Pyridazine fused aromatic ring compound and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a pyridazine fused aromatic ring compound and application thereof, in particular to a compound shown as a formula (I), an isomer thereof, pharmaceutically acceptable salt thereof and application thereof. As an NLRP3 inflammasome inhibitor with a brand new structure, the compound disclosed by the invention has a good inhibition effect on signal transduction induced by the NLRP3 inflammasome. # imgabs0 #

Description

A pyridazine fused aromatic ring compound and its use

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority and benefits of Chinese Patent Application No. 202211682289.0 filed with the State Intellectual Property Office of China on December 27, 2022, Chinese Patent Application No. 202310369110.4 filed with the State Intellectual Property Office of China on April 7, 2023, and Chinese Patent Application No. 202311205493.8 filed with the State Intellectual Property Office of China on September 18, 2023, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and relates to a pyridazine fused aromatic ring compound and its use, and specifically to a compound of formula (I), its isomers and pharmaceutically acceptable salts thereof, and their use. Background Art

[0004] As components of the innate immune system, inflammasomes play a crucial role in immune regulation. It is known that NOD-like and AIM2-like receptors in cells can assemble into structurally similar inflammasomes. The NLRP3 inflammasome is the best-studied inflammasome. It is a multiprotein macromolecular complex composed of NLRP3, the adaptor protein ASC, and the effector caspase-1. It is typically found in macrophages, dendritic cells, microglia, and endothelial cells. NLRP3 protein levels are low in normal cells. When cells are stimulated by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), NLRP3 and pro-inflammatory cytokine gene expression is upregulated through the NF-κB signaling pathway. NLRP3 protein oligomerizes and recruits pro-caspase-1 through ASC to form the NLRP3 inflammasome. Caspase-1 converts from its pro-form to its active form, promoting the release of inflammatory cytokines and accompanied by inflammatory pyroptosis.

[0005] NLRP3 inflammasome activation is accompanied by severe inflammatory responses and is involved in the pathology of various diseases, such as inflammasome-related diseases / disorders or inflammatory diseases. Therefore, the rational design and synthesis of compounds with NLRP3 inflammasome inhibitory activity is of great value in the treatment of inflammatory diseases.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] Structural unit including fused and bicyclic heteroaryls;

[0010] Q and Y are each independently selected from C, Si or N, and one of Q and Y is N;

[0011] Z 1 , Z 2 and Z 3 Each independently selected from C(R 3 )、Si(R 3 ) or N;

[0012] X is selected from -N(R 4 )-(C(R 5 )(R 6 )) m -、-O-(C(R 5 )(R 6 )) m -、-S-(C(R 5 )(R 6 )) m -or-(C(R 5 )(R 6 )) m -;

[0013] R 1 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace;

[0014] R 2 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 3-8 Cycloalkyl, -(CH2) i -(3-8 membered heterocycloalkyl), -(CH2) i -(C 6-10 aryl) or -(CH2) i -(5-9 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R b replace;

[0015] Each R 3 Each independently selected from H, OH, CN, NH2, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2 are optionally substituted independently by 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R c replace;

[0016] Or, Z 1 , Z 2 Each independently selected from C(R 3 ) or Si(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached together to form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace;

[0017] Or, Z 2 , Z 3 Each independently selected from C(R 3 ) or Si(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace;

[0018] R 4 Selected from H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl may be optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN;

[0019] Each R 5 and R 6 Each independently selected from H, OH, NH2, CN, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0020] Each R a Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 2-6 Alkenyl, -(CH2) i C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 2-6 Alkenyl or -(CH2) i C 2-6 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace;

[0021] Each R bEach independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-NH2, -S(=O)2-NH-C 1-3 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-NH-C 3-6 Cycloalkyl, -S(=O)(NH)-C 1-3 Alkyl, -S(=O)(NH)-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-NH-C 1-3 Alkyl or -S(=O)(NH)-C 1-3 The alkyl group is optionally substituted independently with 1, 2 or 3 halogens, OH, NH2 or CN; the -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-NH-C 3-6 Cycloalkyl, -S(=O)(NH)-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace;

[0022] Each R c Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide;

[0023] Each R d Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide;

[0024] Each R e Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide;

[0025] m is selected from 0, 1, 2 or 3;

[0026] i is selected from 0, 1 or 2;

[0027] Each R 4 、R 5 、R 6 、R c 、R d or R e each optionally independently substituted with one or more substituents;

[0028] Optionally, each R 1 、R 2 、R 3 、R a or R b are each independently substituted with one or more other substituents.

