCMS. After cooling to room temperature, 10 mL of saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted twice with 10 mL of tetrahydrofuran. The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate / aqueous ammonia = 1:1:0.1) to give compound 12-4. LC-MS: m / z: 296.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ6.70(s,1H),4.86-4.78(m,1H),4.33-4.16(m,2H),3.06-3.04(m,1H),2.92-2.89(m,1H),2.5 1-2.46(m,2H),2.30-2.24(m,1H),2.02-1.92(m,1H),1.90-1.89(m,1H),1.82-1.71(m,4H),1.11(t,J=7.2Hz,3H).

[0273] Step 4: At room temperature, compound 12-4 (90.0 mg, 0.300 mmol), intermediate M-1 (137 mg, 0.520 mmol), Xphos Pd G3 (25.8 mg, 0.030 mmol), potassium phosphate (258 mg, 1.22 mmol), dioxane (2 mL), and water (0.2 mL) were added to an 8 mL single-neck flask. The reaction was heated at 80 °C for 1 h. The reaction mixture was diluted with water (3 mL) and extracted three times with dichloromethane (6 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun dry. The residue was purified by preparative thin-layer chromatography on a silica gel plate (dichloromethane / amine methanol (7 M) = 20 / 1) to give compound 12-5. LC-MS: m / z: 480.2 (M+H). + .

[0274] Step 5): At room temperature, compound 12-5, dichloromethane (1 mL), and trifluoroacetic acid (1 mL) were added to an 8 mL single-neck flask. The reaction was allowed to proceed at 25°C for 3 hours. The reaction solution was then spin-dried. The residue was purified by high-performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 12. LC-MS: m / z: 436.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.22(s,1H),7.11(s,1H),7.05(s,1H ),6.68(s,1H),4.81-4.77(m,1H),4.21-4.22(m,2H),2.98(d,J=8.8Hz,1H),2 .88(d,J=11.2Hz,1H),2.48-2.44(m,1H),2.30-2.20(m,1H),2.14(s,3H),2. 02-1.92(m,2H),1.78-1.70(m,2H),1.71-1.56(m,2H),1.03(t,J=7.1Hz,3H).

[0275] Example 2: Preparation of Compound 11 [ka] Step 1): At room temperature, compound 2-2 (200.0 mg, 1.30 mmol) and N,N-dimethylformamide (5 mL) were sequentially added to a 40 mL IKA flask. Cesium carbonate (636.0 mg, 1.95 mmol) and compound 3-chloro-7H-pyrrolo[2,3-c]pyridazine (442.88 mg, 1.56 mmol) were then added to the reaction flask. The reaction mixture was stirred at 100 °C for 2 hours. Completion of the reaction mixture was monitored by LCMS. 20 mL of water was added to the reaction mixture, followed by extraction with 50 mL of ethyl acetate twice. The organic phase was concentrated under reduced pressure, and the residue was purified using a silica gel column (tetrahydrofuran / dichloromethane = 0-10%) to obtain compound 11-1. LC-MS: m / z: 265.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.69(d,J=3.4Hz,1H),7.66(s,1H),6.39(d,J=3.4Hz,1H) ,4.60(dd,J=4.8,13.9Hz,1H),4.25(dd,J=5.8,14.0Hz,1H),3.18-3.16(m,1H) ,3.03-3.02(m,1H),2.74-2.69(m,1H),2.35-2.31(m,1H),2.23-2.21(m,1H),1 .82-1.80(m,1H),1.69-1.62(m,1H),1.56-1.52(m,2H),1.10(t,J=7.3Hz,3H).

[0276] Step 2: At 25 °C, compound 11-1 (100 mg, 0.380 mmol), intermediate M-1 (169 mg, 0.640 mmol), XPhos PdG3 (31.9 mg, 0.040 mmol), potassium phosphate (320 mg, 1.51 mmol), water (0.2 mL), and dioxane (2.0 mL) were added to a 25 mL single-neck flask. The mixture was purged with nitrogen three times, and the reaction was stirred at 80 °C for 1 h. The reaction mixture was diluted with saturated sodium chloride solution (3 mL) and extracted three times with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography on a silica gel column (dichloromethane / methanol = 15 / 1) to give compound 11-2. LC-MS: m / z 449.2 [M+H] + .

[0277] Step 3): Compound 11-2 (45.0 mg, 0.100 mmol) and a 4.0 M solution of hydrochloric acid in dioxane (2.0 mL) were added to a 25 mL single-neck flask at 25 °C, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then spin-dried. The crude product was purified by preparative chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 23% to 48% acetonitrile, flow rate: 30 mL / min) to obtain compound 11. LC-MS: m / z 405.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.15(s,1H),7.80(s,1H),7.15(s, 1H),7.10(s,1H),6.60(d,J=3.4Hz,1H),5.14-5.05(m,1H),3.15-3.11(m, 1H),2.88(d,J=11.1Hz,1H),2.63-2.52(m,2H),2.24-2.16(m,1H),2.15- 1.95(m,6H),1.90-1.80(m,1H),1.77-1.67(m,1H),1.05(t,J=7.2Hz,3H).

[0278] Example 3: Preparation of Compound 5 [ka] Step 1): Compound 5-1 (1.00 g, 6.28 mmol) and compound 5-1a (1.14 g, 5.85 mmol) were added to EtOH (10 mL) at room temperature and stirred overnight at reflux. The reaction mixture was directly concentrated, and the residue was purified by column chromatography (0-3% methanol / dichloromethane) to give compound 5-2. LC-MS: m / z: 283.8 (M+H). + .

[0279] Step 2: A solution of compound 5-2 (250 mg, 1.04 mmol) in aqueous ammonia (10 mL, 28%) was stirred at 50° C. for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was added with ethyl acetate (3 mL) and petroleum ether (6 mL). The mixture was stirred for 2 hours and then filtered to give compound 5-3 (150 mg). LC-MS: m / z: 254.9 (M+H). + .

[0280] Step 3: To a mixture of compound 5-3 (100 mg, 0.39 mmol) and intermediate M-1 (207 mg, 0.78 mmol) in dioxane (3 mL) and water (0.5 mL) was added potassium carbonate (162 mg, 1.18 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28.69 mg, 0.04 mmol). The reaction was stirred at 80 °C under nitrogen gas protection for 2 h. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give compound 5-4. LC-MS: m / z: 395.0 (M+H). + .

[0281] Step 4): At room temperature, trifluoroacetic acid (1 mL, 13.42 mmol) was added to a solution of compound 5-4 (120 mg, 0.30 mmol) in dichloromethane (1 mL). The reaction was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-SunFire-C18-10μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 23% - 48% acetonitrile, flow rate: 30 mL / min) to obtain compound 5. LC-MS: m / z: 351.1 (M+H) + .

[0282] Example 4: Preparation of compound 9 [Chemical formula] Step 1): To a solution of compound 4-1 (2.00 g, 13.9 mmol) in ethanol (15 mL) were added compound 9-1 (3.86 g, 18.1 mmol, obtained commercially) and ammonium acetate (1.61 g, 20.90 mmol). The reaction mixture was stirred at 70 °C for 18 hours. The solvent was removed from the reaction solution. The residue was purified by a C18 reverse-phase column (methanol / water = 62%) to obtain compound 9-2. LC-MS: m / z: 337.5 [M+H] + .

[0283] Step 2): At 25 °C, in a one-neck flask were added compound 9-2 (100 mg, 0.300 mmol), intermediate M-1 (195 mg, 0.740 mmol), dioxane (2 mL), water (0.3 mL), potassium phosphate (126 mg, 0.590 mmol), and XPhos Pd G3 (25.1 mg, 0.03 mmol). The reaction was stirred at 80 °C for 2 hours. Water (3 mL) was added to the reaction solution for dilution, and it was extracted 3 times with ethyl acetate (3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by column chromatography on a silica gel column (MeOH / DCM = 1 / 10) to obtain compound 9-3. LC-MS: m / z 521.1 [M+H] + .

[0284] Step 3): Compound 9-3 (70 mg, 0.13 mmol), dichloromethane (1 mL), and trifluoroacetic acid (1 mL, 0.670 mmol) were added to a 25 mL single-neck flask at 25 °C, and the reaction was stirred at room temperature for 1 hour. The reaction solution was spin-dried and purified by preparative separation (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient blending ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 9. LC-MS: m / z 377.1 [M+H] + .

[0285] Example 5: Preparation of Compound 10 [ka] Step 1): To a solution of compound 9-2 (360 mg, 1.07 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL, 13.42 mmol). The reaction was stirred at 25 °C for 3 h, and the reaction solution was concentrated to give compound 10-1. LC-MS: m / z: 237.1 [M+H] + .

[0286] Step 2: A solution of compound 10-1 (360 mg, 1.44 mmol) and acetaldehyde (0.54 mL, 3.06 mmol) in methanol (1 mL) was stirred at 25 °C for 1 h. Sodium cyanoborohydride (191.2 mg, 3.06 mmol) was then added, and the reaction was stirred at 25 °C for 18 h. The reaction mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 10-2. LC-MS: m / z: 265.1 [M+H] + .

[0287] Step 3): Compound 10-2 (150 mg, 0.57 mmol), intermediate M-1 (226 mg, 0.86 mmol), potassium phosphate (481 mg, 2.27 mmol), dioxane (2 mL), and water (0.2 mL) were added to a three-neck flask at room temperature. The mixture was purged with nitrogen three times. XPhos PdG3 (48 mg, 0.06 mmol) was added, and the mixture was purged with nitrogen three times. The reaction mixture was heated to 80 °C, stirred for 1 h, and then slowly returned to room temperature. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (6 mL × 3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (methanol / dichloromethane = 0-10%) to give compound 10-3. LC-MS: m / z: 449.1 [M+H] + .

[0288] Step 4): To a solution of compound 10-3 (60.0 mg, 0.130 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL) at 25 °C, and the reaction was stirred at room temperature for 2 h. The reaction solution was spin-dried, and the crude product was purified by preparative separation (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient mixing ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 10. LC-MS: m / z 405.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.69(d,J=3.4Hz,1H),7.66(s,1H),6.39(d,J=3.4Hz,1H) ,4.60(dd,J=4.8,13.9Hz,1H),4.25(dd,J=5.8,14.0Hz,1H),3.18-3.16(m,1H) ,3.03-3.02(m,1H),2.74-2.69(m,1H),2.35-2.31(m,1H),2.23-2.21(m,1H),1 .82-1.80(m,1H),1.69-1.62(m,1H),1.56-1.52(m,2H),1.10(t,J=7.3Hz,3H).

[0289] Example 6: Preparation of Compound 14 [ka] Step 1): Compound 14-1 (2.00 g, 10.6 mmol), methanol (10 mL), and water (10 mL) were added to a 250 mL single-neck flask at room temperature and stirred. Cyanogen bromide (2.33 mL, 31.74 mmol) was added, and the reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% methanol / dichloromethane) to give compound 14-2. LC-MS: m / z: 213.9 (M+H). + .

[0290] Step 2: Compound 14-2 (100 mg, 0.47 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added to a 50 mL single-neck flask at room temperature and stirred. Intermediate M-1 (123 mg, 0.470 mmol), potassium carbonate (193 mg, 1.40 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium dichloromethane complex (38.2 mg, 0.05 mmol) were added. The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% methanol / dichloromethane) to give compound 14-3. LC-MS: m / z: 354.0 (M+H). +

[0291] Step 3): At room temperature, add compound 14-3 (100 mg, 0.28 mmol) to a 50 mL single-neck flask, then add dichloromethane (2 mL) and TFA (2 mL), stir, and stir the reaction solution at room temperature for 2 hours. The crude product was separated by high performance liquid chromatography (Waters-SunFire-C18-10μm-19*250mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 23% - 48%, flow rate: 30 mL / min) to obtain compound 14. LC-MS: m / z: 310.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 12.7 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 3.36 (s, 2H), 2.07 (s, 3H).

[0292] Example 7: Preparation of Compound 3

Chemical Structure

[0293] Step 2): At room temperature, to a solution of Compound 3-2 (30.0 mg, 0.120 mmol) in acetone (0.5 mL) and water (0.5 mL), add Compound 3-2a (26.7 mg, 0.120 mmol, for the synthesis method, refer to the synthesis of Intermediate B005 on page 39 of US20200361898A1), potassium carbonate (33.6 mg, 0.240 mmol), and Pd(dtbpf)Cl2 (7.85 mg, 0.01 mmol). React the mixture in a microwave reactor at 120 °C for 30 minutes. Evaporate the reaction solution to dryness under reduced pressure. Extract the residue three times with dichloromethane (1 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin-dry. Purify the crude product by preparative HPLC (Waters-SunFire-C18-10μm-19*250mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 23% - 48%, flow rate: 30 mL / min) to obtain Compound 3. LC-MS: m / z 387.3 [M+H] + .

[0294] Example 8: Preparation of Compound 2 [Chemical formula] Step 1): At room temperature, add Compound 2-1 (1.03 mL, 7.74 mmol, purchased from Bide) and pyridine (10 mL) to a 40 mL IKA flask in sequence. After thorough and uniform mixing, continue to add p-toluenesulfonyl chloride (1.62 g, 8.51 mmol). Stir the reaction solution at 25 °C for 16 hours. Monitor the completion of the raw material reaction by LCMS. Concentrate the reaction solution to a dark red mud-like substance using rotary evaporation under reduced pressure. Then add 10 mL of ethanol, shake uniformly to obtain a dark red suspension, and concentrate it again using rotary evaporation under reduced pressure. Add ethanol, concentrate, and repeat three times to obtain a reddish white solid. Add as little ethanol as possible, shake uniformly to obtain a suspension with a large amount of white solid. Filter under reduced pressure, wash the filter residue twice with a small amount of ethanol to obtain a solid. Dry the solid by rotary evaporation under reduced pressure to obtain Compound 2-2. LC-MS: m / z: 284.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.87(d,J=8.3Hz,2H),7.40(d,J=8.3Hz,2H),5.08-5.00(m,1H),3.60-3.56(m,1H),3.43-3.40(m,1H),3.12-3.09(m ,2H),2.69-2.60(m,2H),2.47(s,3H),2.30-2.20(m,1H),2.13-2.05(m,1H),1.96-1.90(m,1H),1.66-1.57(m,1H),1.44(t,J=7.4Hz,3H).

[0295] Step 2): At room temperature, compound 3-chloro-5H-pyrrolo[3,2-c]pyridazine (1.30 g, 8.47 mmol; see WO2022121914A1, page 73, for the synthesis of compound 25c) was added to a 100 mL single-neck flask and dissolved in dimethylformamide (20 mL). Cesium carbonate (11.0 g, 33.9 mmol) and compound 2-2 (5.28 g, 18.62 mmol) were then added to the reaction flask. The reaction mixture was stirred at 100 °C for 6 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 2-3. LC-MS: m / z: 265.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=0.7Hz,1H),7.96-7.94(m,2H),6.93-6.92(m,1H),4.20(d,J=5.3Hz,2H),3.00-2.97(m, 1H),2.82-2.78(m,1H),2.20-2.09(m,2H),1.74-1.73(m,1H),1.58-1.57(m,1H),1.41-1.37(m,2H),0.90(t,J=7.2Hz,3H).

[0296] Step 3: Compound 2-3 (90.0 mg, 0.340 mmol), intermediate M-1 (90.0 mg, 0.340 mmol), potassium phosphate (289 mg, 1.36 mmol), dioxane (2 mL), and water (0.2 mL) were added to a 25 mL three-neck flask at room temperature. The mixture was stirred until uniform. XPhos Pd G3 (29 mg, 0.03 mmol) was added, and the system was further purged with nitrogen gas three times. The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature and extracted with water (10 mL) and ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (0% to 10% methanol / dichloromethane) to give compound 2-4. LC-MS: m / z: 449.2 [M+H] + .

[0297] Step 4): Compound 2-4 (60 mg, 0.13 mmol) and dichloromethane (1 mL) were added to a 25 mL single-neck flask at room temperature and stirred until uniform. Trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7-8. The mixture was extracted three times with dichloromethane (5 mL). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (Phase A was 0.01 mol / L aqueous ammonium bicarbonate solution, and Phase B was acetonitrile) to obtain Compound 2. LC-MS: m / z: 405.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),7.90(d,J=3.6Hz,1H),7.81(s,1H),7. 16(s,1H),7.11(s,1H),6.91(d,J=3.2Hz,1H),4.21-4.17(m,2H),2.99-2.97( m,1H),2.81-2.79(m,1H),2.59-2.56(m,1H),2.19-2.08(m,2H),2.06(s,3H) ,1.72-1.68(m,1H),1.60-1.56(m,1H),1.47-1.42(m,2H),0.91-0.85(m,3H).

[0298] Example 9: Preparation of Compound 4 [ka] Step 1): Compound 4-1 (1.00 g, 6.97 mmol, yield) and compound 4-1a (1.50 g, 7.66 mmol, yield) were added to ethanol (10 mL) at room temperature and stirred overnight at reflux. The reaction mixture was directly concentrated, and the residue was purified by column chromatography (0-3% methanol / dichloromethane) to give compound 4-2. LC-MS: m / z: 240.1 [M+H] + .

[0299] Step 2): To a solution of compound 4-2 in acetonitrile (0.5 mL) and water (0.5 mL) at room temperature, compound 4-2a (97.4 mg, 0.440 mmol, see US20200361898A1, page 39, for the synthesis of intermediate B005), Pd(dtbpf)Cl 2((28.6 mg, 0.040 mmol) and potassium carbonate (122 mg, 0.890 mmol) were added, and the reaction was heated in a microwave reactor at 120 °C for 40 minutes. The reaction mixture was concentrated, and the residue was mixed with water (5 mL). Extracted three times with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by preparative separation (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient blending ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to give compound 4. LC-MS: m / z 352.3 [M+H] + .

[0300] Example 10: Preparation of Compound 6 [ka] Step 1): To a solution of compound 6-1 (1000 mg, 5.32 mmol, yield) in tetrahydrofuran (10 mL) at room temperature, N,N'-carbonyldiimidazole (1.29 g, 7.98 mmol) was added. The reaction was stirred at 70 °C for 3 h. The mixture was then filtered to give compound 6-2. LC-MS: m / z: 214.0 [M+H] + .

