Novel ALPK1 inhibitors

Abstract

The present disclosure is directed to a novel ALPK1 inhibitor having formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof. The present disclosure is also directed to a pharmaceutical composition comprising the novel ALPK1 inhibitor, and its use in treating inflammation-related diseases such as ROSAH syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease. [C1] TIFF2026503588000801.tif26156

Description

[Technical Field]

[0001] The present disclosure is directed to a novel ALPK1 inhibitor or its pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form.The present disclosure is also directed to a pharmaceutical composition comprising the novel ALPK1 inhibitor, and its use in treating inflammation-related diseases such as ROSAH syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease. [Background technology]

[0002] Innate immunity plays an important role in host defense agonists during infection. The mammalian cytoplasmic protein ALPK1 (alpha-kinase 1) has been identified as a new member of the innate immune system and functions as a receptor for ADP-heptose, a bacterial sugar metabolite in the LPS biosynthesis pathway (Nature. 2018, 561(7721):122-126). ADP-heptose is widely present in bacteria. ALPK1 consists of an N-terminal domain (NTD) and a C-terminal kinase domain (KD) connected by a long, extended amorphous region. ADP-heptose can directly bind to the NTD, activating the KD to phosphorylate its substrate, TIFA (TRAF-interacting protein with forkhead-associated domain). The phosphorylated TIFA then oligomerizes and binds and activates TRAF6, resulting in downstream NF-κB activation and ultimately the innate immune response.

[0003] Deregulated activation of ALPK1 correlates with many diseases and disorders. Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disorder called ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome (Genet. Med. 2019, 21(9):2103-2115; J. Clin. Immunol. 2020, 40(2):350-358; Ann. Rheum. Dis. 2022, 81(10):1453-1464). Another ALPK1 gain-of-function mutation is associated with rare skin adnexal tumors, spiroandenoma or spiroandenocarcinoma (Nat. Commun. 2019, 10(1):2213). Rare missense variants in the ALPK1 gene were also reported as a predisposing factor for PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis) syndrome (Eur. J. Hum. Genet. 2019, 27(9):1361-1368). Through genetic and bioinformatic analyses, ALPK1 has been linked to many other inflammation-related diseases, such as inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, and inflammatory skin diseases, as well as neurodegenerative diseases, including Alzheimer's disease (Nat. Commun. 2018, 9(1):3797; J. Mol. Med. 2011, 89(12):1241-1251; Int. J. Epidemiol. 2013, 42(2):466-474; Biomed. Rep. 2019). 13,1(6):940-944;Biomed.Rep.2015,3(3):347-354;Sci.Rep.2016,6:25740;J.Med.Genet.2013,50(6):410-418;Front.Immunol. 2021,12:705751;Nat.Commun.2019,10(1):2213;J.Bone.Miner.Res.2022,37(10):1973-1985;Int.Immunopharmacol.2022,113(Pt A):109330).The relationship between ALPK1 and cancer has been extensively studied, including gastric, breast, oral, lung, and colorectal cancer, as well as the initiation or progression of lymphoblastic leukemia (Sci.Rep.2016,6:27350; Oncotarget.2016,7(50):83278-83293; Am.J.Pathol.20199,189(1):190-199; Gut.Microbes.2022,144(1):2038852).

[0004] To date, there are no approved ALPK1 inhibitors. Although other immunosuppressants or kinase inhibitors have been approved for clinical use in the diseases listed, new treatment options remain urgently needed. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides compounds of formula (I) and subformulas (II), (II-1), (II-2), (III-1), (III-2), (III-3) and (IV) described herein that are inhibitors of ALPK1 activity, and compositions and methods thereof for treating inflammation-related diseases.

[0006] In one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, M1 is selected from CR1 and N; M2 is selected from CR2 and N; M3 is selected from CR3 and N; M4 is selected from CR4 and N; L is selected from a chemical bond, —O—, —S—, and —NH—; Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O)2- and [ka] is selected from Z is -C(R 2s )(R 3s )- or -N(R 2s )- and Ring A is C 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- to 10-membered heteroaryl, preferably phenyl or 5- to 9-membered heteroaryl; R a are H, D, halo, oxo, CN, NO2, NH2, -C 0~6 Alkylene -OH, -C(O)OR x , -C(O)NR y R z , -S(O)NR y R z , -S(O)NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, and amino protecting groups; and one, two, or three halo, oxo, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 and optionally substituted with haloalkyl, where m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R1 is H, D, halo, CN, OR x , N.R. y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, -TC 3~8 Cycloalkyl, -T-4 to 10-membered heterocyclyl, -TC 6~10 aryl, and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R3 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl and C 1~6 haloalkyl; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R1 and R2 together with the carbon atoms to which they are attached represent one, two or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)H, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 2~6 Alkenyl, C2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 Alkynyl-substituted phenyl, preferably containing one, two or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 C optionally substituted with alkynyl-substituted phenyl 5~6 forming a cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxyl, -C 1~6 Alkylene-C 1~6 Haloalkoxyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 C optionally substituted with haloalkyl 5~6 forming a cycloalkyl, a 5- to 7-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; R 1s H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl and phenyl; R2s H, D, C 1~6 Alkyl, C 1~6 Haloalkyl and C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; R 2s2 H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s3 is C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, Or, R 2s2 and R 2s3 together with the atoms to which they are attached, are C optionally substituted with one or two halo 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; Or, R 1s and R 2s3 may be combined with one, two or three halos, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene R 3s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 1s and R 2s together with the nitrogen atom to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 forming a 4- to 6-membered heterocyclyl optionally substituted with haloalkyl; Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 form a bridged bicycloalkyl, or [ka] Forming Y1 is CR 11 or N, Y2 is CR 12 or N, R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; R x , R y and R z are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0007] In another aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, M1 is selected from CR1 and N; M2 is selected from CR2 and N; M3 is selected from CR3 and N; M4 is selected from CR4 and N; L is selected from a chemical bond, —O—, —S—, and —NH—; Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O)2- and [ka] is selected from Z is -C(R 2s )(R 3s )- or -N(R 2s )- and Ring A is selected from phenyl and 5- to 9-membered heteroaryl; R a H, D, halo, CN, NO2, NH2, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; R1 is H, D, Halo, OR x , N.R. y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, -TC 3~8 Cycloalkyl, -T-4 to 10-membered heterocyclyl, -TC 6~10 aryl, and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R3 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl and C 1~6 haloalkyl; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 C optionally substituted with alkynyl-substituted phenyl 5~6 forming a cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxyl, -C1~6 Alkylene-C 1~6 Haloalkoxyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 C optionally substituted with haloalkyl 5~6 forming a cycloalkyl or 5- to 7-membered heterocyclyl; R 1s H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl and phenyl; R 2s H, D, C 1~6 Alkyl, C 1~6 Haloalkyl and C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; R 2s2 H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s3 is C 1~6 Alkyl or C 1~6is haloalkyl, Or, R 2s2 and R 2s3 together with the atoms to which they are attached, are C optionally substituted with one or two halo 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are bonded, C 4~8 forming a bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; Or, R 1s and R 2s3 may be combined with one, two or three halos, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene R 3s is C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 1s and R 2s together with the nitrogen atom to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 forming a 4- to 6-membered heterocyclyl optionally substituted with haloalkyl; Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form C 4~8 Bridged bicycloalkyl or [ka] Forming Y1 is CR 11 or N, Y2 is CR 12 or N, R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; R x , R y and R z are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0008] In another aspect, the disclosure provides pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, a pharmaceutically acceptable excipient, and optionally one or more other therapeutic agents.

[0009] In another aspect, the disclosure provides a kit comprising a first container comprising a compound described herein or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof; optionally, a second container comprising one or more other therapeutic agents; and optionally, a third container comprising a pharmaceutically acceptable excipient for diluting or suspending the compound and / or other therapeutic agents.

[0010] In another aspect, the disclosure provides the use of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, in the manufacture of a medicament for treating an immune and / or inflammatory disease, disorder, or condition associated with excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

[0011] In another aspect, the disclosure provides a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, for use in treating an immune and / or inflammatory disease, disorder, or condition associated with excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

[0012] In another aspect, the present disclosure provides a method of treating an immune and / or inflammatory-related disease, disorder, or condition due to excessive or inappropriate ALPK1-dependent pro-inflammatory signaling in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

[0013] In another embodiment, the disease, disorder, or condition is selected from sepsis, cancer (including lung cancer, colon cancer, and oral squamous cell carcinoma), systemic lupus erythematosus, spiroandenoma, spiroandenocarcinoma, Kawasaki disease, ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine) syndrome, and PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and lymphadenitis) syndrome.

[0014] chemical definition Definitions of certain functional groups and chemical terms are described in more detail herein below.

[0015] When a range of values ​​is listed, each value and subrange within the range is intended to be included. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 It is intended to include alkyl.

[0016] "C 1~6 "Alkyl" refers to a group of linear or branched saturated hydrocarbon groups having 1 to 6 carbon atoms. In some embodiments, C 1~4 Alkyl is preferred. 1~6 Examples of alkyl include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6).1~6 The term "alkyl" also includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0017] "C 2~6 "Alkenyl" refers to a group of straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2~4 Alkenyl is preferred. 2~6 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2~6 The term "alkenyl" also includes heteroalkenyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0018] "C 2~6 "Alkynyl" refers to a group of straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2~4 Alkynyl is preferred. 2~6Examples of alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. 2~6 The term "alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0019] "C 1~6 Alkylene is defined as "C 1~6 It refers to a divalent group of "alkyl." 1~6 "Alkylene" is C 1~6 It refers to a divalent group formed by removing another hydrogen from an alkyl, and can be a substituted or unsubstituted alkylene. In some embodiments, C 2~6 Alkylene, C 1~4 Alkylene and C 2~3 Alkylene is particularly preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Examples of substituted alkylene groups, e.g., those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0020] "C0~6 Alkylene is a chemical bond and a 1~6 "Alkylene" is also included. 0~4 Alkylene is a chemical bond and a 1~4 Contains "alkylene".

[0021] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0022] "C 1~6 "Haloalkyl" refers to any of the above "C" groups substituted with one or more halogen groups. 1~6 represents "alkyl." Examples include mono-, di-, and poly-halogenated alkyls (including fully halogenated alkyls). Monohalogen substituents may have one iodine, bromine, chlorine, or fluorine atom in the group, while dihalogen and polyhalogen substituents may have two or more of the same halogen atoms or a combination of different halogens. In some embodiments, C 1~4 Particularly preferred is haloalkyl. Preferred examples of haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Haloalkyl groups can be substituted at any available attachment point with, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0023] Similarly, "C 2~6 haloalkenyl" and "C 2~4 Haloalkenyl refers to any of the above "C" groups substituted with one or more halogen groups. 2~6 alkenyl" and "C 2~4 "C" stands for "alkenyl". 2~6 haloalkynyl" and "C 2~4 Haloalkynyl refers to any of the above "C" alkynyl groups substituted with one or more halogen groups. 2~6 alkynyl" and "C 2~4It stands for "alkynyl".

[0024] "C 1~6 "Alkoxy" is -OC 1~6 It refers to alkyl groups, and "C 1~4 "Alkoxy" is -OC 1~4 Refers to an alkyl group (e.g., -OCH3). 1~6 "Haloalkoxy" is -OC 1~6 Refers to haloalkyl groups, and "C 1~4 "Haloalkoxy" is -OC 1~4 refers to a haloalkyl group (e.g., -OCF3).

[0025] "C 3~8 "Cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms and 0 heteroatoms. The term cycloalkyl may contain one or more double or triple bonds as long as it is non-aromatic. In some embodiments, C 3~6 Cycloalkyl is particularly preferred. In some embodiments, C 5~6 Cycloalkyl is particularly preferred. In some embodiments, C 4~6 Cycloalkyl is particularly preferred. In some embodiments, C 3~5 Cycloalkyl is particularly preferred. In some embodiments, C 3~4 Cycloalkyl is particularly preferred. Cycloalkyl also includes ring systems in which the cycloalkyl described herein is fused with one or more aryl or heteroaryl groups, and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl system. Cycloalkyl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. Further examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include C 4~8 Bridged bicycloalkyls include, for example, bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like.

[0027] "4- to 10-membered heterocyclyl" refers to a 4- to 10-membered non-aromatic ring system radical having ring carbon atoms and 1 to 5 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as long as valence permits. The term heterocyclyl may contain one or more double or triple bonds, so long as it is non-aromatic. In some embodiments, a 5- to 10-membered heterocyclyl radical is a 5- to 10-membered non-aromatic ring system radical having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, a 5- to 7-membered heterocyclyl radical is a 5- to 7-membered non-aromatic ring system radical having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, a 5- to 6-membered heterocyclyl radical is a 5- to 6-membered non-aromatic ring system radical having ring carbon atoms and 1 to 3 ring heteroatoms is more preferred. In some embodiments, 4- to 6-membered heterocyclyl is preferred, which is a group of 4- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl is fused to one or more cycloalkyl groups, with the point of attachment being on the cycloalkyl ring, or the above heterocyclyl is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclyl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] Specific examples of preferred heterocyclyl groups include pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazolidinyl, dihydrothiazolyl, 2,3-dihydro-benzo[1,4]dioxole, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isodihydrobenzopyranyl, dihydrobenzopyranyl, 1,2-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorene, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxole, 2,3- Dihydro-1H-1k'-benzo[d]isothiazol-6-yl, 2,3-di-benzo[1,4]dioxinyl, dihydrobenzofuran, 2-oxoaziridin-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, 2-oxoazocane-1-yl, 2-oxoazonan-1-yl, 2-oxo These include azecan-1-yl, aziridine, azetidine, pyrrolidinyl, piperidine, azepane, azocane, azonane, azecane, piperidyl, piperazinyl, morpholinyl, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.4]nonane, diazaspiro[4.5]decane, and diazaspiro[5.5]undecane.

[0029] Further examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, etc. Heterocyclyls can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo [3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (eg, spirocyclic bicycles in which the two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2. 2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, etc. The term "saturated," as used in this context, means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0030] "C 6~10 "Aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring systems (e.g., having 6 or 10 shared π electrons in the ring arrangement) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl" e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl groups also include ring systems in which the aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Aryl can be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "5- to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons in the ring arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring. In such cases, the number of carbon atoms still refers to the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 9-membered heteroaryl groups that are 5- to 9-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms are particularly preferred. In some embodiments, 5- to 6-membered heteroaryl groups are groups of 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms. In some embodiments, 5-membered heteroaryl groups are groups of 5-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (such as 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl.Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] Specific examples of preferred heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl), thiazolyl, and thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

[0033] Further examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, Examples include pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, 2,3-dihydrobenzofuran, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, indolinyl, isoindolinyl, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0034] As used herein, when a ring is described as "aromatic," it means that the ring has a continuous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to the Hückel rule (4n+2).

[0035] "Oxo" refers to =O.

[0036] For the avoidance of doubt, unless otherwise stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are understood to be those in which the points of fusion are located on (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero atom bridge (e.g., [ka] )), (ii) located on a single ring atom (spiro-fused ring systems) (e.g., [ka] ), or (iii) located on a contiguous sequence of ring atoms (bridged ring systems with all bridge lengths > 0) (e.g., [ka] It is understood that the term "substituted" includes those having fused rings, including substituted or unsubstituted cyclic rings.

[0037] Furthermore, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include tetrahydrogen, tetrahydrofuran ... 13 C and 14 Contains C.

[0038] Additionally, compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: [ka] A compound containing the moiety: [ka] Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl includes the pyridone or pyrimidone tautomeric forms.

[0039] An "amino protecting group" is used to prevent an amino group from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein. Exemplary amino protecting agents are selected from Cbz, Boc, Fmoc, Alloc, and Teoc.

[0040] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, as defined herein, are optionally substituted groups.

[0041] Exemplary substituents on carbon atoms include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(Rbb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb)2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, Or, two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is replaced by a group, R aa are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or R aa two of the groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb each independently represents hydrogen, —OH, —OR aa , -N(R cc)2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R bb groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(Rff )2、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee)2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, each of said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd the substituents can be linked to form =O or =S; R ee are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, and each of said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, Each R gg each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl, C6-C 10 Aryl, C3-C7 heterocyclyl, C5-C 10 heteroaryl, or two geminal R gg The substituents may be linked to form =O or =S, where X - is the counterion.

[0042] Exemplary substituents on a nitrogen atom include hydrogen, —OH, —OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc)2, -P(=O)(NR cc ) 2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R bonded to a nitrogen atom cc groups are joined to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as described herein.

[0043] Further definitions The present disclosure provides compounds that are inhibitors of ALPK1, compositions containing same, and methods of their use in therapy.

[0044] The term "ALPK1" is used herein interchangeably to refer to isoform 1 (Q96QP1-1) or alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN).

[0045] In order to facilitate understanding of the disclosure described herein, some additional terms are defined below. Generally, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry and pharmacology described herein are well known and commonly used in the art, for example, the nomenclature can be obtained by using the software ChemDraw. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications and other publications mentioned throughout this specification and attached appendices is incorporated herein by reference in its entirety.

[0046] The terms "comprising," "including," "having," or "containing" mean "including but not limited to" and "consisting of," e.g., a composition "comprising" X may consist solely of X or may include something additional (e.g., X+Y). Furthermore, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the embodiment may be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of." As used herein, the articles "a" and "an" refer to one or more (e.g., at least one) of the grammatical object of the article. The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0047] As used herein, "immunotherapeutic agent" or "immunomodulatory agent" refers to a small molecule drug, antibody, or other biological molecule. In some embodiments, a modulatory agent is used to inhibit inhibitory immunoreceptor signals on T cells and / or other immune cells (such as dendritic cells). In some embodiments, a modulatory agent is used to enhance and / or stimulate costimulatory immunoreceptor signals on T cells and / or other immune cells (such as dendritic cells). In some embodiments, biological immunomodulatory agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized.

[0048] The terms "treat," "treating," and "treatment" in the context of treating a disease, disorder, or condition mean alleviating or suppressing a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. In many cases, the beneficial effects a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder, or condition. In some embodiments, the terms "treat," "treating," and "treatment" include achieving a virological cure of a viral disorder, disease, or condition; reducing viral shedding; reducing viral RNA load (e.g., as measured by PCR); shortening the length of hospitalization; shortening the length of stay in an infectious disease ward and / or intensive care unit; or slowing (including halting) the progression / development of respiratory (or other severe) symptoms.

[0049] "Treatment of cancer" refers to one or more of the following effects: (1) inhibition to some extent of tumor growth, including (i) slowing and (ii) complete cessation of growth; (2) reduction in the number of tumor cells; (3) maintenance of tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing, or (iii) complete prevention of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing, or (iii) complete prevention of metastasis; (7) enhancement of an anti-tumor immune response, which may result in (i) maintenance of tumor size, (ii) reduction in tumor size, (iii) delay in tumor growth, (iv) reduction, delay, or prevention of infiltration; and / or (8) reduction to some extent in the severity or number of one or more symptoms associated with the disorder.

[0050] The term "therapeutically effective amount" refers to an amount of a drug or other pharmaceutical agent (e.g., a compound disclosed herein) that elicits the biological and / or medical response of a tissue, system, animal, or human (e.g., a subject or patient) that is desired by a researcher, clinician, or the like. Furthermore, the term "therapeutically effective amount" refers to any amount sufficient to reduce the rate of progression of, prevent the onset of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated, compared to a corresponding subject (e.g., patient) who does not receive such amount. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated. Furthermore, a therapeutically effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0051] As used herein, the term "subject or patient," as used interchangeably herein, refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In some embodiments, the subject is a human being treated by the methods and compositions of the present disclosure. In some embodiments, the methods described herein further include identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors, e.g., tumors lacking T cells or exhausted T cells).

[0052] The term "vaccine" refers to a biological preparation administered to a human or animal to induce or enhance a specific immune response and / or protection against one or more antigens in the human or animal. In some embodiments, the vaccine is a cancer vaccine against one or more antigens of cancer cells.

[0053] The term "adjuvant" refers to a secondary therapeutic agent administered (sequentially in any order or simultaneously) with a primary therapeutic agent to achieve some complementary, synergistic, or other beneficial effect that cannot be achieved through the use of the primary therapeutic agent alone. Adjuvants can be used with vaccines, chemotherapy, or some other therapeutic agent. Adjuvants can enhance the effectiveness of the primary therapeutic agent, reduce the toxicity or side effects of the primary therapeutic agent, or provide some protection to the subject receiving the primary therapeutic agent (for example, but not limited to, improved immune system function).

[0054] As used herein, the term "cancer" refers to a physiological condition in a subject characterized by unregulated or dysregulated cell proliferation or cell death. The term "cancer" includes solid tumors and blood-borne tumors, whether malignant or benign.

[0055] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the general well-being of the subject being treated.

[0056] "API" refers to active pharmaceutical ingredient.

[0057] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or difficulty, commensurate with a reasonable benefit / risk ratio. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0058] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not suppress the biological activity and properties of the compound. In certain examples, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. In some examples, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or by other predetermined methods. There is no particular limitation on the pharmacologically acceptable salt, so long as it can be used in medicine. Examples of salts that the compounds described herein form with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically exemplified by the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0059] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis.

[0060] Furthermore, prodrugs are also included within the context of the present disclosure. As used herein, the term "prodrug" refers to a compound that is converted in vivo into its active form, which has medical effects, such as by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, Edward B. Roche, ed., "Bioreversible Carriers in Drug Design," American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0061] A prodrug is any covalently bonded carrier that releases a compound of Formula (I) in vivo when administered to a patient. Prodrugs are typically prepared by routine manipulation or by modifying functional groups so that the modification can be cleaved in vivo to yield the parent compound. Prodrugs include, for example, compounds disclosed herein in which hydroxy, amine, or sulfhydryl groups are bonded to any group that can be cleaved to form a hydroxy, amine, or sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol, mercapto, and amine functional groups in compounds of Formula (I). Furthermore, in the case of carboxylic acids (—COOH), esters such as methyl esters and ethyl esters can be used. The esters themselves may be active and / or may be hydrolyzed under conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include groups that readily break down in the human body to release the parent acid or its salt.

[0062] All suitable isotopic derivatives of the compounds disclosed herein are also disclosed herein.The isotopic derivatives of the compounds disclosed herein are defined as at least one atom is replaced by the atom with the same atomic number but the atomic mass is different from the atomic mass that is usually found in nature.The examples of isotopes that can be listed for the compounds disclosed herein include hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine isotopes, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 31 P, 32 P, 35 S and 36 Examples include Cl. 3 H and 14Certain isotopic derivatives of the compounds disclosed herein, such as radioactive isotopes of C, are also included and are useful in drug and substrate tissue distribution studies. 3 H, and carbon-14, i.e. 14 C is easier to prepare and detect and is the isotope of choice. 2 Substitution with an isotope such as H has advantages in some treatments due to its better metabolic stability, for example, increased in vivo half-life or reduced dosage, and therefore may be preferred in some cases. Isotopic derivatives of the compounds disclosed herein can be prepared by conventional procedures, such as the descriptive methods or the preparation methods described in the examples below, using appropriate isotopic derivatives of suitable reagents. The term "stable isotope" refers to an isotope that exists stably in nature.

[0063] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0064] The details of one or more embodiments of the disclosure are set forth in the description below. Other features and advantages of the invention will be apparent from the description, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0065] The present disclosure relates to compounds represented by formula (I) and pharmaceutically acceptable salts, stereoisomers, tautomers, stable isotope variants, prodrugs or crystalline forms thereof: [ka] (In the formula, M1 is selected from CR1 and N; M2 is selected from CR2 and N; M3 is selected from CR3 and N; M4 is selected from CR4 and N; L is selected from a chemical bond, —O—, —S—, and —NH—; Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O)2- and [ka] is selected from Z is -C(R 2s )(R 3s )- or -N(R 2s )- and Ring A is C 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- to 10-membered heteroaryl, preferably phenyl or 5- to 9-membered heteroaryl; R a are H, D, halo, oxo, CN, NO2, NH2, -C 0~6 Alkylene -OH, -C(O)OR x , -C(O)NR y R z , -S(O)NR y R z , -S(O)NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, and amino protecting groups; and one, two, or three halo, oxo, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6and optionally substituted with haloalkyl, where m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R1 is H, D, halo, CN, OR x , N.R. y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, -TC 3~8 Cycloalkyl, -T-4 to 10-membered heterocyclyl, -TC 6~10 aryl, and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R3 is H, D, halo, CN, -C 0~6Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl and C 1~6 haloalkyl; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R1 and R2 together with the carbon atoms to which they are attached represent one, two or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)H, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 Alkynyl-substituted phenyl, preferably containing one, two or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 C optionally substituted with alkynyl-substituted phenyl 5~6 forming a cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxyl, -C 1~6 Alkylene-C 1~6 Haloalkoxyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 C optionally substituted with haloalkyl 5~6forming a cycloalkyl, a 5- to 7-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; R 1s H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl and phenyl; R 2s H, D, C 1~6 Alkyl, C 1~6 Haloalkyl and C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; R 2s2 H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s3 is C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, form C 3~6forming a cycloalkyl, Or, R 2s2 and R 2s3 together with the atoms to which they are attached, are C optionally substituted with one or two halo 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; Or, R 1s and R 2s3 may be combined with one, two or three halos, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene R 3s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 1s and R 2s together with the nitrogen atom to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6forming a 4- to 6-membered heterocyclyl optionally substituted with haloalkyl; Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 form a bridged bicycloalkyl, or [ka] Forming Y1 is CR 11 or N, Y2 is CR 12 or N, R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; R x , R y and R z are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0066] The present disclosure further provides compounds represented by formula (I) and pharmaceutically acceptable salts, stereoisomers, tautomers, stable isotope variants, prodrugs or crystalline forms thereof: [ka] (In the formula, M1 is selected from CR1 and N; M2 is selected from CR2 and N; M3 is selected from CR3 and N; M4 is selected from CR4 and N; L is selected from a chemical bond, —O—, —S—, and —NH—; Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O)2- and [ka] is selected from Z is -C(R 2s )(R 3s )- or -N(R 2s )- and Ring A is selected from phenyl and 5- to 9-membered heteroaryl; R a H, D, halo, CN, NO2, NH2, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; R1 is H, D, Halo, OR x, N.R. y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, -TC 3~8 Cycloalkyl, -T-4 to 10-membered heterocyclyl, -TC 6~10 aryl, and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R3 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl and C 1~6 haloalkyl; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 C optionally substituted with alkynyl-substituted phenyl 5~6 forming a cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxyl, -C 1~6 Alkylene-C 1~6 Haloalkoxyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 C optionally substituted with haloalkyl 5~6 forming a cycloalkyl or 5- to 7-membered heterocyclyl; R 1s H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl and phenyl; R 2s H, D, C 1~6 Alkyl, C 1~6 Haloalkyl and C(R 2s1 )(R 2s2 )(R 2s3 ) and R2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; R 2s2 H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s3 is C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 2s2 and R 2s3 together with the atoms to which they are attached, are C optionally substituted with one or two halo 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; Or, R 1s and R 2s3 may be combined with one, two or three halos, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene R 3s is C 1~6 Alkyl and C 1~6 haloalkyl; Or, R2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 1s and R 2s together with the nitrogen atom to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 forming a 4- to 6-membered heterocyclyl optionally substituted with haloalkyl; Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form C 4~8 Bridged bicycloalkyl or [ka] Forming Y1 is CR 11 or N, Y2 is CR 12 or N, R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; R x , R y and R z are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R ztogether with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0067] M1, M2, M3 and M4 In some embodiments, M1 is CR1; in some embodiments, M1 is N.