[0029] In some embodiments of the present disclosure, each R 4 、R 5 、R 6 、R c 、R d or R e Each is independently optionally substituted with 1, 2 or 3 substituents.

[0030] In some embodiments of the present disclosure, each R 1 、R 2 、R 3 、R a or R b Each is independently optionally substituted with one or more other substituents.

[0031] In some embodiments of the present disclosure, the "1, 2 or 3" mentioned in the present disclosure may also be "one or more", for example, it may be "1, 2, 3, 4, 5 or 6".

[0032] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0033] Structural unit is a fused bicyclic heteroaryl group;

[0034] Q and Y are each independently selected from C, Si or N, and one of Q and Y is N;

[0035] Z 1 , Z 2 and Z 3 Each independently selected from C(R 3 )、Si(R 3 ) or N;

[0036] X is selected from -N(R4 )-(C(R 5 )(R 6 )) m -、-O-(C(R 5 )(R 6 )) m -、-S-(C(R 5 )(R 6 )) m -or-(C(R 5 )(R 6 )) m -;

[0037] R 1 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace;

[0038] R 2 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 3-8 Cycloalkyl, -(CH2) i -(3-8 membered heterocycloalkyl), -(CH2) i -(C 6-10 aryl) or -(CH2) i -(5-9 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R b replace;

[0039] Each R 3 Each independently selected from H, OH, CN, NH2, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2 are optionally substituted independently by 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R c replace;

[0040] R 4 Selected from H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl may be optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN;

[0041] Each R 5 and R 6 Each independently selected from H, OH, NH2, CN, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0042] Each R a Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 2-6 Alkenyl, -(CH2) i C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 2-6 Alkenyl or -(CH2) i C 2-6 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace;

[0043] Each R b Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-NH2, -S(=O)2-NH-C 1-3 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-NH-C 3-6 Cycloalkyl, -S(=O)(NH)-C 1-3 Alkyl, -S(=O)(NH)-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-NH-C 1-3 Alkyl or -S(=O)(NH)-C 1-3 The alkyl group is optionally substituted independently with 1, 2 or 3 halogens, OH, NH2 or CN; the -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-NH-C 3-6 Cycloalkyl, -S(=O)(NH)-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace;

[0044] Each R c Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide;

[0045] Each R d Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide;

[0046] Each R eEach independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide;

[0047] m is selected from 0, 1, 2 or 3;

[0048] i is selected from 0, 1 or 2.

[0049] In some embodiments of the present disclosure, the structural unit There is only one fused bicyclic heteroaryl group.

[0050] In some embodiments of the present disclosure, the structural unit It is a fused bicyclic heteroaryl group.

[0051] In some embodiments of the present disclosure, the structural unit It is a fused tricyclic heteroaryl group.

[0052] In some embodiments of the present disclosure, the structural unit It is a fused tricyclic structure, but has only one fused bicyclic heteroaryl group.

[0053] In some embodiments of the present disclosure, the heteroatom in the “heterocycloalkyl” or “partially saturated heterocycloalkyl” described in the present disclosure is selected from N, O, S, Si, P or Se.

[0054] In some embodiments of the present disclosure, the heteroatom in the “heterocycloalkyl” or “heteroaryl” described in the present disclosure is selected from N, O or S.