[0301] Step 2: To a solution of compound 6-2 (400 mg, 1.87 mmol) in phosphorus oxychloride (20 mL), tetramethylammonium chloride (410 mg, 3.74 mmol) was added. The reaction was stirred at 110 °C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and phosphorus oxychloride was removed by distillation under reduced pressure. The mixture was neutralized with saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 6-3. LC-MS: m / z: 233.9 [M+H] + .

[0302] Step 3): To a solution of compound 6-3 (250 mg, 1.08 mmol) in N-methylpyrrolidone (4 mL) was added compound 6-4 (481 mg, 5.38 mmol) and N-methylmorpholine (0.35 mL, 3.23 mmol). The reaction was stirred at 100 °C for 18 h. The reaction solution was purified by C18 liquid chromatography (eluent: 17% acetonitrile in water) to give compound 6-5. LC-MS: m / z: 284.9 [M+H] + .

[0303] Step 4: To a solution of compound 6-5 (100 mg, 0.35 mmol) and intermediate M-1 (93 mg, 0.35 mmol) in dioxane (5 mL) and water (1 mL) at room temperature, potassium carbonate (145 mg, 1.05 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg, 0.04 mmol) were added. The reaction was stirred at 80 °C under nitrogen gas protection for 2 h. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel plate (eluent: dichloromethane / methanol = 10 / 1) to give compound 6-7. LC-MS: m / z: 425.5 [M+H] + .

[0304] Step 5): At room temperature, trifluoroacetic acid (1 mL) was added to a solution of compound 6-7 (60 mg, 0.14 mmol) in dichloromethane (2 mL). The reaction was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated using a high-performance liquid chromatography (Waters-SunFire-C18-10 μm-19 * 250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient blending ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 6. LC-MS: m / z: 381.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.12(s,1H),7.06-7.02(m,2H),3.32(s,2H),2.13(s,3H),1.17(s,6H).

[0305] Example 11: Preparation of Compound 13 [ka] Step 1): Compound 13-1 (50.0 mg, 0.290 mmol), intermediate M-1 (132 mg, 0.500 mmol), Xphos Pd G3 (49.92 mg, 0.06 mmol), potassium phosphate (250 mg, 1.18 mmol), dioxane (2 mL), and water (0.2 mL) were added to an 8 mL single-neck flask at room temperature. The reaction was heated at 80 °C for 1 h under nitrogen gas protection. The reaction mixture was diluted with dichloromethane (10 mL) and saturated aqueous sodium chloride (3 mL), extracted three times with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun dry. The residue was purified by preparative thin-layer chromatography on a silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 13-2. LC-MS: m / z: 354.0 [M+H] + .

[0306] Step 2): At room temperature, in an 8 mL single-neck flask, compound 13-2 was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added. The reaction was allowed to proceed at 25°C for 0.5 hours. The reaction solution was spin-dried. The residue was purified by high-performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 13. LC-MS: m / z: 310.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.96(d,J=9.1Hz,1H),7.39(d,J=9.1Hz,1H),7.17(s,1H),7.09(s,1H),6.35(s,2H),2.15(s,3H).

[0307] Example 12: Preparation of Compound 7 [ka] Step 1): To a solution of compound 7-1 (50.0 mg, 0.280 mmol) in dioxane / water (1.0 mL / 0.2 mL) at room temperature, intermediate M-1 (73.9 mg, 0.280 mmol), potassium carbonate (0.56 mL, 0.56 mmol, 1 M aqueous solution), and SPhos Pd G3 (24.1 mg, 0.03 mmol) were added. The system was purged with nitrogen three times, and the reaction was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun to give crude compound 7-2, which was used directly in the next step without further purification.

[0308] Step 2): To a solution of compound 7-2 (45.0 mg, 0.120 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by preparative separation (Waters-SunFire-C18-10 μm-19 * 250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient blending ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to give compound 7. LC-MS: m / z: 320.1 [M+H] + .

[0309] Example 13: Preparation of Compound 8 [ka] Step 1): At room temperature, compound 8-1 (3.58 g, 18.9 mmol) was added to a single-neck flask, followed by methanol (35 mL). Cyanogen bromide (2.01 g, 18.9 mmol) was added to the rapidly stirring reaction mixture. After the addition was complete, the mixture was allowed to react at 50°C for 2 hours. After the reaction mixture was returned to room temperature, saturated sodium bicarbonate solution (200 mL) was added to the mixture. After the solid precipitated, the mixture was filtered under suction. The filter cake was washed with water (20 mL x 3) and dried to obtain compound 8-2. LC-MS: m / z: 214.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.92(s,2H),7.51(d,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H).

[0310] Step 2): Compound 8-2 (100 mg, 0.470 mmol), intermediate M-1 (248 mg, 0.940 mmol), Pd(dppf)Cl (34.4 mg, 0.050 mmol), potassium carbonate (260 mg, 1.88 mmol), dioxane (2 mL), and water (0.2 mL) were added to a single-neck flask at room temperature. The reaction was heated at 80 °C for 1 h under nitrogen gas protection. The reaction mixture was diluted with dichloromethane (10 mL) and water (5 mL), separated, and extracted three times with dichloromethane (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun to give crude compound 8-3.

[0311] Step 3): At room temperature, compound 8-3 (145 mg, 0.410 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL) were added to a single-neck flask. The reaction was allowed to proceed at 25°C for 1 hour. The reaction solution was evaporated to dryness under reduced pressure. The residue was purified by preparative separation (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient blending ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 8. LC-MS: m / z: 310.0 [M+H] + .

[0312] Example 14: Preparation of Compound 1 [ka] Step 1): At room temperature, a mixture of compound 1-1 (500 mg, 2.66 mmol), cyanogen bromide (282 mg, 2.66 mmol), methanol (5 mL), and water (5 mL) was stirred at 50° C. for 3 hours. The resulting mixture was distilled under reduced pressure, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added to the residue. The mixture was stirred for 2 hours, and then filtered to obtain compound 1-2. LC-MS: m / z: 212.9 [M+H] + .

[0313] Step 2: To a solution of compound 1-2 (600 mg, 2.82 mmol) in tetrahydrofuran (3 mL) at room temperature, di-tert-butyl dicarbonate (799 mg, 3.66 mmol), triethylamine (0.78 mL, 5.63 mmol), and 4-dimethylaminopyridine (1.03 g, 8.45 mmol) were added. The reaction was stirred at 25 °C for 18 hours. The reaction mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 1-3. LC-MS: m / z: 312.9 [M+H] + .

[0314] Step 3: To a mixture of compound 1-3 (160 mg, 0.51 mmol), intermediate M-1 (270 mg, 1.02 mmol), dioxane (3 mL), and water (0.5 mL) at room temperature, potassium carbonate (212 mg, 1.53 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (37.4 mg, 0.050 mmol) were added. The mixture was purged with nitrogen gas three times and stirred at 80 °C for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give compound 1-5. LC-MS: m / z: 353.1 [M+H] + .

[0315] Step 4): At room temperature, trifluoroacetic acid (1 mL) was added to a solution of compound 1-5 (80 mg, 0.23 mmol) in dichloromethane (1 mL). The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated using a high-performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient blending ratio: acetonitrile 23% to 48%, flow rate: 30 mL / min) to obtain compound 1. LC-MS: m / z: 309.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.43(d,J=7.9Hz,1H),7.07(s,1H),7.02(s,1H),6.86(d,J=7.9Hz,1H),6.60(s,2H),2.14(s,3H).

[0316] Example 15: Preparation of Compound 111 [ka] Step 1): Compound 111-1 (10.0 g, 43.3 mmol, prepared as described in the intermediate Step A compound on page 102 of the patent application WO2022078971A1) was added to a 500 mL single-neck flask at room temperature. thionyl chloride (100 mL) was added and stirred. N,N-dimethylformamide (1 mL) was slowly added dropwise. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated, and the residue was added with water. The mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an elution system (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 111-2. 1 H NMR(400MHz,DMSO-d6)δ8.25(d,J=8.5Hz,1H),7.75(d,J=8.5Hz,1H).

[0317] Step 2): Compound 111-3 (1.00 g, 4.28 mmol, Rakuken) and compound 111-2 (923 mg, 4.28 mmol) were dissolved in acetonitrile (20 mL), potassium carbonate (1.78 g, 12.8 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. After that, water (50 mL) was added to the reaction mixture, and dichloromethane (50 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed. After the drying agent was removed, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 111-4. MS m / z (ESI): 415.1 [M+1] + .

[0318] Step 3): Compound 111-4 (1.70 g, 4.11 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give compound 111-5. MS m / z (ESI): 314.9 [M+1] + .

[0319] Step 4): Compound 111-5 (1.50 g, 4.79 mmol) was dissolved in dichloromethane (20 mL), triethylamine (3.32 mL, 23.4 mmol) was added, and the reaction was stirred at 0 °C for 10 minutes. Acetic anhydride (0.47 mL, 5.03 mmol) was added to the reaction mixture, and the reaction was continued at 25 °C for 15 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the drying agent. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 111-6. MS m / z (ESI): 355.0 [M+1] + .

[0320] Step 5: Compound 111-6 (1.15 g, 3.24 mmol) and intermediate M-1 (1.71 g, 6.48 mmol) were dissolved in dioxane (30 mL) and water (6 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (236 mg, 0.320 mmol, adamas) and potassium carbonate (1.78 g, 12.6 mmol) were added. The reaction was purged with nitrogen gas three times and stirred at 80 °C under a nitrogen atmosphere for 18 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, which was then extracted with dichloromethane (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 5 / 10) to give compound 111-7. MS m / z (ESI): 495.3 [M+1] + .

[0321] Step 6): Compound 111-7 (1.26 g, 2.29 mmol) was dissolved in a hydrochloric acid / dioxane solution (12 mL, 4 M), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered to obtain a filter cake. The filter cake was dissolved in methanol (3 mL) and dichloromethane (20 mL), and extracted with saturated sodium bicarbonate solution (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. After removing the drying agent, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 5 / 10) to obtain compound 111. MS m / z (ESI): 451.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.93(d,J=3.8Hz,1H),8.79-8.43(m,1H),7.82-7.65(m,1H),7.07(d,J=14.2Hz,2H),6.98-6.87( m,1H),4.68-4.00(m,2H),3.94-3.80(m,2H),3.74-3.61(m,2H),3.56-3.41(m,2H),3.29-2.95(m,1H),2.12-1.91(m,6H).

[0322] Example 16: Synthesis of Compound 247 [Chemical formula] Step 1): Dissolve Compound 111-5 (80.0 mg, 0.26 mmol) in dichloromethane (5 mL), add trifluoroacetic anhydride (82.0 mg, 0.39 mmol, obtained from Bide), and triethylamine (78.0 mg, 0.77 mmol). Stir and react at room temperature for 2 hours. After the reaction, add the reaction solution to saturated sodium bicarbonate solution (10 ml), extract with dichloromethane (10 mL × 3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and then concentrate the filtrate under reduced pressure. Purify the residue by thin-layer chromatography with an eluent system (dichloromethane / methanol = 20 / 1) to obtain Compound 247-1. MS m / z (ESI): 408.0 [M+1]+.

[0323] Step 2): Dissolve Compound 247-1 (50.0 mg, 0.12 mmol) in a mixed solution of 1,4-dioxane (3 mL) and water (0.6 mL), add Intermediate M-1 (65.0 mg, 0.24 mmol), potassium carbonate (51.0 mg, 0.37 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (8.94 mg, 0.01 mmol). Replace the gas with nitrogen three times, stir and react at 80 °C for 2 hours. After the reaction, add water (15 ml) to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and then concentrate the filtrate under reduced pressure. Purify the residue by thin-layer chromatography with an eluent system (dichloromethane / methanol = 20 / 1) to obtain Compound 247-2. MS m / z (ESI): 547.3 [M+1]+.

[0324] Step 3): Compound 247-2 (50.0 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 2 hours to react. Then, the reaction solution was directly concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, chromatography column: SharpSil-TC18, 30*150 mm, 5 μm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% - 45%, flow rate: 30 mL / min) to obtain Compound 247. MS m / z (ESI): 505.3 [M+1]+. 1 H NMR (400 MHz, DMSO-d6) δ9.92 (s, 1H), 8.71 - 8.63 (m, 1H), 7.77 - 7.73 (m, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 6.96 - 6.92 (m, 1H), 4.63 (s, 1H), 4.10 - 4.07 (m, 1H), 4.00 - 3.93 (m, 2H), 3.87 - 3.82 (m, 2H), 3.67 - 3.56 (m, 2H), 3.49 - 3.44 (m, 1H), 2.07 (s, 3H).

[0325] Example 17: Preparation of Compound 248

Chemical formula

[0326] Step 2): Compound 248-2 (140 mg, 0.49 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then directly concentrated under reduced pressure to give compound 248-3. The residue was used directly in the next step without further purification. MS m / z (ESI): 187.2 [M+1]+.

[0327] Step 3): Compound 111-2 (110 mg, 0.47 mmol) was dissolved in acetonitrile (8 mL), and compound 248-3 (87.8 mg, 0.47 mmol) and potassium carbonate (195 mg, 1.41 mmol) were added. The mixture was stirred at 80 °C for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography using a dichloromethane / methanol mixture (dichloromethane / methanol = 100 / 1 to 20 / 1) to give compound 248-4. MS m / z (ESI): 383.1 [M+1]+.

[0328] Step 4): Compound 248-4 (50.0 mg, 0.13 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.6 mL). Intermediate M-1 (68.9 mg, 0.24 mmol), potassium carbonate (54.1 mg, 0.39 mmol), and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (9.55 mg, 0.01 mmol) were added. The mixture was purged with nitrogen gas three times and stirred at 80°C for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography using an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 248-5. MS m / z(ESI): 523.3 [M+1]+.

[0329] Step 5): Compound 248-5 (50.0 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography column: SharpSil-TC18, 30*150 mm, 5 μm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 38%-45% acetonitrile, flow rate: 30 mL / min) to give compound 248. MS m / z (ESI): 479.3 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.63(d,J=81.9Hz,1H),7.78-7.71(m,1H), 7.08(s,1H),7.05(s,1H),6.93(dd,J=11.9,8.0Hz,1H),4.68-4.63(m,1H),4.14 -4.11(m,1H),3.89-3.78(m,1H),3.70-3.63(m,2H),3.55-3.50(m,2H),3.32-3. 25(m,2H),3.04-2.93(m,1H),2.07(s,3H),1.00-0.96(m,3H),0.90-0.75(m,3H).

[0330] Example 18: Preparation of Compound 249 [ka] Step 1): Dissolve compound 111-5 (80.0 mg, 0.26 mmol) in dichloromethane (5 mL). Add triethylamine (77.6 mg, 0.77 mmol) and difluoroacetic anhydride (67.9 mg, 0.39 mmol, Bide) at 0 °C, stir and react at room temperature for 2 hours. Then, add the reaction solution to saturated sodium bicarbonate solution (15 mL), extract with dichloromethane (10 mL × 3). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and then concentrate the filtrate under reduced pressure. Purify the residue by thin-layer chromatography with an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 249-1. MS m / z (ESI): 390.1 [M+1]+.

[0331] Step 2): Dissolve compound 249-1 (50.0 mg, 0.13 mmol) in a mixed solution of 1,4-dioxane (3 mL) and water (0.6 mL). Add intermediate M-1 (67.5 mg, 0.26 mmol), potassium carbonate (53.0 mg, 0.38 mmol) and dichloropalladium (II) 1,1'-bis(diphenylphosphino)ferrocene (9.35 mg, 0.01 mmol). Replace with nitrogen gas three times, stir and react at 80 °C for 2 hours. Then, add water (15 mL) to the reaction solution, extract with ethyl acetate (10 mL × 3). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and then concentrate the filtrate under reduced pressure. Purify the residue by thin-layer chromatography with an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 249-2. MS m / z (ESI): 531.7 [M+1]+

[0332] Step 3): Compound 249-2 (50.0 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours to react. After that, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, chromatography column: SharpSil-TC18, 30*150 mm, 5 μm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% - 45%, flow rate: 30 mL / min) to obtain Compound 249. MS m / z (ESI): 487.4 [M+1]+. 1 H NMR (400 MHz, DMSO-d6) δ9.91(s,1H),8.67 - 8.52(m,1H),7.77 - 7.10(m,1H),7.07(d,J = 12.2Hz,2H),6.96 - 6.91(m,1H),6.81 - 6.53(m,1H),4.60 - 4.15(m,1H),4.06(d,J = 13.8Hz,1H),4.00 - 3.90(m,2H),3.85 - 3.70(m,2H),3.64 - 3.54(m,2H),3.45 - 3.40(m,1H),2.07(d,J = 2.8Hz,3H).

[0333] Example 19: Preparation of Compound 250

Chemical formula

[0334] Step 2): Compound 250-1 (50.0 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.6 mL). Intermediate M-1 (71.5 mg, 0.27 mmol), potassium carbonate (56.2 mg, 0.41 mmol), and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (9.91 mg, 0.01 mmol) were added. The mixture was purged with nitrogen gas three times and stirred at 80 °C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography using an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 250-2. MS m / z(ESI):509.4[M+1]+.

[0335] Step 3): Compound 250-2 (50.0 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography column: SharpSil-TC18, 30*150 mm, 5 μm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 38%-45% acetonitrile, flow rate: 30 mL / min) to give compound 250. MS m / z (ESI): 465.7 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.02-8.80(m,1H),7.89-7.82(m,1H ),7.12-7.10(m,1H),7.07(s,1H),7.03-6.99(m,1H),4.70-4.60(m,1H),4. 16-4.07(m,1H),3.90-3.83(m,2H),3.70-3.62(m,2H),3.58-3.43(m,2H),3 .38-3.26(m,1H),2.43-2.29(m,2H),2.10-2.07(m,3H),0.97-0.84(m,3H).

[0336] Example 20: Preparation of Compound 253

Chem.

[0337] Example 21: Preparation of Compound 254

Chem.