[0068] In some embodiments, M2 is CR2; in some embodiments, M2 is N.

[0069] In some embodiments, M3 is CR3; in some embodiments, M3 is N.

[0070] In some embodiments, M4 is CR4; in some embodiments, M4 is N.

[0071] L In some embodiments, L is a chemical bond, in some embodiments, L is -O-, in some embodiments, L is -S-, and in some embodiments, L is -NH-.

[0072] Y In some embodiments, Y is -C(O)-, in some embodiments, Y is -C(S)-, in some embodiments, Y is -C(N-OH)-, in some embodiments, Y is -S(O)-, in some embodiments, Y is -S(O)-, and in some embodiments, Y is [ka] is.

[0073] Z In some embodiments, Z is —C(R 2s )(R 3s )-, and in some embodiments, Z is -N(R 2s )-.

[0074] Ring A In some embodiments, ring A is C 3~6 In some embodiments, ring A is cycloalkyl, and in some embodiments, ring A is a 4-6 membered heterocyclyl, in some embodiments, ring A is a 5-10 membered heteroaryl, in some embodiments, ring A is phenyl, and in some embodiments, ring A is a 5-9 membered heteroaryl.

[0075] R a and m In some embodiments, R a is H, and in some embodiments, R a is D, and in some embodiments, R a is halo, and in some embodiments, R a is oxo, and in some embodiments, R a is CN, and in some embodiments, R a is NO, and in some embodiments, R a is OH, and in some embodiments, R a is NH, and in some embodiments, R a Ha-C 1~6 alkylene-OH, and in some embodiments, R a -C(O)OR x and in some embodiments, R a is -C(O)NR y R z and in some embodiments, R a is -S(O)NR y R z and in some embodiments, R a is -S(O)2NR y R z and in some embodiments, R a is C 1~6 alkyl, and in some embodiments, Ra is C 1~6 haloalkyl, and in some embodiments, R a is C 2~6 alkenyl, and in some embodiments, R a is C 2~6 haloalkenyl, and in some embodiments, R a is C 2~6 alkynyl, and in some embodiments, R a is C 2~6 haloalkynyl, and in some embodiments, R a is C 3~6 cycloalkyl, and in some embodiments, R a is a 4- to 6-membered heterocyclyl, and in some embodiments, R a is phenyl, and in some embodiments, R a is a 5-6 membered heteroaryl, and in some embodiments, R a is an amino protecting group, and in some embodiments, the above-listed groups are selected from one, two, or three halo, oxo, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 and optionally substituted with haloalkyl, and in some embodiments, two adjacent R a together with the atoms to which they are attached form a phenyl, and in some embodiments, two adjacent R a together with the atoms to which they are attached form a 5- to 6-membered heteroaryl.

[0076] In some embodiments, m=0, in some embodiments, m=1, in some embodiments, m=2, in some embodiments, m=3, in some embodiments, m=4, and in some embodiments, m=5.

[0077] R1 In some embodiments, R1 is H, in some embodiments, R1 is D, in some embodiments, R1 is halo, in some embodiments, R1 is CN, and in some embodiments, R1 is OR x and in some embodiments, R is NR y R z and in some embodiments, R is C 1~6 alkyl, and in some embodiments, R is C 1~6 haloalkyl, and in some embodiments, R is C 1~6 In some embodiments, R is C 1~6 haloalkoxyl, and in some embodiments, R is C 2~6 alkenyl, and in some embodiments, R is C 2~6 haloalkenyl, and in some embodiments, R is C 2~6 alkynyl, and in some embodiments, R is C 2~6 haloalkynyl, and in some embodiments, R is C 3~8 cycloalkyl, and in some embodiments, R1 is a 4- to 10-membered heterocyclyl.

[0078] R2 and T In some embodiments, R2 is H, in some embodiments, R2 is D, in some embodiments, R2 is halo, in some embodiments, R2 is CN, in some embodiments, R2 is -C 0~6 alkylene-OH, and in some embodiments, R2 is -C(O)C 1~6 alkyl, and in some embodiments, R2 is -C(O)C 1~6 haloalkyl, and in some embodiments, R2 is -C 0~6 alkylene-NH, and in some embodiments, R is C 1~6 alkyl, and in some embodiments, R2 is C 1~6 haloalkyl, and in some embodiments, R2 is C 1~6 In some embodiments, R2 is C 1~6haloalkoxyl, and in some embodiments, R2 is C 2~6 alkenyl, and in some embodiments, R2 is C 2~6 haloalkenyl, and in some embodiments, R2 is C 2~6 alkynyl, and in some embodiments, R2 is C 2~6 haloalkynyl, and in some embodiments, R2 is -TC 3~8 In some embodiments, R2 is -TC-4 to 10-membered heterocyclyl, and in some embodiments, R2 is -TC- 6~10 aryl, and in some embodiments, R2 is -T-5 to 10 membered heteroaryl.

[0079] In some embodiments, T is a chemical bond; in some embodiments, T is —O—; in some embodiments, T is —S—; in some embodiments, T is —NH—.

[0080] R3 In some embodiments, R3 is H, in some embodiments, R3 is D, in some embodiments, R3 is halo, in some embodiments, R3 is CN, in some embodiments, R3 is -C 0~6 alkylene-OH, and in some embodiments, R3 is -C 0~6 alkylene-NH, and in some embodiments, R is C 1~6 alkyl, and in some embodiments, R3 is C 1~6 It is haloalkyl.

[0081] R4 In some embodiments, R4 is H, in some embodiments, R4 is D, in some embodiments, R4 is halo, in some embodiments, R4 is C 1~6 alkyl, and in some embodiments, R4 is C 1~6 It is haloalkyl.

[0082] In some embodiments, R and R, together with the carbon atom to which they are attached, are C 5~6 In some embodiments, R1 and R2, together with the carbon atom to which they are attached, form a 5- to 6-membered heterocyclyl; in some embodiments, R1 and R2, together with the carbon atom to which they are attached, form a phenyl; and in some embodiments, R1 and R2, together with the carbon atom to which they are attached, form a 5- to 6-membered heteroaryl.

[0083] In some embodiments, R and R, together with the carbon atom to which they are attached, are C 5~6 cycloalkyl, and in some embodiments, R2 and R3 together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclyl.

[0084] R 1s In some embodiments, R 1s is H, and in some embodiments, R 1s is D, and in some embodiments, R 1s Ha-C 0~6 Alkylene-OR x and in some embodiments, R 1s Ha-C 0~6 Alkylene-NR y R z and in some embodiments, R 1s is C 1~6 alkyl, and in some embodiments, R 1s is C 1~6 haloalkyl, and in some embodiments, R 1s is C 2~6 alkenyl, and in some embodiments, R 1s is C 2~6 haloalkenyl, and in some embodiments, R 1s is C 2~6 alkynyl, and in some embodiments, R 1s is C 2~6haloalkynyl, and in some embodiments, R 1s is C 3~6 cycloalkyl, and in some embodiments, R 1s is phenyl.

[0085] R 2s In some embodiments, R 2s is H, and in some embodiments, R 2s is D, and in some embodiments, R 2s is C 1~6 alkyl, and in some embodiments, R 2s is C 1~6 haloalkyl, and in some embodiments, R 2s is C(R 2s1 )(R 2s2 )(R 2s3 )

[0086] In some embodiments, R 2s1 is H, and in some embodiments, R 2s1 is D, and in some embodiments, R 2s1 Ha-C 0~6 Alkylene-OR x and in some embodiments, R 2s1 Ha-C 0~6 Alkylene-NR y R z and in some embodiments, R 2s1 is C 1~6 alkyl, and in some embodiments, R 2s1 is C 1~6 haloalkyl, and in some embodiments, R 2s1 is C 2~6 alkenyl, and in some embodiments, R 2s1 is C 2~6 haloalkenyl, and in some embodiments, R 2s1 is C 2~6 alkynyl, and in some embodiments, R 2s1 is C 2~6 haloalkynyl, and in some embodiments, R 2s1 is C3~6 It is cycloalkyl.

[0087] In some embodiments, R 2s2 is H, and in some embodiments, R 2s2 is D, and in some embodiments, R 2s2 is C 1~6 alkyl, and in some embodiments, R 2s2 is C 1~6 It is haloalkyl.

[0088] In some embodiments, R 2s3 is C 1~6 alkyl, and in some embodiments, R 2s3 is C 1~6 It is haloalkyl.

[0089] In some embodiments, R 2s2 and R 2s3 together with the atoms to which they are attached, C 3~6 In some embodiments, R 2s2 and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl.

[0090] In some embodiments, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, C 3~6 Forms a cycloalkyl.

[0091] In some embodiments, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8Forming a bridged bicycloalkyl, in some embodiments, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are attached form a 4- to 8-membered bridged heterocyclyl.

[0092] In some embodiments, R 1s and R 2s3 combines to form C 2~6 Forms an alkylene.

[0093] R 3s In some embodiments, R 3s is H, and in some embodiments, R 3s is D, and in some embodiments, R 3s is C 1~6 alkyl, and in some embodiments, R 3s is C 1~6 It is haloalkyl.

[0094] In some embodiments, R 2s and R 3s together with the carbon atoms to which they are attached, form C 3~6 In some embodiments, R 2s and R 3s together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl.

[0095] In some embodiments, R 1s and R 2s taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl.

[0096] In some embodiments, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 Forming a bridged bicycloalkyl, in some embodiments, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] Form.

[0097] In some embodiments, Y is CR 11 and in some embodiments, Y is N.

[0098] In some embodiments, Y2 is CR 12 and in some embodiments, Y2 is N.

[0099] In some embodiments, R 11 and R 13 is H, and in some embodiments, R 11 and R 13 is D, and in some embodiments, R 11 and R 13 is C 1~6 alkyl, and in some embodiments, R 11 and R 13 is C 1~6 It is haloalkyl.

[0100] In some embodiments, R 12 is H, and in some embodiments, R 12 is D.

[0101] Preparation of Compounds of Formula X and Example Compounds As can be understood by those skilled in the art, methods for synthesizing compounds of the formulas described herein will be clear to those skilled in the art. For example, the compounds described herein can be synthesized, for example, using one or more of the methods described herein. Synthetic chemical transformations and protecting group techniques (protection and deprotection) useful in synthesizing the compounds described herein are known in the art, and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and R.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds described herein are known, can be made by known methods, or are commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein can be replaced with art-recognized alternative equivalents. For example, in many reactions, triethylamine can be replaced with other bases, such as non-nucleophilic bases (e.g., diisopropylethylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0102] Those skilled in the art will understand, for example, 1One will recognize various analytical methods that can be used to characterize the compounds described herein, such as H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a partial list of characterization methods available to one of skill in the art and is not intended to be limiting.

[0103] The present disclosure specifically relates to the following technical solutions: 1. Compounds of formula (I): [ka] (In the formula, M1 is selected from CR1 and N; M2 is selected from CR2 and N; M3 is selected from CR3 and N; M4 is selected from CR4 and N; L is selected from a chemical bond, —O—, —S—, and —NH—; Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O)2- and [ka] is selected from Z is -C(R 2s )(R 3s )- or -N(R 2s )- and Ring A is C 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- to 10-membered heteroaryl, preferably phenyl or 5- to 9-membered heteroaryl; R a are H, D, halo, oxo, CN, NO2, NH2, -C 0~6 Alkylene -OH, -C(O)OR x , -C(O)NR y R z , -S(O)NR y R z , -S(O)NR y R z , C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, and amino protecting groups; and one, two, or three halo, oxo, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 and optionally substituted with haloalkyl, where m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R1 is H, D, halo, CN, OR x , N.R. y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, -TC 3~8 Cycloalkyl, -T-4 to 10-membered heterocyclyl, -TC6~10 aryl, and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R3 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl and C 1~6 haloalkyl; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R1 and R2 together with the carbon atoms to which they are attached represent one, two or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)H, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 Alkynyl-substituted phenyl, preferably containing one, two or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 C optionally substituted with alkynyl-substituted phenyl 5~6 forming a cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxyl, -C 1~6 Alkylene-C 1~6 Haloalkoxyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 C optionally substituted with haloalkyl 5~6 forming a cycloalkyl, a 5- to 7-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; R 1s H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 selected from cycloalkyl and phenyl; R 2s H, D, C 1~6 Alkyl, C 1~6 Haloalkyl and C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; R2s2 H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s3 is C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, Or, R 2s2 and R 2s3 together with the atoms to which they are attached, are C optionally substituted with one or two halo 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 2s1 , R 2s2 and R 2s3 together with the atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; Or, R 1s and R 2s3 may be combined with one, two or three halos, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene R 3s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3stogether with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl or 4- to 6-membered heterocyclyl; Or, R 1s and R 2s together with the nitrogen atom to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 forming a 4- to 6-membered heterocyclyl optionally substituted with haloalkyl; Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 form a bridged bicycloalkyl, or [ka] Forming Y1 is CR 11 or N, Y2 is CR 12 or N, R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; R x , R y and R z are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0104] 2. The compound of formula (I) according to Solution 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M1 is CR1.

[0105] 3. A compound of formula (I) according to Solution 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M2 is CR2.

[0106] 4. A compound of formula (I) according to any one of Solutions 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M3 is CR3.

[0107] 5. A compound of formula (I) according to any one of Solutions 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M4 is CR4.

[0108] 6. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to any one of Solutions 1 to 5, wherein L is a chemical bond.

[0109] 7. A compound of formula (I) according to any one of Solutions 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein L is -NH-.

[0110] 8. The compound of formula (I) according to any one of Solutions 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein Y is selected from —C(O)—, —C(S)—, —C(N—OH)—, —S(O)— and —S(O)—; alternatively, Y is selected from —C(O)—, —C(S)— and —C(N—OH)—; alternatively, Y is selected from —C(O)— and —C(S)—; alternatively, Y is —C(O)—.

[0111] 9.Z is -C(R 2s )(R 3s 9. The compound of formula (I) according to any one of Solutions 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein

[0112] 10.Z is -N(R 2s 9. The compound of formula (I) according to any one of Solutions 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein

[0113] 11. Ring A is selected from phenyl and 5- to 9-membered heteroaryl, and R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R atogether with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; Alternatively, ring A is selected from phenyl and 5-6 membered heteroaryl, and R a may contain one, two or three halo, oxo, or x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, and m=1, 2, or 3; Alternatively, ring A is [ka] Selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; Alternatively, ring A is [ka] Selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; Alternatively, ring A is [ka] Selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; Alternatively, ring A is [ka] Selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 2~4 Alkynyl, C 2~4 selected from haloalkynyl and Boc, and m=0, 1, 2, 3, 4 or 5; Alternatively, ring A is [ka] Selected from R a But, H, D, Halo, CN, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; Alternatively, ring A is [ka] Selected from R aBut, H, D, Halo, NO2, NH2, C 1~6 Alkyl, C 1~6 selected from haloalkyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5; Alternatively, ring A is [ka] Selected from R a But, H, D, Halo, NO2, NH2, C 1~6 Alkyl, C 1~6 selected from haloalkyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5; Alternatively, ring A is [ka] Selected from R a is selected from H, D, halo, NO2, NH2 and Boc, and m=0, 1, 2, 3, 4 or 5; Alternatively, ring A is [ka] Selected from R a But, H, D, Halo, CN, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; Alternatively, ring A is [ka] Selected from R a is selected from H, D, F, Cl, Br, CN and Me, and m=0, 1, 2, 3, 4 or 5; Alternatively, ring A is [ka] Selected from R a is selected from H, D and halo (e.g., F), and m=0, 1, 2, 3, 4, or 5; Alternatively, ring A is [ka] Selected from R a But H, D, halo (F, etc.), C 1~6 Alkyl (e.g. Me) and C 1~6 haloalkyl, where m=0, 1, 2, 3, or 4; Alternatively, ring A is [ka] Selected from R a is selected from H, D and halo (e.g., F), and m=0, 1, 2, or 3; Alternatively, ring A is [ka] and R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; Alternatively, ring A is [ka] [ka] is selected from Alternatively, ring A is [ka] [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] and Alternatively, ring A is [ka] and Alternatively, ring A is [ka] is selected from Alternatively, ring A is [ka] Selected from R a but, [ka] Preferably, R a but, [ka] where m=1, 2 or 3; Alternatively, ring A is [ka] and R a but, [ka] Preferably, R a but, [ka] Preferably [ka] Preferably, R a but, [ka] Preferably, R a but, [ka] where m=1, 2 or 3; Alternatively, ring A is [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0114] 12.R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; Alternatively, R1 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl and C 3~6 cycloalkyl; Alternatively, R1 is H, D, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl, C 1~4 Alkoxyl, C 1~4 Haloalkoxyl and C 3~6 cycloalkyl; Alternatively, R1 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C2~6 haloalkynyl; Alternatively, R1 is H, D, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; Alternatively, R1 is H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R1 may be halo, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R1 is H, D, halo, C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R1 is selected from H, D and halo; Alternatively, R1 is halo; Alternatively, R1 is selected from H, D, F, Cl, CN, Me, CH=CH2, CF3, and cyclopropyl; Alternatively, R1 is selected from H, D, F, Cl, CN, Me, CH=CH2, CF3, OMe, and cyclopropyl; Alternatively, R1 is selected from H, D, F, Cl, CN, Me, CH=CH2 and CF3; Alternatively, R1 is selected from H, D, F, Cl, Me, and CF3; Alternatively, R1 is selected from H, D, F, Cl and Me; Alternatively, R1 is selected from H, D, F, Me, and OMe; Alternatively, R1 is selected from H, D, F and Me; Alternatively, R1 is selected from H, D, Cl and Me; Alternatively, R1 is selected from H, D, F and Cl; Alternatively, R1 is selected from H, D and F; Alternatively, R1 is selected from Cl and Me; Alternatively, R1 is selected from F and Cl; Alternatively, a compound of formula (I) according to any one of Solutions 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R1 is selected from H and D.

[0115] 13.R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -TC 5~6 Cycloalkyl, -T-5 to 10-membered heterocyclyl, -TC 6~10 aryl and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 5~6 Cycloalkyl, 5-10 membered heterocyclyl, C 6~10 selected from aryl, 5- to 10-membered heteroaryl, -O-5- to 6-membered heteroaryl, -NH-5- to 6-membered heteroaryl, -OC(O)-5- to 6-membered heteroaryl, or -NHC(O)-5- to 6-membered heteroaryl; and 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; Alternatively, R2 is H, D, halo, NH2, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1, 2 or 3 halo; Alternatively, R2 is H, D, halo, NH2, -C 0~4 Alkylene -OH, -OC 1~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, C 1~4 selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1 or 2 halo; Alternatively, R2 is H, D, halo, NH2, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; Alternatively, R2 is H, D, halo, NH2, -C 0~4 Alkylene -OH, -OC 1~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 haloalkoxyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; Alternatively, R2 is H, D, halo, -C 0~4 Alkylene -OH, -OC 1~4Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 haloalkoxyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 5~6 Cycloalkyl, 5-10 membered heterocyclyl, C 6~10 selected from aryl, 5- to 10-membered heteroaryl, -O-5- to 6-membered heteroaryl, -NH-5- to 6-membered heteroaryl, -OC(O)-5- to 6-membered heteroaryl, or -NHC(O)-5- to 6-membered heteroaryl; and 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; Alternatively, R2 is H, D, halo, C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -TC 5~6 Cycloalkyl, -T-5-6 membered heterocyclyl, -TC 6~10 aryl and -T-5- to 6-membered heteroaryl, and one, two, three, four, or five halo, oxo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Alkoxyl, C 5~6 Cycloalkyl, 5-6 membered heterocyclyl, C 6~10 aryl, 5- to 6-membered heteroaryl, -O-5- to 6-membered heteroaryl, and -NH-5- to 6-membered heteroaryl; 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Alternatively, R2 is H, D, halo, NH2, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene -OH, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1, 2 or 3 halo; Alternatively, R2 is H, D, halo, NH2, -C 0~4 Alkylene -OH, -OC 1~4 Alkylene -OH, -C(O)C 1~4 Alkyl, -C(O)C 1~4 Haloalkyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, C 1~4 selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1 or 2 halo; Alternatively, R2 is H, D, halo, NH2, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene -OH, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; Alternatively, R2 is H, D, halo, NH2, -C 0~4 Alkylene -OH, -OC1~4 Alkylene -OH, -C(O)C 1~4 Alkyl, -C(O)C 1~4 Haloalkyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 haloalkoxyl; Alternatively, R2 is H, D, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; Alternatively, R2 is H, D, halo, OH, C 1~6 Alkoxy and C 1~6 haloalkoxyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] is selected from Alternatively, R2 is H, D, Cl, OH, Me, CH2F, CHF2, CF3, OMe, CH2OH, NH2, [ka] Selected from 1, 2, 3, 4 or 5 CN, halo, C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; Alternatively, R2 is H, D, halo, -C 0~6Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] Selected from 1, 2, 3, 4 or 5 CN, halo, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 optionally substituted with cycloalkyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] is selected from Alternatively, R2 is H, D, Cl, OH, NH2, Me, CH2F, CHF2, CF3, OMe, CH2OH, [ka] is selected from Alternatively, R2 is H, D, Cl, OH, Me, CH2F, CHF2, CF3, OMe, CH2OH, NH2, [ka] Select from 1, 2, 3, 4 or 5 C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] Select from 1, 2, 3, 4 or 5 C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Alternatively, R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] is selected from Alternatively, R2 is H, D, Cl, OH, NH2, Me, CH2F, CHF2, CF3, OMe, CH2OH, [ka] is selected from Alternatively, R2 is H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, NH2, [ka] is selected from Alternatively, R2 is H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, NH2, [ka] is selected from Alternatively, R2 is H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, -C(O)Me, NH2, [ka] is selected from Alternatively, R2 is selected from H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, -C(O)Me, and NH2; Alternatively, R2 is selected from H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, and NH2; Alternatively, R2 is selected from H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, and CH2OH; Alternatively, R2 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl, C 4~6 selected from cycloalkyl and 5- to 6-membered heterocyclyl; Alternatively, R2 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl and C 3~8 cycloalkyl; Alternatively, R2 is H, D, halo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; Alternatively, R2 is H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R2 is H, D, halo, OH, C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R2 is H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R2 may be C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R2 is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH2, C≡CH, [ka] is selected from Alternatively, R2 is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH2, C≡CH, [ka] is selected from Alternatively, R2 is H, D, Cl, OH, Me, CH2F 、 CHF2 and CF3, Alternatively, R2 is selected from H, D, Cl, OH, OMe, and OCHF2; Alternatively, R2 is selected from H, D, Cl, Me, and cyclopropyl; Alternatively, R2 is selected from H, D, Me, and CF3; Alternatively, R2 is selected from H, D and Me; Alternatively, R2 is selected from H and D; Alternatively, a compound of formula (I) according to any one of Solutions 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R2 is Me.

[0116] 14.R3 is H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R3 is H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R3 is selected from H, D, halo, and OH; Alternatively, R3 is selected from H, D and halo; Alternatively, R3 is H, D, halo, OH, C 1~6 Alkoxy and C 1~6 haloalkoxyl; Alternatively, R3 is H, D, halo, OH, C 1~4 Alkoxy and C 1~4 haloalkoxyl; Alternatively, R3 is selected from H, D, F, Br, OH and OMe; Alternatively, R3 is selected from H, D, F, Br and OH; Alternatively, R3 is selected from H, D, F and OH; Alternatively, R3 is selected from H, D and OH; Alternatively, R3 is selected from H, D and F; Alternatively, a compound of formula (I) according to any one of Solutions 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R3 is selected from H and D.

[0117] 15.R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R4 is selected from H, D and halo; Alternatively, R4 is selected from H, D, F and Me; Alternatively, R4 is selected from H, D and F; Alternatively, a compound of formula (I) according to any one of Solutions 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R4 is selected from H and D.