[0055] In some embodiments of the present disclosure, the “heterocycloalkyl”, “partially saturated heterocycloalkyl” or “heteroaryl” described in the present disclosure contains 1, 2 or 3 ring heteroatoms selected from N, O, S, Si, P, Se; or, contains 1, 2 or 3 ring heteroatoms selected from N, O, S; or, contains 1 or 2 ring heteroatoms selected from N, O, S.

[0056] In some embodiments of the present disclosure, Q and Y are each independently selected from C or N, and one of Q and Y is N.

[0057] In some embodiments of the present disclosure, only one of Q and Y is N, and the other is Si or C.

[0058] In some embodiments of the present disclosure, one and only one of Q and Y is N, and the other is C.

[0059] In some embodiments of the present disclosure, Q is selected from N, and Y is selected from C.

[0060] In some embodiments of the present disclosure, Q is selected from C and Y is selected from N.

[0061] In some embodiments of the present disclosure, Z 1 , Z 2 and Z 3 Each independently selected from C(R 3 ) or N.

[0062] In some embodiments of the present disclosure, Q and Y are each independently selected from C or N, and one of Q and Y is N; Z 1 , Z 2 and Z 3 Each independently selected from C(R 3 ) or N.

[0063] In some embodiments of the present disclosure, Z 1 Selected from N, Z 2 and Z 3 Selected from C(R 3 ).

[0064] In some embodiments of the present disclosure, Z 1 and Z 2 Selected from N, Z 3 Selected from C(R 3 ).

[0065] In some embodiments of the present disclosure, Z 1 and Z 3 Selected from N, Z 2 Selected from C(R 3 ).

[0066] In some embodiments of the present disclosure, Z 2 Selected from N, Z 1 and Z 3 Selected from C(R 3 ).

[0067] In some embodiments of the present disclosure, Z 2 and Z 3 Selected from N, Z 1 Selected from C(R 3 ).

[0068] In some embodiments of the present disclosure, Z 3 Selected from N, Z 1 and Z 2 Selected from C(R 3 ).

[0069] In some embodiments of the present disclosure, Z 1 , Z 2 and Z 3 All selected from C(R 3 ).

[0070] In some embodiments of the present disclosure, Z 1 , Z 2 and Z 3 All are selected from N.

[0071] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 1 Selected from N, Z 2 and Z 3 Selected from C(R 3 ).

[0072] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 1 and Z 2 Selected from N, Z 3 Selected from C(R 3 ).

[0073] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 1 and Z 3 Selected from N, Z 2 Selected from C(R 3 ).

[0074] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 2 Selected from N, Z 1 and Z 3 Selected from C(R 3 ).

[0075] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 2 and Z 3 Selected from N, Z 1 Selected from C(R 3 ).

[0076] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 3 Selected from N, Z 1 and Z 2 Selected from C(R 3 ).

[0077] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 1 , Z 2 and Z 3 All selected from C(R 3 ).

[0078] In some embodiments of the present disclosure, Q is selected from N, Y is selected from C, Z 1 , Z 2 and Z 3 All are selected from N.

[0079] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 1 Selected from N, Z 2 and Z 3 Selected from C(R 3 ).

[0080] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 1 and Z 2 Selected from N, Z 3 Selected from C(R 3 ).

[0081] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 1 and Z 3 Selected from N, Z 2 Selected from C(R 3 ).

[0082] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 2 Selected from N, Z 1 and Z 3 Selected from C(R 3 ).

[0083] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 2 and Z 3 Selected from N, Z 1 Selected from C(R 3 ).

[0084] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 3 Selected from N, Z 1 and Z 2 Selected from C(R 3 ).

[0085] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 1 , Z 2 and Z 3 All selected from C(R 3 ).

[0086] In some embodiments of the present disclosure, Q is selected from C, Y is selected from N, Z 1 , Z 2 and Z 3 All are selected from N.

[0087] In some embodiments of the present disclosure, each R 3Each is independently selected from H, OH, CN, NH2, halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl, the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 being optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl being optionally independently substituted with 1, 2 or 3 R c replace.

[0088] In some embodiments of the present disclosure, each R c Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

[0089] In some embodiments of the present disclosure, each R c are each independently selected from OH or methyl.