[0338] Example 22: Preparation of Compound 252 [ka] Step 1): Compound 252-1 (500 mg, 2.16 mmol, prepared by the method disclosed in Intermediate 20-3 on page 66 of the specification of patent application WO2022 / 166890Al) and chloromethyl methyl ether (0.25 mL, 3.27 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.72 mL, 4.3 mmol) was added. The reaction solution was stirred at 25°C for 18 hours. After that, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. After removing the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 252-2.

[0339] Step 2: Compound 252-2 (300 mg, 1.10 mmol) was dissolved in anhydrous tetrahydrofuran and n-butyllithium (0.57 mL, 2.33 mmol, 2.5 M) was added at -40 °C. The reaction mixture was stirred at -40 °C for half an hour, and then isopropoxyboronic acid pinacol ester (0.45 mL, 2.20 mmol) was added and the reaction mixture was continued at 25 °C for 2 hours. Ice water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 252-3. 1 H NMR(400MHz,CDCl3)δ8.09(s,1H),7.53(d,J=8.3Hz,1H),7.29(t,J=8.0Hz,1H),6.96(d,J=7.8Hz,1H),5.31(s,2H),3.51(s,3H),1.38(s,12H).

[0340] Step 3: Compound 252-3 (200 mg, 0.62 mmol) and compound 111-6 (155 mg, 0.44 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (45.7 mg, 0.06 mmol, adamas) and potassium carbonate (172 mg, 1.25 mmol) were added. The reaction was purged with nitrogen gas three times and stirred at 80 °C under a nitrogen atmosphere for 18 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. After removing the drying agent, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give compound 252-4. MS m / z(ESI):469.2[M+1]+.

[0341] Step 4): Compound 252-4 (80 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient mixing ratio: acetonitrile 46%-95%, flow rate: 25 mL / min) to obtain compound 252. MS m / z (ESI): 425.2 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.70-8.40(m,1H),8.00(s,1H),7.76- 7.69(m,1H),7.65-7.57(m,1H),7.35(d,J=8.0Hz,1H),7.16(t,J=7.9Hz,1H) ,6.74(d,J=7.7Hz,1H),4.79-4.53(m,1H),4.19-4.05(m,1H),3.93-3.84(m ,2H),3.76-3.63(m,2H),3.62-3.46(m,2H),3.42-3.30(m,1H),2.01(s,3H).

[0342] Example 23: Preparation of Compound 251 [ka] Step 1): Compound 251-1 (500 mg, 2.35 mmol, net) and chloromethyl methyl ether (0.23 mL, 3.05 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.78 mL, 4.69 mmol) was added. The reaction mixture was stirred at 25°C for 18 hours. After that, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 251-2.

[0343] Step 2: Compound 251-2 (300 mg, 1.17 mmol) was dissolved in anhydrous tetrahydrofuran, and n-butyllithium (0.93 mL, 2.33 mmol, 2.5 M hexane solution) was added at −78°C. The reaction mixture was stirred at −78°C for 1 hour, followed by the addition of isopropoxyboronic acid pinacol ester (0.38 mL, 1.87 mmol), and the reaction mixture was continued at −78°C for 1 hour. Ice water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 251-3. 1 H NMR(400MHz,CDCl3)δ7.57(d,J=7.4Hz,1H),7.01(d,J=7.4Hz,1H),5.09(s,2H),3.56( s,3H),2.99(t,J=7.4Hz,2H),2.93(t,J=7.5Hz,2H),2.10-2.00(m,2H),1.33(s,12H).

[0344] Step 3: Compound 251-3 (230 mg, 0.76 mmol) and compound 111-6 (188 mg, 0.53 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (55.3 mg, 0.08 mmol, adamas) and potassium carbonate (209 mg, 1.51 mmol) were added. The reaction was purged with nitrogen gas three times and stirred at 80 °C under a nitrogen atmosphere for 18 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give compound 251-4. MS m / z(ESI): 453.6 [M+1]+.

[0345] Step 4): Compound 251-4 (130 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient mixing ratio: acetonitrile 46%-95%, flow rate: 25 mL / min) to obtain compound 251. MS m / z (ESI): 409.2 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.56(s,1H),8.84-8.41(m,1H),7.88-7.78(m,1H),7.70-7.64(m,2H),6.78(d,J=8.0Hz,1H ),4.79-4.01(m,2H),3.93-3.83(m,2H),3.77-3.63(m,2H),3.55-3.37(m,3H),2.90-2.85(m,4H),2.12-1.88(m,5H).

[0346] Example 24: Preparation of Compound 255 [ka] Step 1: Compound 255-1 (1.00 g, 3.26 mmol, prepared by the method disclosed in Journal of Agricultural and Food Chemistry (1995), 43(3), 804-8) was added to tetrahydrofuran (15 mL), stirred evenly, and purged with nitrogen gas three times. The reaction mixture was cooled to -70 °C, and n-butyllithium (1.60 mL, 3.91 mmol, 2.5 M tetrahydrofuran solution) was slowly added, controlling the temperature below -65 °C. The reaction mixture was stirred for 30 minutes, and triisopropyl borate (0.92 g, 4.88 mmol) was slowly added. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 hours. The reaction mixture was slowly added to ice water (20 mL), extracted with ethyl acetate (8 mL × 3), and the organic phase was dried over saturated brine and anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was used directly in the next step without further purification. Compound 255-2 was obtained. MS m / z(ESI):273.1[M+1]+.

[0347] Step 2: Compound 255-2 (500 mg, 0.92 mmol) and compound 111-6 (100 mg, 0.28 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (67.2 mg, 0.09 mmol, adamas) and potassium carbonate (254 mg, 1.84 mmol) were added. The reaction was purged with nitrogen gas three times and stirred at 80 °C under a nitrogen atmosphere for 18 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. After removing the drying agent, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give compound 255-3. MS m / z(ESI):503.8[M+1]+.

[0348] Step 3): Compound 255-3 (160 mg, 0.22 mmol) was dissolved in methanol (15 mL) and 10% wet palladium-carbon (20 mg, Adams) was added. The reaction mixture was stirred under a hydrogen atmosphere for 18 h. After completion of the reaction, the mixture was filtered to remove the palladium-carbon. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 46% to 95% acetonitrile, flow rate: 25 mL / min) to obtain compound 255. MS m / z (ESI): 413.3 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.59-9.40(m,1H),8.72-8.36(m,1H),7.77-7.59(m,1H),6.97-6.83(m,1H),6.32(s,2H),4.67-4 .08(m,1H),4.07-3.80(m,3H),3.72(s,3H),3.69-3.57(m,2H),3.56-3.43(m,2H),3.20-2.87(m,1H),2.07-1.92(m,6H).

[0349] Example 25: Preparation of Compound 257 [ka] Step 1): At 0 °C, cyclopropanecarbonyl chloride (126 μL, 1.39 mmol) was added to a solution containing compound 248-1 (150 mg, 0.69 mmol), triethylamine (192 μL, 1.39 mmol), and dichloromethane (1 mL). The reaction mixture was stirred at 25 °C for 0.5 hours, after which water (20 mL) was added and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure to give compound 257-1. MS m / z (ESI): 307.2 [M+23] + .

[0350] Step 2): Compound 257-1 (190 mg, 0.67 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 257-2. MS m / z (ESI): 185.0 [M+1] + .

[0351] Step 3: Potassium carbonate (277 mg, 2.00 mmol) was added to a solution of compound 111-2 (156 mg, 0.67 mmol), compound 257-2 (123 mg, 0.67 mmol), and acetonitrile (3 mL). The reaction mixture was stirred at 25 °C for 18 hours. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the drying agent. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 257-3. MS m / z (ESI): 383.0 [M+1] + .

[0352] Step 4: 1,1'-Bisdiphenylphosphinoferrocene palladium dichloride (28.8 mg, 0.04 mmol) was added to a solution of compound 257-3 (150 mg, 0.39 mmol), intermediate M-1 (156 mg, 0.59 mmol), potassium carbonate (109 mg, 0.79 mmol), water (0.5 mL), and dioxane (2.5 mL). After purging with nitrogen gas three times, the mixture was stirred at 80 °C for 2 h. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the drying agent. The residue was purified by silica gel column chromatography using a dichloromethane / methanol mixture (dichloromethane / methanol = 40 / 1 to 15 / 1) to give compound 257-4. MS m / z (ESI): 521.6 [M+1]. + .

[0353] Step 5): Trifluoroacetic acid (1 mL) was added to a solution of compound 257-4 (100 mg, 0.19 mmol) and dichloromethane (3 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 42%-52%, flow rate: 25 mL / min) to give compound 257. MS m / z (ESI): 477.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ10.12-9.87(m,1H),8.89-8.54(m,1H),7.84-7.70(m,1H),7.16-7.01(m,2H),6.99-6.89(m,1H),4.70-4.46(m,1) H),4.13-3.85(m,3H),3.67-3.59(m,2H),3.47-3.30(m,2H),3.18-2.94(m,1H),2.15-2.01(m,3H),2.00-1.81(m,1H),0.77-0.29(m,4H).

[0354] Example 26: Preparation of Compound 258 [ka] Step 1): At room temperature, compound 248-1 (80.0 mg, 0.37 mmol, Rakuken) and triethylamine (110 mg, 1.09 mmol) were added to dichloromethane (2 mL) and stirred until homogeneous. The mixture was cooled to 0 °C in an ice bath, and methanesulfonyl chloride (64.0 mg, 0.56 mmol) was slowly added. The mixture was then slowly warmed to room temperature and reacted for 2 hours. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (5 mL × 3). The organic phase was dried over saturated brine and anhydrous sodium sulfate, and the solvent was removed under reduced pressure. This was used directly in the next step without further purification. Compound 258-1 was obtained. MS m / z (ESI): 195.0 [M-100]+.

[0355] Step 2): At room temperature, compound 258-1 (120 mg, 0.41 mmol) was added to dichloromethane (1 mL) and stirred until homogeneous. Trifluoroacetic acid (1 mL) was slowly added and the mixture was allowed to react at room temperature for 1 hour. The solvent was removed from the reaction mixture under reduced pressure to give compound 258-2, which could be used directly in the next step without purification. MS m / z (ESI): 194.9 [M+1]+.

[0356] Step 3): At room temperature, compound 258-2 (119 mg, 0.52 mmol), compound 111-2 (100 mg, 0.43 mmol), and potassium carbonate (178 mg, 1.29 mmol) were added to acetonitrile (3 mL) and stirred until uniform. The reaction mixture was heated to 70 °C and reacted for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (5 mL × 3). The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound 258-3. MS m / z (ESI): 392.6 [M+1]+.

[0357] Step 4): Compound 258-3 (110 mg, 0.28 mmol), intermediate M-1 (124 mg, 0.47 mmol), potassium carbonate (118 mg, 0.85 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (41.0 mg, 0.06 mmol) were added to dioxane (3 mL) and water (0.3 mL) at room temperature. The mixture was stirred evenly and purged with nitrogen gas three times. The mixture was then heated to 80 °C and reacted for 2 h. The reaction mixture was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (6 mL × 3). The organic phase was dried over saturated brine and anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound 258-4. MS m / z (ESI): 531.2 [M+1]+.

[0358] Step 5): At room temperature, compound 258-4 (50.0 mg, 0.09 mmol) was added to dichloromethane (1 mL) and stirred until homogeneous. Trifluoroacetic acid (1 mL) was slowly added and the mixture was allowed to react at room temperature for 1 hour. The solvent was removed from the reaction mixture under reduced pressure. The residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 33%-67%, flow rate: 25 mL / min) to obtain compound 258. MS m / z (ESI): 487.2 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.71(s,1H),7.77(d,J=8.0Hz,1H),7.09(s,1H),7.05(s,1H),6.94(d,J=8.1Hz,1H), 3.99-3.97(m,1H),3.86-3.78(m,2H),3.71-3.65(m,2H),3.60-3.57(m,1H),3.45-3.40(m,3H),3.04(s,3H),2.08(s,3H).

[0359] Example 27: Preparation of Compound 260 [ka] Step 1): At room temperature, compound 248-1 (100 mg, 0.46 mmol, ╢de) and triethylamine (0.200 mL, 1.39 mmol) were added to dichloromethane (2 mL) and stirred until uniform. The mixture was cooled to 0 °C in an ice bath, and cyclopropanesulfonyl chloride (0.10 mL, 0.92 mmol, ╢de) was slowly added. After the addition was complete, the mixture was slowly warmed to room temperature and reacted for 18 hours. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (5 mL x 3). The organic phase was dried over saturated brine and anhydrous sodium sulfate, and the solvent was removed under reduced pressure. This was used directly in the next step without further purification. Compound 260-1 was obtained. MS m / z (ESI): 221.0 [M-100]+.

[0360] Step 2): At room temperature, compound 260-1 (130 mg, 0.41 mmol) was added to dichloromethane (1 mL) and stirred until homogeneous. Trifluoroacetic acid (1 mL) was slowly added and the mixture was allowed to react at room temperature for 1 hour. The solvent was removed from the reaction solution under reduced pressure. Compound 260-2 was obtained, which could be used directly in the next step without purification. MS m / z (ESI): 221.0 [M+1]+.

[0361] Step 3): At room temperature, compound 111-2 (75 mg, 0.32 mmol), compound 260-2 (85.0 mg, 0.39 mmol), and potassium carbonate (133 mg, 0.96 mmol) were added to acetonitrile (3 mL) and stirred until uniform. The reaction mixture was heated to 70 °C and reacted for 2 hours. The reaction mixture was cooled, filtered, and the filter cake was washed with dichloromethane (5 mL × 3). The solvent was removed under reduced pressure. Compound 260-3 was obtained. MS m / z (ESI): 419.0 [M+1]+.

[0362] Step 4): Compound 260-3 (60.0 mg, 0.14 mmol), intermediate M-1 (62 mg, 0.23 mmol), potassium carbonate (60 mg, 0.43 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.03 mmol) were added to dioxane (2 mL) and water (0.2 mL) at room temperature. The mixture was stirred evenly and purged with nitrogen gas three times. The mixture was then heated to 80 °C and reacted for 2 h. The reaction mixture was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (6 mL x 3). The organic phase was dried over saturated brine and anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound 260-4. MS m / z (ESI): 555.2 [M-1].

[0363] Step 5): Compound 260-4 (50 mg, 0.09 mmol) was added to dichloromethane (1 mL) at room temperature, stirred evenly, and trifluoroacetic acid (1 mL) was slowly added. The mixture was allowed to react at room temperature for 1 hour. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: 35% to 65% acetonitrile, flow rate: 25 mL / min) to obtain compound 260. MS m / z (ESI): 513.0 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.68(s,1H),7.75(d,J=8.0Hz,1H),7.09(s,1H),7.05(s,1H),6.93(d,J=8.0Hz,1H),4.02-3.95( m,1H),3.88-3.81(m,2H),3.74-3.66(m,2H),3.64-3.60(m,1H),3.49-3.47(m,3H),2.76-2.73(m,1H),2.07(s,3H),1.00-0.90(m,4H).

[0364] Example 28: Preparation of Compound 259 [ka] Step 1): Ethanesulfonyl chloride (44.0 μL, 0.46 mmol, Rakuken) was added to a solution containing compound 248-1 (50.0 mg, 0.23 mmol, BiDu), triethylamine (64.0 μL, 0.46 mmol), and dichloromethane (1 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h, after which water (20 mL) was added and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 259-1. MS m / z (ESI): 331.0 [M+23]+.

[0365] Step 2): Compound 259-1 (70 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 259-2. MS m / z (ESI): 209.0 [M+1]+.

[0366] Step 3): Potassium carbonate (145 mg, 1.05 mmol) was added to a solution of compound 111-2 (82.0 mg, 0.35 mmol), compound 259-2 (73.0 mg, 0.35 mmol), and acetonitrile (5 mL). The reaction mixture was stirred at 25 °C for 18 hours. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the drying agent. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to give compound 259-3. MS m / z (ESI): 407.0 [M+1]+.

[0367] Step 4: 1,1'-Bisdiphenylphosphinoferrocene palladium dichloride (18.0 mg, 0.02 mmol) was added to a solution of compound 259-3 (100 mg, 0.25 mmol), intermediate M-1 (130 mg, 0.49 mmol), potassium carbonate (68.0 mg, 0.49 mmol), water (0.5 mL), and dioxane (2.5 mL). The mixture was purged with nitrogen three times and stirred at 80 °C for 2 h. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the drying agent. The residue was purified by silica gel column chromatography using a dichloromethane / methanol mixture (dichloromethane / methanol = 40 / 1 to 15 / 1) to give compound 259-4. MS m / z(ESI): 545.7 [M+1]+.

[0368] Step 5): Trifluoroacetic acid (1 mL) was added to a solution of compound 259-4 (80.0 mg, 0.15 mmol) and dichloromethane (3 mL). The mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 45%-55%, flow rate: 25 mL / min) to give compound 259. MS m / z (ESI): 501.0 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.72(s,1H),7.78(d,J=8.0Hz,1H),7.09(s,1H),7.05(s,1H),6.95(d,J=8.0Hz,1H),3.98 -3.91(m,1H),3.89-3.80(m,2H),3.77-3.64(m,3H),3.58-3.53(m,3H),3.19-3.10(m,2H),2.08(s,3H),1.16(t,J=7.2Hz,3H).

[0369] Example 29: Preparation of Compound 420 [ka] Step 1): Compound 420-1 (1.00 g, 4.67 mmol, prepared by the method disclosed in Intermediate 33 on page 84 of the specification in the patent application "WO2014198594A1") and cuprous chloride (0.320 g, 3.27 mmol, Bide) were dissolved in concentrated hydrochloric acid (12 mL), and a solution of sodium nitrite (0.520 g, 7.48 mmol, Bide) in water (1 mL) was added at 5 °C. The reaction solution was stirred at 5 °C for 1 hour, then the reaction solution was slowly poured into a saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was diluted with dichloromethane (20 mL). After separating the aqueous phase, it was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration and removal of the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 100 / 1 to 40 / 1) to obtain Compound 420-2. MS m / z (ESI): 232.9, 234.9 [M+H]+. 1 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 9.5 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H).