[0118] 16. R1 and R2, together with the carbon atoms to which they are attached, form a 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; Alternatively, R1 and R2 together with the carbon atoms to which they are attached form a phenyl or 5-6 membered heteroaryl; Alternatively, R1 and R2 together with the carbon atoms to which they are attached form C 5~6 forming a cycloalkyl or phenyl, Alternatively, R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may represent one, two or three halo, CN or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may form one or two Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming Alternatively, R and R together with the carbon atoms to which they are attached may represent one, two, or three halo or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may form one or two Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming Alternatively, R1 and R2, together with the carbon atoms to which they are attached, may form Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming Alternatively, R1 and R2, together with the carbon atoms to which they are attached, may form one, two, or three halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming Alternatively, R1 and R2, together with the carbon atoms to which they are attached, may form one, two, or three halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming Alternatively, R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 optionally substituted with haloalkyl [ka] Forming Alternatively, R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, CN, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] Forming Alternatively, R1 and R2 together with the carbon atoms to which they are attached may be [ka] 16. A compound of formula (I) according to any one of Solutions 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms:

[0119] 17. R2 and R3, together with the carbon atoms to which they are attached, may form one, two, three, or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxyl or -C 1~6 Alkylene-C 1~6 forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkoxyl; Alternatively, R2 and R3 together with the carbon atoms to which they are attached form C 5~6 forming a cycloalkyl or a 5- to 7-membered heterocyclyl; Alternatively, R2 and R3, together with the carbon atoms to which they are attached, may represent one, two, three, or four halo, C 1~6 Alkyl or C 1~6 forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkyl; Alternatively, R2 and R3, together with the carbon atoms to which they are attached, may represent one, two, three, or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; Alternatively, R2 and R3 together with the carbon atom to which they are attached form a 5-6 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 halo; Alternatively, R2 and R3 together with the carbon atoms to which they are attached form C 5~6 forming a cycloalkyl or a 5- to 6-membered heterocyclyl; Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] Forming Alternatively, R2 and R3 together with the carbon atoms to which they are attached represent: [ka] 17. A compound of formula (I) according to any one of Solutions 1 to 16, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms:

[0120] 18.R 1s But, H, D, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; Alternatively, R 1s But H, D, -C 0~6 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; Alternatively, R 1s But, H, D, OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; Alternatively, R 1s But C 1~6 Alkyl, C 1~6 Haloalkyl, C3~6 selected from cycloalkyl and phenyl; Alternatively, R 1s But C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; Alternatively, R 1s But C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl and C 2~4 haloalkenyl; Alternatively, R 1s But C 1~4 Alkyl, C 1~4 Haloalkyl and C 2~4 alkenyl, Alternatively, R 1s But C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 1s But C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R 1s But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 1s But H, C 1~6 Alkyl, C 1~6 haloalkyl; Alternatively, R 1s is selected from H, D, OH, Me, Et, iPr, CHF, CHF, CF, CHOH, CH=CH and C≡CH; Alternatively, R 1s is selected from H, D, OH, Me, Et, iPr, CF3, CH=CH2 and C≡CH; Alternatively, R 1s is selected from H, D, Me, CHF2 and CF3; Alternatively, R 1s is selected from H, D, Me and CHF2; Alternatively, R 1s is selected from H, Me and Et; Alternatively, R 1s is selected from H and Me; Alternatively, R 1s is selected from Me, cyclopropyl and phenyl; Alternatively, R 1s is selected from Me, Et, CHF, CHF, CF and CH=CH; Alternatively, R 1s is selected from Me, Et, CF3 and CH=CH2; Alternatively, R 1s is selected from Me and cyclopropyl; Alternatively, R 1s is selected from Me and CHF2; Alternatively, R 1s is Me, Alternatively, R 1s A compound of formula (I) according to any one of Solutions 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein

[0121] 19.R 2s But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s But H, D, C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R 2s But C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s But C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R 2s is selected from H, D and Me; Alternatively, R 2s is selected from H and D; Alternatively, R 2s 19. The compound of formula (I) according to any one of Solutions 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein

[0122] 20.R 2s is C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s1 But H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; Alternatively, R 2s1 But H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; Alternatively, R 2s1 But H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s1 But -C 0~6 Alkylene-OR x , C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; Alternatively, R 2s1 But -C 0~6 Alkylene-OH, C1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s1 But H, D, -C 0~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl and C 3~6 cycloalkyl; Alternatively, R 2s1 But H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; Alternatively, R 2s1 But H, D, -C 0~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; Alternatively, R 2s1 But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s1 But H, D, C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R 2s1 But -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s1 But -C 0~6 Alkylene-OR x , C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s1 But C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s1 is selected from H, D, OH, Me, Et, CHF, CHF, CF, CHOH, CHCHOH, C≡CH and cyclopropyl; Alternatively, R 2s1 is selected from H, D, OH, Me, Et, CHF, CHF, CF, CHOH, CHCHOH and C≡CH; Alternatively, R 2s1 is selected from H, D and Me; Alternatively, R 2s1 is selected from Me, CHF, CHOH, CHOCH and cyclopropyl; Alternatively, R 2s1 is selected from Me, CHF, CHOH and cyclopropyl; Alternatively, R 2s1 is selected from Me, Et, iPr, CHF, CHF and CHOH; Alternatively, R 2s1 is selected from Me, Et, iPr, CHF and CHF; Alternatively, R 2s1 is selected from Me and CHOH; Alternatively, R 2s1 19. The compound of formula (I) according to any one of Solutions 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein

[0123] 21.R 2s is C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s2But H, D, -C 1~4 Alkylene-OH, C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R 2s2 But H, D, C 1~6 Alkyl or C 1~6 is haloalkyl, Alternatively, R 2s2 But H, D, C 1~4 Alkyl or C 1~4 is haloalkyl, Alternatively, R 2s2 But C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s2 is selected from H, D and Me; Alternatively, R 2s2 The compound of formula (I) according to any one of Solutions 1 to 20, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein is Me.

[0124] 22.R 2s is C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s3 But C 1~6 Alkyl or C 1~6 is haloalkyl, Alternatively, R 2s3 But C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 2s3 But C 1~4 Alkyl or C 1~4 is haloalkyl, Alternatively, R 2s3 22. The compound of formula (I) according to any one of Solutions 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein

[0125] 23.R2s is C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Alternatively, R 2s2 and R 2s3 taken together with the carbon atom to which they are attached to form cyclopropyl; or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0126] 24.R 2s is C(R 2s1 )(R 2s2 )(R 2s3 ) and R 2s1 and R 2s2 together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, Alternatively, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, Alternatively, R 2s1 and R 2s2 taken together with the carbon atom to which they are attached to form cyclopropyl; or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0127] 25.R 2s is C(R 2s1 )(R 2s2 )(R 2s3 ) and R 1s and R 2s3 taken together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or two halo; Alternatively, R 1sand R 2s3 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with one or two halo; Alternatively, R 1s and R 2s3 together with the atoms to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Alternatively, R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl, Alternatively, R 1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl optionally substituted with OH; Alternatively, R 1s and R 2s3 are taken together with the atom to which they are attached to form a 4- to 5-membered heterocyclyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0128] 26.R 3s But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Alternatively, R 3s But C 1~4 Alkyl and C 1~4 haloalkyl; Alternatively, R 3s is selected from H and D; Alternatively, R 3s A compound of formula (I) according to any one of Solutions 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein is Me.

[0129] 27.R 2s and R 3stogether with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl, Alternatively, R 2s and R 3s together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~5 forming a cycloalkyl, Alternatively, R 2s and R 3s together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~4 forming a cycloalkyl, Alternatively, R 2s and R 3s together with the carbon atoms to which they are attached, C 3~4 forming a cycloalkyl, Alternatively, R 2s and R 3s together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one or two F or Me; Alternatively, R 2s and R 3s together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl optionally substituted with one or two F; Alternatively, R 2s and R 3s together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or two F; Alternatively, R 2s and R 3s taken together with the carbon atom to which they are attached form cyclopropyl. A compound of formula (I) according to any one of Solutions 1 to 26, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0130] 28.R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl, Alternatively, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, can contain one, two or three halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 4~8 forming a bridged bicycloalkyl, Alternatively, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, Alternatively, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming Alternatively, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming Alternatively, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] 28. A compound of formula (I) according to any one of Solutions 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms:

[0131] 29.R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, Alternatively, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] Forming Alternatively, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] wherein Y1 is CR 11 or N, and Y2 is CR 12 or N and R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; Alternatively, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] wherein Y1 is CR 11 and Y2 is CR 12 and R11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; Alternatively, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] wherein Y1 is CR 11 and Y2 is CR 12 and R 11 H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 and R 13 is independently selected from H and D; Alternatively, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] wherein Y1 is CR 11 and Y2 is CR 12 and R 11 , R 12 and R 13 is independently selected from H and D; or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0132] 30. The compound is: [ka] having a formula selected from wherein the variables are defined in any one of Solutions 1 to 29. A compound of formula (I) according to any one of Solutions 1 to 29, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0133] 31.Formula (II): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Y is selected from —C(O)—, —C(S)—, —C(N—OH)—, —S(O)—, and —S(O)—; Ring A is selected from phenyl and 5- to 9-membered heteroaryl; R a H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R1 and R4 are independently selected from H, D and halo; R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -TC 5~6Cycloalkyl, -T-5 to 10-membered heterocyclyl, -TC 6~10 aryl and -T-5 to 10-membered heteroaryl, and is selected from one, two, three, four, or five CN, halo, oxo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R3 is H, D, halo, CN, -C 0~6 Alkylene -OH, -C 0~6 Alkylene-NH2, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached form a 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R 1s H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R 2s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 3s is C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl, Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, form C 4~8 forming a bridged bicycloalkyl, The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0134] 32. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Y is selected from —C(O)—, —C(S)—, —C(N—OH)—, —S(O)—, and —S(O)—; Ring A is [ka] is selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R1 and R4 are independently selected from H, D and halo; R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 5~6 Cycloalkyl, 5-10 membered heterocyclyl, C 6~10 selected from aryl, 5- to 10-membered heteroaryl, -O-5- to 6-membered heteroaryl, -NH-5- to 6-membered heteroaryl, -OC(O)-5- to 6-membered heteroaryl, or -NHC(O)-5- to 6-membered heteroaryl; and 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; R3 is H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached form a 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R 1s But H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R 2s But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 3s But C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 forming a cycloalkyl, Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, The compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 31, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0135] 33.Formula (II-1): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; X is selected from O, S and N—OH; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 is selected from H, D, F and Cl; R2 is H, D, Cl, OH, Me, CH2F, CHF2, CF3, OMe, CH2OH, NH2, [ka] Selected from one, two, three, four or five CN, halo, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; R3 is selected from H, D, F, Br and OH; R4 is selected from H, D and F; or R1 and R2 together with the carbon atoms to which they are attached represent [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached are [ka] Forming R 1s is selected from H, D, OH, Me, Et, iPr, CHF, CHF, CF, CHOH, CH=CH and C≡CH; R 2s is selected from H, D and Me; R 3s is Me, Or, R 2s and R 3stogether with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one or two F or Me, Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] Forming The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0136] 34. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; X is selected from O, S and N—OH; Ring A is [ka] is selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; R1 and R4 are independently selected from H, D and halo; R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] Selected from 1, 2, 3, 4 or 5 CN, halo, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 optionally substituted with cycloalkyl; R3 is H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached form a phenyl or 5-6 membered heteroaryl; or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R 1s But H, D, -C 0~6 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; R 2s But H, D, C 1~4 Alkyl and C 1~4 haloalkyl; R 3s But C 1~4 Alkyl and C1~4 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~5 forming a cycloalkyl, Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, The compound of formula (II-1) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 33, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0137] 35.Formula (II-2): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R a is one, two or three halo, oxo, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, and m=1, 2, or 3; R1 is H, D, Halo, C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming R 1s , R 2s and R 3s are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl, The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0138] 36. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a but, [ka] where m=1, 2 or 3; R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, Halo, C 1~6 Alkyl, C 1~6Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming R 1s , R 2s and R 3s But independently, H, D, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 35, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0139] 37. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a but, [ka] where m=1, 2 or 3; R1, R2, R3 and R4 are independently selected from H, D and halo; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming R 1s But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s is independently selected from H and D; Or, R 2s and R 3s together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 36, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0140] 38. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a but, [ka] where m=1, 2 or 3; R1, R2, R3 and R4 are independently selected from H, D and halo; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming R 1s is selected from H, D, Me and CHF2; R 2s and R 3s is independently selected from H and D; Or, R 2s and R 3s together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 37, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0141] 39.Formula (II-2): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2, together with the carbon atoms to which they are attached, may form one, two, or three halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0142] 40. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 is selected from H and D; R4 is selected from H, D and halo; R 1s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 39, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0143] 41. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 is selected from H and D; R4 is selected from H, D and F; R 1s is selected from H, D, Me, CHF2 and CF3; R 2s and R 3s together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 40, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0144] 42. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2, together with the carbon atoms to which they are attached, may form one, two, or three halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R1s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 40, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0145] 43. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 is selected from H and D; R4 is selected from H, D and halo; R 1s H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 42, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0146] 44. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 is selected from H and D; R4 is selected from H, D and F; R 1s is selected from H, D, Me, CHF2 and CF3; R 2s and R 3s together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 43, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0147] 45.Formula (II-2): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 and R4 are independently selected from H, D and halo; R2 and R3, together with the carbon atoms to which they are attached, [ka] Forming R 1s is C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0148] 46. ​​M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 is a halo, R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s But C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 45, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0149] 47. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from Ra is selected from H and D, and m=1, 2 or 3; R1 is selected from F and Cl; R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s is selected from Me and CHF2; R 2s and R 3s together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 46, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0150] 48. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 and R4 are independently selected from H, D and halo; R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R1s But C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 46, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0151] 49. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 is a halo, R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s But C 1~6 Alkyl and C 1~6 haloalkyl; R 2s and R 3s together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 48, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0152] 50. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 is selected from F and Cl; R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s is selected from Me and CHF2; R 2s and R 3s together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 49, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0153] 51.Formula (II-2): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 2~4 Alkynyl, C 2~4 selected from haloalkynyl and Boc, and m=0, 1, 2, 3, 4 or 5; R1 and R4 are independently selected from H, D and halo; R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 haloalkoxyl, [ka] is selected from R3 is H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached form a phenyl or 5-6 membered heteroaryl; or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R 1s are H, D, OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; R 2s H, D, C 1~4 Alkyl and C 1~4 haloalkyl; R 3s is C 1~4 Alkyl and C 1~4 haloalkyl; Or, R 2s and R 3s together with the carbon atoms to which they are attached, form a C optionally substituted with one or two halo 3~5 forming a cycloalkyl, Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0154] 52. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 is selected from H, D, F and Cl; R2 is H, D, Cl, OH, NH2, Me, CH2F, CHF2, CF3, OMe, CH2OH, [ka] is selected from R3 is selected from H, D, F, Br and OH; R4 is selected from H, D and F; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is selected from H, D, OH, Me, Et, iPr, CHF, CHF, CF, CHOH, CH=CH and C≡CH; R 2s is selected from H, D and Me; R 3s is Me, Or, R 2s and R 3s together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl optionally substituted with one or two F; Or, R 1s , R 2s and R 3s together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 51, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0155] 53. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a But, H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2 or 3; R1 and R4 are independently selected from H, D and halo; R2 and R3 are independently H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; or R2 and R3 together with the carbon atom to which they are attached form a 5- to 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 halo; R 1s But C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl and C 2~4 haloalkenyl; R 2s and R 3s together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~4forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 51, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0156] 54. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D and halo, and m=0, 1, 2 or 3; R1 and R4 are independently selected from H, D and halo; R2 is H, D, halo, OH, C 1~4 Alkyl and C 1~4 haloalkyl; R3 is selected from H, D, halo, and OH; or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s But C 1~4 Alkyl, C 1~4 Haloalkyl and C 2~4 alkenyl, R 2s and R 3s together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~4 forming a cycloalkyl, The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 51, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0157] 55. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2 or 3; R1 is selected from H, D, F and Cl; R2 is H, D, Cl, OH, Me, CH2F 、 CHF2 and CF3, R3 is selected from H, D, F and OH; R4 is selected from H, D and F; or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is selected from Me, Et, CHF, CHF, CF and CH=CH; R 2s and R 3s together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl optionally substituted with one or two F; The compound of formula (II-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 51, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0158] 56.Formula (III-1): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a H, D, Halo, CN, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R2 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl, C 4~6 selected from cycloalkyl and 5- to 6-membered heterocyclyl; R3 is H, D, Halo, C1~6 Alkyl and C 1~6 haloalkyl; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R1 and R2 together with the carbon atoms to which they are attached form C 5~6 forming cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; Y1 is CR 11 or N, Y2 is CR 12 or N, R 11 and R 13 are independently H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 is selected from H and D; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0159] 57.Formula (III-2): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from Ra H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, or 4; R1 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 is H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R3 is selected from H and D; R4 is selected from H, D and halo; or R1 and R2 together with the carbon atoms to which they are attached represent [ka] Forming R 11 , R 12 and R 13 is independently selected from H and D; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0160] 58. Ring A is [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, selected from:

[0161] 59. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D, F and Me, where m=0, 1, 2, 3 or 4; R1 is selected from H, D, F and Me; R2 is selected from H, D, Me, and CF3; R3 is selected from H and D; R4 is selected from H, D and F; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming R 11 , R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three or four deuterium atoms.

[0162] 60. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D and halo, and m=0, 1, 2 or 3; R1 is selected from H, D and halo; R2 is Me, R3 is selected from H and D; R4 is selected from H, D and halo; R 11 , R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein Me may be substituted with one, two or three deuterium atoms.

[0163] 61. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D and F, and m=0, 1, 2 or 3; R1 is selected from H, D and F; R2 is Me, R3 is selected from H and D; R4 is selected from H, D and F; R 11 , R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein Me may be substituted with one, two or three deuterium atoms.

[0164] 62. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a But, H, D, Halo, CN, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R2 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl, C 4~6 selected from cycloalkyl and 5- to 6-membered heterocyclyl; R3 is selected from H, D and halo; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached form C 5~6 forming cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; R 11 and R 13 But independently, H, D, C 1~6 Alkyl and C 1~6haloalkyl; R 12 is selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0165] 63. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D, F, Cl, Br, CN and Me, and m=0, 1, 2, 3, 4 or 5; R1 is selected from H, D, F, Me, and OMe; R2 is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH2, C≡CH, [ka] is selected from R3 is selected from H, D and F; R4 is selected from H, D, F and Me; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming R 11 and R 13 is independently selected from H, D and Me; R12 is selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0166] 64. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a But, H, D, Halo, CN, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; R1 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl and C 3~8 cycloalkyl; R3 is selected from H, D and halo; R4 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached form C 5~6 forming a cycloalkyl or phenyl, R 11 But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0167] 65. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D, F, Cl, Br, CN and Me, and m=0, 1, 2, 3, 4 or 5; R1 is selected from H, D, F and Me; R2 is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH2, C≡CH, [ka] is selected from R3 is selected from H, D and F; R4 is selected from H, D, F and Me; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming R 11 is selected from H, D and Me; R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0168] 66. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1, R3, and R4 are independently selected from H, D, and halo; R2 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R 11 But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0169] 67. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1, R3, and R4 are independently selected from H, D, and F; R2 is selected from H, D, Cl, Me and cyclopropyl; R 11 is selected from H, D and Me; R 12 and R 13 is independently selected from H and D; The compound of formula (III-2) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 57, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0170] 68.Formula (IV): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R a is one, two or three halo, oxo, OR x , N.R. y R z , C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 3~6 selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, and m=1, 2, or 3; R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, C 1~6 Alkyl or C 1~6optionally substituted with haloalkyl [ka] Forming Or, R2 and R3 together with the carbon atom to which they are attached form C 5~6 forming a cycloalkyl or 5- to 7-membered heterocyclyl; R 1s is H, R 2s1 -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl and C 1~6 haloalkyl; R 2s2 and R 2s3 independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl, R x , R y and R z are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0171] 69. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a but, [ka] where m=1, 2 or 3; R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, OH, C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached represent one, two or three halo, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached form C 5~6 forming a cycloalkyl or 5- to 7-membered heterocyclyl; R 1s is H, R 2s1 But -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl and C 1~6 haloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C4~8 forming a bridged bicycloalkyl, R x , R y and R z However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 68, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0172] 70. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a but, [ka] where m=1, 2 or 3; R1 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 is H, D, halo, OH, C 1~6Alkoxy and C 1~6 haloalkoxyl; R3 and R4 are independently selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H, R 2s1 But -C 1~6 Alkylene-OR X , C 1~6 Alkyl and C 1~6 haloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming R x But H, C 1~6 Alkyl and C 1~6 haloalkyl; The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 69, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0173] 71. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a but, [ka] where m=1, 2 or 3; R1 is selected from H, D, Cl and Me; R2 is selected from H, D, Cl, OH, OMe, and OCHF2; R3 and R4 are independently selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H, R 2s1 is selected from Me, Et, iPr, CHF, CHF and CHOH; R2s2 and R 2s3 is independently selected from Me and Et; Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to Solution 70, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0174] 72. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a but, [ka] where m=1, 2 or 3; R1 is H, D, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 10-membered heterocyclyl; R2 is H, D, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H, R 2s1 , R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 4~8 forming a bridged bicycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 68, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0175] 73. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a but, [ka] Preferably [ka] where m=1, 2 or 3; R1 is H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 is H, D, halo, OH, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R3 and R4 are independently selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H, R 2s1 , R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 72, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0176] 74. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a but, [ka] Preferably [ka] where m=1, 2 or 3; R1 is selected from H, D, Cl and Me; R2 is selected from H, D, Cl, OH, OMe, and OCHF2; R3 and R4 are independently selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H, R 2s1 is selected from Me, Et, iPr, CHF and CHF; R 2s2 and R 2s3 is independently selected from Me and Et; Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 73, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0177] 75.Formula (IV): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 optionally substituted with haloalkyl [ka] Forming R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s is H, R 2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R 2s2 and R 2s3 independently, C 1~6 Alkyl and C 1~6haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, can contain one, two or three halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 4~8 forming a bridged bicycloalkyl, R x , R y and R z However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0178] 76. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 and R4 are independently selected from H and D; R 1s is H, R 2s1 is selected from Me, CHF, CHOH, CHOCH and cyclopropyl; R 2s2 and R 2s3 But it is Me, Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 75, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0179] 77. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2, together with the carbon atoms to which they are attached, may form one, two, or three halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 optionally substituted with haloalkyl [ka] Forming R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s is H, R 2s1 But H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6cycloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, can contain one, two or three halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 4~8 forming a bridged bicycloalkyl, R x , R y and R z However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 75, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0180] 78. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 and R4 are independently selected from H and D; R 1s is H, R 2s1 But -C 0~6 Alkylene-OR x , C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming R x But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 selected from cycloalkyl and 4- to 6-membered heterocyclyl; The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 77, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0181] 79. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 and R4 are independently selected from H and D; R 1s is H, R 2s1is selected from Me, CHF, CHOH, CHOCH and cyclopropyl; R 2s2 and R 2s3 But it is Me, Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 78, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0182] 80. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2, together with the carbon atoms to which they are attached, may represent one, two or three halo, CN, C 1~6 Alkyl or C1~6 optionally substituted with haloalkyl [ka] Forming R3 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s is H, R 2s1 But H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, can contain one, two or three halo, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 4~8 forming a bridged bicycloalkyl, R x , R y and R z However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 75, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0183] 81. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 and R4 are independently selected from H and D; R 1s is H, R 2s1 But -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6haloalkyl; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 80, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0184] 82. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 and R2 together with the carbon atoms to which they are attached form [ka] Forming R3 and R4 are independently selected from H and D; R 1s is H, R 2s1is selected from Me, CHF, CHOH and cyclopropyl; R 2s2 and R 2s3 But it is Me, Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 81, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0185] 83.Formula (IV): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 and R3, together with the carbon atoms to which they are attached, [ka] Forming R 1s is H, C 1~6 Alkyl, C 1~6 haloalkyl; R 2s1 H, D, -C 0~6 Alkylene-OR x , -C 0~6 Alkylene-NR y R z , C 1~6 Alkyl and C 1~6 haloalkyl; R 2s2 and R 2s3 independently, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with OH; R 2s1 and R 2s2 together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, R x , R y and R z However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 cycloalkyl and 4- to 6-membered heterocyclyl, or R y and R z together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0186] 84. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1, Halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s But H, C 1~6 Alkyl, C 1~6 haloalkyl; R 2s1 But -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; R1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl optionally substituted with OH; R 2s1 and R 2s2 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 83, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0187] 85. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=1, 2 or 3; R1 is selected from Cl and Me; R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s is selected from H, Me and Et; R 2s1 is selected from Me and CHOH; R 2s2 is Me, R 2s3 is Me, R 1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl optionally substituted with OH; R 2s1 and R 2s2 together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 84, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0188] 86. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=1, 2 or 3; R1 and R4 are independently H, D, halo, C 1~6 Alkyl and C 1~6 haloalkyl; R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s But H, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s1 But -C 0~6 Alkylene-OH, C 1~6 Alkyl and C1~6 haloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 83, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0189] 87. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=1, 2 or 3; R1 is a halo, R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s But H, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s1 But -C 0~6 Alkylene-OH, C 1~6Alkyl and C 1~6 haloalkyl; R 2s2 and R 2s3 But independently, C 1~6 Alkyl and C 1~6 haloalkyl; R 1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 86, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0190] 88. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A [ka] and R a is selected from H and D, and m=1, 2 or 3; R1 is Cl, R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R4 is selected from H and D; R 1s is selected from H and Me; R 2s1 is selected from Me and CHOH; R 2s2 is Me, R2s3 is Me, R 1s and R 2s3 together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 87, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0191] 89.Formula (IV): [ka] (In the formula, M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] [ka] is selected from R a H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; R1 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl and C 3~6 cycloalkyl; R2 is H, D, halo, NH2, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene -OH, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1, 2 or 3 halo; R3 is H, D, halo, OH, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R4 is selected from H, D and halo; or R1 and R2, together with the carbon atoms to which they are attached, may represent one, two, or three halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming or R2 and R3, together with the carbon atoms to which they are attached, represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene-C 1~6 Alkoxy or -C 1~6 Alkylene-C 1~6 forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkoxyl; R 1s is H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 H, D, -C0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl and C 3~6 cycloalkyl; R 2s2 H, D, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s3 is C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form a C optionally substituted with one or two halo 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl, The groups described above may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0192] 90. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] [ka] is selected from R a is selected from H, D and halo, and m=0, 1, 2, 3, 4 or 5; R1 is H, D, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl, C 1~4 Alkoxyl, C 1~4 Haloalkoxyl and C 3~6 cycloalkyl; R2 is H, D, halo, NH2, -C 0~4 Alkylene -OH, -OC 1~4 Alkylene -OH, -C(O)C 1~4 Alkyl, -C(O)C 1~4 Haloalkyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxyl, C 1~4 selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1 or 2 halo; R3 is H, D, halo, OH, C 1~4 Alkoxy and C 1~4 haloalkoxyl; R4 is selected from H, D and halo; or R1 and R2 together with the carbon atoms to which they are attached form one or two Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkylene -OH, -C 1~4 Alkylene-C 1~4 Alkoxy or -C 1~4 Alkylene-C 1~4 forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkoxyl; R 1s But H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 But H, D, -C 0~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl and C 3~6 cycloalkyl; R 2s2 But H, D, C 1~4 Alkyl or C 1~4 is haloalkyl, R 2s3 But C 1~4 Alkyl or C 1~4 is haloalkyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R 2s2 and R 2s3together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~6 forming a cycloalkyl, Or, R 2s1 , R 2s2 and R 2s3 together with the carbon atoms to which they are attached, form one or two halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 C optionally substituted with haloalkynyl 4~8 forming a bridged bicycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0193] 91. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 is selected from H, D, F, Cl, CN, Me, CH=CH2, CF3 and cyclopropyl; R2 is H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, -C(O)Me, NH2, [ka] is selected from R3 is selected from H, D, F, Br, OH and OMe; R4 is selected from H, D and F; or R1 and R2 together with the carbon atoms to which they are attached represent Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s But H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 is selected from H, D, OH, Me, Et, CHF, CHF, CF, CHOH, CHCHOH, C≡CH and cyclopropyl; R 2s2 is selected from H, D and Me; R 2s3 is Me, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, Or, R 2s1 , R 2s2 and R2s3 together with the carbon atoms to which they are attached, [ka] Forming The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0194] 92. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a But, H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; R1 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl and C 3~6 cycloalkyl; R2 is H, D, halo, NH2, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene -OH, -C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, C1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R3 is H, D, halo, OH, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R4 is selected from H, D and halo; or R1 and R2, together with the carbon atoms to which they are attached, represent one, two, or three halo or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl or C 1~6 forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkyl; R 1s But H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 But H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R 2s2 But C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s3 But C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 1s and R 2s3together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~6 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0195] 93. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D and halo, and m=0, 1, 2, 3, 4 or 5; R1 is H, D, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl, C 2~4 Haloalkynyl, C 1~4 Alkoxyl, C 1~4 Haloalkoxyl and C 3~6 cycloalkyl; R2 is H, D, halo, NH2, -C 0~4 Alkylene -OH, -OC 1~4 Alkylene -OH, -C(O)C 1~4Alkyl, -C(O)C 1~4 Haloalkyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 haloalkoxyl; R3 is H, D, halo, OH, C 1~4 Alkoxy and C 1~4 haloalkoxyl; R4 is selected from H, D and halo; or R1 and R2 together with the carbon atoms to which they are attached form one or two Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl or C 1~6 forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkyl; R 1s But H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 But H, D, -C 0~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; R 2s2 But C 1~4 Alkyl or C 1~4 is haloalkyl, R 2s3 But C 1~4 Alkyl or C 1~4 is haloalkyl, Or, R 1s and R2s3 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~6 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0196] 94. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 is selected from H, D, F, Cl, CN, Me, CH=CH2, CF3, OMe and cyclopropyl; R2 is selected from H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, CH2OH, -C(O)Me and NH2; R3 is selected from H, D, F, Br, OH and OMe; R4 is selected from H, D and F; or R1 and R2 together with the carbon atoms to which they are attached form one or two Br or C 2~6 Optionally substituted with alkynyl-substituted phenyl [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H or Me, R 2s1 is selected from H, D, OH, Me, Et, CHF, CHF, CF, CHOH, CHCHOH and C≡CH; R 2s2 is Me, R 2s3 is Me, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl and cyclopentyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0197] 95. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a But, H, D, Halo, C 1~6 Alkyl and C 1~6 haloalkyl, where m=0, 1, 2, 3, 4, or 5; R1 is H, D, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R2 is H, D, halo, -C 0~6 Alkylene -OH, -OC 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxyl; R3 is selected from H, D, halo, and OH; R4 is selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s But H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 But H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl and C2~6 haloalkynyl; R 2s2 But C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s3 But C 1~6 Alkyl or C 1~6 is haloalkyl, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~5 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0198] 96. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D and halo, and m=0, 1, 2, 3, 4 or 5; R1 is H, D, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~6 Alkenyl, C 2~6Haloalkenyl, C 2~6 Alkynyl and C 2~6 haloalkynyl; R2 is H, D, halo, -C 0~4 Alkylene -OH, -OC 1~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 haloalkoxyl; R3 is selected from H, D, halo, and OH; R4 is selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s But H, C 1~6 Alkyl or C 1~6 is haloalkyl, R 2s1 But H, D, -C 0~4 Alkylene-OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Haloalkenyl, C 2~4 Alkynyl and C 2~4 haloalkynyl; R 2s2 But C 1~4 Alkyl or C 1~4 is haloalkyl, R 2s3 But C 1~4 Alkyl or C 1~4 is haloalkyl, Or, R 1s and R 2s3together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R 2s2 and R 2s3 together with the carbon atoms to which they are attached, optionally substituted with one or two halo groups. 3~5 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0199] 97. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 is selected from H, D, F, Cl, CN, Me, CH=CH2 and CF3; R2 is selected from H, D, Cl, Br, OH, Me, CH2F, CHF2, CF3, OMe, OCH2CH2OH, and CH2OH; R3 is selected from H, D, F, Br and OH; R4 is selected from H and D; or R1 and R2 together with the carbon atoms to which they are attached [ka] Forming or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s is H or Me, R 2s1 is selected from H, D, OH, Me, Et, CHF, CHF, CF, CHOH, CHCHOH and C≡CH; R 2s2 is Me, R 2s3 is Me, Or, R 1s and R 2s3 together with the atoms to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Or, R 2s2 and R 2s3 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl and cyclopentyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 89, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0200] 98.R 1s and R 2s3 are bonded to one, two or three halo, OH, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated; The compound of formula (IV) according to Solution 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the other variables are defined in any one of Solutions 1 to 29.