[0090] In some embodiments of the present disclosure, each R 3 Each is independently selected from H, OH, CN, NH2, halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3 or -N(CH3)2, and the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3 or -N(CH3)2 is optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN.

[0091] In some embodiments of the present disclosure, each R 3 Each is independently selected from H, OH, CN, NH2, F, Cl, Br, I, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

[0092] In some embodiments of the present disclosure, each R 3 Each is independently selected from H, F, Cl, methyl or trifluoromethyl.

[0093] In some embodiments of the present disclosure, each R 3 are each independently selected from H.

[0094] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3and the atoms to which they are attached together to form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace.

[0095] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached together to form C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0096] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached together to form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from N, O, S, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from N, O, S, wherein C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0097] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached together to form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, phenyl or 5-6 membered heteroaryl containing 1 or 2 ring heteroatoms selected from N, O, S, wherein the C5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0098] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached together to form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, phenyl or 5-6 membered heteroaryl containing 1 or 2 ring heteroatoms selected from N, O, S, wherein the C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0099] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached together to form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, or 5 membered heteroaryl containing 1 or 2 ring heteroatoms selected from N, O, S, wherein the C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl or 5 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0100] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

[0101] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

[0102] In some embodiments of the present disclosure, Z 1 , Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

[0103] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace.

[0104] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 5-6Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0105] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1, 2 or 3 ring heteroatoms selected from N, O, S, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0106] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, phenyl or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, wherein C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0107] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, phenyl or 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, wherein C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0108] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached together to form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, or 5 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, wherein the C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl or 5 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0109] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

[0110] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

[0111] In some embodiments of the present disclosure, Z 2 , Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

[0112] In some embodiments of the present disclosure, the structural unit Selected from

[0113] In some embodiments of the present disclosure, the structural unit Selected from

[0114] In some embodiments of the present disclosure, the structural unit Selected from

[0115] In some embodiments of the present disclosure, the structural unit Selected from

[0116] In some embodiments of the present disclosure, the structural unit Selected from

[0117] In some embodiments of the present disclosure, the structural unit Selected from

[0118] In some embodiments of the present disclosure, the structural unit Selected from

[0119] In some embodiments of the present disclosure, X is selected from -N(R 4 )-, -O-, -S-, or -(C(R 5 )(R 6 )) m -.

[0120] In some embodiments of the present disclosure, R 4 is selected from H, methyl, ethyl or isopropyl.

[0121] In some embodiments of the present disclosure, R 4 Selected from H.

[0122] In some embodiments of the present disclosure, each R5 and R 6 are each independently selected from H or OH.

[0123] In some embodiments of the present disclosure, each R 5 and R 6 are each independently selected from H.

[0124] In some embodiments of the present disclosure, X is selected from -NH-, -O-, -S-, -CH2-, or -CH2CH2-.

[0125] In some embodiments of the present disclosure, X is selected from -NH-.

[0126] In some embodiments of the present disclosure, R 1 Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0127] In some embodiments of the present disclosure, R 1 Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, phenyl, or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a replace.

[0128] In some embodiments of the present disclosure, R 1 phenyl, or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein the phenyl or 5-6 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace.

[0129] In some embodiments of the present disclosure, R 1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl is optionally independently substituted by 1, 2 or 3 R a replace.

[0130] In some embodiments of the present disclosure, R 1is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein the phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl is optionally independently substituted by 1, 2 or 3 R a replace.

[0131] In some embodiments of the present disclosure, R 1 is selected from phenyl, said phenyl being optionally independently substituted by 1, 2 or 3 R a replace.

[0132] In some embodiments of the present disclosure, R 1 Selected from

[0133] In other embodiments of the present disclosure, each R a Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 are optionally substituted independently by 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace.

[0134] In other embodiments of the present disclosure, each R a Each independently selected from OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or -(CH2) i C 2-4 Alkynyl, said, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or -(CH2) i C 2-4 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN.