[0370] Step 2): Compound 420-2 (100 mg, 0.430 mmol), Compound A (104 mg, 0.560 mmol), potassium carbonate (178 mg, 1.29 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (31.5 mg, 40 μmol, Bide) were dissolved in dioxane (2.5 mL) and water (0.5 mL). The reaction solution was heated to 80 °C under a nitrogen gas atmosphere and reacted for 2 hours. The reaction solution was diluted with dichloromethane (5 mL) and water (5 mL), and after separating the aqueous phase, it was extracted with dichloromethane (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration and removal of the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 100 / 1 to 40 / 1) to obtain Compound 420-3. MS m / z (ESI): 294.9 [M+H]+.

[0371] Step 3): Compound 420-3 (100 mg, 0.430 mmol) was dissolved in morpholine (1 mL). The mixture was heated to 200 °C in a microwave oven and reacted at this temperature for 30 minutes. The reaction mixture was poured into water (5 mL). The aqueous phase was extracted with dichloromethane (5 mL × 3). The combined organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. After filtration to remove the drying agent, the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (chromatographic column: Waters-SunFire-C18-10 μm-19 * 250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32% to 48%, flow rate: 25 mL / min) to obtain compound 420. MS m / z (ESI): 346.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6):δ10.22(s,1H),8.07(d,J=9.2Hz,1H),7.46(d,J=9.2Hz, 1H),6.87(d,J=13.3Hz,2H),3.77-3.67(m,4H),3.55-3.48(m,4H),2.07(s,3H).

[0372] Example 30: Preparation of Compound 419 [ka] Step 1): Compound 439-2 (150 mg, 360 μmol) was dissolved in dioxane (6 mL) and treated with (R)-4-Boc-3-aminomethylmorpholine (156 mg, 720 μmol, Rakuken), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (41.6 mg, 72.0 μmol), sodium tert-butoxide (69.1 mg, 720 μmol), and tris(dibenzylideneacetone)dipalladium. The mixture was purged with nitrogen gas three times and stirred at 100 °C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 419-1. MS m / z (ESI): 453.6 [M-Boc+1] + ,

[0373] Step 2): Compound 419-1 (100 mg, 181 μmol) was dissolved in dichloromethane (2 mL), hydrogen chloride / dioxane (4 mL, 4 M) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was used directly in the next step without further purification to obtain compound 419-2. MS m / z (ESI): 409.3 [M+1] + ,

[0374] Step 3): Compound 419-2 (60 mg, 147 μmol) was dissolved in dichloromethane (5 mL). Triethylamine (44.6 mg, 441 μmol) and acetic anhydride (15.0 mg, 147 μmol) were added at 0°C. After stirring for 30 minutes at 0°C, the reaction mixture was mixed with aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography column: SharpSil-TC18, 30 x 150 mm, 5 μm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 38% to 45% acetonitrile, flow rate: 30 mL / min) to obtain compound 419. MS m / z (ESI): 451.2 [M+1] + , 1 H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.08-7.90(m,1H),7.52-7.38(m,1H),7.33-6.86(m,3H) ,4.75-3.75(m,4H),3.70-3.35(m,4H),3.30-2.93(m,1H),2.20-2.09(m,3H),2.05-1.89(m,3H).

[0375] Example 31: Preparation of Compound 425 [ka] Step 1): Compound 424-5 (50 mg, 120 μmol), (R)-4-Boc-3-aminomethylmorpholine (26 mg, 120 μmol, Rakuken), tris(dibenzylideneacetone)dipalladium (11 mg, 12.0 μmol), sodium tert-butoxide (34 mg, 360 μmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (7.0 mg, 12.0 μmol) were dissolved in dioxane at room temperature. The mixture was added to 2 mL of ethanol, stirred evenly, purged with nitrogen gas three times, heated to 80 °C, and reacted for 3 hours. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (6 mL x 3). The organic phases were combined, washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound 425-1. MS m / z (ESI): 467.3 [M-Boc+1] + ,

[0376] Step 2): Trifluoroacetic acid (1 mL) was added to a solution containing compound 425-1 (50 mg, 180 μmol) and dichloromethane (2 mL). The reaction was stirred at 25° C. for 1 hour. After concentrating the reaction under reduced pressure, compound 425-2 was obtained and used directly in the next step without purification. MS m / z (ESI): 423.4 [M+1] + ,

[0377] Step 3): Compound 425-2 (30 mg, 71 μmol), triethylamine (8.0 mg, 79 μmol), and acetic anhydride (7.0 mg, 69 μmol) were dissolved in dichloromethane (2 mL). The reaction mixture was stirred at 25° C. for 2 hours, and then mixed with dichloromethane (10 mL) and water (5 mL). The aqueous phase was separated and extracted with dichloromethane (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 425-3. MS m / z (ESI): 507.3 [M+1] + ,

[0378] Step 4): Compound 425-3 (40 mg, 79 μmol) and potassium carbonate (17 mg, 180 μmol) were dissolved in methanol (2 mL). The resulting mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was mixed with dichloromethane (10 mL) and water (5 mL). The aqueous phase was separated and extracted with dichloromethane (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient mixing ratio: 32% to 48% acetonitrile, flow rate: 25 mL / min) to obtain compound 425. MS m / z (ESI): 465.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),7.30-7.22(m,2H),7.15-7.11(m,1H),6.89-6.56(m,1H),5.37-5.30(m,1H),4.60-4.0 0(m,2H),3.89-3.81(m,2H),3.58-3.51(m,2H),3.18-2.87(m,1H),2.82-2.59(m,1H),2.13-1.97(m,8H),1.48-1.44(m,1H).

[0379] Example 32: Preparation of Compound 451 [ka] Step 1): To a solution of compound 451-1 (10.0 g, 64.8 mmol, An Niji) in methanol (220 mL) was added sodium methoxide methanol solution (12 mL, 30% methanol solution), and the mixture was stirred at 25 °C under a nitrogen atmosphere for 30 minutes. The mixture was then cooled to 0 °C, and liquid bromine (3.33 mL, 64.8 mmol) was added. The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water (100 mL), stirred, filtered, and the filter cake was collected and dried under vacuum to give compound 451-2. MS m / z (ESI): 233.0 [M+1] + ,

[0380] Step 2): To a solution of compound 451-2 (6.00 g, 25.7 mmol) in methanol (60 mL) was added Raney nickel (3.00 g), and the mixture was stirred at 25 °C under hydrogen gas (1 atm) for 3 hours. The mixture was filtered, and the filtrate was concentrated to give compound 451-3. MS m / z (ESI): 204.9 [M+1] + ,

[0381] Step 3): To a solution of compound 451-3 (1.00 g, 4.93 mmol) in ethanol (10 mL), potassium hydroxide (330 mg, 5.91 mmol) and carbon disulfide (7 mL) were added, and the mixture was stirred at 80 °C under a nitrogen atmosphere for 24 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to give compound 451-4. MS m / z (ESI): 245.0 [M+1] + ,

[0382] Step 4): At 0 °C under a nitrogen atmosphere, a solution of compound 451-4 (1.00 g, 4.08 mmol) in dichloromethane (15 mL) was added with thionyl chloride (0.90 mL, 12.4 mmol) and N,N-dimethylformamide (0.80 mL, 10.3 mmol). The mixture was stirred at 25 °C under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), water (20 mL) was added, and the organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 451-5. MS m / z (ESI): 247.0 [M+1] + ,

[0383] Step 5): Compound (R)-4-Boc-3-aminomethylmorpholine (577 mg, 2.67 mmol, Rakuken) and compound 451-5 (440 mg, 1.78 mmol) were dissolved in acetonitrile (5 mL), potassium carbonate (246 mg, 1.78 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. After the reaction mixture was added with water (30 mL), the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1 to 15 / 1) to give compound 451-6. MS m / z (ESI): 429.2 [M+1] + ,

[0384] Step 6): Compound 451-6 (430 mg, 1.01 mmol) was dissolved in dioxane (4 mL), hydrogen chloride / dioxane (4 mL, 4 M) was added, and the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give compound 451-7. MS m / z (ESI): 328.8 [M+1] + ,

[0385] Step 7): Compound 451-7 (430 mg, 1.31 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.55 mL, 3.94 mmol) was added, and the mixture was stirred at 0 °C for 10 minutes. Acetic anhydride (0.13 mL, 1.38 mmol) was added to the reaction mixture, and the mixture was allowed to react at 25 °C for 15 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the drying agent. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 451-8. MS m / z (ESI): 371.1 [M+1] + ,

[0386] Step 8: Compound 451-8 (130 mg, 0.35 mmol) and intermediate M-1 (167 mg, 0.63 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (25.7 mg, 0.035 mmol, adamas) and potassium carbonate (146 mg, 1.06 mmol) were added. The reaction was purged with nitrogen gas three times and stirred at 80 °C under a nitrogen atmosphere for 18 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, which was then extracted with dichloromethane (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give compound 451-9. MS m / z (ESI): 509.4 [M+1] + ,

[0387] Step 9): Compound 451-9 (150 mg, 0.29 mmol) was dissolved in a hydrogen chloride / dioxane solution (4 mL, 4 M). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient blend ratio: 32% to 48% acetonitrile, flow rate: 25 mL / min) to obtain compound 451. MS m / z (ESI): 465.7 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.75-8.41(m,1H),7.06(d,J=11.5Hz,2H),6.84-6.76(m,1H),4.67-4 .08(m,1H),4.07-3.69(m,3H),3.68-3.42(m,4H),3.29-2.93(m,1H),2.44-2.36(m,3H),2.11-1.93(m,6H).

[0388] Example 33: Preparation of Compound 452 [ka] Step 1: Compound 451-8 (130 mg, 0.352 mmol) and compound 253-1 (164 mg, 0.882 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (25.7 mg, 0.04 mmol, adamas) and potassium carbonate (195 mg, 1.41 mmol) were added. The reaction was purged with nitrogen gas three times and stirred at 80 °C under a nitrogen atmosphere for 18 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, which was then extracted with dichloromethane (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 46%-95%, flow rate: 25 mL / min) to obtain compound 452. MS m / z (ESI): 431.3 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ9.79-9.70(m,1H),8.72-8.36(m,1H),6.83-6.72(m,3H),4.67-4.08(m,1H),4.07-3 .68(m,3H),3.67-3.50(m,3H),3.47-3.35(m,1H),3.30-2.94(m,1H),2.43-2.36(m,3H),2.08-1.93(m,6H).

[0389] Example 34: Preparation of Compound 453 [ka] Step 1): At room temperature, a mixture of compound 444-1 and compound 444-1A (200 mg, 479 μmol) was added to (R)-4-Boc-3-aminomethylmorpholine (1.08 g, 5.0 mmol, Rakuken) and heated to 190 °C in a microwave oven for 30 minutes. After cooling to room temperature, water (15 mL) was added and extracted with dichloromethane / methanol (10 / 1, 5 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a mixture of compound 453-1 and compound 453-1A. MS m / z (ESI): 509.8 [M+1] + ,

[0390] Step 2): At room temperature, a mixture of compound 453-1 and compound 453-1A (240 mg, 434 μmol) was added to hydrogen chloride / dioxane (4 mL, 4 M) and reacted at room temperature for 1 hour. The solvent was removed under reduced pressure, and dichloromethane (15 mL), water (5 mL), and saturated sodium bicarbonate solution (5 mL) were added. The mixture was stirred, allowed to stand, and the layers were separated. The aqueous layer was extracted with dichloromethane (5 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 100 to 1 / 10) to give a mixture of compound 453-2 and compound 453-2A. MS m / z (ESI): 409.7 [M+1] + ,

[0391] Step 3): At room temperature, a mixture of compound 453-2 and compound 453-2A (150 mg, 367 μmol) was added to dichloromethane (3 mL), triethylamine (148 mg, 1.47 mmol) was added, and the mixture was stirred uniformly. Acetic anhydride (45.0 mg, 440 μmol) was slowly added, and the mixture was allowed to react at room temperature for 3 hours. The solvent was removed under reduced pressure, and dichloromethane (15 mL), water (5 mL), and aqueous sodium bicarbonate (5 mL) were added. The mixture was stirred for 5 minutes, allowed to stand, and the layers were separated. The aqueous phase was extracted with dichloromethane (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: 30% to 70% acetonitrile, flow rate: 25 mL / min) to obtain compound 453. MS m / z (ESI): 451.6 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.06-9.03(m,1H),7.35-6.98(m,4H),4.60-4.08(m,1 H),3.99-3.82(m,3H),3.61-3.38(m,4H),3.27-2.95(m,1H),2.16(s,3H),2.02-1.98(m,3H).

[0392] Example 35: Preparation of Compound 454 [ka] Step 1): Compound 454-1 (16.0 g, 40.7 mmol, prepared by the method disclosed in the intermediate of step 3 on page 94 of the specification of patent application WO2023159148A2) was dissolved in methanol (60 mL), and 10% wet palladium on carbon (500 mg) was added. The resulting mixture was stirred under a hydrogen gas (1 atm) atmosphere for 18 hours, filtered, and the filtrate was concentrated to give compound 454-2. MS m / z (ESI): 259.6 [M+1]+ ,

[0393] Step 2): Compound 439-2 (100 mg, 0.241 mmol), compound 454-2 (93 mg, 0.361 mmol), tris(dibenzylideneacetone)dipalladium (21.9 mg, 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.7 mg, 0.051 mmol), and sodium tert-butoxide (46.7 mg, 0.481 mmol, Bide) were mixed with dioxane (3 mL). The resulting mixture was heated to 100 °C under a nitrogen gas atmosphere and reacted for 2 hours, then cooled. The reaction mixture was mixed with dichloromethane (5 mL) and water (5 mL), allowed to stand, and separated. After separation, the aqueous phase was extracted with dichloromethane (5 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 454-3. MS m / z (ESI): 481.3 [M+1] + ,

[0394] Step 3): Compound 454-3 (100 mg, 0.21 mmol) was dissolved in a hydrogen chloride / dioxane solution (4 mL, 4 M), and the reaction solution was stirred at 25 °C for 2 hours for reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19*250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32% - 48%, flow rate: 25 mL / min) to obtain compound 454. MS m / z (ESI): 437.7 [M+1] + , 1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.00(d,J=9.1Hz,1H),7.42(d,J=9.1Hz,1H),7.17(s ,1H),7.11(s,1H),6.87(d,J=8.3Hz,1H),4.52-4.12(m,1H),3.81-3.72(m,1H),3.50(t,J= 6.1Hz,2H),3.03-2.95(m,1H),2.76-2.65(m,1H),2.44(t,J=6.1Hz,2H),2.16(s,3H),2.14 -2.01(m,2H),1.92-1.82(m,1H),1.75-1.66(m,1H),1.57-1.46(m,1H),1.41-1.30(m,1H).

[0395] Example 36: Preparation of Compound 455 [ka] Step 1): At room temperature, a mixture of compound 444-1 and compound 444-1A (100 mg, 240 μmol) was added to compound 454-2 (1.5 mL), heated to 190 °C in a microwave, and reacted for 1 hour. After cooling to room temperature, water (15 mL) was added, and the mixture was extracted with dichloromethane / methanol (10 / 1, 5 mL x 3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to give a mixture of compound 455-1 and compound 455-1A. MS m / z (ESI): 481.4 [M+1] + .

[0396] Step 2): At room temperature, a mixture of compound 455-1 and compound 455-1A (100 mg, 208 μmol) was added to hydrogen chloride / dioxane (2 mL, 4 M) and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (Gilson_306_1741, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 20% to 80%, flow rate: 25 mL / min) to obtain compound 455. MS m / z (ESI): 437.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ10.29(s,1H),9.05(d,J=6.7Hz,1H),7.14(s,1H),7.09(s,1H), 7.02(d,J=6.7Hz,1H),6.94(d,J=8.4Hz,1H),4.50-4.35(m,1H),3.75-3.73(m,1H),3.52- 3.49(m,2H),3.00-2.98(m,1H),2.74-2.68(m,1H),2.47-2.44(m,2H),2.16(s,3H),2.11- 2.07(m,2H),1.88-1.85(m,1H),1.72-1.68(m,1H),1.56-1.47(m,1H),1.39-1.34(m,1H).

[0397] Example 37: Preparation of Compound 456 [ka] Step 1): At room temperature, compound 424-5 (150 mg, 350 μmol), compound 454-2 (90 mg, 350 μmol), tris(dibenzylideneacetone)dipalladium (32 mg, 30.0 μmol), sodium tert-butoxide (100 mg, 1.04 mmol), and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (21 mg, 30.0 μmol) were added to dioxane (2 mL), stirred evenly, and purged with nitrogen gas three times. The resulting mixture was heated to 80 °C and reacted for 3 hours. The reaction mixture was mixed with water (20 mL) and extracted with ethyl acetate (6 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to obtain compound 456-1. MS m / z(ESI):495.3[M+H] + ,

[0398] Step 2): Compound 456-1 (20 mg, 30.0 μmol) was added to a 50 mL single-neck flask at room temperature, and hydrogen chloride / dioxane solution (2 mL, 4 M) was added and stirred. The reaction mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient blend ratio: 32% to 48% acetonitrile, flow rate: 25 mL / min) to obtain compound 456. MS m / z (ESI): 451.2 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.86 - 6.65 (m, 1H), 5.38 - 5.28 (m, 1H), 4.53 - 3.34 (m, 2H), 3.24 - 2.55 (m, 2H), 2.33 (s, 1H), 2.15 (s, 3H), 2.09 - 1.95 (m, 3H), 1.91 - 1.82 (m, 1H), 1.76 - 1.67 (m, 1H), 1.61 - 1.42 (m, 2H), 1.30 - 1.25 (m, 4H).