[0201] 99. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a But, H, D, halo, NO2, NH2, -C 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 haloalkynyl and amino protecting groups, and m=0, 1, 2, 3, 4, or 5, or two adjacent R a together with the atom to which they are attached form phenyl or 5- to 6-membered heteroaryl; R1 and R4 are independently selected from H, D and halo; R2 is H, D, halo, -C 0~6 Alkylene-OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 5~6 Cycloalkyl, 5-10 membered heterocyclyl, C 6~10selected from aryl, 5- to 10-membered heteroaryl, -O-5- to 6-membered heteroaryl, -NH-5- to 6-membered heteroaryl, -OC(O)-5- to 6-membered heteroaryl, or -NHC(O)-5- to 6-membered heteroaryl; and 1~6 Alkylene-OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; R3 is H, D, halo, OH, C 1~6 Alkyl and C 1~6 haloalkyl; or R2 and R3 together with the carbon atoms to which they are attached represent one, two, three or four halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl or -C(O)C 1~6 forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R 1s and R 2s3 are bonded to one, two or three halo, OH, C 1~6 Alkyl or C 1~6 C optionally substituted with haloalkyl 2~6 Forming an alkylene R 2s1 But H, D, C 1~6 Alkyl and C 1~6 haloalkyl; R 2s2 But H, D, -C 0~6 Alkylene-OH, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, C 3~6 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 98, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0202] 100. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H, D and halo, and m=0, 1, 2 or 3; R1 is selected from H, D and halo; R2 is H, D, Halo, C 1~4 Alkyl and C 1~4 haloalkyl; R3 is selected from H, D and halo; R4 is selected from H and D; or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s and R 2s3 can be bonded to one, two or three halo, OH, C 1~4 Alkyl or C 1~4 C optionally substituted with haloalkyl 2~4 Forming an alkylene R 2s1 But H, D, C 1~4 Alkyl and C 1~4 haloalkyl; R2s2 But H, D, -C 1~4 Alkylene-OH, C 1~4 Alkyl and C 1~4 haloalkyl; Or, R 2s1 and R 2s2 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 98, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0203] 101. M1 is selected from CR1 and N, preferably CR1; M2 is selected from CR2 and N, preferably CR2; M3 is selected from CR3 and N, preferably CR3; M4 is selected from CR4 and N, preferably CR4; Ring A is [ka] is selected from R a is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R1 is Cl, R2 is Cl; R3 is selected from H and D; R4 is selected from H and D; or R2 and R3 together with the carbon atoms to which they are attached [ka] Forming R 1s and R 2s3 is bonded to a C optionally substituted with one or two OH 2~3 Forming an alkylene R 2s1 is selected from H, D and Me; R 2s2 is selected from H, D, Me and CHOH; Or, R 2s1 and R 2s2 together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof as described in Solution 98, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

[0204] 102. A compound selected from the group consisting of the compounds set forth in Tables 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

[0205] 103. A compound according to any one of Solutions 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof; a pharmaceutically acceptable excipient, and optionally one or more other therapeutic agents A pharmaceutical composition comprising:

[0206] 104. a first container comprising the compound of any one of Solutions 1-102 or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof; optionally, a second container containing one or more other therapeutic agents; and Optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound and / or other therapeutic agent. A kit comprising:

[0207] 105. Use of a compound according to any one of Solutions 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, in the manufacture of a medicament for treating an immune and / or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

[0208] 106. A compound according to any one of Solutions 1-102 or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof for use in treating an immune and / or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

[0209] 107. A method for treating an immune and / or inflammatory-related disease, disorder, or condition caused by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling in a subject in need thereof, comprising administering to the subject a compound described in any one of Solutions 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

[0210] 108. The use according to solution 105, or the compound for use according to solution 106, or the method according to solution 107, wherein said disease, disorder or condition is selected from sepsis, cancer, systemic lupus erythematosus, spiroandenoma, spiroandenocarcinoma, Kawasaki disease, ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine) syndrome, PFAPA (periodic fevers, aphthous stomatitis, pharyngitis and lymphadenitis) syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease.

[0211] 109. The use or compound or method for use according to solution 108, wherein said cancer is selected from lung cancer, colon cancer and oral squamous cell carcinoma.

[0212] 110. The use or compound or method for use according to solution 108, wherein said disease or disorder is ROSAH.

[0213] 111. The use or compound or method for use according to solution 108, wherein said disease or disorder is PFAPA.

[0214] 112. The use or compound or method for use according to solution 108, wherein said disease or disorder is spiradenoma or spiradenoma carcinoma.

[0215] 113. The use or compound or method for use according to solution 108, wherein said disease or disorder is sepsis.

[0216] 114. The use or compound or method for use according to solution 108, wherein said disease or disorder is systemic lupus erythematosus.

[0217] 115. The use or compound or method for use according to solution 108, wherein said disease or disorder is Kawasaki disease.

[0218] 116. The use or compound or method for use according to solution 108, wherein the subject carries one or more genetic mutations in ALPK1.

[0219] Reverse Amide (Example A) General method 1 [ka] Halogenation of compound 1-1 with or without Pd catalysis yields compound 1-2, which is further coupled with amines in the presence of coupling reagents such as HATU, HOBt, etc. Compound 1-4 was synthesized from compound 1-3 and key intermediates such as boric acid / ester, tin, etc. in the presence of Pd or Cu and other heavy metals as catalysts.

[0220] Example 1: Preparation of N-(tert-butyl)-2,3-dichloro-4-hydroxy-6-(1H-pyrazol-1-yl)benzamide (Compound A10) [ka] Step 1: Synthesis of 2,3-dichloro-6-iodo-4-methoxy-benzoic acid [ka] A mixture of 2,3-dichloro-4-methoxybenzoic acid (300 mg, 1.36 mmol), NIS (610.71 mg, 2.71 mmol), and Pd(OAc) (30.47 mg, 135.72 μmol) in DMF (3 mL) was stirred at 60 °C for 12 h. The resulting mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EA / PE, 0-100%) to give the title compound (300 mg, 63.71% yield) as a white solid.

[0221] Step 2: Synthesis of N-tert-butyl-2,3-dichloro-6-iodo-4-methoxy-benzamide [ka] A mixture of 2,3-dichloro-6-iodo-4-methoxybenzoic acid (300 mg, 864.72 μmol), DIPEA (223.52 mg, 1.73 mmol), HATU (493.19 mg, 1.30 mmol), and 2-methylpropan-2-amine (63.24 mg, 864.72 μmol) in DMF (3 mL) was stirred at 50 °C for 2 h, then diluted with water (10 mL), extracted with EA (10 mL × 3), and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EA / PE, 0-50%) to give the title compound (270 mg, 77.66% yield) as a white solid.

[0222] Step 3: Synthesis of N-(tert-butyl)-2,3-dichloro-4-methoxy-6-(pyrazol-1-yl)-benzamide [ka] A mixture of N-tert-butyl-2,3-dichloro-6-iodo-4-methoxy-benzamide (100 mg, 248.72 μmol), CsCO (162.08 mg, 497.44 μmol), CuI (4.74 mg, 24.87 μmol), and 1H-pyrazole (16.93 mg, 248.72 μmol) in DMF (2 mL) was stirred at 110 °C for 2 h. The resulting mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EA / PE, 0-30%) to give the title compound (60 mg, 70.49% yield) as a white solid.

[0223] Step 4: Synthesis of N-(tert-butyl)-2,3-dichloro-4-hydroxy-6-(pyrazol-1-yl)-benzamide [ka] To a solution of N-tert-butyl-2,3-dichloro-4-methoxy-6-pyrazol-1-yl-benzamide (60 mg, 175.33 μmol) in DCM (2 mL) was added BBr3 (87.85 mg, 350.65 μmol) at 0° C. The mixture was stirred at 0° C. for 2 h, then diluted with MeOH (10 mL) and concentrated in vacuo to give a residue which was purified by preparative HPLC (0-90% water in acetonitrile) to give the title compound (4 mg, 6.95% yield) as a white solid.

[0224] Example 2: Preparation of N-(tert-butyl)-4-chloro-6-(thiazol-4-yl)-2,3-dihydrobenzofuran-5-carboxamide (Compound A6) [ka] Step 1: Synthesis of 2-(3-bromo-2-chloro-6-fluorophenyl)ethan-1-ol [ka] To a solution of 1-bromo-2-chloro-4-fluorobenzene (75.0 g, 358 mmol) in DMF (750 mL) was added LDA (2 M in THF, 215 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 3 h, followed by the addition of oxirane (31.5 g, 716 mmol) at −78° C., and then warmed to 25° C. and stirred for 9 h. The mixture was quenched by the addition of saturated aqueous NH4Cl (1 L) at 0° C. and extracted with EtOAc (600 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by column chromatography eluting with EA in PE from 25 to 100% to give the title compound (41.0 g, 45% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.81 - 7.59(m,1H),7.31 - 7.09(m,1H),5.02 - 4.81(m,1H),3.77 - 3.48(m,2H),3.15 - 2.86(m,2H).

[0225] Step 2: Synthesis of 5-bromo-4-chloro-2,3-dihydrobenzofuran [ka] To a solution of 2-(3-bromo-2-chloro-6-fluorophenyl)ethan-1-ol (40.0 g, 158 mmol) in THF (300 mL) was added dropwise NaH (14.2 g, 355 mmol, 60% purity) at 0 °C. The mixture was stirred at 75 °C for 12 h, then quenched by the addition of saturated aqueous NH4Cl (500 mL) at 0 °C, extracted with EtOAc (300 mL × 3), and the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography eluting with 25-100% EA in PE to give the title compound (22.0 g, 63% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.45(d,J=8.4 Hz,1H),6.72(d,J=8.4 Hz,1H),4.63(t,J=8.4 Hz,2H),3.27(t,J=8.4 Hz,2H).

[0226] Step 3: Synthesis of methyl 4-chloro-2,3-dihydrobenzofuran-5-carboxylate [ka] To a solution of 5-bromo-4-chloro-2,3-dihydrobenzofuran (22.0 g, 93.9 mmol) in THF (220 mL) was added n-BuLi (2.5 M in hexane, 41.4 mL) dropwise at −78° C. After the mixture was stirred at −78° C. for 1 h, methyl carbonochloridate (13.3 g, 142 mmol, 10.9 mL) was added at −78° C. The reaction was warmed to 25° C. and stirred for 15 h, then quenched by the addition of saturated aqueous NH4Cl (500 mL) at 0° C. and extracted with EtOAc (300 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue that was purified by column chromatography eluting with EA in PE (25-100%) to give the title compound (10.0 g, 50% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.73(d,J=8.4 Hz,1H),6.82(d,J=8.4 Hz,1H),4.69(t,J=8.8 Hz,2H),3.80(s,3H),3.25(t,J=8.7 Hz,2H).MS(ESI)m / z [M+H] + 213.1, 215.1(Cl).

[0227] Step 4: Synthesis of 4-chloro-2,3-dihydrobenzofuran-5-carboxylic acid [ka] A mixture of methyl 4-chloro-2,3-dihydrobenzofuran-5-carboxylate (10.0 g, 47.2 mmol) and LiOH (3.38 g, 141 mmol) in MeOH (100 mL) and water (20 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH, and the residue was diluted with water (80 mL) and extracted with DCM (60 mL × 3). The aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (5.00 g, 54% yield) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 13.43 - 12.26(m,1H),7.73(d,J=8.3 Hz,1H),6.80(d,J=8.5 Hz,1H),4.68(t,J=8.8 Hz,2H),3.24(t,J=8.8 Hz,2H).MS(ESI)m / z [MH] - 197.0, 199.0 (Cl).

[0228] Step 5: Synthesis of 4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxylic acid [ka] A mixture of 4-chloro-2,3-dihydrobenzofuran-5-carboxylic acid (600 mg, 2.09 mmol), iodobenzene diacetate (1.62 g, 5.04 mol), I2 (1.28 g, 5.04 mol), and Pd(OAc)2 (113 mg, 505 μmol) in DMF (12 mL) was stirred at 40 °C for 12 h. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 um; mobile phase: [water(HCl)-ACN]; B%: 20%~55%, 8 min) to give the title compound (300 mg, 31% yield) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.24(s,1H),4.63(t,J=8.8 Hz,2H),3.19(t,J=8.7 Hz,2H).MS(ESI)m / z [MH] -322.9, 324.8(Cl).

[0229] Step 6: Synthesis of N-(tert-butyl)-4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxamide [ka] A mixture of 4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxylic acid (300 mg, 925 μmol), HATU (527 mg, 139 μmol), and DIPEA (239 mg, 185 μmol, 322 μL) in DCM (3 mL) was stirred at 25° C. for 0.5 h, and then 2-methylpropan-2-amine (81.2 mg, 1.11 mmol, 117 μL) was added. The reaction was stirred at 25° C. for 15.5 h, then quenched by adding water (10 mL) at 25° C. and extracted with DCM (6 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%~70%, 8 min) to give the title compound (148.5 mg, yield 42%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 18.01(s,1H),7.18(s,1H),4.61(t,J=8.7 Hz,2H),3.16(t,J=8.8 Hz,2H),1.34(s,9H).MS(ESI)m / z [MH] - 377.9, 379.9 (Cl).

[0230] Step 7: Synthesis of N-(tert-butyl)-4-chloro-6-(thiazol-4-yl)-2,3-dihydrobenzofuran-5-carboxamide [ka] A mixture of N-(tert-butyl)-4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxamide (25 mg, 65.9 μmol), 4-(tributylstannyl)thiazole (29.6 mg, 79.0 μmol), and Pd(PPh3)4 (7.61 mg, 6.59 μmol) in dioxane (0.2 mL) was stirred at 110° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%~65%, 8 min) to give the title compound (2.0 mg, 9% yield) as a pale yellow solid. 1 H NMR(400 MHz,MeOD)δ 9.13 - 8.96(m,1H),7.77(s,1H),7.06(s,1H),4.67(t,J=8.8 Hz,2H),3.30 - 3.27(m,2H),1.31(s,9H).MS(ESI)m / z [M+H] + 337.0,339.0(Cl).

[0231] Example 3: Preparation of 5-bromo-N-(tert-butyl)-2-(2-ethynylphenyl)-1-naphthamide (compound A47) [ka] Step 1: Synthesis of 5-bromo-2-iodo-1-naphthoic acid [ka] To a solution of 5-bromonaphthalene-1-carboxylic acid (1 g, 3.98 mmol) in DMF (30 mL) was added NIS (1.08 g, 4.78 mmol) and Pd(OAc) (89.42 mg, 398.29 μmol) at room temperature. The mixture was stirred at 65 °C for 4 hours. The crude mixture was concentrated and purified by column chromatography (PE / EA = 1 / 1) to give the title compound (550 mg, 36.63% yield) as an off-white solid. MS (ESI) m / z [M+H] + 376.9, 378.9 (Br).

[0232] Step 2: Synthesis of 5-bromo-N-(tert-butyl)-2-iodo-1-naphthamide [ka] To a solution of 5-bromo-2-iodo-naphthalene-1-carboxylic acid (200 mg, 530.54 μmol) and 2-methylpropan-2-amine (388.02 mg, 5.31 mmol) in DMF (5 mL), N-ethyl-N-isopropyl-propan-2-amine (274.28 mg, 2.12 mmol, 369.64 μL) and HATU (403.46 mg, 1.06 mmol) were added at room temperature. The mixture was stirred at 70 °C for 4 h, then concentrated and purified by preparative HPLC (0.5% FA in MeCN with water = 95% to 10%) to give the title compound (200 mg, 87.24% yield) as a white solid. MS (ESI) m / z [M+H] + 431.9,433.9(Br).

[0233] Step 3: Synthesis of 5-bromo-N-(tert-butyl)-2-(2-((trimethylsilyl)ethynyl)phenyl)-1-naphthamide [ka] To a solution of trimethyl-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethynyl]silane (120 mg, 399.63 μmol) and 5-bromo-N-tert-butyl-2-iodo-naphthalene-1-carboxamide (220 mg, 509.15 μmol) in dioxane (5 mL) and water (1 mL), Pd(dppf)Cl (29.24 mg, 39.96 μmol) and NaCO (84.71 mg, 799.27 μmol) were added at room temperature. The mixture was stirred at 80 °C for 2 hours. The crude mixture was purified by silica gel column (PE / EA = 10 / 1) to give the title compound (70 mg, 36.61% yield) as a white solid.

[0234] Step 4: Synthesis of 5-bromo-N-(tert-butyl)-2-(2-ethynylphenyl)-1-naphthamide [ka] To a solution of 5-bromo-N-tert-butyl-2-[2-(2-trimethylsilylethynyl)phenyl]naphthalene-1-carboxamide (35 mg, 73.15 μmol) in THF (2 mL) was added N,N-diethylethanamine trihydrofluoride (990 mg, 6.14 mmol) at room temperature. The mixture was stirred at 50° C. overnight, then concentrated and purified by preparative HPLC to give the title compound (8 mg, 26.92% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.19(d,J=8.8 Hz,1H),7.95(dd,J=14.6,7.9 Hz,2H),7.88(s,1H),7.65(d,J=8.7 Hz,1H),7.62 - 7.58(m,1H),7.55(dd,J=10.6,5.2 Hz,2H),7.44(dd,J=7.4,1.6 Hz,2H),4.00(s,1H),1.16(s,9H).MS(ESI)m / z [M+H] + 406.0,408.0(Br).

[0235] The following compounds (A1-A159) in Table 1 were synthesized using the appropriate starting materials and corresponding intermediates in a similar manner as described for Examples 1, 2, and 3.

[0236] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16

[0237] General Method 2

change

[0238] Example 4: Preparation of N-(tert-butyl)-5-chloro-7-(1H-pyrazol-1-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (compound A180) [ka] Step 1: Synthesis of 2-chloro-6-iodo-3,4-dimethoxybenzoic acid [ka] To a solution of 2-chloro-3,4-dimethoxy-benzoic acid (3 g, 13.85 mmol) and Pd(OAc) (621.85 mg, 2.77 mmol) in DMF (40 mL) was added NIS (4.05 g, 18.00 mmol) at room temperature, then stirred at 60° C. for 28 h. The mixture was concentrated and purified by C-flash chromatography (0-30% ACN in water) to give the title compound (3 g, 63.24% yield) as a yellow solid.