[0135] In other embodiments of the present disclosure, each R a Each independently selected from C 2-4Alkenyl, C 2-4 Alkynyl or -(CH2) i C 2-4 Alkynyl, the C 2-4 Alkenyl, C 2-4 Alkynyl or -(CH2) i C 2-4 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN.

[0136] In some embodiments of the present disclosure, each R a Each is independently selected from OH, CN, NH2, halogen, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl, the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 being optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl being optionally independently substituted with 1, 2 or 3 R d In other embodiments of the present disclosure, each R a Each independently selected from The R a Optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN.

[0137] In some embodiments of the present disclosure, each R a Each is independently selected from F, Cl, Br, I, =O, OH, CN, NH2, methyl or methoxy, wherein the methyl or methoxy is optionally substituted with 1, 2 or 3 halogens, OH, NH2 or CN. In other embodiments of the present disclosure, each R a Each independently selected from ethyl, The R a Optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN.

[0138] In some embodiments of the present disclosure, each R a Each is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl or methoxy, wherein the methyl or methoxy is optionally substituted with 1, 2 or 3 halogens, OH, NH2 or CN. In other embodiments of the present disclosure, each R a Each independently selected from ethyl, The R aOptionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN.

[0139] In some embodiments of the present disclosure, each R a Each is independently selected from F, Cl, =O, OH or trifluoromethyl. In some embodiments of the present disclosure, each R a Each is independently selected from F, Cl, OH or trifluoromethyl. In other embodiments of the present disclosure, each R a Each independently selected from trifluoromethoxy, difluoromethoxy, CF3CH2-, CN,

[0140] In some embodiments of the present disclosure, each R a Each is independently selected from OH or trifluoromethyl.

[0141] In other embodiments of the present disclosure, each R a Each independently selected from

[0142] In some embodiments of the present disclosure, each R d Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

[0143] In some embodiments of the present disclosure, R 1 Selected from In other embodiments of the present disclosure, R 1 Selected from

[0144] In some embodiments of the present disclosure, R 1 Selected from

[0145] In other embodiments of the present disclosure, R 1 Selected from

[0146] In some embodiments of the present disclosure, R 2 Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -(CH2) i C 3-6 Cycloalkyl, -(CH2) i -(3-6 membered heterocycloalkyl), -(CH2) i -phenyl or -(CH2) i -(5-6 membered heteroaryl), the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R b replace.

[0147] In some embodiments of the present disclosure, R 2 Selected from C 1-4 Alkyl, -(CH2) i C 3-6 Cycloalkyl, -(CH2) i -(3-6 membered heterocycloalkyl), -(CH2) i -phenyl or -(CH2) i -(5-6 membered heteroaryl), the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R b replace.

[0148] In some embodiments of the present disclosure, R 2 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R b replace.

[0149] In some embodiments of the present disclosure, R 2 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, phenyl, or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R b replace.

[0150] In some embodiments of the present disclosure, R 2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, thiirane, aziridine, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein R 2 Optionally independently 1, 2 or 3 R b replace.

[0151] In some embodiments of the present disclosure, R 2 is selected from n-propyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or piperidinyl, wherein R 2 Optionally independently 1, 2 or 3 R b In other embodiments of the present disclosure, R 2 is selected from cyclobutyl, cyclohexyl or piperidinyl, wherein R 2 Optionally independently 1, 2 or 3 R b replace.

[0152] In some embodiments of the present disclosure, R 2 is selected from piperidinyl, said piperidinyl being optionally independently substituted by 1, 2 or 3 R b replace.

[0153] In some embodiments of the present disclosure, each R b Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 are optionally substituted independently by 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace.