[0399] Example 38: Preparation of Compound 457

Chemical Structure

[0400] Step 2): A mixture of Compound 457-1 and Compound 457-1A (164 mg, 0.390 mmol) and triethylamine (0.161 mL, 1.16 mmol) were dissolved in dichloromethane (2 mL). Acetyl chloride (79.3 mg, 0.780 mmol) was slowly added dropwise to the reaction mixture at 0 °C. The reaction mixture was reacted at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a mixture of Compound 457-2 and 457-2A. MS m / z (ESI): 507.5 [M+H] + ,

[0401] Step 3: A mixture of compound 457-2 and compound 457-2A (197 mg, 0.390 mmol) was dissolved in methanol (3 mL) and water (0.3 mL), and potassium carbonate (107 mg, 0.780 mmol) was added. The reaction mixture was allowed to react at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the solvent was removed. The pH of the residue was adjusted to 7-8 with dilute hydrochloric acid (1.0 M) and extracted with dichloromethane (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: 32% to 48% acetonitrile, flow rate: 25 mL / min) to obtain a crude product. The crude product was purified by chiral separation (chromatography column: ChiralCel OX, 250 × 30 mm ID, 5 μm, mobile phase: A: carbon dioxide, B: ethanol, gradient: 35% B, flow rate: 150 mL / min) to obtain compound 457. MS m / z (ESI): 465.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6):δ10.34-10.14(m,1H),7.37-7.33(s,1H),7.12(s,1H),7.07(s,1H),6.99(s,1H),4.14 -3.97(m,2H),3.91-3.84(m,2H),3.61-3.46(m,4H),3.10-2.83(m,1H),2.66(s,3H),2.13(s,3H),2.09(s,3H).

[0402] Biological Testing 1.NLPR3 binding assay In this experiment, binding experiments were evaluated using fluorescence polarization technology detection.

[0403] The fluorescent probe used in this study was compound NP3-301 in the Journal of Molecular Biology (2021) 433, 167309, which was synthesized by ourselves with reference to the literature.

[0404] His6-Flag-TEV-NLRP3(134-1036) protein (SEQ NO. 1) was from custom expression by Kaihui Ruizhi Biotechnology (Shanghai) Co., Ltd. (ChemPartner).

[0405] Prepare 1X experimental detection buffer components: 50 mM Hepes, pH 7.4, 150 mM NaCl, 2.5 mM MgCl, 0.005% Tween-20, 1 mM TCEP, 100 µM ATP.

[0406] First, 2.5 μL of 4X compound solution was added to a black shallow 384-well plate (Greiner, 784076), the shallow well plate was sealed, and centrifuged at 1000 rpm for 1 min. Then, 2X NLPR3 protein solution (final concentration 30 nM) was added, the shallow well plate was sealed, centrifuged at 1000 rpm for 1 min, and incubated at room temperature for 60 min. Finally, 2.5 μL of 4X NP3-301 (final concentration 0.5 nM) was added, the shallow well plate was sealed, centrifuged at 1000 rpm for 1 min, and incubated at room temperature for 30 min. Fluorescence polarization values ​​were read using an Envision at λex = 485 ± 20 nm and λem = 535 ± 25 nm. Data were analyzed using GraphPad Prism 9.5.0, and the IC50 values ​​of compounds competing with NP3-301 for binding to His6-Flag-TEV-NLRP3 (134-1036) were calculated using a four-parameter logistic fit. The compounds of the present invention have good NLRP3 binding activity, and the test results of some representative compounds are shown in Table 1.

[0407] [Table 1] In Table 1, A represents IC50 ≤ 100 nM, B represents 100 nM < IC50 ≤ 500 nM, C represents 500 nM < IC50 ≤ 1000 nM, and D represents IC50 > 1000 nM.

[0408] 2. Experiment for detecting the effect of NLRP3 inhibitor on IL-1β secretion by THP-1 cells In this experiment, the PerkinElmer AlphaLISA_human_IL1β kit (AL220 C / F) was used, and the detection buffer was RPMI-1640 + 10% FBS. All of AlphaLISA Immunoassay Buffer, AlphaLISA Anti-IL1β Acceptor beads, Streptavidin (SA)-coated Donor beads, and Biotinylated Antibody Anti-IL1β were included in the kit.

[0409] The THP1 cell density was 4*10 5The cells were adjusted to cells / ml, and PMA (final concentration: 50 nM) was added. 200 μL / well of the cells were seeded into a 96-well flat-bottom plate and incubated overnight at 37°C in 5% CO2 (preferably for <16 h). The next day, the supernatant was discarded and the cells were washed twice with DPBS (200 μL / well). 198 μL / well of LPS solution (final concentration: 100 ng / ml) was added and the cells were incubated at 37°C in 5% CO2 for 3 h. 1 μL of the compound at the appropriate concentration according to the experimental MAP was added to each well and incubated at 37°C in 5% CO2 for 1 h. 1 μL of nigericin (final concentration: 10 μM) was further added to each well and the cells were incubated overnight at 5% CO2 (>18 h). On the third day, 5 μL of the supernatant was diluted 20-fold and the content of IL-Iβ in the supernatant was detected using the Human Interleukin 1 beta (IL1β) Kit. The AlphaLISA test value was read using Envision: Ex = 680 / Em = 570. GraphPad Prism 9.5.0 was used to analyze the data, and the IC50 values ​​of the compounds in IL-1β antagonism were calculated using a four-parameter logistic fit. It was found that the compounds of the present invention have good inhibitory activity against IL-1β maturation and secretion in THP-1 cells. The test results of some representative compounds of the present invention are shown in Table 2.

[0410] [Table 2] In Table 2, A represents IC50<50 nM, B represents 50 nM≦IC50<100 nM, C represents 100 nM≦IC50<500 nM, and D represents IC50≧500 nM.

[0411] 3. Liver microsome metabolic stability experiment Purpose of the study: This study examined the metabolic stability of compounds in liver microsomes from different genera and species, such as humans, rats, and mice, and tested the remaining amount of compounds after incubation with liver microsomes from different genera and species, such as humans, rats, and mice.

[0412] Experimental Method (1) Solution preparation Preparation of 500 μM solutions of the target compound and positive control: Take 5 μL of each 10 mM stock solution, add it to 95 μL of acetonitrile, and mix evenly for 30 s. Preparation of 6 mM NADPH solution: Dilute a 100 mM stock aliquot with Mg-Mg-K-Buffer.

[0413] (2) Sample preparation 2.1 Reaction mixture 2.1.1 Liver microsome solution: Take 18.75 μL of 20 mg / mL HLM, RLM, MLM, DLM, and MOLM (final concentration: 0.5 mg / ml) and place them in a 96-well plate. 2.1.2 Add 1.5 μL of a 500 μM solution of each compound to each well. 2.1.3 479.8 μL of phosphate buffer solution was taken and added to each compound well, and mixed uniformly in a shaking mixer at 1000 rpm for 10 s.

[0414] 2.2. Dispensing samples into plates 30 μL of each of the above samples was taken and dispensed into a new 96-deep well plate (NADPH-containing group n=2, 0 and 45 min, NADPH-free group (n=1)), and marked as 0, 5, 15, 30 and 45 min, respectively.

[0415] 2.3.Incubation After pre-incubating the above samples at 37°C for 5 minutes, 15 μL of 6 mM NADPH preheated at 37°C was added in order to the 45, 30, 15, and 5 minute samples to start the reaction. 15 μL of Mg-K-Buffer solution was added to the NADPH-free group, and the mixture was mixed uniformly at 1000 rpm for 10 seconds on a shaking mixer. The mixture was then incubated (the lid was closed without sealing).

[0416] 3. Sample Post-processing To the sample at 0 min, 200 μL of acetonitrile as an internal standard was added, followed by NADPH, which was then sealed and shaken for 1 min to mix evenly. The mixture was then stored at 4°C and prepared for centrifugation. After the incubation of the remaining samples was completed, add 200 μL of acetonitrile internal standard to each, seal, shake for 1 minute to mix evenly, store at 4°C, and prepare for centrifugation. After incubation, the mixture was vortexed for 1 minute to mix evenly, then centrifuged at 4000 rpm for 50 minutes. 80 μL of the supernatant was taken and placed in a 96-well plate containing 160 μL of pure water. The mixture was mixed evenly for 30 seconds and centrifuged at 4000 rpm for 5 minutes to prepare for testing.

[0417] (3) Data analysis The slope was calculated using the LN value of the compound concentration percentage and time as the coordinate axis, and the remaining amount of the compound after incubation with liver microsomes was calculated using the slope and formula. The compounds of the present invention showed good stability in liver microsomes of different genera, and the test results of representative compounds (remaining amount of test compound after 45 minutes of incubation with liver microsomes) are shown in Table 3.

[0418] [Table 3]

[0419] 4. In vitro evaluation of human liver microsomal CYP450 enzyme inhibitory activity (1) Purpose of the test In this experiment, the compound, liver microsomes, and different CYP subtype enzyme substrates were incubated in a water bath at 37°C to measure the amount of substrate metabolites produced, and the inhibitory effect of the compound of the present disclosure on CYP enzymes was evaluated based on the magnitude of IC50.

[0420] (2) Experimental method i. Dilute the compounds with DMSO (Aladdin, catalog number: D103273-500ml) to concentrations of 0, 0.02, 0.06, 0.2, 0.6, 2, and 6 mM. The positive control inhibitors and concentrations for each CYP subtype are shown in Table 4.

[0421] [Table 4]

[0422] ii. Each CYP subtype enzyme substrate solution was formulated in phosphate buffer (Sigma: V900050-500G). The CYP subtype enzyme substrates and concentrations are shown in Table 5.

[0423] [Table 5]

[0424] iii. Sample incubation: 1 μL of each compound and CYP subtype enzyme positive control inhibitor were placed in a 96-deep-well plate (A-gen:P-1.0-RD-96-S), and 169 μL of 0.05 mg / mL liver microsomes (BioIVT, IHG) in phosphate buffer (0.2 mg / mL liver microsomes were used for CYP2C19). After uniform mixing, the plate was placed in a shaking water bath (Shanghai Jinghong Experimental Equipment Co., Ltd., DK-500) at 37°C and incubated for 15 min. 10 μL of substrate (1 μL of substrate was added to CYP3A4-Testosterone) and 20 μL of 10 mM NADPH in phosphate buffer (MCE, HYF003 / CS-4998) were added, mixed uniformly, and incubated in a shaking water bath for the following times: CYP1A2: 20 min, CYP2C9: 10 min, CYP2C19: 10 min, CYP2D6: 10 min, CYP3A4-Testosterone: 10 min, CYP3A4-Midazolam: 5 min. The reaction was terminated by adding 400 μL of ice-cold acetonitrile / methanol (v / v, 1:1) containing internal standards (500 nM tolbutamide, 5 nM terfenadine). After centrifugation at 4000 rpm for 40 min at 4°C, the supernatant was collected and diluted with purified water based on the substrate metabolite response. The concentrations were then detected by UPLC-MS / MS (Sciex, Q-Trap 4500). The C18 chromatography column was a Kinetex 2.6u C18 100A (50 mm x 3 mm).

[0425] (3) Data analysis The inhibitory effect of the compound on each P450 enzyme in human liver microsomes was calculated as the percentage reduction in metabolite formation compared to the non-inhibited control (i.e., blank DMSO). The IC50 value for each P450 enzyme in human liver microsomes was calculated using Graphpad Prism software using the remaining activity and the logarithm of the inhibitor concentration, and the calculation formula is as follows: Area Ratio=Peak Area Analyte / Peak Area Internal Standard Remaining Activity(%)=Area Ratio test compound / Area Ratio vehicle × 100%

[0426] The compounds of the present disclosure had weak inhibitory effects on the enzyme activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The test results of representative compounds are shown in Table 6.

[0427] [Table 6]

[0428] 5. Evaluation of hERG ion channel inhibitory effects (1) Purpose of the test In this experiment, the inhibitory effect of compounds on the hERG ion channel was detected using a manual patch clamp electrophysiological method, and cardiac safety was evaluated based on the inhibitory rate or IC50 value at a single concentration of the compound.

[0429] (2) Experimental method The cells used in this study were a HEK293 cell line (#60187, provided by BPS, Inc.; passages P3 to P23 were used for experimental studies) transfected with hERG cDNA and stably expressing the hERG channel. Cell culture was performed in a medium containing MEM medium, 10% (v / v) inactivated fetal bovine serum, 1 mM sodium pyruvate, 500 μg of geneticin, 0.1 mM non-essential amino acids, and 100 U of penicillin-streptomycin. HEK293 hERG cells were grown in culture flasks containing the above medium and cultured in a 37°C, 5% CO2-containing incubator. They were passaged approximately three times a week, and cell confluency was maintained between 40% and 80%. 24 to 48 hours before electrophysiological experiments, HEK293 hERG cells were transferred to glass slides pretreated with 0.05 mg / ml polylysine (PDL) and 1 × 10 4The HEK293 hERG cells were plated in 48-well plates at a density of 1000 cells / well and grown under the same medium and culture conditions. The density of HEK293 hERG cells on each cover glass was sufficient to allow the majority of cells to reach their individual requirements.

[0430] The extracellular fluid components used in the hERG assay were as follows (mM): 145 NaCl, 4 KCl, 2 CaCl2, 1 mgCl2, 10 glucose, and 10 HEPES (pH adjusted to 7.40 with NaOH). The intracellular fluid components were as follows (mM): 130 KCl, 2 MgCl2, 5 EGTA, 10 HEPES, and 5 Na2ATP (pH adjusted to 7.25 with KOH).

[0431] To obtain IC50 values ​​for compounds, the compounds were tested at the following concentrations (30, 10, 3, 1, 0.3, and 0.1 μM). Prior to testing, the compounds were first diluted in a gradient dilution fashion with DMSO to stock solutions of 10, 3, 1, 0.3, and 0.1 mM, and then further diluted with extracellular solution to the final μM test concentrations. The final DMSO concentration in each compound solution was between 0.1% and 0.3%. All compound solutions were typically sonicated for 5 to 10 minutes and thoroughly shaken to ensure complete dissolution of the compounds. All test solutions were rotated for at least 10 minutes to ensure uniform mixing.

[0432] For electrophysiological testing, whole-cell currents were recorded using a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany). The specific test method was as follows: A circular glass slide on which HEK293 cells stably expressing hERG channels were grown was placed in an electrophysiological recording chamber under an inverted microscope. The recording chamber was continuously perfused with extracellular solution (approximately 1 milliliter per minute). The experimental procedure employed standard whole-cell patch clamp current recording techniques. Unless otherwise specified, experiments were performed at room temperature (~25°C). The cells were voltage clamped at -80 mV. The cell clamp voltage was depolarized to +30 mV to activate the hERG potassium channel, and after 5 seconds, it was further clamped to -50 mV to eliminate inactivation and generate a tail current. The peak value of the tail current was used as the hERG current magnitude. After the hERG current recorded in the above step has reached a stable state by continuing the extracellular solution perfusion in the recording chamber, different concentrations of the test compound can be perfused until the drug's hERG current inhibitory effect reaches a stable state.

[0433] (3) Data analysis The inhibitory rate of the compound at each concentration against the hERG ion channel was calculated using Excel software. Graphpad Prism 9.0 software was used to plot the dose-response curve of the test compound, with the % hERG inhibition rate on the vertical axis and the concentration of the test compound on the horizontal axis. Curve fitting was performed using log (inhibitor) vs. response—variable slope (four parameters) parameters to calculate IC50, with the specific parameters of the equation being as follows: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)). The compounds of the present disclosure have low inhibitory effect on the hERG ion channel. The test results of some representative compounds are shown in Table 7 below.

[0434] [Table 7]

[0435] 6. Mouse Pharmacokinetic Evaluation of Compounds Objective of the experiment: ICR male mice were selected as test animals, and the LC-MS / MS method was used to quantitatively measure the plasma drug concentrations at different time points in mice after intravenous injection or oral gavage of the test compound, thereby evaluating the pharmacokinetic characteristics of the test drug in the mouse body.

[0436] Test materials: ICR mice (male, 15–35 g, 5–10 weeks old, Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.)

[0437] Testing Procedure A: A clear solution of the test compound was injected into the tail vein of ICR mice (unfasted, vehicle: 5% DMSO / 10% Solutol / 85% Saline) and then orally administered by force to ICR mice (fasted for 10-14 hours). For intravenous administration, blood samples were collected from the submandibular venous plexus at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed uniformly, and centrifuged at 6,800 g for 6 minutes at 2-8°C to obtain plasma. For oral gavage, blood samples were collected from the submandibular venous plexus at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed uniformly, and centrifuged at 6,800 g for 6 minutes at 2-8°C to obtain plasma. Blood concentrations were measured by LC-MS / MS, and relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin™ Version 7.0 (Pharsight, USA) pharmacokinetic software with the linear-logarithmic trapezoidal method based on a non-compartmental model. The compounds of the present disclosure have good pharmacokinetic characteristics in mice, and the test results of representative compounds are shown in Table 8.

[0438] [Table 8]

[0439] 7. Rat Pharmacokinetic Evaluation of Compounds Objective of the experiment: Male SD rats were selected as test animals, and the LC-MS / MS method was used to quantitatively measure the plasma drug concentrations at different time points after intravenous injection or oral gavage of the test compound in the rats, thereby evaluating the pharmacokinetic characteristics of the test drug in the rat body.

[0440] Test materials: SD rats (male, 160-300 g, 5-10 weeks old, Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.)

[0441] Testing Procedure A: A clear solution of the test compound was injected into the tail vein of SD rats (unfasted) (vehicle: 5% DMSO / 10% solutol / 85% saline) and orally administered to SD rats (fasted for 10-14 hours, with free access to water) (vehicle: 5% DMSO / 10% solutol / 85% saline) by force. For intravenous administration, blood was collected from the jugular vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed uniformly, and centrifuged at 6,800 g for 6 minutes at 2-8°C to obtain plasma. For oral gavage, blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed uniformly, and centrifuged at 6,800 g for 6 minutes at 2-8°C to obtain plasma. Blood concentration was measured by LC-MS / MS method, and related pharmacokinetic parameters were calculated by the linear-logarithmic trapezoidal method based on a non-compartmental model using Phoenix WinNonlin™ Version 7.0 (Pharsight, USA) pharmacokinetic software. The compounds of the present disclosure have good pharmacokinetic characteristics in rats, and the test results of representative compounds are shown in Table 9.

[0442] [Table 9]

[0443] 8. Study on the efficacy of compounds on iodoacetic acid-induced osteoarthritis in SD rat knees Objective of the experiment: The efficacy of MCC950 (a positive control compound) and Compound 111 of the present invention was evaluated in an iodoacetic acid (MIA)-induced knee osteoarthritis model in SD rats.