[0239] Step 2: Synthesis of N-(tert-butyl)-2-chloro-6-iodo-3,4-dimethoxybenzamide [ka] To a solution of 2-chloro-6-iodo-3,4-dimethoxybenzoic acid (1 g, 2.92 mmol), 2-methylpropan-2-amine (427.06 mg, 5.84 mmol), and DIPEA (1.13 g, 8.76 mmol) in DMF (10 mL) was added HATU (1.33 g, 3.50 mmol) at room temperature. The mixture was then stirred for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (60 mL × 2). The combined organic layers were concentrated and purified by silica gel chromatography (0-40% EA in PE) to give the title compound (830 mg, 71.49% yield) as a yellow solid.

[0240] Step 3: Synthesis of N-(tert-butyl)-2-chloro-3,4-dihydroxy-6-iodobenzamide [ka] To a solution of N-tert-butyl-2-chloro-6-iodo-3,4-dimethoxy-benzamide (830 mg, 2.09 mmol) in DCM (5 mL) was added BBr (2.09 g, 8.35 mmol) at room temperature, followed by stirring at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (60 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by silica gel chromatography (0-100% EA in PE) to give the title compound (700 mg, 90.74% yield) as a yellow solid.

[0241] Step 4: Synthesis of N-(tert-butyl)-5-chloro-7-iodo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide [ka] To a solution of N-tert-butyl-2-chloro-3,4-dihydroxy-6-iodo-benzamide (350 mg, 947.02 μmol) in DMF (5 mL) was added 1,2-dibromoethane (355.81 mg, 1.89 mmol) at room temperature, followed by stirring at 80° C. for 2 h. The reaction mixture was diluted with water (40 mL) and extracted with EA (40 mL × 2). The combined organic layers were concentrated and purified by silica gel chromatography (0-100% EA in PE) to give the title compound (280 mg, 74.73% yield) as a yellow solid.

[0242] Step 5: Synthesis of N-(tert-butyl)-5-chloro-7-(1H-pyrazol-1-yl)-2,3-dihydrobenzo-[b][1,4]dioxine-6-carboxamide (Compound A180) [ka] To a solution of N-(tert-butyl)-5-chloro-7-iodo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (62 mg, 157.24 μmol) and 1H-pyrazole (21.41 mg, 314.47 μmol) in DMF (3 mL), CuI (5.99 mg, 31.45 μmol) and CsCO (102.46 mg, 314.47 μmol) were added at room temperature under nitrogen, and the mixture was stirred at 90 °C for 3 h. The crude product was purified by C18 flash chromatography (0–70% ACN in water) to give the title compound (15.94 mg, 30.18% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.09(s,1H),7.94(d,J=2.4 Hz,1H),7.65(d,J=1.6 Hz,1H),7.05(s,1H),6.42(t,J=2.4 Hz,1H),4.43 - 4.38(m,2H),4.36 - 4.32(dd,J=5.2,2.2 Hz,2H),1.20(s,9H).MS(ESI)m / z [M+H] + 336.1, 338.1(Cl).

[0243] Example 5: Preparation of N-(tert-butyl)-5-chloro-7-(1H-imidazol-2-yl)-2,3-dihydrobenzo-[b][1,4]dioxine-6-carboxamide (Compound A200) [ka] Step 1: Synthesis of 2-(tributylstannyl)-1H-imidazole [ka] To a solution of 2-bromo-1H-imidazole (300 mg, 2.04 mmol) in THF (4 mL) was added n-BuLi (2.5 M in hexane, 0.9 mL) dropwise under a N atmosphere at −78° C., followed by stirring at −78° C. for 1 h. Then, BuSnCl (797.30 mg, 2.45 mmol) was added dropwise, followed by stirring at −78° C. for another 30 min and then at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with EA (15 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and then concentrated in vacuo to give the crude title compound (700 mg, 96.03% yield), which was used without further purification.

[0244] Step 2: Synthesis of N-(tert-butyl)-5-chloro-7-(1H-imidazol-2-yl)-2,3-dihydro-benzo[b][1,4]dioxine-6-carboxamide (Compound A200) [ka] A mixture of Pd(PPh)4 (26.28 mg, 22.75 μmol), N-tert-butyl-5-chloro-7-iodo-2,3-dihydro-1,4-benzodioxine-6-carboxamide (90 mg, 227.49 μmol), tributyl(1H-imidazol-2-yl)stannane (162.48 mg, 454.98 μmol), LiCl (28.93 mg, 682.47 μmol), and CuI (8.67 mg, 45.50 μmol) in dioxane (4 mL) was stirred at 100 °C under nitrogen for 8 h. The resulting mixture was concentrated and purified by C18 flash chromatography (0–30% ACN in water) to give the title compound (20 mg, 26.18% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 11.53(s,1H),7.94(s,1H),7.20(s,1H),7.15(s,1H),6.95(s,1H),4.39(d,J=2.8 Hz,2H),4.32(d,J=2.7 Hz,2H),1.28(s,9H).MS(ESI)m / z [M+H] + 336.1, 338.1(Cl).

[0245] The following compounds (A160-A250) in Table 2 were synthesized in a similar manner as described for Examples 4 and 5 using the appropriate starting materials and corresponding intermediates.

[0246] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0247] General method 3 [ka] Compound 3-1 was iodinated with NIS / or I2 in the presence of catalytic Pd to form compound 3-2, which was further coupled with an amine intermediate in the presence of coupling reagents such as HATU or HOBt to form intermediate 3-3. Under heavy metal catalysis or basic conditions, intermediate 3-3 was further activated to a borate / OTf intermediate, which was further coupled with another borate / halide intermediate to form final product 3-4.

[0248] Example 6: Preparation of N-(tert-butyl)-2-methyl-6-(1H-pyrazol-1-yl)-3-(1H-pyrazol-3-yl)benzamide (compound A263) [ka] Step 1: Synthesis of 3-bromo-6-iodo-2-methylbenzoic acid [ka] To a solution of 3-bromo-2-methylbenzoic acid (5 g, 23.26 mmol) and Pd(OAc)2 (387.21 mg, 2.33 mmol) in DMF (45 mL) was added NIS (8.53 g, 27.91 mmol) at room temperature. The mixture was stirred at 60 °C for 10 h, then concentrated in vacuo, and the residue was purified by flash column chromatography (EA / PE = 20-80%) to give the title compound (6.7 g, 84.47% yield) as a yellow solid. MS (ESI) m / z [M+H] + 341.1, 343.1(Br).

[0249] Step 2: Synthesis of 3-bromo-N-(tert-butyl)-6-iodo-2-methylbenzamide [ka] To a solution of 3-bromo-6-iodo-2-methylbenzoic acid (6.7 g, 19.65 mmol) in DMF (30 mL) was added HATU (11.21 g, 29.48 mmol) and DIPEA (3.81 g, 29.48 mmol) at room temperature. After stirring at room temperature for 40 min, 2-methylpropan-2-amine (1.72 g, 23.58 mmol) was added and stirred until the benzoic acid was consumed. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (EA / PE = 10-60%) to give the title compound (4.37 g, 11.04 mmol, 56.18% yield) as a white solid. MS (ESI) m / z [M+H] + 396.2, 398.2(Br).

[0250] Step 3: Synthesis of 3-bromo-N-(tert-butyl)-2-methyl-6-(1H-pyrazol-1-yl)-benzamide [ka] To a solution of 3-bromo-N-(tert-butyl)-6-iodo-2-methylbenzamide (3 g, 7.58 mmol) in DMF (30 mL) was added 1H-pyrazole (0.62 g, 9.09 mmol), CsCO (4.94 g, 15.16 mmol), CuI (144.74 mg, 0.76 mmol), and L-proline (174.54 mg, 1.52 mmol) at room temperature. After stirring at 80 °C for 6 h, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (EA / PE = 10-50%) to give the title compound (1.7 g, 66.75% yield) as a white solid. MS (ESI) m / z [M+H] + 336.0,338.1(Br).

[0251] Step 4: Synthesis of N-(tert-butyl)-2-methyl-6-(1H-pyrazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] To a solution of 3-bromo-N-(tert-butyl)-2-methyl-6-(1H-pyrazol-1-yl)benzamide (1.7 g, 5.06 mmol) in dioxane (20 mL) was added (Bpin)2 (1.54 g, 6.07 mmol), KOAc (993.18 mg, 10.12 mmol), and Pd(dppf)Cl2 (184.94 mg, 0.25 mmol) at room temperature. After stirring at 100 °C for 4 h under a N2 atmosphere, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (EA / PE = 10-50%) to give the title compound (1.3 g, 67.08% yield) as a white solid. MS (ESI) m / z [M+H] + 384.2.

[0252] Step 5: Preparation of N-(tert-butyl)-2-methyl-6-(1H-pyrazol-1-yl)-3-(1H-pyrazol-3-yl)benzamide (Compound A263) [ka] To a solution of N-(tert-butyl)-2-methyl-6-(1H-pyrazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (60 mg, 0.16 mmol) in dioxane (5 mL) and water (0.5 mL) was added 3-bromo-1H-pyrazole (28.22 mg, 0.19 mmol), KPO (101.88 mg, 0.48 mmol), and Pd(dppf)Cl (5.85 mg, 8 μmol) at room temperature. After stirring under N at 100 °C for 1 h, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (EA / PE = 10-80%) to give the title compound (26.03 mg, 50.31% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 13.00(s,1H),8.09(s,1H),8.02(d,J=2.4 Hz,1H),7.80(s,1H),7.69(d,J=2.0 Hz,1H),7.58(s,1H),7.42(d,J=8.4 Hz,1H),6.51(s,1H),6.45(t,J=2.0 Hz,1H),2.40(s,3H),1.22(s,9H).MS(ESI)m / z [M+H] + 324.0.

[0253] Example 7: Preparation of N-(tert-butyl)-2'-ethynyl-5-hydroxy-4-(1H-pyrazol-3-yl)-[1,1'-biphenyl]-2-carboxamide (compound A278) [ka] Step 1: Synthesis of 5-bromo-2-iodo-4-methoxybenzoic acid [ka] To a solution of 3-bromo-4-methoxybenzoic acid (4.6 g, 19.91 mmol) in DMF (50 mL) was added NIS (4.48 g, 19.91 mmol) and Pd(OAc) (446.99 mg, 1.99 mmol). The mixture was stirred at 80 °C for 16 h, then diluted with 50 mL of EA, washed with water, dried, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 1 / 1) to give the title compound (1.1 g, 14.07% yield).

[0254] Step 2: Synthesis of 5-bromo-N-(tert-butyl)-2-iodo-4-methoxybenzamide [ka] To a solution of 5-bromo-2-iodo-4-methoxybenzoic acid (0.5 g, 1.40 mmol) in DMF (1.26 mL) was added DIPEA (543.12 mg, 4.20 mmol), HATU (639.15 mg, 1.68 mmol), and tert-butylamine (204.91 mg, 2.80 mmol). The mixture was stirred at 60 °C for 2 h, then diluted with 15 mL of EA, washed with water, dried, and concentrated. The residue was purified by silica gel column (EA / PE = 0-25%) to give the title compound (0.3 g, 51.97% yield).

[0255] Step 3: Synthesis of 4-bromo-N-(tert-butyl)-5-methoxy-2'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide [ka] To a solution of 5-bromo-N-tert-butyl-2-iodo-4-methoxy-benzamide (0.1 g, 242.68 μmol) and trimethyl-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethynyl]silane (72.87 mg, 242.68 μmol) in water (0.5 mL) and dioxane (4 mL) was added Pd(dppf)Cl (35.50 mg, 48.54 μmol) and KPO (154.54 mg, 728.05 μmol). The mixture was stirred at 90 °C under N for 1 h, then diluted with 15 mL of EA, washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (EA / PE, 0-20%) to give the title compound (0.08 g, 71.9% yield).

[0256] Step 4: Synthesis of N-(tert-butyl)-5-methoxy-4-(1H-pyrazol-3-yl)-2'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide [ka] To a solution of 5-bromo-N-tert-butyl-4-methoxy-2-[2-(2-trimethylsilylethynyl)-phenyl]benzamide (0.08 g, 174.50 μmol) and 1H-pyrazol-3-ylboronic acid (19.53 mg, 174.50 μmol) in dioxane (4 mL) and water (0.5 mL) was added Pd(dppf)Cl (28.50 mg, 34.90 μmol) and KPO (111.12 mg, 523.49 μmol). The mixture was stirred at 100 °C under N for 3 h, then diluted with 15 mL of EA, washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (EA / PE = 0-10%) to give the title compound as a white solid (0.04 g, 51.44% yield).

[0257] Step 5: Synthesis of N-(tert-butyl)-2'-ethynyl-5-hydroxy-4-(1H-pyrazol-3-yl)-[1,1'-biphenyl]-2-carboxamide (Compound A278) [ka] To a solution of N-tert-butyl-4-methoxy-5-(1H-pyrazol-3-yl)-2-[2-(2-trimethylsilyl-ethynyl)phenyl]benzamide (0.04 g, 89.76 μmol) in DCM (2 mL) was added BBr3. The mixture was stirred at room temperature for 2 h and then at 50 °C for 24 h. After quenching with MeOH, the mixture was concentrated and purified by column chromatography on silica gel (EA / PE = 0-20%) to give the title compound (2 mg, 6.2% yield). 1 H NMR(400 MHz,DMSO-d6)δ 13.25(s,1H),11.16(s,1H),7.93(s,1H),7.89(s,1H),7.55(dd,J=7.6,1.6 Hz,1H),7.44 - 7.36(m,2H),7.35 -7.29(m,1H),6.96(s,1H),6.83(s,1H),6.72(s,1H),4.03(s,1H),1.12(s,9H).MS(ESI)m / z [M+H] + 359.9.

[0258] The following compounds (A251-A285) in Table 3 were synthesized using the appropriate starting materials and corresponding intermediates in a similar manner as described for Examples 6 and 7.

[0259] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0260] General method 4 [ka] Compound 4-2 was synthesized from 4-1 and CO2 in the presence of basic conditions such as LDA, NaHMDS, etc. Compound 4-3 was then prepared using the same general method 1.

[0261] Example 8: Preparation of 6-(2-aminobenzo[d]thiazol-4-yl)-N-(tert-butyl)-2,3-dichloro-benzamide (compound A292) [ka] Step 1: Synthesis of 2,3-dichloro-6-iodobenzoic acid [ka] To a solution of 1,2-dichloro-4-iodo-benzene (5 g, 18.32 mmol) in THF (50 mL) was added LDA (2 M in THF, 18.32 mmol, 10 mL) at −78° C. under nitrogen. After stirring for 20 min, dry ice was added and the reaction was allowed to warm to room temperature over 3 h. The mixture was diluted with water and extracted with EA. The aqueous layer was acidified with dilute aqueous HCl and then extracted twice with EA. The organic layer was concentrated and purified by column chromatography (0-25% EA in PE) to give the title compound (4.2 g, 72.33% yield) as a yellow solid.

[0262] Step 2: Synthesis of N-(tert-butyl)-2,3-dichloro-6-iodobenzamide [ka] A mixture of HATU (1.56 g, 4.10 mmol), 2,3-dichloro-6-iodo-benzoic acid (1 g, 3.16 mmol), 2-methylpropan-2-amine (461.56 mg, 6.31 mmol), and DIPEA (1.22 g, 9.47 mmol, 1.65 mL) in DMF (10 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (0-30% EA in PE) to give the title compound (1 g, 85.18% yield) as a white solid.

[0263] Step 3: Synthesis of tert-butyl N-(4-bromo-1,3-benzothiazol-2-yl)carbamate [ka] To a solution of BocO (3.81 g, 17.46 mmol), DMAP (106.65 mg, 872.99 μmol), and EtN (1.77 g, 17.46 mmol, 2.43 mL) in DCM (20 mL) was added 4-bromo-1,3-benzothiazol-2-amine (2 g, 8.73 mmol), followed by stirring at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3), and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-30% EA in PE) to afford the title compound (2 g, 69.59% yield) as a white solid.

[0264] Step 4: Synthesis of [2-(tert-butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid [ka] A mixture of Pd(dppf)Cl (444.52 mg, 607.51 μmol), (Bpin) (3.09 g, 12.15 mmol), KOAc (1.19 g, 12.15 mmol), and tert-butyl N-(4-bromo-1,3-benzothiazol-2-yl)carbamate (2 g, 6.08 mmol) in dioxane (20 mL) was stirred at 80 °C for 4 h, then diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried and concentrated in vacuo to give a residue that was purified by column chromatography on silica gel (0-40% EA in PE) to give the title compound (1.6 g, 89.54% yield) as a white solid.

[0265] Step 5: Synthesis of tert-butyl N-[4-[2-(tert-butylcarbamoyl)-3,4-dichloro-phenyl]-1,3-benzothiazol-2-yl]carbamate [ka] To a solution of N-tert-butyl-2,3-dichloro-6-iodo-benzamide (100 mg, 268.80 μmol), [2-(tert-butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (79.06 mg, 268.80 μmol) in dioxane (4 mL) and water (1 mL) was added Pd(dppf)Cl (19.67 mg, 26.88 μmol) and KPO (114.11 mg, 537.59 μmol). The mixture was stirred at 80 °C for 4 h, then diluted with water (5 mL) and extracted with EA (5 mL × 3). The organic layers were combined and concentrated, and the residue was purified by column chromatography on silica gel (0-40% EA in PE) to give the title compound (60 mg, 45.15% yield) as a white solid.

[0266] Step 6: Synthesis of 6-(2-amino-1,3-benzothiazol-4-yl)-N-tert-butyl-2,3-dichloro-benzamide (compound A292) [ka] To a solution of tert-butyl N-[4-[2-(tert-butylcarbamoyl)-3,4-dichloro-phenyl]-1,3-benzothiazol-2-yl]carbamate (60 mg, 121.35 μmol) in DCM (3 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 4 h, then concentrated and the residue purified by column chromatography on silica gel (0-40% EA in PE) to afford the title compound (10.59 mg, 22.13% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.70 - 7.57(m,5H),7.33(d,J=8.3 Hz,1H),7.23(dd,J=7.5,1.3 Hz,1H),7.02(t,J=7.7 Hz,1H),1.04(s,9H).MS(ESI)m / z [M+H] + 394.1, 396.1, 398.1 (2Cl).

[0267] The following compounds (A286-A325) in Table 4 were synthesized in a similar manner as described for Example 8 using the appropriate starting materials and corresponding intermediates.

[0268] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0269] General method 5 [ka] Bromination of compound 5-1 in the presence of NBS or other brominating reagents produced intermediate 5-2, which was cyclized with NaNO under acidic conditions to form compound 5-3. Compound 5-3 was alkylated under basic conditions to give two isomers, 5-4a and 5-4b. The final products 5-5a or 5-5b can be synthesized from 5-4a or 5-4b by using methods similar to General Method 1.

[0270] Example 9: Preparation of N-(tert-butyl)-1-methyl-5-(1H-pyrazol-1-yl)-1H-indazole-4-carboxamide (compound A327) [ka] Step 1: Synthesis of methyl 3-amino-6-bromo-2-methylbenzoate [ka] To a solution of methyl 3-amino-2-methylbenzoate (2 g, 12.11 mmol) in ACN (24.25 mL) was added NBS (2.15 g, 12.11 mmol, 1.03 mL). The resulting solution was stirred at 25 °C for 1 h, then concentrated under reduced pressure and purified by flash chromatography on silica gel (EA / PE = 0-30%) to give the title compound (1.5 g, 48.73% yield) as a yellow oil. MS (ESI) m / z [M+H] + 244.1, 246.1(Br).

[0271] Step 2: Synthesis of methyl 5-bromo-1H-indazole-4-carboxylate [ka] To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (1.2 g, 4.92 mmol) in water (2 mL) and AcOH (10 mL) was added NaNO (440.99 mg, 6.39 mmol) in portions. The resulting solution was stirred at 60 °C for 1 h, then concentrated under reduced pressure, and the residue was purified by C18-preparative HPLC (ACN / water 0-40%) to give the title compound (690 mg, 49.52% yield) as a yellow solid. MS (ESI) m / z [M+H] + 255.1, 257.1(Br).

[0272] Step 3: Synthesis of methyl 5-bromo-1-methyl-1H-indazole-4-carboxylate [ka] To a mixture of K2CO3 (980.92 mg, 7.06 mmol) and methyl 5-bromo-1H-indazole-4-carboxylate (600 mg, 2.35 mmol) in ACN (1.30 mL) was added iodomethane (500.83 mg, 3.53 mmol, 219.66 μL). The resulting solution was stirred at 50 °C for 1 h, then concentrated under reduced pressure, and the residue was purified by C18-preparative HPLC (ACN / water 0-60%) to give the title compound (300 mg, 42.65% yield) as a yellow solid. MS (ESI) m / z [M+H] + 269.2, 271.2(Br).

[0273] Step 4: Synthesis of 5-bromo-1-methyl-1H-indazole-4-carboxylic acid [ka] To a solution of methyl 5-bromo-1-methyl-indazole-4-carboxylate (300 mg, 1.11 mmol) in methanol (5 mL) was added a solution of NaOH (445.91 mg, 11.15 mmol) dissolved in water (5 mL). The resulting solution was stirred at 50 °C for 1 h, then concentrated under reduced pressure, and the residue was purified by C18-preparative HPLC (ACN / water 0-60%) to give the title compound (260 mg, 87.78% yield) as a yellow solid. MS (ESI) m / z [M+H] + 255.0,257.0(Br).

[0274] Step 5: Synthesis of 5-bromo-N-(tert-butyl)-1-methyl-1H-indazole-4-carboxamide [ka] A solution of 5-bromo-1-methyl-indazole-4-carboxylic acid (300 mg, 1.18 mmol), 2-methylpropan-2-amine (86.02 mg, 1.18 mmol), HATU (447.21 mg, 1.18 mmol), and DIPEA (455.17 mg, 3.53 mmol) in DMF (5 mL) was stirred at 80 °C for 3 h. The resulting solution was concentrated under reduced pressure, and the residue was purified by C18-preparative HPLC (ACN / water 0-60%) to give the title compound (150 mg, 39.47% yield) as a yellow solid. MS (ESI) m / z [M+H] + 310.0,312.0(Br).

[0275] Step 6: Synthesis of N-(tert-butyl)-1-methyl-5-(1H-pyrazol-1-yl)-1H-indazole-4-carboxamide (compound A327) [ka] A mixture of 5-bromo-N-tert-butyl-1-methyl-indazole-4-carboxamide (50 mg, 161.19 μmol), 1H-pyrazole (109.73 mg, 1.61 mmol), CuI (30.70 mg, 161.19 μmol), CsCO (157.65 mg, 483.58 μmol), and (1R,2R)-(−)-1,2-diaminocyclohexane (36.81 mg, 322.38 μmol) in DMF (1.2 mL) was stirred at 110° C. for 1 h. The resulting solution was concentrated under reduced pressure and purified by C18-preparative HPLC (ACN / water 0–60%) to give the title compound (2.9 mg, 5.75% yield) as a red solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.99(t,J=1.8 Hz,2H),7.91(s,1H),7.80(dd,J=8.9,1.0 Hz,1H),7.70(d,J=1.8 Hz,1H),7.60(d,J=8.9 Hz,1H),6.48(t,J=2.1 Hz,1H),4.11(s,3H),1.28(s,9H).MS(ESI)m / z [M+H] + 297.9.

[0276] The following compounds in Table 5 (A326-A344 and A438-A439) were synthesized in a similar manner as described for Example 9 using the appropriate starting materials and corresponding intermediates.

[0277] [Table 5-1] [Table 5-2] [Table 5-3]

[0278] General method 5-1 [ka] Intermediate 5-1-2 was synthesized using CDI and 5-1-1, which was then nitrated in the presence of KNO3 / H2SO4 to form intermediate 5-1-3. Ring opening under basic conditions gave 5-1-4, which was then brominated to give compound 5-1-5. An indole intermediate was prepared from 5-1-5 using DMF-DMA and then reduced with Fe powder. Alkylation of 5-1-6a under basic conditions gave intermediate 5-1-6b. Hydrolysis of the ester under basic conditions gave acid compound 5-1-7, which could then be used to prepare the final compound 5-1 using a method similar to General Method 1.

[0279] Example 10: Preparation of 5-(2-aminobenzo[d]thiazol-4-yl)-N-(tert-butyl)-1H-indole-4-carboxamide (compound A346) [ka] Step 1: Synthesis of 5-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] A mixture of CDI (6.97 g, 43.00 mmol) and 2-amino-6-methyl-benzoic acid (5 g, 33.08 mmol) in dioxane (50 mL) was stirred at room temperature for 5 hours. The resulting mixture was concentrated, filtered, and the precipitate was dried to give the title compound (5 g, 85.33% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.65(s,1H),7.57(t,J=7.8 Hz,1H),7.06(d,J=7.5 Hz,1H),7.00(d,J=8.2 Hz,1H),2.60(s,3H).MS(ESI)m / z [M+H] + 178.1.

[0280] Step 2: Synthesis of 5-methyl-6-nitro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a mixture of 5-methyl-1H-3,1-benzoxazine-2,4-dione (5 g, 28.22 mmol) in HSO (30 mL) was added KNO (2.85 g, 28.22 mmol) at 0 °C, followed by stirring at 0 °C for 2 h. The mixture was quenched with ice water. The crude product was filtered, and the precipitate was dried to give the title compound (4 g, 63.80% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.09(s,1H),8.17(d,J=8.9 Hz,1H),7.14(d,J=9.0 Hz,1H),2.69(s,3H).MS(ESI)m / z [M+H] + 223.0.