[0154] In some embodiments of the present disclosure, each Rb Each is independently selected from OH, CN, NH2, halogen, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl, the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 being optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl being optionally independently substituted with 1, 2 or 3 R e In other embodiments of the present disclosure, each R b Each is independently selected from -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-NH2, -S(=O)2-NH-CH3, -S(=O)2-NH-CH2CH3, -S(=O)2-cyclopropyl, -S(=O)2-NH-cyclopropyl, -S(=O)(NH)-CH3, -S(=O)(NH)-CH2CH3, -S(=O)(NH)-cyclopropyl, the -S(=O)2-C H3, -S(=O)2-CH2CH3, -S(=O)2-NH-CH3, -S(=O)2-NH-CH2CH3, -S(=O)(NH)-CH3 or -S(=O)(NH)-CH2CH3 are optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the -S(=O)2-cyclopropyl, -S(=O)2-NH-cyclopropyl or -S(=O)(NH)-cyclopropyl are optionally independently substituted with 1, 2 or 3 R e replace.

[0155] In some embodiments of the present disclosure, each R b Each is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl or methoxy, wherein the methyl or methoxy is optionally substituted with 1, 2 or 3 halogens, OH, NH2 or CN. In other embodiments of the present disclosure, each R b Each is independently selected from ethyl, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-cyclopropyl or -S(=O)(NH)-CH3, and the ethyl, -S(=O)2-CH3, -S(=O)(NH)-CH3 or -S(=O)2-cyclopropyl is optionally independently substituted by 1, 2 or 3 halogens, OH, NH2 or CN.

[0156] In some embodiments of the present disclosure, each R bEach is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl or trifluoromethyl. In other embodiments of the present disclosure, each R b Each is independently selected from ethyl, 2-hydroxyethyl, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-cyclopropyl or -S(=O)(NH)-CH3.

[0157] In some embodiments of the present disclosure, each R b Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

[0158] In some embodiments of the present disclosure, each R b are each independently selected from OH or methyl.

[0159] In other embodiments of the present disclosure, each R b Each is independently selected from OH, methyl, ethyl, 2-hydroxyethyl, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-cyclopropyl or -S(=O)(NH)-CH3.

[0160] In other embodiments of the present disclosure, each R b Each is independently selected from OH, methyl or ethyl.

[0161] In some embodiments of the present disclosure, each R e Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

[0162] In some embodiments of the present disclosure, R 2 Selected from In other embodiments of the present disclosure, R 2 Selected from

[0163] In some embodiments of the present disclosure, R 2 Selected from

[0164] In some embodiments of the present disclosure, the R 2 A group that is in single enantiomeric form, enriched in one enantiomer, or in racemic form.

[0165] In some embodiments of the present disclosure, R 2 Selected from

[0166] In some embodiments of the present disclosure, m is selected from 0 or 1.

[0167] In some embodiments of the present disclosure, i is selected from 0 or 1.

[0168] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-1a) or a compound of formula (I-1b), or a pharmaceutically acceptable salt thereof,

[0169] in,

[0170] R 1 、R 2 , Z 1 , Z 2 and Z 3 As defined for the compounds of formula (I).

[0171] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-2a), a compound of formula (I-2b), a compound of formula (I-2c) or a compound of formula (I-2d), or a pharmaceutically acceptable salt thereof,

[0172] in,

[0173] R 1 、R 2 、R a 、R b , Z 1 , Z 2 and Z 3 As defined for the compounds of formula (I).

[0174] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-2c-1), a compound of formula (I-2c-2), a compound of formula (I-2d-1) or a compound of formula (I-2d-2), or a pharmaceutically acceptable salt thereof,

[0175] in,

[0176] R 1 、R b , Z 1 , Z 2 and Z 3 As defined for the compounds of formula (I).

[0177] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-3a) or a compound of formula (I-3b), or a pharmaceutically acceptable salt thereof,

[0178] in,

[0179] R a 、R b , Z 1 , Z 2 and Z 3 As defined for the compounds of formula (I).

[0180] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-3a-1), a compound of formula (I-3a-2), a compound of formula (I-3b-1) or a compound of formula (I-3b-2), or a pharmaceutically acceptable salt thereof,

[0181] in,

[0182] R a 、R b , Z 1 , Z 2 and Z 3 As defined for the compounds of formula (I).

[0183] Some other embodiments of the present disclosure are formed by any combination of the above variables.