[0444] Test materials: Experimental SD rat, male, 4 weeks old.

[0445] Experimental Method: Model induction began after the experimental animals were acclimated to the animal environment for 7 days. On Day 0, rats were anesthetized, the hair around the left knee joint was removed, and the skin was disinfected. The left leg was flexed 90° to expose the patellar plateau. The central depression of the plateau was touched to locate the femoral condyle, patella, and ligament. An injection needle was inserted below the patella on both sides of the patellar ligament toward the femoral condyle. When a clear sensation of air was felt, 50 μL of iodoacetic acid solution was injected. On Day 7, rats were divided into groups based on the width of the knee joint on the induced side. The groups were a normal control group (healthy controls not subjected to model generation, 5% DMSO + 10% solutol + 85% saline), a model blank control group (5% DMSO + 10% solutol + 85% saline), MCC950 30 mg / kg, and Compound 111 of the present invention 30 mg / kg. From Day 7, the normal control group and the model blank control group were orally administered with the vehicle (5% DMSO + 10% Solutol + 85% Saline) once daily, while the other groups were orally administered with the corresponding compound once daily, continuing until the end of administration on Day 42. The rats' knee joint width and body weight were measured on Days 7, 14, 21, 28, 35, and 42.

[0446] Testing Conclusion: The efficacy of MCC950 (positive control compound) and Compound 111 of the present invention in an iodoacetic acid (MIA)-induced SD rat knee osteoarthritis model tested in this experiment is shown in Figures 1 and 2. The results of once-daily oral administration of the compounds showed that, compared to the blank control group, both MCC950 (positive control compound) and Compound 111 of the present invention were able to significantly inhibit the enlargement of the knee joint in the knee osteoarthritis model rats from day 21 to day 42 after model creation without affecting the rat body weight.

[0447] The technical solution of the present invention is not limited to the specific embodiments described above, and all technical modifications made based on the technical solution of the present invention are within the protection scope of the present invention.

Claims

1. A compound of formula I or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, 【Chemistry 1-1】 where: 【Chemistry 2-1】 is connected to ring A, 【Chemistry 3-1】 is connected to ring B, Ring A and ring B are each independently selected from a 5- to 6-membered heteroaryl group, a 5- to 6-membered heterocyclic group, and a phenyl group; Ring C is selected from a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a phenyl-fused 4- to 7-membered cycloalkyl group, a phenyl-fused 4- to 7-membered heterocyclic group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered heterocyclic group, a 4- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; Each R ｃ are independently hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, hydroxy C １－６ Alkyl group, C １－６ Alkoxy-C １－６ Alkyl group, R ｃ１ S (O) ２ -, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be selected from the group consisting of deuterium, halogen, hydroxyl group, amino group, cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R ｃ can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Each R ａ and R ｂ are independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, oxo, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, C １－６ Haloalkoxy group, hydroxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), -C(=O)-(C １－６ alkyl), a 3- to 6-membered heterocyclic group optionally substituted with a hydroxy group; L １ is a linking group, C ３－６ cycloalkylene group, -NR ２ -, -O-, -S-, -C(=O)-, -(CR ３ R ４ ), ａ -NR ２ -(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -NR ２ -, -O-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -O-, -S-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -S-, -C(=O)-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -C(=O)-, -(CR ３ R ４ ), ａ -(CR ９ =CR １０ ), -(CR ９ =CR １０ )-(CR ３ R ４ ), ａ -, -C(=O)-O-, -O-C(=O)-, -C(=O)-NR ２ -, -(CR ３ R ４ ), ａ -C(=O)-NR ２ -, -NR ２ -C(=O)-, -(CR ３ R ４ ), ａ -NR ２ -C(=O)-, -S(=O) ２ -NR ２ -, -NR ２ -S(=O) ２ -, -NR ２ - (CR ３ R ４ ) ａ -C(=O)-, -C(=O)-(CR ３ R ４ ) ａ -NR ２ -, -NR ２ - (CR ３ R ４ ) ａ —C(═O)—NR ５ -, -NR ２ -C(=O)-(CR ３ R ４ ) ａ -NR ５ -, -C(=S)-NR ２ -, -NR ２ -C(=S)-; L ２ is a bond, -NR ６ -, -O-, -S-, -NR ６ - (CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -NR ６ -, -O-(CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -O-, -S-(CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -S-; Each R ２ , R ５ , R ６ , R ９ and R １０ are each independently hydrogen, deuterium, or C １－６ alkyl groups, Each R ３ , R ４ , R ７ and R ８ are each independently hydrogen, deuterium, halogen, oxo, a hydroxy group, an amino group, C １－６ alkyl groups, R １ represents hydrogen, a hydroxy group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ alkyl-O—C(═O)—, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ The alkyl-O—C(═O)—, 3- to 10-membered cycloalkyl group, 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered bicyclic heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered heteroaryl group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -CH ２ -C(=O)O-R ｃ４ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -CH ２ -C(=O)-N(R ｃ４ ) (R ｃ４ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ , -CR ｃ７ R ｃ８ -CN, -(CH ２ ) ｓ -R ｃ９ is further substituted with 1, 2, or 3 substituents selected from Each R ｃ１ and R ｃ２ are independently hydrogen, C １－６ Alkyl group, C １－６ Haloalkoxy group, C ３－６ selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group; R ｃ３ is hydrogen, deuterium, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group and C ３－６ The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), R ｃ４ is hydrogen, deuterium, C １－６ alkyl groups, R ｃ５ and R ｃ６ is hydrogen, deuterium, C １－６ Alkyl group, C ３－６ cycloalkyl groups, or R ｃ５ and R ｃ６ form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, １－６ Alkyl group, C ３－６ The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally be substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), R ｃ７ and R ｃ８ is hydrogen, deuterium, C １－６ alkyl group, or R ｃ７ and R ｃ８ form a 3- to 6-membered cycloalkyl group together with the C atom to which they are attached, R ｃ９ is selected from a 3- to 6-membered heterocyclic group, said heterocyclic group optionally containing hydrogen, deuterium, C １－６ substituted with one, two or three alkyl groups; R １１ is hydrogen, deuterium, C １－６ selected from alkyl groups, 3- to 6-membered monocyclic heterocyclic groups; each a and b is independently 1, 2, 3, or 4; each s, n, m, and p is independently selected from 0, 1, 2, 3, or 4; As a condition, 【Chemistry 4-1】 is hydrogen, C １－６ A compound of Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated compounds), or prodrugs thereof, which is not an alkyl group.

2. Groups relating to ring A and ring B 【Chemistry 5-1】 teeth, 【Chemistry 6-1】 is selected from the group Each M １ , M ２ , M ３ , M ４ , U １ , U ２ are each independently selected from CH and N; Each U ３ , U ４ , U ５ , U ６ are each independently CH ２ , NH, O, S.

3. Groups relating to ring A and ring B 【Chemistry 7-1】 teeth, 【Chemistry 8-1】 is selected from the group Each M １ , M ２ , M ３ , M ４ , U １ , U ２ are each independently selected from CH and N; Each U ３ , U ４ , U ５ , U ６ are each independently CH ２ , NH, O, S.

4. Groups relating to ring A and ring B 【Chemistry 9-1】 teeth, 【Chemistry 10-1】 【Chemistry 11-1】 【Chemistry 12-1】 is selected from the group Each M １ , M ２ , M ３ , M ４ , M ５ , M ６ , U １ , U ２ are each independently selected from CH and N; Each U ３ , U ４ , U ５ , U ６ are each independently CH ２ , NH, O, S.

5. The compounds have the structure shown in Formula VIII-3 or VIII-4: 【Chemistry 13-1】 Here, R １ represents a hydroxy group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ alkyl-O—C(═O)—, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ The alkyl-O—C(═O)—, 3- to 10-membered cycloalkyl group, 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered bicyclic heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered heteroaryl group, —CR ｃ７ R ｃ８ -CN, -(CH ２ ) ｓ -R ｃ９ and R ｃｎ is R in claim 1 ｃ as defined in The conditions are to simultaneously satisfy the following 1) to 45), １） 【Chemistry 14-1】 but 【Chemistry 15-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 16-1】 It is not based on ２） 【Chemistry 17-1】 but 【Chemistry 18-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ -NH-CH ２ - and at the same time, R １ but, 【Chemistry 19-1】 It is not based on ３） 【Chemistry 20-1】 but 【Chemistry 21-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is a bond and at the same time, R １ but, 【Chemistry 22-1】 It is not based on ４） 【Chemistry 23-1】 but 【Chemistry 24-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 25-1】 It is not based on ５） 【Chemistry 26-1】 but 【Chemistry 27-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is a bond and at the same time, R １ but, 【Chemistry 28-1】 It is not based on ６） 【Chemistry 29-1】 but 【Chemistry 30-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ -NH-CH ２ - and at the same time, R １ but, 【Chemistry 31-1】 It is not based on ７） 【Chemistry 32-1】 but 【Chemistry 33-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ Ga-CH ２ - and at the same time, R １ but, 【Chemistry 34-1】 It is not based on ８） 【Chemistry 35-1】 but 【Chemistry 36-1】 and L ２ is the bond, 【Chemistry 37-1】 but 【Chemistry 38-1】 and L １ is -NH- and at the same time, R １ but, 【Chemistry 39-1】 It is not based on ９） 【Chemistry 40-1】 but 【Chemistry 41-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 42-1】 It is not based on １０） 【Chemistry 43-1】 but 【Chemistry 44-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 45-1】 It is not based on １１） 【Chemistry 46-1】 but 【Chemistry 47-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 48-1】 It is not based on １２） 【Chemistry 49-1】 but 【Chemistry 50-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 51-1】 It is not based on １３） 【Chemistry 52-1】 but 【Chemistry 53-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 54-1】 It is not based on １４） 【Chemistry 55-1】 but 【Chemistry 56-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 57-1】 It is not based on １５） 【Chemistry 58-1】 but 【Chemistry 59-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 60-1】 It is not based on １６） 【Chemistry 61-1】 but 【Chemistry 62-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 63-1】 It is not based on １７） 【Chemistry 64-1】 but 【Chemistry 65-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 66-1】 It is not based on １８） 【Chemistry 67-1】 but 【Chemistry 68-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 69-1】 It is not based on １９） 【Chemistry 70-1】 but 【Chemistry 71-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 72-1】 It is not based on ２０） 【Chemistry 73-1】 but 【Chemistry 74-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 75-1】 It is not based on ２１） 【Chemistry 76-1】 but 【Chemistry 77-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 78-1】 It is not based on ２２） 【Chemistry 79-1】 but 【Chemistry 80-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 81-1】 It is not based on ２３） 【Chemistry 82-1】 but 【Chemistry 83-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 84-1】 It is not based on ２４） 【Chemistry 85-1】 but 【Chemistry 86-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 87-1】 It is not based on ２５） 【Chemistry 88-1】 but 【Chemistry 89-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 90-1】 It is not based on ２６） 【Chemistry 91-1】 but 【Chemistry 92-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 93-1】 It is not based on ２７） 【Chemistry 94-1】 but 【Chemistry 95-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 96-1】 It is not based on ２８） 【Chemistry 97-1】 but 【Chemistry 98-1】 and L ２ is the bond, 【Chemistry 99-1】 but 【Chemistry 100-1】 and L １ is -NH- and at the same time, R １ but, 【Chemistry 101-1】 It is not based on ２９） 【Chemistry 102-1】 but 【Chemistry 103-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 104-1】 It is not based on ３０） 【Chemistry 105-1】 but 【Chemistry 106-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 107-1】 It is not based on ３１） 【Chemistry 108-1】 but 【Chemistry 109-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemical 110-1】 It is not based on ３２） 【Chemistry 111-1】 but 【Chemistry 112-1】 and 【Chemistry 113-1】 but 【Chemistry 114-1】 and L １ is -NH- and at the same time, R １ but, 【Chemical Engineering 115-1】 It is not based on ３３） 【Chemistry 116-1】 but 【Chemistry 117-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 118-1】 It is not based on ３４） 【Chemistry 119-1】 but 【Chemical 120-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 121-1】 It is not based on ３５） 【Chemistry 122-1】 but 【Chemistry 123-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 124-1】 It is not based on ３６） 【Chemistry 125-1】 but 【Chemistry 126-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 127-1】 It is not based on ３７） 【Chemistry 128-1】 but 【Chemistry 129-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 130-1】 It is not based on ３８） 【Chemistry 131-1】 but 【Chemistry 132-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 133-1】 It is not based on ３９） 【Chemistry 134-1】 but 【Chemistry 135-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is -NH- and at the same time, R １ but, 【Chemistry 136-1】 It is not based on ４０） 【Chemistry 137-1】 but 【Chemistry 138-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is a bond and at the same time, R １ but, 【Chemistry 139-1】 It is not based on ４１） 【Chemistry 140-1】 but 【Chemistry 141-1】 and L ２ is the bond, 【Chemistry 142-1】 but 【Chemistry 143-1】 and L １ is a bond and at the same time, R １ but, 【Chemistry 144-1】 It is not based on ４２） 【Chemistry 145-1】 but 【Chemistry 146-1】 and L ２ is a bond, and L １ is —NH—, and R １ but 【Chemistry 147-1】 At the same time, 【Chemistry 148-1】 but, 【Chemistry 149-1】 It is not based on ４３） 【Chemical 150-1】 but 【Chemistry 151-1】 and L ２ is a bond, and L １ is —NH—, and R １ but 【Chemistry 152-1】 At the same time, 【Chemistry 153-1】 but, 【Chemistry 154-1】 It is not based on ４４） 【Chemistry 155-1】 but 【Chemistry 156-1】 and L ２ is a bond, m=p=0 or R ａ =R ｂ = H, and L １ is a bond and at the same time, R １ but, 【Chemistry 157-1】 It is not based on ４５） 【Chemistry 158-1】 The compound of any one of claims 1 to 4, which is not

6. Groups relating to ring A and ring B 【Chemistry 159-1】 is selected from the group 【Chemistry 160-1】 represents rings A and B from left to right, or rings A and B from right to left; Here, R ａｂ are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl; 2. The compound of claim 1, wherein each k is independently selected from 0, 1, 2, 3, or 4.

7. Groups relating to ring A and ring B 【Chemistry 161-1】 is selected from the group 【Chemistry 162-1】 represents rings A and B from left to right, or rings A and B from right to left; Here, R ａｂ are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl; 2. The compound of claim 1, wherein each k is independently selected from 0, 1, 2, 3, or 4.

8. Groups relating to ring A and ring B 【Chemistry 163-1】 is selected from the group 【Chemistry 164-1】 The compound of claim 1 , wherein the bicyclic group: represents ring A and ring B from left to right, or represents ring A and ring B from right to left.

9. Groups relating to ring A and ring B 【Chemistry 165-1】 is selected from the group 【Chemistry 166-1】 The compound of claim 1 , wherein the bicyclic group: represents ring A and ring B from left to right, or represents ring A and ring B from right to left.

10. The compound according to any one of claims 1 to 9, wherein Ring C is selected from a 6- to 10-membered aryl group, a 5- to 6-membered heteroaryl group, a phenyl-fused 5- to 6-membered heteroaryl group, a phenyl-fused 4- to 6-membered cycloalkyl group, a phenyl-fused 4- to 6-membered heterocyclic group, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-fused 4- to 6-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 4- to 6-membered heterocyclic group, a 5- to 6-membered cycloalkyl group, and a 5- to 6-membered heterocyclic group.

11. The compound according to any one of claims 1 to 10, wherein Ring C is selected from a 6- to 10-membered aryl group, a 5- to 6-membered heteroaryl group, a phenyl-fused 5- to 6-membered heteroaryl group, a phenyl-fused 4- to 6-membered cycloalkyl group, a phenyl-fused 4- to 6-membered heterocyclic group, a nitrogen-containing 6-membered heteroaryl-fused 5- to 6-membered heteroaryl group, a nitrogen-containing 6-membered heteroaryl-fused 4- to 6-membered cycloalkyl group, a nitrogen-containing 6-membered heteroaryl-fused 4- to 6-membered heterocyclic group, a 5- to 6-membered cycloalkyl group, and a 5- to 6-membered heterocyclic group.

12. Groups related to ring C 【Chemistry 167-1】 teeth, 【Chemistry 168-1】 is selected from the group wherein rings C1 and C2 are each independently selected from a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, and a 6-membered cycloalkyl group; preferably, rings C1 and C2 are each independently selected from a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, a 2,3-dihydrofuranyl group, a 2,3-dihydrothienyl group, a 2,3-dihydropyrrolyl group, a 2,3-dihydrodioxinyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; E １ , E ２ , E ３ , E ４ and E ５ are each independently CH ２ , O, S, NH, and the condition is １ , E ２ , E ３ , E ４ and E ５ The compound according to any one of claims 1 to 11, wherein at least one of is NH and together form a stable ring.

13. Groups related to ring C 【Chemistry 169-1】 teeth, 【Chemistry 170-1】 The compound according to any one of claims 1 to 12, selected from the group:

14. Groups related to ring C 【Chemistry 171-1】 teeth, 【Chemistry 172-1】 【Chemistry 173-1】 The compound according to any one of claims 1 to 13, selected from the group:

15. Each R ａ and R ｂ are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, an oxo group, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an n-propyl group, an isopropyl group, a dimethylamino group, and an acetyl group.

16. Each R ｃ are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C １－４ Alkoxy group, C １－４ Haloalkoxy group, C １－４ Alkyl group, C １－４ Haloalkyl group, hydroxy C １－４ Alkyl group, C １－４ Alkoxy-C １－２ Alkyl group, R ｃ１ S (O) ２ -, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and the phenyl group may optionally be selected from the group consisting of deuterium, halogen, hydroxyl group, amino group, cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R ｃ can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Optionally, each R ｃ are independently fluorine, chlorine, bromine, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, cyclohexenyl, oxetanyl, phenyl, 4-chloro-phenyl, 2-chloro-4-fluoro-phenyl, 4-hydroxyphenyl, 4-methyl-phenyl, 4-fluoro-phenyl, pyridyl, cyclobutylamino, 【Chemistry 174-1】 methylsulfonyl group, or two R ｃ and form, together with the C atom to which they are linked, a cyclopentenyl group, a 2,3-dihydrofuranyl group, a cyclobutenyl group, a thienyl group, a 1,4-dioxanyl group, a pyridyl group, a cyclopenta-1,3-dienyl group, a phenyl group, or a dioxinyl group.