[0281] Step 3: Synthesis of methyl 6-amino-2-methyl-3-nitrobenzoate [ka] A mixture of 5-methyl-6-nitro-1H-3,1-benzoxazine-2,4-dione (4 g, 18.01 mmol) and Na2CO3 (1.91 g, 18.01 mmol) in methanol (40 mL) was stirred at 0 °C for 0.5 h and then at room temperature for 3 h. The resulting mixture was concentrated and purified by flash chromatography on silica gel (0-40% EA in PE) to give the title compound (3.5 g, 92.48% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.89(d,J=9.2 Hz,1H),6.67(d,J=9.2 Hz,1H),6.58(s,2H),3.87(s,3H),2.38(s,3H).MS(ESI)m / z [M+H] + 211.1.

[0282] Step 4: Synthesis of methyl 6-bromo-2-methyl-3-nitrobenzoate [ka] To an ice-cold solution of HBr (30% in acetic acid, 20 mL) and water (40 mL) was added methyl 6-amino-2-methyl-3-nitrobenzoate (3.5 g, 16.65 mmol), followed by the dropwise addition of NaNO (1.34 g, 19.48 mmol) in water (5 mL). The mixture was stirred at 0 °C for 0.5 h, after which CuBr (0.6 g, 4.18 mmol) was added. The resulting mixture was stirred at room temperature for an additional 1.5 h, then diluted with water (60 mL) and extracted with EA (100 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by chromatography on silica gel (0-30% EA in PE) to give the title compound (4 g, 87.65% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.99(d,J=8.8 Hz,1H),7.88 - 7.83(m,1H),3.94(s,3H),2.39(s,3H).MS(ESI)m / z [M+H] + 274.0,276.0(Br).

[0283] Step 5: Synthesis of methyl 5-bromo-1H-indole-4-carboxylate [ka] To a solution of methyl 6-bromo-2-methyl-3-nitrobenzoate (1 g, 3.65 mmol) in DMF (10 mL) was added DMF-DMA (1.30 g, 10.95 mmol, 1.47 mL) at room temperature. The mixture was stirred at 130 °C for 5 h and then concentrated in vacuo. The residue was dissolved in AcOH (10 mL), followed by the addition of Fe powder (3.39 g, 60.76 mmol). The resulting mixture was stirred at 100 °C for 7 h, then diluted with water (60 mL) and extracted with EA (100 mL × 2). The combined organic layers were concentrated and purified by chromatography on silica gel (0-30% EA in PE) to give the title compound (600 mg, 77.73% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.57(s,1H),7.52(t,J=2.8 Hz,1H),7.49(dd,J=8.6,0.7 Hz,1H),7.36 - 7.31(m,1H),6.49(t,J=2.1 Hz,1H),3.93(s,3H).MS(ESI)m / z [M+H] + 254.0,256.0(Br).

[0284] Step 6: Synthesis of 5-bromo-1H-indole-4-carboxylic acid [ka] To a solution of methyl 5-bromo-1H-indole-4-carboxylate (200 mg, 787.15 μmol) in water (2 mL) was added NaOH (62.97 mg, 1.57 mmol). The mixture was stirred at 80° C. for 12 h, then acidified with dilute aqueous HCl and extracted twice with EA. The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography (0-60% EA in PE) to give the title compound (160 mg, 84.67% yield) as a white solid. MS (ESI) m / z [M+H] + 240.0,242.0(Br).

[0285] Step 7: Synthesis of 5-bromo-N-(tert-butyl)-1H-indole-4-carboxamide [ka] A mixture of HATU (304.12 mg, 799.82 μmol), 5-bromo-1H-indole-4-carboxylic acid (160 mg, 666.52 μmol), 2-methylpropan-2-amine (97.49 mg, 1.33 mmol, 140.08 μL), and DIPEA (258.43 mg, 2.00 mmol, 348.29 μL) in DMF (4 mL) was stirred at room temperature for 2 h, then diluted with water (20 mL) and extracted with EA (40 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (0-30% EA in PE) to give the title compound (170 mg, 86.41% yield) as a white solid. MS (ESI) m / z [M+H] + 295.1, 297.1(Br).

[0286] Step 8: Synthesis of tert-butyl (4-(4-(tert-butylcarbamoyl)-1H-indol-5-yl)benzo[d]thiazol-2-yl)carbamate [ka] A mixture of Pd(dppf)Cl (123.83 mg, 169.39 μmol), 5-bromo-N-tert-butyl-1H-indole-4-carboxamide (50 mg, 169.39 μmol), [2-(tert-butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (64.77 mg, 220.21 μmol), and KPO (35.96 mg, 169.39 μmol) in water (0.5 mL) and dioxane (4 mL) was stirred at 90 °C for 2 h. The resulting mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel (0-40% EA in PE) to give the title compound (50 mg, 63.54% yield) as a white solid. MS (ESI) m / z [M+H] + 465.2.

[0287] Step 9: Synthesis of 5-(2-aminobenzo[d]thiazol-4-yl)-N-(tert-butyl)-1H-indole-4-carboxamide (compound A346) [ka] To a solution of tert-butyl N-[4-[4-(tert-butylcarbamoyl)-1H-indol-5-yl]-1,3-benzothiazol-2-yl]carbamate (50 mg, 107.62 μmol) in DCM (4 mL) was added TFA (1.48 g, 12.98 mmol, 1 mL). The mixture was stirred at room temperature for 8 h, then concentrated, and the residue was purified by C18-preparative HPLC (0-70% ACN in water) to give the title compound (8 mg, 20.40% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 11.18(s,1H),7.65(d,J=7.7 Hz,1H),7.53(s,2H),7.39(dd,J=8.2,5.5 Hz,2H),7.10(d,J=6.4 Hz,1H),7.02(t,J=7.6 Hz,1H),6.97(d,J=8.3 Hz,1H),6.91(s,1H),6.41(s,1H),0.99(s,9H).MS(ESI)m / z [M+H] + 365.1.

[0288] Example 11: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-7-yl)-1H-indole-4-carboxamide (compound A347) [ka] Step 1: Synthesis of methyl 5-bromo-1-methyl-1H-indole-4-carboxylate [ka] To a mixture of methyl 5-bromo-1H-indole-4-carboxylate (200 mg, 787.15 μmol) and CsCO (512.94 mg, 1.57 mmol) in DMF (5 mL) was added CHCl (335.18 mg, 2.36 mmol, 147.01 μL). The mixture was stirred at room temperature for 2 h, then diluted with water (20 mL) and extracted with EA (40 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by chromatography on silica gel (0-40% EA in PE) to give the title compound (200 mg, 94.77% yield) as a white solid. MS (ESI) m / z [M+H] + 268.0,270.0(Br).

[0289] Step 2: Synthesis of 5-bromo-1-methyl-1H-indole-4-carboxylic acid [ka] To a mixture of methyl 5-bromo-1-methyl-indole-4-carboxylate (200 mg, 745.97 μmol) in water (2 mL) was added NaOH (59.67 mg, 1.49 mmol). The mixture was stirred at 80° C. for 12 h, then acidified with dilute aqueous HCl, and then extracted twice with EA. The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography (0-60% EA in PE) to give the title compound (170 mg, 89.69% yield) as a white solid. MS (ESI) m / z [M+H] + 254.0,256.0(Br).

[0290] Step 3: Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-1-methyl-1H-indole-4-carboxamide [ka] A mixture of HATU (179.58 mg, 472.29 μmol), 5-bromo-1-methyl-indole-4-carboxylic acid (100 mg, 393.58 μmol), bicyclo[1.1.1]pentan-1-amine (65.44 mg, 787.15 μmol), and DIPEA (152.60 mg, 1.18 mmol, 205.66 μL) in DMF (2 mL) was stirred at room temperature for 2 h, then diluted with water (20 mL) and extracted with EA (40 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by chromatography on silica gel (0-30% EA in PE) to give the title compound (100 mg, 79.60% yield) as a white solid. MS (ESI) m / z [M+H] + 319.0,321.0(Br).

[0291] Step 4: Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-7-yl)-1H-indole-4-carboxamide (compound A347) [ka] A mixture of Pd(dppf)Cl (18.32 mg, 25.06 μmol), N-(1-bicyclo[1.1.1]pentanyl)-5-bromo-1-methyl-indole-4-carboxamide (80 mg, 250.63 μmol), pyrazolo[1,5-a]pyridin-7-ylboronic acid (52.77 mg, 325.82 μmol), and KPO (159.60 mg, 751.89 μmol) in water (0.5 mL) and dioxane (4 mL) was stirred at 90 °C for 2 h. The resulting mixture was concentrated in vacuo, and the residue was purified by C-prep HPLC (0-70% ACN in water) to give the title compound (31 mg, 34.70% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 8.36(s,1H),7.89(d,J=2.2 Hz,1H),7.73 - 7.65(m,1H),7.60(d,J=8.5 Hz,1H),7.47(d,J=3.1 Hz,1H),7.37(d,J=8.5 Hz,1H),7.25(dd,J=8.8,6.9 Hz,1H),6.85 - 6.76(m,1H),6.67(d,J=2.2 Hz,1H),6.47(d,J=3.0 Hz,1H),3.87(s,3H),2.30(s,1H),1.78(s,6H).MS(ESI)m / z [M+H] + 357.2.

[0292] The following compounds (A345-A387) in Table 6 were synthesized using the appropriate starting materials and corresponding intermediates in a similar manner as described for Examples 10 and 11.

[0293] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0294] General method 5-2 [ka] Compound 5-2-2 could be synthesized from 5-2-1 by using a method similar to General Method 1 for Sonogashira coupling with N-protected but-3-yn-1-amine to form 5-2-3, which was then cyclized under basic conditions to form 5-2-4. CC or CN coupling of the corresponding reagent with compound 5-2-5, resulting from oxidation of 5-2-4, in the presence of Pd, Cu, or other heavy metal catalysts finally afforded the target product 5-2-6.

[0295] Example 12: Preparation of 5-(3-(1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-N-(tert-butyl)-1H-indole-4-carboxamide (compound A388) [ka] Step 1: Synthesis of tert-butyl 5-bromo-4-(tert-butylcarbamoyl)-1H-indole-1-carboxylate [ka] To a solution of 5-bromo-N-tert-butyl-1H-indole-4-carboxamide (2.5 g, 8.47 mmol), TEA (2.57 g, 25.41 mmol, 3.54 mL), and DMAP (103.47 mg, 8.47 mmol) in DCM (15 mL) was added BocO (3.70 g, 16.94 mmol, 3.89 mL) at room temperature. The mixture was stirred at room temperature for 3 h and concentrated to give a residue, which was purified by silica gel chromatography (0-10% EA in PE) to give the title compound (2.3 g, 68.7% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.16(s,1H),7.96(dd,J=8.8,0.8 Hz,1H),7.73(d,J=3.7 Hz,1H),7.50(d,J=8.8 Hz,1H),6.50(dd,J=3.7,0.8 Hz,1H),1.63(s,9H),1.40(s,9H).MS(ESI)m / z [M+H] +395.1, 397.1(Br).

[0296] Step 2: Synthesis of tert-butyl 4-(tert-butylcarbamoyl)-5-(4-((4-methylphenyl)sulfonamido)but-1-yn-1-yl)-1H-indole-1-carboxylate [ka] To a solution of tert-butyl 5-bromo-4-(tert-butylcarbamoyl)indole-1-carboxylate (1 g, 2.53 mmol), N-but-3-ynyl-4-methyl-benzenesulfonamide (1.13 g, 5.06 mmol), CuI (96.36 mg, 0.51 mmol), LiCl (536 mg, 12.65 mmol), and Pd(PPh)Cl (184.93 mg, 252.98 μmol) in DMF (10 mL) was added TEA (1.28 g, 12.65 mmol, 1.76 mL) at room temperature under nitrogen. The mixture was stirred at 80° C. for 5 h, then cooled and diluted with water (20 mL). The aqueous layer was extracted twice with EA (40 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give a residue that was purified by silica gel chromatography (0-30% EA in PE) to give the title compound (730 mg, 53.67% yield) as a solid. MS (ESI) m / z [M+H] + 538.2.

[0297] Step 3: Synthesis of tert-butyl 4-(tert-butylcarbamoyl)-5-(3-iodo-1-tosyl-1H-pyrrol-2-yl)-1H-indole-1-carboxylate [ka] To a solution of tert-butyl 4-(tert-butylcarbamoyl)-5-[4-(p-tolylsulfonylamino)but-1-ynyl]indole-1-carboxylate (730 mg, 1.36 mmol) and K2CO3 (562.93 mg, 4.07 mmol) in acetonitrile (60.00 mL) was added I2 (262.57 mg, 2.05 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 5 hours and then concentrated to give the crude intermediate, which was dissolved in DMF (12.00 mL) followed by the addition of DBU (6.19 g, 40.69 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours and then diluted with water (20 mL). The aqueous phase was extracted twice with EA (40 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a residue which was purified by silica gel chromatography (0-15% EA in PE) to give the title compound (470 mg, 52.38% yield) as a solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.98(d,J=8.5 Hz,1H),7.79(d,J=3.7 Hz,1H),7.65(d,J=3.5 Hz,1H),7.49(d,J=8.5 Hz,2H),7.43(d,J=8.4 Hz,2H),6.75(d,J=3.7 Hz,1H),6.64(d,J=3.4 Hz,1H),6.42 - 6.32(m,2H),2.42(s,3H),1.66(s,9H),1.21(s,9H).MS(ESI)m / z [M+H] + 662.1.

[0298] Step 4: Synthesis of tert-butyl 4-(tert-butylcarbamoyl)-5-(3-iodo-1H-pyrrol-2-yl)-1H-indole-1-carboxylate [ka] To a solution of tert-butyl 4-(tert-butylcarbamoyl)-5-[3-iodo-1-(p-tolylsulfonyl)pyrrol-2-yl]indole-1-carboxylate (470 mg, 710.45 μmol) in THF (5 mL) was added TBAF (2 mL, 1N in THF) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated to give a residue, which was purified by silica gel chromatography (0-30% EA in PE) to give the title compound (350 mg, 97.10% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 11.10(s,1H),8.12(d,J=8.5 Hz,1H),7.76(d,J=3.7 Hz,1H),7.29(d,J=8.6 Hz,1H),6.89(t,J=2.8 Hz,1H),6.74(d,J=3.7 Hz,1H),6.55(s,1H),6.26(t,J=2.6 Hz,1H),1.65(s,9H),1.19(s,9H).MS(ESI)m / z [M+Na] + 530.0.

[0299] Step 5: Synthesis of tert-butyl 5-(3-(1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-4-(tert-butylcarbamoyl)-1H-indole-1-carboxylate [ka] A mixture of tert-butyl 4-(tert-butylcarbamoyl)-5-(3-iodo-1H-pyrrol-2-yl)indole-1-carboxylate (0.124 g, 244.40 μmol), (1-tert-butoxycarbonylpyrazol-3-yl)boronic acid (77.72 mg, 366.60 μmol), Pd(PPh3)4 (28.24 mg, 24.44 μmol), and Na2CO3 (129.52 mg, 1.22 mmol) in a mixture of water / ethanol / toluene (1 / 2 / 2, 8 mL) was heated at 120 °C for 2 h under nitrogen, then cooled and extracted with EA. The combined organic layers were concentrated and purified by silica gel chromatography (0-50% EA in PE) to give the title compound (50 mg, 37.4% yield) as a white solid. MS (ESI) m / z [M+H] + 548.2.

[0300] Step 6: Synthesis of 5-(3-(1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-N-(tert-butyl)-1H-indole-4-carboxamide (compound A388) [ka] To a solution of tert-butyl 5-(3-(1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-4-(tert-butylcarbamoyl)-1H-indole-1-carboxylate (42 mg, 76.7 μmol) in THF (3 mL) was added MeONa (41.8 mg, 231.57 μmol, 30% w / w in methanol) at room temperature. The mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EA. The combined organic layers were concentrated to give a residue which was purified by silica gel chromatography (0-70% EA in PE) to give the title compound (10 mg, 30.67% yield) as a gray solid. 1H NMR(400 MHz,DMSO-d6)δ 12.43(s,1H),11.27(s,1H),10.79(t,J=2.7 Hz,1H),7.48 - 7.37(m,2H),7.30(s,1H),6.91(d,J=8.3 Hz,1H),6.78(t,J=2.7 Hz,1H),6.50(t,J=2.6 Hz,1H),6.44(s,1H),5.67(s,1H),1.05(s,9H).MS(ESI)m / z [M+H] + 348.2.

[0301] Example 13: Preparation of 5-(3-(1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-1H-indole-4-carboxamide (compound A397) [ka] Step 1: Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-1H-indole-4-carboxamide [ka] To a solution of 5-bromo-1H-indole-4-carboxylic acid (1.0 g, 4.2 mmol), bicyclo[1.1.1]pentan-1-amine (0.52 g, 6.2 mmol), and DIPEA (1.6 g, 12.5 mmol) in DMF (10 mL) was added HATU (1.9 g, 5.0 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with HO (30 mL), and the aqueous phase was extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (0–10% EA in DCM) to give the title product (1.2 g, 93.6% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.38(s,1H),8.86(s,1H),7.42(q,J=3.7 Hz,1H),7.35(dd,J=8.6,0.9 Hz,1H),7.22(d,J=8.6 Hz,1H),6.28(t,J=2.4 Hz,1H),2.46(s,1H),2.10(s,6H).MS(ESI)m / z [M+H] + 305.1, 307.1(Br).

[0302] Step 2: Synthesis of tert-butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-bromo-1H-indole-1-carboxylate [ka] To a solution of N-(1-bicyclo[1.1.1]pentanyl)-5-bromo-1H-indole-4-carboxamide (1.2 g, 4.0 mmol) and DMAP (98.4 mg, 0.8 mmol) in DCM (15 mL) was added di-tert-butyl dicarbonate (0.88 g, 4.0 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. HO (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with DCM (30 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (0–30% EA in PE) to give the title compound (1.4 g, 86.4% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.02(s,1H),7.98(d,J=8.9 Hz,1H),7.74(d,J=3.7 Hz,1H),7.52(d,J=8.8 Hz,1H),6.52 - 6.47(m,1H),2.48(s,1H),2.11(s,6H),1.63(s,9H).MS(ESI)m / z [M+H] + 405.1, 407.1(Br).

[0303] Step 3: Synthesis of tert-butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-(4-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-1H-indole-1-carboxylate [ka] A mixture of TEA (1.7 g, 16.8 mmol), tert-butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-bromo-indole-1-carboxylate (1.4 g, 3.4 mmol), tert-butyl N-but-3-ynylcarbamate (1.42 g, 8.4 mmol), CuI (0.26 g, 1.3 mmol), LiCl (0.7 g, 16.8 mmol), and Pd(PPh)Cl (0.25 g, 0.34 mmol) in DMF (8 mL) was stirred at 80 °C under nitrogen for 2 h. The reaction mixture was cooled, diluted with HO (20 mL), and the aqueous phase was extracted with EA (30 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (0-30% EA in PE) to afford the title compound (1.48 g, 89.4% yield) as a grey solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.84(s,1H),8.04(d,J=8.6 Hz,1H),7.72(d,J=3.8 Hz,1H),7.36(d,J=8.6 Hz,1H),6.97(q,J=5.7 Hz,1H),6.59(d,J=3.8 Hz,1H),3.18(q,J=6.8 Hz,2H),2.53(d,J=7.1 Hz,2H),2.47(s,1H),2.11(s,6H),1.63(s,9H),1.38(s,9H).MS(ESI)m / z [M+H] + 494.3.

[0304] Step 4: Synthesis of tert-butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrrol-2-yl)-1H-indole-1-carboxylate [ka] A mixture of bis(pyridine)iodine(I) hexafluorophosphate (2.6 g, 6.0 mmol), tert-butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-[4-(tert-butoxycarbonylamino)but-1-ynyl]indole-1-carboxylate (1.48 g, 3.0 mmol), and dipotassium carbonate (1.24 g, 9.0 mmol) in acetonitrile (100 mL) was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, and then the residue was dissolved in DMF (10 mL). DBU (3.66 g, 24.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with HO (40 mL), and the aqueous phase was extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (0-10% EA in PE) to give the title compound (0.9 g, 48.6% yield) as a grey solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.14(d,J=8.5 Hz,1H),7.77(d,J=3.8 Hz,1H),7.59(s,1H),7.39(d,J=3.4 Hz,1H),7.17(d,J=8.5 Hz,1H),6.73(d,J=3.8 Hz,1H),6.45(d,J=3.4 Hz,1H),2.38(s,1H),1.92(s,6H),1.65(s,9H),1.10(s,9H).MS(ESI)m / z [M+H] + 618.1.

[0305] Step 5: Synthesis of tert-butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-(1-(tert-butoxycarbonyl)-3-(1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-1H-indole-1-carboxylate [ka] A mixture of Pd(PPh3)4 (75 mg, 65 μmol), tert-butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-(1-tert-butoxycarbonyl-3-iodo-pyrrol-2-yl)indole-1-carboxylate (0.2 g, 324 μmol), (1-tert-butoxycarbonylpyrazol-3-yl)boronic acid (137 mg, 648 μmol), and disodium carbonate (172 mg, 1.62 mmol) in a water / ethanol / toluene (1 / 2 / 2, 15 mL) mixture was stirred at 100 °C for 8 h under nitrogen. The reaction mixture was cooled, diluted with HO (20 mL), and extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-80% EA in PE) to give the title compound (40 mg, 18.8% yield) as a light brown solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.01(d,J=8.5 Hz,1H),7.71(d,J=3.7 Hz,1H),7.62(d,J=1.6 Hz,1H),7.48(d,J=3.6 Hz,1H),7.38(s,1H),7.20(d,J=8.5 Hz,1H),6.78(d,J=3.7 Hz,1H),6.49(d,J=1.6 Hz,1H),6.40(d,J=3.4 Hz,1H),2.42(s,1H),1.98(s,6H),1.62(s,9H),1.43(s,9H),1.14(s,9H).MS(ESI)m / z [M-Boc+H] + 558.3.

[0306] Step 6: Synthesis of 5-(3-(1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-1H-indole-4-carboxamide (compound A397) [ka] To a solution of tert-butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-[1-tert-butoxycarbonyl-3-(1-tert-butoxycarbonylpyrazol-3-yl)pyrrol-2-yl]indole-1-carboxylate (40 mg, 61 μmol) in THF (3 mL) at room temperature, a solution of sodium methoxide (approximately 30% w / w in methanol, 32.9 mg, 183 μmol) was added, and the reaction was stirred at room temperature for 1 h. The mixture was diluted with HO (10 mL), and the aqueous phase was extracted with EA (12 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–70% EA in PE) to afford the title compound (10 mg, 46.0% yield) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.45(s,1H),11.30(s,1H),10.66(s,1H),7.74(s,1H),7.49 - 7.37(m,2H),7.29(s,1H),6.93(d,J=8.3 Hz,1H),6.79(t,J=2.7 Hz,1H),6.48(t,J=2.7 Hz,1H),6.42(t,J=2.7 Hz,1H),5.66(s,1H),2.34(s,1H),1.84(s,6H).MS(ESI)m / z [M+H] + 358.2.

[0307] Example 14: Preparation of N-(tert-butyl)-5-(3-(thiazol-4-yl)-1H-pyrrol-2-yl)-1H-indole-4-carboxamide (compound A396) [ka] Step 1: Synthesis of tert-butyl 4-(tert-butylcarbamoyl)-5-(3-thiazol-4-yl-1H-pyrrol-2-yl)indole-1-carboxylate [ka] A mixture of Pd(PPh3)4 (9.1 mg, 7.9 μmol), tert-butyl 4-(tert-butylcarbamoyl)-5-(3-iodo-1H-pyrrol-2-yl)indole-1-carboxylate (40 mg, 79 μmol), tributyl(thiazol-4-yl)stannane (59 mg, 158 μmol), CuI (3.0 mg, 15.8 μmol), and LiCl (10 mg, 237 μmol) in dioxane (2 mL) was stirred at 100 °C for 8 h. The reaction mixture was diluted with HO (20 mL), and the aqueous phase was extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–30% EA in PE) to give the title compound (15 mg, 40.9% yield) as a gray solid. MS(ESI) m / z [M+H] + 465.2.

[0308] Step 2: Synthesis of N-(tert-butyl)-5-(3-(thiazol-4-yl)-1H-pyrrol-2-yl)-1H-indole-4-carboxamide (Compound A396) [ka] To a solution of tert-butyl 4-(tert-butylcarbamoyl)-5-(3-thiazol-4-yl-1H-pyrrol-2-yl)indole-1-carboxylate (15 mg, 32.3 μmol) in THF (2 mL) was added MeONa (11.6 mg, 64.6 μmol, 30% w / w in methanol) at room temperature. The mixture was stirred at room temperature for 1 h and then concentrated to give a residue, which was purified by preparative HPLC (Daisogel-C18-5-100, 0-60% acetonitrile in water) to give the title compound (2 mg, 17% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.27(s,1H),10.87(s,1H),8.90(d,J=1.9 Hz,1H),7.44 - 7.37(m,2H),6.96(d,J=1.9 Hz,1H),6.93 - 6.86(m,2H),6.78(t,J=2.7 Hz,1H),6.53 - 6.48(m,2H),1.02(s,9H).MS(ESI)m / z [M+H] + 365.0.