[0184] The present disclosure also provides a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

[0185] In some embodiments of the present disclosure, the compounds described herein are in the form of a single enantiomer, in the form of an enriched enantiomer, or in racemic form.

[0186] The present disclosure also provides a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0187] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable carrier.

[0188] The present disclosure also provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease (eg, a disease mediated by NLRP3 inflammasome).

[0189] The present disclosure also provides a method for treating or preventing a disease (e.g., a disease mediated by NLRP3 inflammasome), comprising administering a therapeutically or prophylactically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a mammal (preferably a human) in need of such treatment or prevention.

[0190] The present disclosure also provides use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in treating or preventing diseases (e.g., diseases mediated by NLRP3 inflammasome).

[0191] The present disclosure also provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease (eg, a disease mediated by NLRP3 inflammasome).

[0192] In some embodiments of the present disclosure, the NLRP3 inflammasome-mediated disease is selected from: an inflammasome-related disease / disorder or an inflammatory disease.

[0193] Technical Effects

[0194] The compounds disclosed herein are novel NLRP3 inflammasome inhibitors with a novel structure. They exhibit potent inhibitory effects on NLRP3 inflammasome-induced signaling, strong anti-pyroptosis activity against J774A.1 cells, and potent inhibitory activity against IL-1β expression in THP-1 cells, as well as robust in vivo inhibitory activity. The compounds disclosed herein exhibit favorable pharmacokinetic properties and are promising candidates for development as novel NLRP3 inflammasome inhibitors.

[0195] Related definitions

[0196] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0197] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0198] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure, which are prepared by reacting the compounds of the present disclosure with relatively nontoxic acids or bases. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in a neat solution or a suitable inert solvent. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent. Certain specific compounds of the present disclosure contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0199] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0200] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0201] Unless otherwise indicated, for compounds having one or more stereoisomers, the bonds to the chiral centers are represented by solid lines. The ranges indicated encompass all compounds in single enantiomeric form, in form enriched in one enantiomer, or in racemic form.

[0202] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0203] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0204] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0205] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and extended drug biological half-life. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. For example, it should be understood that compounds of Formula (I) disclosed herein in which one or more hydrogen atoms are replaced by deuterium atoms are still within the scope of the compounds of Formula (I) disclosed herein.

[0206] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0207] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0208] The term "one or more substitutions" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, and the number of substituents includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, based on chemical achievable basis.

[0209] The "substituents" described herein include, but are not limited to, the terms "alkyl", "alkoxy", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "partially saturated cycloalkyl", "heterocycloalkyl", "partially saturated heterocycloalkyl", "heteroaryl", "aryl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituents" include protium, deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide, sulfoxide, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, cycloalkyl group, halo-cycloalkyl group, alkenyl group, halo-alkenyl group, cycloalkenyl group, halo-cycloalkenyl group, alkynyl group, halo-alkynyl group, cycloalkynyl group, halo-cycloalkynyl group, heteroalkyl group, halo-heteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, aralkyl group, arylalkoxy group, arylalkylthio group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroaralkyl group, heteroarylalkoxy group, heteroarylalkylthio group, heterocyclyl group, heterocyclyloxy group, heterocyclic group alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0210] In some embodiments herein, the “substituent” is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 Alkylene or 6-10 membered aryloxy. When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0211] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0212] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0213] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, Z 1 and Z 2 R on 3 and the atoms to which they are attached form When the structural unit Can be It can also be For example, Z 2 and Z 3 R on 3 and the atoms to which they are attached form When the structural unit Can be It can also be

[0214] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0215] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-4 and C 1-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0216] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0217] Unless otherwise specified, the term “C 1-3"Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-2 、C 2-3 , C3 and C2 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), and the like.

[0218] The term "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0219] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0220] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl can be C 2-4 Alkenyl or C 2-3 Alkenyl. 2-4 Alkenyl groups include C 2-3 , C4, C3 and C2 alkenyl, etc.; C 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like.