17. Each R ２ , R ５ and R ６ are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, and an isopropyl group; Each R ３ , R ４ , R ７ and R ８ are each independently selected from hydrogen, deuterium, oxo, hydroxy, amino, methyl, ethyl, propyl, and isopropyl; The compound of any one of claims 1 to 16, wherein each a and b is independently 1 or 2.

18. L １ is a bond, -NR ２ -, -O-, -S-, -C(=O)-, -NR ２ - (CR ３ R ４ ) ａ -, - (CR ３ R ４ ) ａ -NR ２ -, -O-(CR ３ R ４ ) ａ -, - (CR ３ R ４ ) ａ -O-, -S-(CR ３ R ４ ) ａ -, - (CR ３ R ４ ) ａ -S-, where a is 1 or 2; L ２ is a bond, -NR ６ -, -NR ６ - (CR ７ R ８ ) ｂ The compound according to any one of claims 1 to 17, wherein the group is selected from -, -O-, and -S-.

19. 19. The compound of any one of claims 1 to 18, wherein each s, n, m and p is independently selected from 0, 1, 2 or 3.

20. R １ represents hydrogen, a hydroxy group, an amino group, a carboxyl group, C １－４ Alkyl group, C １－４ Alkoxy group, NHR １１ -C(=O)-, C １－４ Alkyl-C(=O)-O-, C １－４ alkyl-O—C(═O)—, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered spiro bicyclic heterocyclic group, a 6- to 11-membered bridged bicyclic heterocyclic group, a 6- to 11-membered fused bicyclic heterocyclic group, a phenyl group, a naphthyl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C １－４ Alkyl group, C １－４ Alkoxy group, NHR １１ -C(=O)-, C １－４ Alkyl-C(=O)-O-, C １－４ The alkyl-O—C(═O)—, 3- to 6-membered cycloalkyl group, 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered spiro bicyclic heterocyclic group, 6- to 11-membered bridged bicyclic heterocyclic group, 6- to 11-membered fused bicyclic heterocyclic group, phenyl group, naphthyl group, and 5- to 10-membered heteroaryl group each independently optionally represent hydrogen, deuterium, halogen, hydroxy group, amino group, oxo, C １－４ Alkyl group, hydroxy C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Alkoxy group, C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -CH ２ -C(=O)O-R ｃ４ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -CH ２ -C(=O)-N(R ｃ４ ) (R ｃ４ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ , -CR ｃ７ R ｃ８ -CN, -(CH ２ ) ｓ -R ｃ９ is further substituted with 1, 2, 3 substituents selected from R １１ is hydrogen, deuterium, C １－４ The compound according to any one of claims 1 to 4 and 6 to 19, wherein the alkyl group is selected from the group consisting of an alkyl group and a 3- to 6-membered monocyclic heterocyclic group.

21. R １ represents hydrogen, a hydroxy group, an amino group, a carboxyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, NH ２ -C(=O)-, CH ３ NH-C(=O)-, CH ３ CH ２ NH-C(=O)-, CH ３ -C(=O)-O-, CH ３ CH ２ -C(=O)-O-, CH ３ -OC(=O)-, CH ３ CH ２ -O-C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, tetrahydro-2H-pyranyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, quinolyl, isoquinolyl, or 【Chemistry 175-1】 is selected from the group Here, the methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, NH ２ -C(=O)-, CH ３ NH-C(=O)-, CH ３ CH ２ NH-C(=O)-, CH ３ -C(=O)-O-, CH ３ CH ２ -C(=O)-O-, CH ３ -OC(=O)-, CH ３ CH ２ —O—C(═O)—, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a 1,4-dioxanyl group, a tetrahydro-2H-pyranyl group, a phenyl group, a naphthyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a triazolyl group, a quinolyl group, an isoquinolyl group, 【Chemistry 176-1】 are each independently any of hydrogen, deuterium, halogen, a hydroxy group, an amino group, oxo, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ , -CR ｃ７ R ｃ８ The compound of any one of claims 1 to 4, 6 to 20, further substituted with 1, 2, or 3 substituents selected from -CN.

22. R １ is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, or a 6- to 11-membered bicyclic heterocyclic group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is selected from the group consisting of -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ６ R ｃ５ , -P(=O)R ｃ５ R ｃ６ and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, a hydroxy group, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－４ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; R ｃ３ is C １－６ Alkyl group, C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group and C ３－６ The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), R ｃ５ and R ｃ６ is H, deuterium, C １－６ Alkyl group, C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group and C ３－６ The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ 20. The compound of any one of claims 1 to 19, further substituted with 1 to 3 substituents selected from: alkyl;

23. R １ represents a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 177-1】 a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 178-1】 is -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ５ R ｃ６ , -P(=O)R ｃ５ R ｃ６ and wherein the cyclopentane group, the cyclohexane group, the azetidinyl group, the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, the piperazinyl group, 【Chemistry 179-1】 is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－４ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; Preferably, R １ represents a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 180-1】 a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 181-1】 is -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ５ R ｃ６ , -P(=O)R ｃ５ R ｃ６ and wherein the tetrahydropyrrolyl group, piperidinyl group, morpholinyl group, piperazinyl group, 【Chemistry 182-1】 is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ Cycloalkyl group, C １－６ Alkoxy-C １－４ further substituted with 1, 2, or 3 substituents selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group; More preferably, R １ is selected from a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, or a piperazinyl group, and the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, or the piperazinyl group is selected from a —C(═O)—R ｃ３ , -S(=O) ２ -R ｃ３ , -P(=O)R ｃ５ R ｃ６ and the tetrahydropyrrolyl, piperidinyl, morpholinyl or piperazinyl group is optionally substituted with one substituent selected from deuterium, halogen, hydroxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－４ The compound of any one of claims 1 to 19, further substituted with one or two substituents selected from alkyl groups.

24. R １ teeth, 【Chemistry 183-1】 The compound according to any one of claims 1 to 19, selected from:

25. The compound has the structure shown in Formula II: 【Chemistry 184-1】 The compound according to any one of claims 1 to 4 and 6 to 24.

26. The compound has the structure shown in Formula III: 【Chemistry 185-1】 The compound according to any one of claims 1 to 4 and 6 to 25.

27. The compounds have the structure shown in formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or IV-10: 【Chemistry 186-1】 The compound according to any one of claims 1 to 4 and 6 to 26.

28. The compounds have the structure shown in Formula V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, V-9, or V-10: 【Chemistry 187-1】 The compound according to any one of claims 1 to 4 and 6 to 27.

29. The compounds have the structure shown in formula VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7 VI-8, VI-9, or VI-10: 【Chemistry 188-1】 Here, n １ The compound according to any one of claims 1 to 4 and 6 to 28, wherein is 0, 1, 2 or 3.

30. The compounds have the structure shown in Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VII-9, or VII-10: 【Chemistry 189-1】 Here, n ２ The compound according to any one of claims 1 to 4 and 6 to 29, wherein is 0, 1 or 2.

31. The compounds have the structure shown in Formula VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, VIII-9, VIII-10, VIII-11, or VIII-12: 【Chemistry 190-1】 The compound according to any one of claims 1 to 4 and 6 to 30.

32. The compounds have the structure shown in formula IX-1, IX-2, IX-3, IX-4, IX-5, or IX-6: 【Chemistry 191-1】 The compound according to any one of claims 1 to 4 and 6 to 31.

33. A compound shown in formula VIII-1 or VIII-2, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug thereof, 【Chemistry 192-1】 Each R ｃｎ are independently hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, hydroxy C １－６ Alkyl group, C １－６ Alkoxy-C １－６ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be selected from the group consisting of deuterium, halogen, hydroxyl group, amino group, cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ alkoxy groups, or two R ｃｎ can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Each R ａ and R ｂ are independently hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, C １－６ Haloalkoxy group, hydroxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), -C(=O)-(C １－６ alkyl), a 3- to 6-membered heterocyclic group optionally substituted with a hydroxy group; L １ is a bond, C ３－６ cycloalkylene group, -NR ２ -, -O-, -S-, -C(=O)-, -(CR ３ R ４ ), ａ -, -NR ２ -(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -NR ２ -, -O-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -O-, -S-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -S-, -C(=O)-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -C(=O)-, -(CR ３ R ４ ), ａ -(CR ９ =CR １０ ), -(CR ９ =CR １０ )-(CR ３ R ４ ), ａ -, -C(=O)-O-, -O-C(=O)-, -C(=O)-NR ２ -, -(CR ３ R ４ ), ａ -C(=O)-NR ２ -, -NR ２ -C(=O)-, -(CR ３ R ４ ), ａ -NR ２ -C(=O)-, -S(=O) ２ -NR ２ -, -NR ２ -S(=O) ２ -, -NR ２ - (CR ３ R ４ ) ａ -C(=O)-, -C(=O)-(CR ３ R ４ ) ａ -NR ２ -, -NR ２ - (CR ３ R ４ ) ａ —C(═O)—NR ５ -, -NR ２ -C(=O)-(CR ３ R ４ ) ａ -NR ５ -, -C(=S)-NR ２ -, -NR ２ -C(=S)-; L ２ is a bond, -NR ６ -, -O-, -S-, -NR ６ - (CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -NR ６ -, -O-(CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -O-, -S-(CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -S-; Each R ２ , R ５ , R ６ , R ９ and R １０ are each independently hydrogen, deuterium, or C １－６ alkyl groups, Each R ３ , R ４ , R ７ and R ８ are each independently hydrogen, deuterium, halogen, oxo, a hydroxy group, an amino group, C １－６ alkyl groups, R １ represents hydrogen, a hydroxy group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ alkyl-O—C(═O)—, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein the amino group, C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ The alkyl-O—C(═O)—, 3- to 10-membered cycloalkyl group, 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered bicyclic heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered heteroaryl group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -C(O)-N(R ｃ６ ) (R ｃ５ ), -CH ２ -C(=O)-N(R ｃ４ ) (R ｃ４ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ and further substituted with 1, 2, or 3 substituents selected from Each R ｃ１ and R ｃ２ are independently hydrogen, C １－６ Alkyl group, C １－６ Haloalkoxy group, C ３－６ selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group; R ｃ３ is hydrogen, deuterium, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ cycloalkyl groups, wherein said C ３－６ The cycloalkyl group may optionally contain deuterium, a hydroxy group, a halogen, C １－６ further substituted with 1 to 3 substituents selected from alkyl groups; R ｃ４ is hydrogen, deuterium, C １－６ alkyl groups, R ｃ５ and R ｃ６ is hydrogen, deuterium, C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ cycloalkyl groups, or R ｃ５ and R ｃ６ form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, ３－６ The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally contain deuterium, a hydroxy group, a halogen, C １－６ further substituted with 1 to 3 substituents selected from alkyl groups; R １１ is hydrogen, deuterium, C １－６ selected from alkyl groups, 3- to 6-membered monocyclic heterocyclic groups; each a and b is independently 1, 2, 3, or 4; each m is 0 or 1; each p is 0, 1, or 2; each s and n is independently selected from 0, 1, 2, 3, or 4; The conditions are to simultaneously satisfy the following 1) and 2) １） 【Chemistry 193-1】 is H, methyl group, ethyl group, CHF ２ , not Boc, ２） 【Chemistry 194-1】 【Chemistry 195-1】 or a compound shown in Formula VIII-1 or VIII-2, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug thereof, which is not

34. The compound has the structure shown in Formula VIII-1: 【Chemistry 196-1】 34. The compound of claim 33.

35. L ２ 35. The compound of claim 33 or 34, wherein is a bond.

36. R ａ and R ｂ are each independently selected from hydrogen, deuterium, F, Cl, Br, a cyano group, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a dimethylamino group, and an acetyl group, and preferably, R ａ and R ｂ are each independently selected from hydrogen, deuterium, F, Cl, Br, a methyl group, and an ethyl group, and more preferably, R ａ and R ｂ are each independently selected from hydrogen, deuterium, and a methyl group.

37. Each R ｃｎ are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C １－４ Alkoxy group, C １－４ Haloalkoxy group, C １－４ Alkyl group, C １－４ Haloalkyl group, hydroxy C １－４ Alkyl group, C １－４ Alkoxy-C １－２ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, and a phenyl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, and the phenyl group may optionally be selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ alkoxy groups, or two R ｃｎ can form, together with the C atom to which they are attached, a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group or a 5- to 6-membered heteroaryl group, Preferably, each R ｃｎ are independently fluorine, chlorine, bromine, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, phenyl, 4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-hydroxyphenyl, cyclobutylamino, 【Chemistry 197-1】 or two R ｃｎ form together with the C atom to which they are attached a cyclopentyl or tetrahydrofuranyl group, More preferably, each R ｃｎ are independently selected from fluorine, chlorine, bromine, a hydroxy group, a methoxy group, an ethoxy group, a methyl group, an ethyl group, a trifluoromethyl group, a difluoromethyl group, a trifluoromethoxy group, and a difluoromethoxy group. 【Request Item 38】 【Chemistry 198-1】 teeth, 【Chemistry 199-1】 is selected from Preferably, wherein: 【Chemistry 200-1】 teeth, 【Chemistry 201-1】 38. The compound according to any one of claims 33 to 37, selected from:

39. L １ is a linking group, C ３－６ cycloalkylene group, -NR ２ -, -O-, -S-, -C(=O)-, -(CR ３ R ４ ), ａ -NR ２ -(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ [[ID=2,6]]-NR ２ -, -O-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -O-, -S-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -S-, -C(=O)-(CR ３ R ４ ), ａ -(CR ３ R ４ ), ａ -C(=O)-, -(CR ３ R ４ ), ａ -(CR ９ =CR １０ ), -(CR ９ =CR １０ )-(CR ３ R ４ ), ａ -, -C(=O)-O-, -O-C(=O)-, -C(=O)-NR ２ -, -(CR ３ R ４ ), ａ -C(=O)-NR ２ -, -NR ２ -C(=O)-, -(CR ３ R ４ ), ａ -NR ２ -C(=O)-, -S(=O) ２ -NR ２ -, -NR ２ -S(=O) ２ -, -NR ２ - (CR ３ R ４ ) ａ -C(=O)-, -C(=O)-(CR ３ R ４ ) ａ -NR ２ - is selected from, Preferably, L １ is a bond, C ３－６ Cycloalkylene group, —C(═O)—, —(CR ３ R ４ ) ａ -, - (CR ３ R ４ ) ａ - (CR ９ =CR １０ ) -, -(CR ３ R ４ ) ａ —C(═O)—NR ２ -, - (CR ３ R ４ ) ａ -NR ２ 39. The compound of any one of claims 33 to 38, wherein the compound is selected from: -C(=O)-.

40. Each R ２ are each independently hydrogen, deuterium, or C １－４ alkyl groups, Each R ３ , R ４ are each independently hydrogen, deuterium, halogen, a hydroxy group, or C １－４ 40. The compound of claim 39, wherein the group is selected from alkyl groups.

41. L １ represents a bond, a methylene group, —C(═O)—, a cyclopropylene group, 【Chemical Engineering 202-1】 n-propylene group, n-butylene group, ethylene group, 【Chemical Engineering 203-1】 Preferably, L １ The compound according to any one of claims 33 to 40, wherein is selected from a bond, a methylene group, -C(=O)-, and a cyclopropylene group.