[0309] Example 15: Preparation of 5-(3-(2H-1,2,3-triazol-4-yl)-1H-pyrrol-2-yl)-N-(tert-butyl)-1H-indole-4-carboxamide (compound A405) [ka] Step 1: Synthesis of tert-butyl 5-(1-(tert-butoxycarbonyl)-3-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-1H-pyrrol-2-yl)-4-(tert-butylcarbamoyl)-1H-indole-1-carboxylate [ka] A mixture of Pd(PPh3)4 (33.3 mg, 21.4 μmol), tert-butyl 5-(1-tert-butoxycarbonyl-3-iodo-pyrrol-2-yl)-4-(tert-butylcarbamoyl)indole-1-carboxylate (130 mg, 214 μmol), 2-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)triazole (179 mg, 642 μmol), and KF (37.3 mg, 642 μmol) in dioxane (2 mL) and water (0.2 mL) was stirred at 80 °C for 5 h. The reaction mixture was diluted with HO (20 mL), and the aqueous phase was extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EA in PE) to give the title compound (29 mg, 21.4% yield) as a grey solid. MS (ESI) m / z [M+H] + 633.2.

[0310] Step 2: Synthesis of 5-(3-(2H-1,2,3-triazol-4-yl)-1H-pyrrol-2-yl)-N-(tert-butyl)-1H-indole-4-carboxamide (compound A405) [ka] To a solution of tert-butyl 5-[1-tert-butoxycarbonyl-3-(2-tetrahydropyran-2-yltriazol-4-yl)pyrrol-2-yl]-4-(tert-butylcarbamoyl)indole-1-carboxylate (29 mg, 45.8 μmol) in methanol (1 mL) at room temperature, 6 N HCl in HO (0.25 mL, 1.5 mmol) was added, and the mixture was stirred at 65 °C for 8 h and then concentrated to give a residue, which was purified by preparative HPLC (Daisogel-C18-5-100, 0-30% acetonitrile in water) to give the title compound (5.8 mg, 36.3% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 14.39(s,1H),11.31(s,1H),10.87(s,1H),7.46 - 7.39(m,2H),7.11(s,1H),6.93(d,J=8.3 Hz,1H),6.84(t,J=2.7 Hz,1H),6.71(s,1H),6.51(t,J=2.5 Hz,1H),6.45(t,J=2.7 Hz,1H),1.08(s,9H).MS(ESI)m / z [M+H] + 349.2.

[0311] Example 16: Preparation of N-(tert-butyl)-5-(3-(4-fluoro-1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-1H-indole-4-carboxamide (compound A407) [ka] Step 1: Synthesis of tert-butyl 5-(1-(tert-butoxycarbonyl)-3-(1-(tert-butoxycarbonyl)-4-fluoro-1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-4-(tert-butylcarbamoyl)-1H-indole-1-carboxylate [ka] A mixture of Pd(PPh3)4 (26.6 mg, 23.1 μmol), tert-butyl 5-(1-tert-butoxycarbonyl-3-iodo-pyrrol-2-yl)-4-(tert-butylcarbamoyl)indole-1-carboxylate (140 mg, 230.5 μmol), tert-butyl 4-fluoro-3-trimethylstannyl-pyrazole-1-carboxylate (161 mg, 462 μmol), CuI (8.8 mg, 46.1 μmol), and LiCl (29.3 mg, 693 μmol) in dioxane (3 mL) was stirred at 100 °C for 8 h. The reaction mixture was cooled and diluted with HO (20 mL), and the aqueous phase was extracted with EA (30 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EA in PE) to give the title compound (50 mg, 38.4% yield) as a grey solid. MS (ESI) m / z [M+H] + 666.2.

[0312] Step 2: Synthesis of N-(tert-butyl)-5-(3-(4-fluoro-1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-1H-indole-4-carboxamide (compound A407) [ka] To a solution of tert-butyl 5-(1-(tert-butoxycarbonyl)-3-(1-(tert-butoxycarbonyl)-4-fluoro-1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-4-(tert-butylcarbamoyl)-1H-indole-1-carboxylate (50 mg, 88.4 μmol) in THF (2 mL) was added a solution of sodium methanolate (approximately 30% w / w in methanol, 14.3 mg, 265 μmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between EA (10 mL) and water (5 mL). The aqueous layer was extracted with EA (10 mL × 2), and the organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Daisogel-C18-5-100, 30% acetonitrile in water) to give the title compound (10 mg, 31.0% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.42 - 12.04(m,1H),11.37 - 11.11(m,1H),11.09 - 10.60(m,1H),7.81 - 6.67(m,6H),6.47(t,J=2.6 Hz,1H),6.38 - 6.16(m,1H),1.33 - 0.87(m,9H).MS(ESI)m / z [M+H] + 366.1.

[0313] General method 6 [ka]

[0314] Example 17: Preparation of 6-(3-(1H-pyrazol-3-yl)-1H-pyrrol-2-yl)-N-(tert-butyl)-2-chloro-3-methoxybenzamide (compound A416) [ka] Step 1: Synthesis of 1-(3-bromo-1H-pyrrol-1-yl)-2,2-dimethylpropan-1-one [ka] To a solution of 3-bromo-1H-pyrrole (2.1 g, 14.4 mmol), DMAP (175.7 mg, 1.44 mmol), and TEA (2.18 g, 21.6 mmol, 3.01 mL) in DCM (20 mL) was added 2,2-dimethylpropanoyl chloride (2.25 g, 18.7 mmol, 2.29 mL) dropwise at 0 °C. The solution was stirred at room temperature for 16 h. The reaction mixture was then evaporated to dryness under reduced pressure, and the crude product was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (50 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The resulting crude material was purified by silica gel chromatography (0–5% EA in PE) to give the title compound (2.7 g, 81.6% yield) as an oil. 1 H NMR(400 MHz,CDCl3)δ 7.43(dd,J=2.4,1.6 Hz,1H),7.36(dd,J=3.5,2.4 Hz,1H),6.26(dd,J=3.5,1.6 Hz,1H),1.44(s,9H).

[0315] Step 2: Synthesis of 3-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole [ka] To 1-(3-bromopyrrol-1-yl)-2,2-dimethylpropan-1-one (700 mg, 3.04 mmol) in DCM (15 mL) at room temperature under nitrogen, BBr3 (2N in DCM, 1.23 g, 1.7 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction was then quenched with a solution of pinacol (539.2 mg, 4.56 mmol) and TEA (3.08 g, 30.4 mmol, 4.24 mL) at 0 °C, and the resulting mixture was a...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, M １ is CR １ and N; M ２ is CR ２ and N; M ３ is CR ３ and N; M ４ is CR ４ and N; L is selected from a chemical bond, —O—, —S—, and —NH—; Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ２ - and 【Chemistry 2】 is selected from Z is -C(R ２ｓ ) (R ３ｓ )- or -N(R ２ｓ ) - and Ring A is C ３～６ selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl, preferably phenyl or 5- to 9-membered heteroaryl; R ａ is H, D, halo, oxo, CN, NO ２ , N.H. ２ , -C ０～６ Alkylene -OH, -C(O)OR ｘ , —C(O)NR ｙ R ｚ , -S(O)NR ｙ R ｚ , -S(O) ２ NR ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, and an amino protecting group; ｘ , N.R. ｙ R ｚ , C １～６ Alkyl or C １～６ and optionally substituted with haloalkyl, m=0, 1, 2, 3, 4, or 5, or two adjacent R ａ together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R １ H, D, Halo, CN, OR ｘ , N.R. ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ２ H, D, halo, CN, -C ０～６ Alkylene -OH, -C ０～６ Alkylene-NH ２ , -C(O)C １～６ Alkyl, —C(O)C １～６ Haloalkyl, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ haloalkynyl, -T-C ３～８ Cycloalkyl, -T-4 to 10-membered heterocyclyl, -T-C ６～１０ aryl, and -T-5 to 10-membered heteroaryl, and １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R ３ H, D, halo, CN, -C ０～６ Alkylene -OH, -C ０～６ Alkylene-NH ２ , C １～６ Alkyl and C １～６ haloalkyl; R ４ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, may be one, two or three halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)H, —C(O)C １～６ Alkyl, —C(O)C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl or C ２～６ C optionally substituted with alkynyl-substituted phenyl ５～６ forming a cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached, represent one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C １～６ Alkylene-C １～６ Alkoxyl, -C １～６ Alkylene-C １～６ Haloalkoxyl, —C(O)C １～６ Alkyl or —C(O)C １～６ C optionally substituted with haloalkyl ５～６ forming a cycloalkyl, a 5- to 7-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl; R １ｓ are H, D, and -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ selected from cycloalkyl and phenyl; R ２ｓ H, D, C １～６ Alkyl, C １～６ Haloalkyl and C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) are selected from R ２ｓ１ are H, D, and -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl and C ３～６ cycloalkyl; R ２ｓ２ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ３ But C １～６ Alkyl or C １～６ is haloalkyl, Or, R ２ｓ１ and R ２ｓ２ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R ２ｓ２ and R ２ｓ３ together with the atoms to which they are attached, represent C optionally substituted with one or two halo ３～６ forming a cycloalkyl or 4- to 6-membered heterocyclyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the atoms to which they are attached, may contain one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ forming a bridged bicycloalkyl or forming a 4- to 8-membered bridged heterocyclyl; Or, R １ｓ and R ２ｓ３ are joined to form one, two or three halo, OR ｘ , N.R. ｙ R ｚ , C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ２～６ Forming an alkylene R ３ｓ H, D, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, may be one or two halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ３～６ forming a cycloalkyl or 4- to 6-membered heterocyclyl, Or, R １ｓ and R ２ｓ together with the nitrogen atom to which they are attached, one or two halo, C １～６ Alkyl or C １～６ forming a 4- to 6-membered heterocyclyl optionally substituted with haloalkyl; Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, may be one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ form a bridged bicycloalkyl, or 【Transformation 3】 Forming Y １ is CR １１ or N, Y ２ is CR １２ or N, R １１ and R １３ are independently H, D, C １～６ Alkyl and C １～６ haloalkyl; R １２ is selected from H and D; R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated. or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

2. M １ is CR １ 2. The compound of formula (I) of claim 1, wherein:

3. M ２ is CR ２ 3. The compound of formula (I) of claim 1 or 2, wherein:

4. M ３ is CR ３ 4. The compound of formula (I) according to any one of claims 1 to 3, wherein:

5. M ４ is CR ４ 5. The compound of formula (I) according to any one of claims 1 to 4, wherein:

6. 6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein L is a chemical bond.

7. 6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein L is -NH-.

8. 8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein Y is -C(O)-.

9. Z is -C(R ２ｓ ) (R ３ｓ 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein:

10. Z is -N(R ２ｓ 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein:

11. Ring A is selected from phenyl and 5- to 9-membered heteroaryl; R ａ But, H, D, Halo, NO ２ , N.H. ２ , -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ haloalkynyl and amino protecting groups, m=0, 1, 2, 3, 4, or 5, or two adjacent R ａ is taken together with the atom to which they are attached to form phenyl or 5-6 membered heteroaryl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

12. R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ 12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, selected from cycloalkyl and 4- to 10-membered heterocyclyl.

13. R ２ But H, D, halo, -C ０～６ Alkylene-OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, -T-C ５～６ Cycloalkyl, -T-5 to 10-membered heterocyclyl, -T-C ６～１０ aryl and -T-5 to 10 membered heteroaryl, and 1, 2, 3, 4 or 5 of CN, halo, oxo, -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ 13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, optionally substituted with cycloalkyl or 5-6 membered heterocyclyl.

14. R ３ But, H, D, Halo, OH, C １～６ Alkyl and C １～６ 14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the compound is selected from haloalkyl.

15. R ４ But, H, D, Halo, C １～６ Alkyl and C １～６ 15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the compound is selected from haloalkyl.

16. R １ and R ２ is taken together with the carbon atom to which they are attached to form a 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

17. R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C １～６ Alkylene-C １～６ Alkoxyl or -C １～６ Alkylene-C １～６ 17. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a 5- to 7-membered heterocyclyl optionally substituted with haloalkoxyl.

18. R １ｓ But H, D, OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ 18. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, selected from haloalkynyl.

19. R ２ｓ But H, D, C １～６ Alkyl and C １～６ 19. The compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to any one of claims 1 to 18, wherein the compound is selected from haloalkyl.

20. R ２ｓ is C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) and R ２ｓ１ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl and C ３～６ 20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein:

21. R ２ｓ is C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) and R ２ｓ２ But H, D, -C １～４ Alkylene-OH, C １～４ Alkyl and C １～４ 21. The compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to any one of claims 1 to 20, wherein the compound is selected from haloalkyl.

22. R ２ｓ is C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) and R ２ｓ３ But C １～６ Alkyl or C １～６ 22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which is haloalkyl.

23. R ２ｓ is C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) and R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ 23. The compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a cycloalkyl.

24. R ２ｓ is C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) and R ２ｓ１ and R ２ｓ２ together with the carbon atoms to which they are attached, C ３～６ 24. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a cycloalkyl.

25. R ２ｓ is C(R ２ｓ１ ) (R ２ｓ２ ) (R ２ｓ３ ) and R １ｓ and R ２ｓ３ is taken together with the atom to which they are attached to form a 4- to 7-membered heterocyclyl optionally substituted with one or two halo, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

26. R ３ｓ But H, D, C １～６ Alkyl and C １～６ 26. The compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof according to any one of claims 1 to 25, wherein the compound is selected from haloalkyl.

27. R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ３～６ 27. The compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a cycloalkyl.

28. R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ 28. A compound of formula (I) according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a bridged bicycloalkyl.

29. R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ４～８ 29. A compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a bridged bicycloalkyl.

30. The compound is: 【Chemistry 4】 having a formula selected from 30. A compound of formula (I) according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the variables are defined in any one of claims 1 to 29.

31. Formula (II): 【Transformation 5】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Y is —C(O)—, —C(S)—, —C(N—OH)—, —S(O)—, and —S(O) ２ - is selected from, Ring A is selected from phenyl and 5- to 9-membered heteroaryl; R ａ But, H, D, Halo, NO ２ , N.H. ２ , -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ haloalkynyl and amino protecting groups, m=0, 1, 2, 3, 4, or 5, or two adjacent R ａ together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R １ and R ４ is independently selected from H, D and halo; R ２ H, D, halo, -C ０～６ Alkylene-OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, -T-C ５～６ Cycloalkyl, -T-5 to 10-membered heterocyclyl, -T-C ６～１０ aryl and -T-5 to 10 membered heteroaryl, and 1, 2, 3, 4 or 5 of CN, halo, oxo, -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; T is a chemical bond, —O—, —S—, or —NH—; R ３ H, D, halo, CN, -C ０～６ Alkylene -OH, -C ０～６ Alkylene-NH ２ , C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached form a 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ２ｓ But H, D, C １～６ Alkyl and C １～６ haloalkyl; R ３ｓ But C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ３～６ forming a cycloalkyl, Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

32. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Y is —C(O)—, —C(S)—, —C(N—OH)—, —S(O)—, and —S(O) ２ - is selected from, Ring A is 【Transformation 6】 is selected from R ａ But, H, D, Halo, NO ２ , N.H. ２ , -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ haloalkynyl and amino protecting groups, m=0, 1, 2, 3, 4, or 5, or two adjacent R ａ together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R １ and R ４ is independently selected from H, D and halo; R ２ But H, D, halo, -C ０～６ Alkylene-OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C ５～６ Cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ selected from aryl, 5- to 10-membered heteroaryl, —O-5- to 6-membered heteroaryl, —NH-5- to 6-membered heteroaryl, —OC(O)-5- to 6-membered heteroaryl, or —NHC(O)-5- to 6-membered heteroaryl; and １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; R ３ H, D, halo, OH, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached form a 5- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ２ｓ But H, D, C １～６ Alkyl and C １～６ haloalkyl; R ３ｓ But C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ３～６ forming a cycloalkyl, Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, 32. The compound of formula (II) of claim 31 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

33. Formula (II-1): 【Transformation 7】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from X is selected from O, S and N—OH; Ring A is 【Transformation 8】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ is selected from H, D, F and Cl; ( ２ は、|、|、|、、、、| ２ F、CF ２ 、|F ３ 、|||、|| ２ H、\H ２ 、 【Chemistry 9】 and one, two, three, four or five of CN, halo, -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; R ３ is selected from H, D, F, Br and OH; R ４ is selected from H, D and F; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 10】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 11】 Forming R １ｓ is H, D, OH, Me, Et, iPr, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ OH, CH=CH ２ and C≡CH; R ２ｓ is selected from H, D and Me; R ３ｓ is Me, Or, R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with one or two F or Me, Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, 【Chemistry 12】 Forming The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (II) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

34. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from X is selected from O, S and N—OH; Ring A is 【Chemistry 13】 is selected from R ａ But, H, D, Halo, NO ２ , N.H. ２ , -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkynyl, C ２～６ haloalkynyl and amino protecting groups, m=0, 1, 2, 3, 4, or 5, or two adjacent R ａ together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R １ and R ４ is independently selected from H, D and halo; R ２ But H, D, halo, -C ０～６ Alkylene-OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ haloalkoxyl, 【Chemistry 14】 and one, two, three, four or five of CN, halo, C １～６ Alkyl, C １～６ haloalkyl or C ３～６ optionally substituted with cycloalkyl; R ３ H, D, halo, OH, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ But H, D, -C ０～６ Alkylene-OH, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl and C ２～４ haloalkynyl; R ２ｓ H, D, C １～４ Alkyl and C １～４ haloalkyl; R ３ｓ is C １～４ Alkyl and C １～４ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atom to which they are attached, form a C optionally substituted with one or two halo ３～５ forming a cycloalkyl, Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, The compound of formula (II-1) according to claim 33, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

35. Formula (II-2): 【Chemistry 15】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R ａ is one, two or three halo, oxo, OR ｘ , N.R. ｙ R ｚ , C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ３～６ selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ２ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, represent one, two or three halo, C １～６ Alkyl or C １～６ optionally substituted with haloalkyl 【Chemistry 16】 Forming R １ｓ , R ２ｓ and R ３ｓ But independently, H, D, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, form C ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ forming a bridged bicycloalkyl, The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

36. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 17】 and R ａ but, [Chemistry 18] and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ２ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 19】 Forming R １ｓ , R ２ｓ and R ３ｓ But independently, H, D, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, The compound of formula (II-2) according to claim 35, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

37. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 20】 and R ａ but, 【Chemistry 21】 and m=1, 2, or 3; R １ , R ２ , R ３ and R ４ is independently selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 22】 Forming R １ｓ H, D, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ is independently selected from H and D; Or, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, The compound of formula (II-2) according to claim 36, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

38. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 23】 and R ａ but, 【Chemistry 24】 and m=1, 2, or 3; R １ , R ２ , R ３ and R ４ is independently selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 25】 Forming R １ｓ H, D, Me and CHF ２ is selected from R ２ｓ and R ３ｓ is independently selected from H and D; Or, R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) according to claim 37, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

39. Formula (II-2): 【Chemistry 26】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 27】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, may represent one, two or three halo, C １～６ Alkyl or C １～６ optionally substituted with haloalkyl 【Chemistry 28】 Forming R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ H, D, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

40. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 29】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Transformation 30】 Forming R ３ is selected from H and D; R ４ is selected from H, D and halo; R １ｓ H, D, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, The compound of formula (II-2) according to claim 39, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

41. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 31】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 32】 Forming R ３ is selected from H and D; R ４ is selected from H, D and F; R １ｓ But, H, D, Me, CHF ２ and C.F. ３ is selected from R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) according to claim 40, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

42. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 33】 and R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, may be one, two or three halo, C １～６ Alkyl or C １～６ optionally substituted with haloalkyl 【Transformation 34】 Forming R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ H, D, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, The compound of formula (II-2) according to claim 40, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

43. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 35】 and R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Transformation 36】 Forming R ３ is selected from H and D; R ４ is selected from H, D and halo; R １ｓ H, D, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, The compound of formula (II-2) according to claim 42, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

44. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 37】 and R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Transformation 38】 Forming R ３ is selected from H and D; R ４ is selected from H, D and F; R １ｓ But, H, D, Me, CHF ２ and C.F. ３ is selected from R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) according to claim 43, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

45. Formula (II-2): 【Chemistry 39】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 40】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ and R ４ is independently selected from H, D and halo; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 41】 Forming R １ｓ But C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

46. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 42】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ is the halo, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 43】 Forming R ４ is selected from H and D; R １ｓ But C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, The compound of formula (II-2) according to claim 45, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

47. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 44】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ is selected from F and Cl; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 45】 Forming R ４ is selected from H and D; R １ｓ Me and CHF ２ is selected from R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) according to claim 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

48. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 46】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ and R ４ is independently selected from H, D and halo; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 47】 Forming R １ｓ But C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, The compound of formula (II-2) according to claim 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

49. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 48】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ is the halo, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 49】 Forming R ４ is selected from H and D; R １ｓ But C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, The compound of formula (II-2) according to claim 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

50. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is [Transformation 50] is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ is selected from F and Cl; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 51】 Forming R ４ is selected from H and D; R １ｓ Me and CHF ２ is selected from R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, The compound of formula (II-2) according to claim 49, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

51. Formula (II-2): 【Chemistry 52】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 53】 is selected from R ａ H, D, Halo, NO ２ , N.H. ２ , -C １～６ Alkylene-OH, C ２～４ Alkynyl, C ２～４ selected from haloalkynyl and Boc, and m=0, 1, 2, 3, 4, or 5; R １ and R ４ is independently selected from H, D and halo; R ２ H, D, halo, -C ０～６ Alkylene-OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ haloalkoxyl, 【Chemistry 54】 is selected from R ３ H, D, halo, OH, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ are H, D, OH, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl and C ２～４ haloalkynyl; R ２ｓ H, D, C １～４ Alkyl and C １～４ haloalkyl; R ３ｓ is C １～４ Alkyl and C １～４ haloalkyl; Or, R ２ｓ and R ３ｓ together with the carbon atom to which they are attached, form a C optionally substituted with one or two halo ３～５ forming a cycloalkyl, Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

52. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 55】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ is selected from H, D, F and Cl; ( ２ が、; ２ 、||、|| ２ F、CF ２ 、|F ３ 、|||、|| ２ .、 【Transformation 56】 is selected from R ３ is selected from H, D, F, Br and OH; R ４ is selected from H, D and F; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 57】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 58】 Forming R １ｓ is H, D, OH, Me, Et, iPr, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ OH, CH=CH ２ and C≡CH; R ２ｓ is selected from H, D and Me; R ３ｓ is Me, Or, R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl optionally substituted with one or two F; Or, R １ｓ , R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, 【Chemistry 59】 Forming 52. The compound of formula (II-2) according to claim 51, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

53. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 60】 is selected from R ａ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, or 3; R １ and R ４ is independently selected from H, D and halo; R ２ and R ３ However, independently, H, D, halo, OH, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ and R ３ together with the carbon atom to which they are attached form a 5- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 halo; R １ｓ But C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl and C ２～４ haloalkenyl; R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C optionally substituted with one or two halo ３～４ forming a cycloalkyl, 52. The compound of formula (II-2) according to claim 51, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

54. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 61】 is selected from R ａ is selected from H, D and halo, and m=0, 1, 2 or 3; R １ and R ４ is independently selected from H, D and halo; R ２ But, H, D, Halo, OH, C １～４ Alkyl and C １～４ haloalkyl; R ３ is selected from H, D, halo, and OH; Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Transformation 62】 Forming R １ｓ But C １～４ Alkyl, C １～４ Haloalkyl and C ２～４ alkenyl, R ２ｓ and R ３ｓ together with the carbon atoms to which they are attached, C optionally substituted with one or two halo ３～４ forming a cycloalkyl, 52. The compound of formula (II-2) according to claim 51, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

55. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 63】 is selected from R ａ is selected from H and D, and m=0, 1, 2 or 3; R １ is selected from H, D, F and Cl; R ２ H, D, Cl, OH, Me, CH ２ F, CHF ２ and C.F. ３ is selected from R ３ is selected from H, D, F and OH; R ４ is selected from H, D and F; Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 64】 Forming R １ｓ But, Me, Et, CH ２ F, CHF ２ , C.F. ３ and CH=CH ２ is selected from R ２ｓ and R ３ｓ together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl optionally substituted with one or two F; 52. The compound of formula (II-2) according to claim 51, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

56. Formula (III-1): 【Transformation 65】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical Formula 66】 is selected from R ａ But H, D, Halo, CN, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, 4, or 5; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ２ But H, D, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl, C ２～４ Haloalkynyl, C ４～６ selected from cycloalkyl and 5- to 6-membered heterocyclyl; R ３ H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; R ４ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, C ５～６ forming cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; Y １ is CR １１ or N, Y ２ is CR １２ or N, R １１ and R １３ are independently H, D, C １～６ Alkyl and C １～６ haloalkyl; R １２ is selected from H and D; The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

57. Formula (III-2): 【Transformation 67】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 68】 is selected from R ａ H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, or 4; R １ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ H, D, C １～６ Alkyl and C １～６ haloalkyl; R ３ is selected from H and D; R ４ is selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Transformation 69】 Forming R １１ , R １２ and R １３ is independently selected from H and D; The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

58. Ring A is 【Transformation 70】 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, selected from:

59. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 71】 is selected from R ａ is selected from H, D, F and Me, and m=0, 1, 2, 3 or 4; R １ is selected from H, D, F and Me; R ２ H, D, Me and CF ３ is selected from R ３ is selected from H and D; R ４ is selected from H, D and F; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 72】 Forming R １１ , R １２ and R １３ is independently selected from H and D; The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned group is optionally substituted with one, two, three or four deuterium atoms.

60. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 73】 is selected from R ａ is selected from H, D and halo, and m=0, 1, 2 or 3; R １ is selected from H, D and halo; R ２ is Me, R ３ is selected from H and D; R ４ is selected from H, D and halo; R １１ , R １２ and R １３ is independently selected from H and D; The compound of formula (III-2) according to claim 57, wherein the Me is optionally substituted with one, two, or three deuterium atoms, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

61. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 74】 is selected from R ａ is selected from H, D and F, and m=0, 1, 2 or 3; R １ is selected from H, D and F; R ２ is Me, R ３ is selected from H and D; R ４ is selected from H, D and F; R １１ , R １２ and R １３ is independently selected from H and D; The compound of formula (III-2) according to claim 57, wherein the Me is optionally substituted with one, two, or three deuterium atoms, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

62. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 75】 is selected from R ａ But H, D, Halo, CN, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, 4, or 5; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ２ But H, D, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl, C ２～４ Haloalkynyl, C ４～６ selected from cycloalkyl and 5- to 6-membered heterocyclyl; R ３ is selected from H, D and halo; R ４ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, C ５～６ forming cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; R １１ and R １３ But independently, H, D, C １～６ Alkyl and C １～６ haloalkyl; R １２ is selected from H and D; 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

63. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 76】 is selected from R ａ is selected from H, D, F, Cl, Br, CN, and Me, and m=0, 1, 2, 3, 4, or 5; R １ is selected from H, D, F, Me and OMe; R ２ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ２ , C≡CH, 【Chemical 77】 is selected from R ３ is selected from H, D and F; R ４ is selected from H, D, F and Me; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Transformation 78】 Forming R １１ and R １３ is independently selected from H, D and Me; R １２ is selected from H and D; 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

64. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 79】 is selected from R ａ But H, D, Halo, CN, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, 4, or 5; R １ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ But H, D, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl, C ２～４ Haloalkynyl and C ３～８ cycloalkyl; R ３ is selected from H, D and halo; R ４ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, C ５～６ forming a cycloalkyl or phenyl, R １１ But H, D, C １～６ Alkyl and C １～６ haloalkyl; R １２ and R １３ is independently selected from H and D; 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

65. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 80】 is selected from R ａ is selected from H, D, F, Cl, Br, CN, and Me, and m=0, 1, 2, 3, 4, or 5; R １ is selected from H, D, F and Me; R ２ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ２ , C≡CH, 【Chemistry 81】 is selected from R ３ is selected from H, D and F; R ４ is selected from H, D, F and Me; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 82】 Forming R １１ is selected from H, D and Me; R １２ and R １３ is independently selected from H and D; 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

66. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 83】 and R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ , R ３ and R ４ is independently selected from H, D and halo; R ２ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl; R １１ But H, D, C １～６ Alkyl and C １～６ haloalkyl; R １２ and R １３ is independently selected from H and D; 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

67. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical 84】 and R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ , R ３ and R ４ is independently selected from H, D and F; R ２ is selected from H, D, Cl, Me and cyclopropyl; R １１ is selected from H, D and Me; R １２ and R １３ is independently selected from H and D; 58. The compound of formula (III-2) according to claim 57, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

68. Formula (IV): 【Chemical 85】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R ａ is one, two or three halo, oxo, OR ｘ , N.R. ｙ R ｚ , C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ３～６ selected from cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ２ But, H, D, Halo, OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, represent one, two or three halo, C １～６ Alkyl or C １～６ optionally substituted with haloalkyl 【Chemical 86】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, C ５～６ forming a cycloalkyl or a 5- to 7-membered heterocyclyl, R １ｓ is H, R ２ｓ１ But, -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ forming a bridged bicycloalkyl, R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

69. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 87】 is selected from R ａ but, 【Chemical 88】 and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ２ But, H, D, Halo, OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, may form one, two or three halo, C １～６ Alkyl or C １～６ optionally substituted with haloalkyl 【Chemistry 89】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, C ５～６ forming a cycloalkyl or a 5- to 7-membered heterocyclyl, R １ｓ is H, R ２ｓ１ But, -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; 69. The compound of formula (IV) of claim 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

70. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 90】 is selected from R ａ but, 【Chemistry 91】 and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ But, H, D, Halo, OH, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ３ and R ４ is independently selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 92】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 93】 Forming R １ｓ is H, R ２ｓ１ But, -C １～６ Alkylene-OR Ｘ , C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemical 94】 Forming R ｘ But H, C １～６ Alkyl and C １～６ haloalkyl; 70. The compound of formula (IV) of claim 69, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

71. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical 95】 is selected from R ａ but, 【Chemistry 96】 and m=1, 2, or 3; R １ is selected from H, D, Cl and Me; R ２ H, D, Cl, OH, OMe and OCHF ２ is selected from R ３ and R ４ is independently selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 97】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chem.98】 Forming R １ｓ is H, R ２ｓ１ But, Me, Et, iPr, CH ２ F, CHF ２ and C.H. ２ OH, R ２ｓ２ and R ２ｓ３ is independently selected from Me and Et; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chem.99】 Forming 71. The compound of formula (IV) of claim 70, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

72. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 100】 and R ａ but, 【Chemistry 101】 and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 10-membered heterocyclyl; R ２ But, H, D, Halo, OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemical Engineering 102】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 103】 Forming R １ｓ is H, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ４～８ forming a bridged bicycloalkyl, 69. The compound of formula (IV) of claim 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

73. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical 104】 and R ａ but, 【Chemistry 105】 Preferably 【Chemistry 106】 and m=1, 2, or 3; R １ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ But, H, D, Halo, OH, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ３ and R ４ is independently selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 107】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 108】 Forming R １ｓ is H, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemistry 109】 Forming 73. The compound of formula (IV) of claim 72, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

74. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical 110】 and R ａ but, 【Chemistry 111】 Preferably 【Chemistry 112】 and m=1, 2, or 3; R １ is selected from H, D, Cl and Me; R ２ H, D, Cl, OH, OMe and OCHF ２ is selected from R ３ and R ４ is independently selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 113】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemical 114】 Forming R １ｓ is H, R ２ｓ１ But, Me, Et, iPr, CH ２ F and CHF ２ is selected from R ２ｓ２ and R ２ｓ３ is independently selected from Me and Et; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemical 115】 Forming 74. The compound of formula (IV) of claim 73, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

75. Formula (IV): 【Chemistry 116】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 117】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, may contain one, two or three halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ optionally substituted with haloalkyl 【Chemistry 118】 Forming R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ is H, R ２ｓ１ But H, D, -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl; Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may form one, two or three halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ４～８ forming a bridged bicycloalkyl, R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

76. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical 119】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Chemical 120】 Forming R ３ and R ４ is independently selected from H and D; R １ｓ is H, R ２ｓ１ But Me, CH ２ F, CH ２ OH, CH ２ OCH ３ and cyclopropyl; R ２ｓ２ and R ２ｓ３ is Me, Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl; Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemistry 121】 Forming 76. The compound of formula (IV) of claim 75, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein said groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

77. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 122】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, may contain one, two or three halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ optionally substituted with haloalkyl 【Chemical 123】 Forming R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ is H, R ２ｓ１ But H, D, -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl; Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may form one, two or three halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ４～８ forming a bridged bicycloalkyl, R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; 76. The compound of formula (IV) of claim 75, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein said groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

78. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 124】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 125】 Forming R ３ and R ４ is independently selected from H and D; R １ｓ is H, R ２ｓ１ But, -C ０～６ Alkylene-OR ｘ , C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl; Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemistry 126】 Forming R ｘ But H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ selected from cycloalkyl and 4- to 6-membered heterocyclyl; 78. The compound of formula (IV) of claim 77, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

79. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 127】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 128】 Forming R ３ and R ４ is independently selected from H and D; R １ｓ is H, R ２ｓ１ But Me, CH ２ F, CH ２ OH, CH ２ OCH ３ and cyclopropyl; R ２ｓ２ and R ２ｓ３ is Me, Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl; Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemistry 129】 Forming 79. The compound of formula (IV) of claim 78, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

80. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 130】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, may contain one, two or three halo, CN, C １～６ Alkyl or C １～６ optionally substituted with haloalkyl 【Chemistry 131】 Forming R ３ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ is H, R ２ｓ１ But H, D, -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may form one, two or three halo, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ４～８ forming a bridged bicycloalkyl, R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; 76. The compound of formula (IV) of claim 75, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein said groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

81. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 132】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 133】 Forming R ３ and R ４ is independently selected from H and D; R １ｓ is H, R ２ｓ１ But, -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemistry 134】 Forming 81. The compound of formula (IV) of claim 80, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

82. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 135】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ and R ２ together with the carbon atoms to which they are attached, 【Transformation 136】 Forming R ３ and R ４ is independently selected from H and D; R １ｓ is H, R ２ｓ１ But Me, CH ２ F, CH ２ OH and cyclopropyl; R ２ｓ２ and R ２ｓ３ is Me, Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, 【Chemistry 137】 Forming 82. The compound of formula (IV) of claim 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

83. Formula (IV): 【Chemistry 138】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 139】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ and R ３ together with the carbon atoms to which they are attached, [Chemical 140] Forming R １ｓ But H, C １～６ Alkyl, C １～６ haloalkyl; R ２ｓ１ are H, D, and -C ０～６ Alkylene-OR ｘ , -C ０～６ Alkylene -NR ｙ R ｚ , C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with OH; R ２ｓ１ and R ２ｓ２ together with the carbon atoms to which they are attached, form C ３～６ forming a cycloalkyl, R ｘ , R ｙ and R ｚ However, independently, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ cycloalkyl and 4- to 6-membered heterocyclyl, or R ｙ and R ｚ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

84. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 141】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ But, Halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 142】 Forming R ４ is selected from H and D; R １ｓ But H, C １～６ Alkyl, C １～６ haloalkyl; R ２ｓ１ But, -C ０～６ Alkylene-OH, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 5-membered heterocyclyl optionally substituted with OH; R ２ｓ１ and R ２ｓ２ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, 84. The compound of formula (IV) of claim 83, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

85. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 143】 is selected from R ａ is selected from H and D, and m=1, 2 or 3; R １ is selected from Cl and Me; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 144】 Forming R ４ is selected from H and D; R １ｓ is selected from H, Me and Et; R ２ｓ１ Me and CH ２ OH, R ２ｓ２ is Me, R ２ｓ３ is Me, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 5-membered heterocyclyl optionally substituted with OH; R ２ｓ１ and R ２ｓ２ together with the carbon atom to which they are attached form cyclopropyl, 85. The compound of formula (IV) of claim 84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

86. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 145】 and R ａ is selected from H and D, and m=1, 2 or 3; R １ and R ４ But independently, H, D, halo, C １～６ Alkyl and C １～６ haloalkyl; R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 146】 Forming R １ｓ But H, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ１ But, -C ０～６ Alkylene-OH, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl; 84. The compound of formula (IV) of claim 83, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

87. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 147】 and R ａ is selected from H and D, and m=1, 2 or 3; R １ is the halo, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 148】 Forming R ４ is selected from H and D; R １ｓ But H, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ１ But, -C ０～６ Alkylene-OH, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ and R ２ｓ３ But independently, C １～６ Alkyl and C １～６ haloalkyl; R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl; 87. The compound of formula (IV) of claim 86, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein said groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

88. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 149】 and R ａ is selected from H and D, and m=1, 2 or 3; R １ is Cl, R ２ and R ３ together with the carbon atoms to which they are attached, [Chemical 150] Forming R ４ is selected from H and D; R １ｓ is selected from H and Me; R ２ｓ１ Me and CH ２ OH, R ２ｓ２ is Me, R ２ｓ３ is Me, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl; 88. The compound of formula (IV) of claim 87, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

89. Formula (IV): 【Chemistry 151】 (In the formula, M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 152-1】 【Chemistry 152-2】 is selected from R ａ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, 4, or 5; R １ But H, D, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl and C ３～６ cycloalkyl; R ２ H, D, halo, NH ２ , -C ０～６ Alkylene -OH, -O-C １～６ Alkylene -OH, -C(O)C １～６ Alkyl, —C(O)C １～６ Haloalkyl, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1, 2 or 3 halo; R ３ But, H, D, Halo, OH, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ４ is selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, represent one, two or three halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl or C ２～６ Optionally substituted with alkynyl-substituted phenyl 【Chemistry 153】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, represent one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C １～６ Alkylene-C １～６ Alkoxyl or -C １～６ Alkylene-C １～６ forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkoxyl; R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ are H, D, and -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl and C ３～６ cycloalkyl; R ２ｓ２ H, D, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ３ But C １～６ Alkyl or C １～６ is haloalkyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached, C optionally substituted with one or two halo ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ forming a bridged bicycloalkyl, The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated.

31. The compound of formula (I) of claim 30, which is a compound of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

90. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 154-1】 【Chemistry 154-2】 is selected from R ａ is selected from H, D and halo, and m=0, 1, 2, 3, 4 or 5; R １ But H, D, Halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl, C ２～４ Haloalkynyl, C １～４ Alkoxyl, C １～４ Haloalkoxyl and C ３～６ cycloalkyl; R ２ But, H, D, Halo, NH ２ , -C ０～４ Alkylene -OH, -O-C １～４ Alkylene -OH, -C(O)C １～４ Alkyl, —C(O)C １～４ Haloalkyl, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxyl, C １～４ selected from haloalkoxyl and 5-membered heteroaryl, optionally substituted with 1 or 2 halo; R ３ But, H, D, Halo, OH, C １～４ Alkoxyl and C １～４ haloalkoxyl; R ４ is selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, form one or two Br or C ２～６ Optionally substituted with alkynyl-substituted phenyl 【Chemistry 155】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C １～４ Alkylene -OH, -C １～４ Alkylene-C １～４ Alkoxyl or -C １～４ Alkylene-C １～４ forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkoxyl; R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ But H, D, -C ０～４ Alkylene-OH, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl, C ２～４ Haloalkynyl and C ３～６ cycloalkyl; R ２ｓ２ But H, D, C １～４ Alkyl or C １～４ is haloalkyl, R ２ｓ３ But C １～４ Alkyl or C １～４ is haloalkyl, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached, C optionally substituted with one or two halo ３～６ forming a cycloalkyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, may contain one or two halo, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ C optionally substituted with haloalkynyl ４～８ forming a bridged bicycloalkyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

91. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 156-1】 【Chemistry 156-2】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ is H, D, F, Cl, CN, Me, CH=CH ２ , C.F. ３ and cyclopropyl; R ２ が、H、D、C-、Br、OH、Me、CH ２ F、CHF ２ 、CF ３ ,Oｭe,OCH ２ HH ２ OH, CH ２ OH、-C(O)Me、NH ２ 、 【Chemistry 157】 is selected from R ３ is selected from H, D, F, Br, OH and OMe; R ４ is selected from H, D and F; Or, R １ and R ２ together with the carbon atom to which they are attached, form Br or C ２～６ Optionally substituted with alkynyl-substituted phenyl 【Chemistry 158】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 159】 Forming R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ is H, D, OH, Me, Et, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ OH, CH ２ CH ２ selected from OH, C≡CH and cyclopropyl; R ２ｓ２ is selected from H, D and Me; R ２ｓ３ is Me, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, Or, R ２ｓ１ , R ２ｓ２ and R ２ｓ３ together with the carbon atoms to which they are attached, [Chemical 160] Forming 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

92. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 161】 is selected from R ａ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, 4, or 5; R １ But H, D, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl and C ３～６ cycloalkyl; R ２ But, H, D, Halo, NH ２ , -C ０～６ Alkylene -OH, -O-C １～６ Alkylene -OH, -C(O)C １～６ Alkyl, —C(O)C １～６ Haloalkyl, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ３ But, H, D, Halo, OH, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ４ is selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, form one, two or three halo or C ２～６ Optionally substituted with alkynyl-substituted phenyl 【Chemistry 162】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl or C １～６ forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ２ｓ２ But C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ３ But C １～６ Alkyl or C １～６ is haloalkyl, Or, R １ｓ and R ２ｓ３ together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached, C optionally substituted with one or two halo ３～６ forming a cycloalkyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

93. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 163】 is selected from R ａ is selected from H, D and halo, and m=0, 1, 2, 3, 4 or 5; R １ But H, D, Halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl, C ２～４ Haloalkynyl, C １～４ Alkoxyl, C １～４ Haloalkoxyl and C ３～６ cycloalkyl; R ２ But, H, D, Halo, NH ２ , -C ０～４ Alkylene -OH, -O-C １～４ Alkylene -OH, -C(O)C １～４ Alkyl, —C(O)C １～４ Haloalkyl, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxyl and C １～４ haloalkoxyl; R ３ But, H, D, Halo, OH, C １～４ Alkoxyl and C １～４ haloalkoxyl; R ４ is selected from H, D and halo; Or, R １ and R ２ together with the carbon atoms to which they are attached, form one or two Br or C ２～６ Optionally substituted with alkynyl-substituted phenyl 【Chemistry 164】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl or C １～６ forming a 5- to 7-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ But H, D, -C ０～４ Alkylene-OH, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl and C ２～４ haloalkynyl; R ２ｓ２ But C １～４ Alkyl or C １～４ is haloalkyl, R ２ｓ３ But C １～４ Alkyl or C １～４ is haloalkyl, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached, C optionally substituted with one or two halo ３～６ forming a cycloalkyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

94. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 165】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ is H, D, F, Cl, CN, Me, CH=CH ２ , C.F. ３ , OMe and cyclopropyl; R ２ H, D, Cl, Br, OH, Me, CH ２ F, CHF ２ , C.F. ３ , OMe, OCH ２ CH ２ OH, CH ２ OH, —C(O)Me and NH ２ is selected from R ３ is selected from H, D, F, Br, OH and OMe; R ４ is selected from H, D and F; Or, R １ and R ２ together with the carbon atoms to which they are attached, form one or two Br or C ２～６ Optionally substituted with alkynyl-substituted phenyl 【Chemistry 166】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 167】 Forming R １ｓ is H or Me, R ２ｓ１ is H, D, OH, Me, Et, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ OH, CH ２ CH ２ selected from OH and C≡CH; R ２ｓ２ is Me, R ２ｓ３ is Me, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl and cyclopentyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

95. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemical 168】 is selected from R ａ But, H, D, Halo, C １～６ Alkyl and C １～６ haloalkyl, where m=0, 1, 2, 3, 4, or 5; R １ But H, D, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ２ But H, D, halo, -C ０～６ Alkylene -OH, -O-C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl and C １～６ haloalkoxyl; R ３ is selected from H, D, halo, and OH; R ４ is selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 169】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 170】 Forming R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ２ｓ２ But C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ３ But C １～６ Alkyl or C １～６ is haloalkyl, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached, C optionally substituted with one or two halo ３～５ forming a cycloalkyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

96. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 171】 is selected from R ａ is selected from H, D and halo, and m=0, 1, 2, 3, 4 or 5; R １ But H, D, Halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl and C ２～６ haloalkynyl; R ２ But H, D, halo, -C ０～４ Alkylene -OH, -O-C １～４ Alkylene-OH, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxyl and C １～４ haloalkoxyl; R ３ is selected from H, D, halo, and OH; R ４ is selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 172】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 173】 Forming R １ｓ But H, C １～６ Alkyl or C １～６ is haloalkyl, R ２ｓ１ But H, D, -C ０～４ Alkylene-OH, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Haloalkenyl, C ２～４ Alkynyl and C ２～４ haloalkynyl; R ２ｓ２ But C １～４ Alkyl or C １～４ is haloalkyl, R ２ｓ３ But C １～４ Alkyl or C １～４ is haloalkyl, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached, C optionally substituted with one or two halo ３～５ forming a cycloalkyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

97. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 174】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ is H, D, F, Cl, CN, Me, CH=CH ２ and C.F. ３ is selected from R ２ H, D, Cl, Br, OH, Me, CH ２ F, CHF ２ , C.F. ３ , OMe, OCH ２ CH ２ OH and CH ２ OH, R ３ is selected from H, D, F, Br and OH; R ４ is selected from H and D; Or, R １ and R ２ together with the carbon atoms to which they are attached, 【Chemistry 175】 Forming Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 176】 Forming R １ｓ is H or Me, R ２ｓ１ is H, D, OH, Me, Et, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ OH, CH ２ CH ２ selected from OH and C≡CH; R ２ｓ２ is Me, R ２ｓ３ is Me, Or, R １ｓ and R ２ｓ３ together with the atom to which they are attached form a 5-membered heterocyclyl optionally substituted with one or two halo; Or, R ２ｓ２ and R ２ｓ３ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl and cyclopentyl, 90. The compound of formula (IV) of claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

98. R １ｓ and R ２ｓ３ are bonded to one, two or three halo, OH, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ２～６ Forming an alkylene The above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms until fully deuterated; 90. The compound of formula (IV) according to claim 89, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the other variables are defined in any one of claims 1 to 29.

99. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 177】 is selected from R ａ But, H, D, Halo, NO ２ , N.H. ２ , -C １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ haloalkynyl and amino protecting groups, m=0, 1, 2, 3, 4, or 5, or two adjacent R ａ together with the atom to which they are attached form phenyl or a 5- to 6-membered heteroaryl; R １ and R ４ is independently selected from H, D and halo; R ２ But H, D, halo, -C ０～６ Alkylene-OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C ５～６ Cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ selected from aryl, 5- to 10-membered heteroaryl, —O-5- to 6-membered heteroaryl, —NH-5- to 6-membered heteroaryl, —OC(O)-5- to 6-membered heteroaryl, or —NHC(O)-5- to 6-membered heteroaryl; and １～６ Alkylene-OH, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ optionally substituted with cycloalkyl or 5- to 6-membered heterocyclyl; R ３ H, D, halo, OH, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ and R ３ together with the carbon atoms to which they are attached, may form one, two, three or four halo, C １～６ Alkyl, C １～６ Haloalkyl, —C(O)C １～６ Alkyl or —C(O)C １～６ forming a 5- to 6-membered heterocyclyl optionally substituted with haloalkyl; R １ｓ and R ２ｓ３ are bonded to one, two or three halo, OH, C １～６ Alkyl or C １～６ C optionally substituted with haloalkyl ２～６ Forming an alkylene R ２ｓ１ But H, D, C １～６ Alkyl and C １～６ haloalkyl; R ２ｓ２ But H, D, -C ０～６ Alkylene-OH, C １～６ Alkyl and C １～６ haloalkyl; Or, R ２ｓ１ and R ２ｓ２ together with the carbon atoms to which they are attached, C ３～６ forming a cycloalkyl, 99. The compound of formula (IV) of claim 98, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

100. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Chemistry 178】 is selected from R ａ is selected from H, D and halo, and m=0, 1, 2 or 3; R １ is selected from H, D and halo; R ２ But, H, D, Halo, C １～４ Alkyl and C １～４ haloalkyl; R ３ is selected from H, D and halo; R ４ is selected from H and D; Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 179】 Forming R １ｓ and R ２ｓ３ are bonded to one, two or three halo, OH, C １～４ Alkyl or C １～４ C optionally substituted with haloalkyl ２～４ Forming an alkylene R ２ｓ１ But H, D, C １～４ Alkyl and C １～４ haloalkyl; R ２ｓ２ But H, D, -C １～４ Alkylene-OH, C １～４ Alkyl and C １～４ haloalkyl; Or, R ２ｓ１ and R ２ｓ２ together with the carbon atoms to which they are attached, C ３～５ forming a cycloalkyl, 99. The compound of formula (IV) of claim 98, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

101. M １ But, CR １ and N, preferably CR １ is selected from M ２ But, CR ２ and N, preferably CR ２ is selected from M ３ But, CR ３ and N, preferably CR ３ is selected from M ４ But, CR ４ and N, preferably CR ４ is selected from Ring A is 【Transformation 180】 is selected from R ａ is selected from H and D, and m=0, 1, 2, 3, 4, or 5; R １ is Cl, R ２ is Cl, R ３ is selected from H and D; R ４ is selected from H and D; Or, R ２ and R ３ together with the carbon atoms to which they are attached, 【Chemistry 181】 Forming R １ｓ and R ２ｓ３ is bonded to a C optionally substituted with one or two OH ２～３ Forming an alkylene R ２ｓ１ is selected from H, D and Me; R ２ｓ２ H, D, Me and CH ２ OH, Or, R ２ｓ１ and R ２ｓ２ together with the carbon atom to which they are attached form cyclopropyl, 99. The compound of formula (IV) of claim 98, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with one, two, three, four, five or more deuterium atoms up to full deuteration.

102. A compound selected from the group consisting of the compounds set forth in Tables 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

103. A compound according to any one of claims 1 to 102 or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof; a pharmaceutically acceptable excipient, and optionally one or more other therapeutic agents A pharmaceutical composition comprising:

104. a first container comprising the compound of any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof; optionally, a second container containing one or more other therapeutic agents; and Optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound and / or other therapeutic agent. A kit comprising:

105. 103. Use of a compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, in the manufacture of a medicament for treating an immune and / or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

106. 103. A compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, for use in treating an immune and / or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

107. 103. A method of treating an immune and / or inflammatory related disease, disorder or condition caused by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 102 or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

108. 107. The use of claim 105, or the compound for use of claim 106, or the method of claim 107, wherein the disease, disorder or condition is selected from sepsis, cancer, systemic lupus erythematosus, spiroandenoma, spiroandenocarcinoma, Kawasaki disease, ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine) syndrome, PFAPA (periodic fevers, aphthous stomatitis, pharyngitis and lymphadenitis) syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease.

109. 109. The use or compound or method for use of claim 108, wherein said cancer is selected from lung cancer, colon cancer and oral squamous cell carcinoma.

110. 109. The use or compound or method for use of claim 108, wherein said disease or disorder is ROSAH.

111. 109. The use or compound or method for use of claim 108, wherein said disease or disorder is PFAPA.

112. 109. The use or compound or method for use of claim 108, wherein said disease or disorder is spiradenoma or spiradenoma carcinoma.

113. 109. The use or compound or method for use of claim 108, wherein said disease or disorder is sepsis.

114. 109. The use or compound or method for use of claim 108, wherein said disease or disorder is systemic lupus erythematosus.

115. 109. The use or compound or method for use of claim 108, wherein said disease or disorder is Kawasaki disease.

116. 109. The use or compound or method for use of claim 108, wherein said subject carries one or more genetic mutations in ALPK1.

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