42. R １ is C １－６ Alkyl group, C １－６ Alkoxy group, NHR １１ -C(=O)-, C １－６ Alkyl-C(=O)-O-, C １－６ is selected from alkyl-O-C(=O)-, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkyl-C(=O)-O-, C １－６ The alkyl-O—C(═O)—, 3- to 10-membered cycloalkyl group, 3- to 6-membered monocyclic heterocyclic group, 6- to 11-membered bicyclic heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group each independently optionally include hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -C(O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ and further substituted with 1, 2, or 3 substituents selected from Preferably, R １ is C １－３ Alkyl group, NHR １１ -C(=O)-, a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C １－３ The alkyl group, the 3- to 10-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the 6- to 11-membered bicyclic heterocyclic group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group each independently optionally include deuterium, halogen, a hydroxy group, an oxo group, a cyano group, C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -C(O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ and further substituted with 1, 2, or 3 substituents selected from More preferably, R １ is a methyl group, an ethyl group, an isopropyl group, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a tetrahydropyranyl group, a thietanyl group, an oxetanyl group, an azetidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a cyclobutane group, a cyclopentane group, a cyclohexane group, an n-heptane group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrazolyl group, a furyl group, a triazolyl group, or —C(═O)—NH ２ , 【Chemical Engineering 204-1】 wherein said methyl group, ethyl group, isopropyl group, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, tetrahydropyranyl group, thietanyl group, oxetanyl group, azetidinyl group, piperidinyl group, morpholinyl group, piperazinyl group, cyclobutane group, cyclopentane group, cyclohexane group, n-heptane group, phenyl group, pyridinyl group, pyrimidinyl group, pyrrolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group, furyl group, triazolyl group, 【Chemical Engineering 205-1】 are each independently optionally selected from deuterium, halogen, a hydroxy group, an oxo group, a cyano group, C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -C(O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ and further substituted with 1, 2, or 3 substituents selected from Even more preferably, R １ is selected from a methyl group, an isopropyl group, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a tetrahydropyranyl group, a thietanyl group, an oxetanyl group, an azetidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a cyclobutane group, a cyclopentane group, a cyclohexane group, an n-heptane group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrazolyl group, a furyl group, and a triazolyl group, wherein the methyl group, the isopropyl group , pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, tetrahydropyranyl group, thietanyl group, oxetanyl group, azetidinyl group, piperidinyl group, morpholinyl group, piperazinyl group, cyclobutane group, cyclopentane group, cyclohexane group, n-heptane group, phenyl group, pyridinyl group, pyrimidinyl group, pyrrolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group, furyl group, and triazolyl group each independently optionally contain deuterium, halogen, hydroxy group, oxo, cyano group, C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -O(R ｃ１ ), -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -C(O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ 42. The compound of any one of claims 33 to 41, further substituted with 1, 2, or 3 substituents selected from:

43. -L １ -R １ teeth, 【Chemical Engineering 206-1】 【Chemistry 207-1】 is selected from Preferably, -L １ -R １ teeth, 【Chemistry 208-1】 is selected from More preferably, -L １ -R １ teeth, 【Chemistry 209-1】 43. The compound according to any one of claims 33 to 42, selected from:

44. A compound represented by formula (X-1) or (X-2) or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated compound), or prodrug thereof, 【Chemical Engineering 210-1】 where: Ring C is selected from a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a phenyl-fused 4- to 7-membered cycloalkyl group, a phenyl-fused 4- to 7-membered heterocyclic group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 4- to 7-membered heterocyclic group, a 4- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; Each R ｃｎ are independently hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, hydroxy C １－６ Alkyl group, C １－６ Alkoxy-C １－６ Alkyl group, R ｃ１ S (O) ２ -, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be selected from the group consisting of deuterium, halogen, hydroxyl group, amino group, cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R ｃｎ can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; Each R ａ and R ｂ are independently hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, C １－６ Haloalkoxy group, hydroxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), -C(=O)-(C １－６ alkyl), a 3- to 6-membered heterocycloalkyl group optionally substituted with a hydroxy group; L １ is a linking group, C ３－６ cycloalkylene group, -NR ２ -, -O-, -S-, -C(=O)-, -(CR ３ R ４ ), ａ -, -NR ２ -(CR ３ R ４ ), ａ -, -(CR ３ R[[ID=2:3]] ４ ), ａ -NR ２ -, -O-(CR ３ R ４ ), ａ -, -(CR<000125:0>R ４ ), ａ -O-, -S-(CR ３ R ４ ), ａ -, -(CR ３ R ４ ), ａ -S-, -C(=O)-(CR ３ R ４ ), ａ -, -(CR ３ R ４ ), ａ -C(=O)-, -(CR ３ R ４ ), ａ -(CR ９ =CR １０ ), - (CR ９ =CR １０ )-(CR ３ R ４ ), ａ -, -C(=O)-O-, -O-C(=O)-, -C(=O)-NR ２ -, -(CR ３ R ４ [[ID=:0]]), ａ -C(=O)-NR ２ -, -NR ２ -C(=O)-, -(CR ３ R ４ ), ａ -NR ２ -C(=O)-, -S(=O) ２ -NR ２ -, -NR ２ -S(=O) ２ -, -NR ２ - (CR ３ R ４ ) ａ -C(=O)-, -C(=O)-(CR ３ R ４ ) ａ -NR ２ -, -NR ２ - (CR ３ R ４ ) ａ —C(═O)—NR ５ -, -NR ２ -C(=O)-(CR ３ R ４ ) ａ -NR ５ -, -C(=S)-NR ２ -, -NR ２ -C(=S)-; L ２ is a bond, -NR ６ -, -O-, -S-, -NR ６ - (CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -NR ６ -, -O-(CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -O-, -S-(CR ７ R ８ ) ｂ -, - (CR ７ R ８ ) ｂ -S-; Each R ２ , R ５ , R ６ , R ９ and R １０ are each independently hydrogen, deuterium, or C １－６ alkyl groups, Each R ３ , R ４ , R ７ and R ８ are each independently hydrogen, deuterium, halogen, oxo, a hydroxy group, an amino group, C １－６ alkyl groups, R １ is selected from a 3- to 10-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 6- to 11-membered bicyclic heterocyclic group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, and the 3- to 10-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the 6- to 11-membered bicyclic heterocyclic group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each selected from the group consisting of -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ５ R ｃ６ , -P(=O)R ｃ５ R ｃ６ and the 3- to 10-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the 6- to 11-membered bicyclic heterocyclic group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, a hydroxy group, an oxo group, a cyano group, C １－６ Alkyl group, hydroxy C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; Each R ｃ１ and R ｃ２ are independently hydrogen, C １－６ Alkyl group, C １－６ Haloalkoxy group, C ３－６ selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group; R ｃ３ is C １－６ Alkyl group, C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group and C ３－６ The cycloalkyl group may optionally be substituted with deuterium, halogen, hydroxy, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), R ｃ５ and R ｃ６ is H, deuterium, C １－６ Alkyl group, C ３－６ cycloalkyl groups, or R ｃ５ and R ｃ６ form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, １－６ Alkyl group, C ３－６ The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally be substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), each a and b is independently 1, 2, 3, or 4; each m is 0 or 1; each p is 0, 1, or 2; each s and n is independently selected from 0, 1, 2, 3, or 4; As a condition, 【Chemistry 211-1】 or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated compound), or prodrug thereof.

45. The compounds have the structure shown in Formula VIII-3 or VIII-4: 【Chemistry 212-1】 45. The compound of claim 44.

46. The compound has the structure shown in Formula VIII-3: 【Chemistry 213-1】 46. ​​A compound according to claim 44 or 45.

47. R １ is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, or a 6- to 11-membered bicyclic heterocyclic group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is selected from the group consisting of -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ５ R ｃ６ , -P(=O)R ｃ５ R ｃ６ and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, or the 6- to 11-membered bicyclic heterocyclic group is optionally substituted with one or two substituents selected from hydrogen, deuterium, halogen, a hydroxy group, oxo, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; Each R ｃ１ and R ｃ２ are independently hydrogen, C １－６ Alkyl group, C １－６ Haloalkoxy group, C ３－６ selected from a cycloalkyl group or a 4- to 7-membered heterocyclic group; R ｃ３ is C １－６ Alkyl group, C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group and C ３－６ The cycloalkyl group may optionally be substituted with deuterium, halogen, a hydroxy group, an amino group, a cyano group, oxo, a C alkyl group, a C alkoxy group, a C haloalkyl group, a C haloalkoxy group, a C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), and R ｃ５ and R ｃ６ is H, deuterium, C １－６ Alkyl group, C ３－６ cycloalkyl groups, or R ｃ５ and R ｃ６ form a 4- to 6-membered heterocyclic group together with the N atom to which they are linked, １－６ Alkyl group, C ３－６ The cycloalkyl group and the 4- to 6-membered heterocyclic group may optionally be substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), each a and b is independently 1, 2, 3, or 4; each m is 0 or 1; each p is 0, 1, or 2; 47. The compound of any one of claims 44 to 46, wherein each s and n is independently selected from 0, 1, 2, 3, or 4.

48. L ２ The compound of any one of claims 44 to 47, wherein is a bond.

49. R ａ and R ｂ are each independently selected from hydrogen, deuterium, F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, 1-hydroxyethyl-1-yl, methylamino, dimethylamino, acetyl, and 3-hydroxyazetidinyl, and preferably R ａ and R ｂ are each independently selected from hydrogen, deuterium, F, Cl, Br, a methyl group, and an ethyl group, and more preferably, R ａ and R ｂ are each independently selected from hydrogen, deuterium, and a methyl group.

50. Each R ｃｎ are independently hydrogen, deuterium, fluorine, chlorine, bromine, a hydroxy group, an amino group, a cyano group, C １－４ Alkoxy group, C １－４ Haloalkoxy group, C １－４ Alkyl group, C １－４ Haloalkyl group, hydroxy C １－４ Alkyl group, C １－４ Alkoxy-C １－２ Alkyl group, R ｃ１ -S(O) ２ -, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be selected from the group consisting of deuterium, halogen, hydroxyl group, amino group, cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ substituted with 1 to 3 substituents selected from alkoxy groups; Or two R ｃｎ can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ optionally substituted with 1 to 3 substituents selected from haloalkyl groups; Preferably, each R ｃｎ are independently fluorine, chlorine, bromine, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, cyclohexenyl, oxetanyl, phenyl, 4-chloro-phenyl, 2-chloro-4-fluoro-phenyl, 4-hydroxyphenyl, 4-methyl-phenyl, 4-fluoro-phenyl, pyridyl, cyclobutylamino, 【Chemistry 214-1】 or two R ｃｎ form together with the C atoms to which they are attached a cyclopentenyl group, a 2,3-dihydrofuranyl group, a cyclobutenyl group, a thienyl group, a 1,4-dioxanyl group, a pyridyl group, a cyclopenta-1,3-dienyl group, a phenyl group, or a 1,4-dioxa-2-hexenyl group, More preferably, each R ｃｎ are independently selected from fluorine, chlorine, bromine, a hydroxy group, a cyano group, a methoxy group, an ethoxy group, a methyl group, an ethyl group, a trifluoromethyl group, a difluoromethyl group, a trifluoromethoxy group, and a difluoromethoxy group. 【Request Item 51】 【Chemistry 215-1】 teeth, 【Chemistry 216-1】 【Chemistry 217-1】 is selected from Preferably, wherein: 【Chemistry 218-1】 teeth, 【Chemistry 219-1】 51. The compound according to any one of claims 44 to 50, selected from:

52. L ２ is a bond, -NR ６ -, -O-, -S-, -NR ６ - (CR ７ R ８ ) ｂ１ -, - (CR ７ R ８ ) ｂ１ -NR ６ -, -O-(CR ７ R ８ ) ｂ１ -, - (CR ７ R ８ ) ｂ１ -O-, -S-(CR ７ R ８ ) ｂ１ -, - (CR ７ R ８ ) ｂ１ -S-, where b1 is 1 or 2; Preferably, L ２ is a bond, -NR ６ -, -NR ６ - (CR ７ R ８ ) ｂ１ -, - (CR ７ R ８ ) ｂ１ -NR ６ -, where b1 is 1 or 2; More preferably, L ２ is -NR ６ -, -NR ６ - (CR ７ R ８ ) ｂ１ -, - (CR ７ R ８ ) ｂ１ -NR ６ -, where b1 is 1; Even more preferably, L ２ is -NH-, -NH-(CR ７ R ８ ) - is selected from Even more preferably, L ２ is -NH-, -NH-CH ２ 52. The compound according to any one of claims 44 to 51, selected from:

53. Here, R １ represents a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemical 220-1】 a cyclopentane group, a cyclohexane group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 221-1】 is -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ５ R ｃ６ , -P(=O)R ｃ５ R ｃ６ and wherein the cyclopentane group, the cyclohexane group, the azetidinyl group, the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, the piperazinyl group, 【Chemistry 222-1】 is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ further substituted with 1, 2, or 3 substituents selected from a cycloalkyl group and a 3- to 6-membered monocyclic heterocyclic group; Preferably, R １ represents a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 223-1】 a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 224-1】 is -C(=O)-R ｃ３ , -S(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -C(=O)-NR ｃ５ R ｃ６ , -P(=O)R ｃ５ R ｃ６ and wherein the tetrahydropyrrolyl group, piperidinyl group, morpholinyl group, piperazinyl group, 【Chemistry 225-1】 is optionally hydrogen, deuterium, halogen, hydroxy group, oxo, C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ Cycloalkyl group, C １－６ Alkoxy-C １－６ further substituted with 1, 2, or 3 substituents selected from an alkyl group and a 3- to 6-membered monocyclic heterocyclic group; More preferably, R １ represents a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 226-1】 a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, 【Chemistry 227-1】 is -C(=O)-R ｃ３ , -S(=O) ２ -R ｃ３ , -P(=O)R ｃ５ R ｃ６ and wherein the tetrahydropyrrolyl group, piperidinyl group, morpholinyl group, piperazinyl group, 【Chemistry 228-1】 is optionally deuterium, halogen, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy-C １－６ further substituted with one or two substituents selected from alkyl groups; More preferably, where R １ teeth, 【Chemistry 229-1】 【Chemistry 230-1】 is selected from Even more preferably, where R １ teeth, 【Chemistry 231-1】 53. The compound according to any one of claims 44 to 52, selected from:

54. The compounds have the structure shown in Formula VIII-8 or VIII-12: 【Chemistry 232-1】 Here, each R ｃ are independently hydrogen, deuterium, halogen, a hydroxy group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C １－６ Alkoxy-C １－６ Alkyl group, R ｃ１ S (O) ２ -, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, a phenyl group, and a 5- to 6-membered heteroaryl group, and the 3- to 6-membered cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group may optionally be selected from the group consisting of deuterium, halogen, hydroxyl group, amino group, cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ substituted with 1, 2, or 3 substituents selected from alkoxy groups; Or two R ｃ can form a 3- to 6-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, a 6-membered aryl group or a 5- to 6-membered heteroaryl group together with the C atom to which they are attached, and the 3- to 6-membered cycloalkyl group, the 4- to 7-membered heterocyclic group, the 6-membered aryl group or the 5- to 6-membered heteroaryl group can optionally contain deuterium, halogen, a hydroxy group, an amino group, a cyano group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl groups; L ２ is a bond, -NR ６ -, -O-, -S-; R ａ , R ｂ , R ｃ , R ｃ１ , R ６ , R １ , L １ , n, m, p are as defined in claim 1, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound), or prodrug thereof according to any one of claims 1 to 4, 6 to 27.

55. The compound has the structure shown in Formula VIII-8: 【Chemistry 233-1】 55. The compound of claim 54.

56. R １ is a 3- to 6-membered monocyclic heterocyclic group, and the 3- to 6-membered monocyclic heterocyclic group may optionally contain deuterium, halogen, a hydroxy group, an oxo group, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) Ｓ -O(R ｃ１ ), -(CH ２ ) Ｓ -N(R ｃ１ ) (R ｃ２ ), C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered heteroaryl group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ and preferably, the R １ is selected from a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, and a 1,4-oxathiyl group, and the tetrahydropyrrolyl group, the piperidinyl group, the morpholinyl group, the piperazinyl group, and the 1,4-oxathiyl group each independently optionally contain deuterium, halogen, a hydroxy group, an amino group, oxo, C １－４ Alkyl group, C １－４ Haloalkyl group, hydroxy C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ and preferably, the R １ is selected from a morpholinyl group, and the morpholinyl group is optionally selected from deuterium, halogen, hydroxyl group, amino group, oxo, C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ and more preferably, wherein R １ teeth, 【Chemistry 234-1】 56. The compound of claim 54 or 55, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, selected from:

57. The compound has the structure shown in Formula VIII-9: 【Chemistry 235-1】 Here, R １ is a 3- to 6-membered monocyclic heterocyclic group, and the 3- to 6-membered monocyclic heterocyclic group may optionally contain deuterium, halogen, a hydroxy group, a cyano group, C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy C １－６ Alkyl group, C １－６ Alkoxy group, -(CH ２ ) ｓ -N(R ｃ１ ) (R ｃ２ ) -, C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ and preferably, the R １ is selected from a morpholinyl group and a piperidinyl group, and the morpholinyl group and the piperidinyl group each independently optionally contain deuterium, halogen, a hydroxy group, an amino group, C １－４ Alkyl group, C １－４ Alkoxy group, C ３－６ a cycloalkyl group, a 3- to 6-membered monocyclic heterocyclic group, —C(═O)—R ｃ３ , -S(O)-R ｃ３ , -S(O) ２ -R ｃ３ , -C(=O)OR ｃ３ , -N(R ｃ４ )-C(=O)-R ｃ３ , -CH ２ -N(R ｃ４ )-C(=O)-R ｃ４ , -C(=O)-N(R ｃ６ ) (R ｃ５ ), -N(R ｃ４ )-C(=O)-N(R ｃ６ ) (R ｃ５ ), -P(=O)R ｃ５ R ｃ６ and more preferably, the R １ teeth, 【Chemistry 236-1】 is selected from R ａ , R ｂ , R ｃ , R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R., L. ２ , L １ , s, n, m, p are as defined in claim 1; As a condition, 【Chemistry 237-1】 or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated compound) or prodrug thereof, according to any one of claims 1 to 4 and 6 to 27, which is not

58. The compound is 【Chemistry 238-1】 【Chemistry 239-1】 【Chemistry 240-1】 【Chemistry 241-1】 【Chemistry 242-1】 【Chemistry 243-1】 【Chemistry 244-1】 【Chemistry 245-1】 【Chemistry 246-1】 【Chemistry 247-1】 【Chemistry 248-1】 【Chemistry 249-1】 【Chemistry 250-1】 【Chemistry 251-1】 【Chemistry 252-1】 【Chemistry 253-1】 【Chemistry 254-1】 58. The compound of any one of claims 1 to 57, selected from:

59. 60. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 58, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof.

60. 60. A combination comprising a therapeutically effective amount of a compound of any one of claims 1 to 58 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitroxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds (preferably deuterated) or prodrugs thereof, and one or more therapeutic agents.

61. 61. The combination of claim 60, wherein the one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists, steatosis inhibitors, antifibrotic agents, JAK inhibitors, checkpoint inhibitors, chemotherapy, radiation therapy and surgery, urate-lowering therapy, anabolic agents and cartilage regeneration therapy, blockers of IL-17, complement inhibitors, Bruton's tyrosine kinase inhibitors (BTK inhibitors), Toll-like receptor inhibitors (TLR7 / 8 inhibitors), CAR-T therapy, antihypertensive agents, cholesterol-lowering agents, leukotriene A4 hydrolase (LTAH4) inhibitors, SGLT2 inhibitors, beta2-agonists, anti-inflammatory agents, nonsteroidal anti-inflammatory drugs ("NSAIDs"), acetylsalicylic acid drugs (ASAs), regenerative therapy treatment, treatment of cystic fibrosis, and treatment of atherosclerosis.

62. 62. The application of a compound according to any one of claims 1 to 58, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, or a combination according to any one of claims 60 to 61, as a drug.

63. 59. Use of a compound according to any one of claims 1 to 58, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, in the treatment of the following diseases or disorders in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of said disease or disorder:

64. 59. A method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder, said method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 58, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof.

65. 60. Use of a compound according to any one of claims 1 to 58, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated) or prodrug thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of said disease or disorder.

66. The disease or disorder may be an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, such as autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic fever syndrome), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute and chronic arthropathy), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation).

66. The method of claim 64 or the use of a compound according to claim 62-63 selected from the group consisting of neuroinflammatory related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

67. 59. A method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 58, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound (preferably deuterated), or prodrug thereof.

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