[0221] Unless otherwise specified, “C 2-6 "Alkynyl" is used to denote a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0222] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated hydrocarbon cycloalkyl group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl; it can be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctyl, and the like.

[0223] Unless otherwise specified, the term “C 3-8 "Partially saturated cycloalkyl" refers to a partially saturated hydrocarbon cycloalkyl group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spiro, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Partially saturated cycloalkylcycloalkyl; it may be monovalent, divalent or polyvalent.

[0224] Unless otherwise specified, the term “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0225] Unless otherwise specified, the term "3-8 membered heterocycloalkyl" means a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N, P, Si or Se, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized and the carbon, silicon, nitrogen, phosphorus and sulfur heteroatoms are optionally oxidized (i.e., Si=O, C=O, NO, P=O and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl", a heteroatom may occupy the position at which the heteroalkyl ring connects to the rest of the molecule. The 3-8 membered heterocycloalkyl includes 3-6 membered heterocycloalkyl, etc. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, oxirane, thiirane, aziridine, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenanyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0226] Unless otherwise specified, the term "3-8 membered partially saturated heterocycloalkyl" means a partially saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N, P, Si or Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the carbon, silicon, nitrogen, phosphorus and sulfur heteroatoms may be optionally oxidized (i.e., Si=O, C=O, NO, P=O and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-8 membered partially saturated heterocycloalkyl", a heteroatom may occupy the position at which the heteroalkyl ring is connected to the rest of the molecule. The 3-8 membered partially saturated heterocycloalkyl includes 3-6 membered partially saturated heterocycloalkyl, 5-6 membered partially saturated heterocycloalkyl, etc.

[0227] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N, P, Si or Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the carbon, silicon, nitrogen, phosphorus and sulfur heteroatoms are optionally oxidized (i.e., C=O, NO, P=O and S(O) p, p is 1 or 2). It is a monocyclic ring system. In addition, with respect to the "3-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 3-membered, 4-membered, 5-membered and 6-membered heterocycloalkyls. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, oxirane, thiirane, aziridine, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0228] Unless otherwise specified, the term "5-9 membered heteroaryl" refers to a cyclic group consisting of 5 to 9 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., C=O, NO and S(O) p, p is 1 or 2). It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The 5-9 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-9 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-9 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl) oxazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl and 6-quinolyl, etc.), etc.

[0229] Unless otherwise specified, the term “C 6-10 "Aryl" refers to a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic ring system, in which each ring is aromatic. It can be monovalent, divalent or polyvalent. 6-10 Aryl includes C9, C 10 and C6 aryl. 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0230] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0231] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0232] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0233] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0234] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically or prophylactically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0235] The therapeutic or prophylactic dose of the disclosed compounds may be determined, for example, based on the specific use for treatment or prevention, the manner in which the compound is administered, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. In certain embodiments, the dosage range is about 0.001 mg / kg to about 200 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0236] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0237] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0238] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0239] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0240] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0241] In some embodiments, some of the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0242] Route 1:

[0243] Route 2:

[0244] Route 3:

[0245] Among them, Z 1 , Z 2 , Z 3 、R 1 and R 2 As described above for the compound of formula (I).

[0246] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0247] The raw materials or intermediates used in the embodiments of the present disclosure can be obtained from commercial sources or prepared by methods of the prior art.

[0248] An important consideration in synthetic route planning in the art is the selection of appropriate protecting groups for reactive functional groups (such as the amino group in the present disclosure). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0249] For the purpose of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure.

[0250] All reagents used in this disclosure were commercially available and used without further purification. DETAILED DESCRIPTION

[0251] The present disclosure is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0252] Example 1

[0253] Reaction process:

[0254] Step A: 1-1 (8 g, 57.5 mmol) and hydrazine hydrate (71.5 g, 2.23 mol) were added to ethanol (70 mL). The mixture was heated to 90°C and reacted for 16 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, washed with water (10 mL) and ethanol (5 mL), and the filter cake was collected and dried in vacuo at 40°C to obtain 1-2 (6.6 g).

[0255] MS (ESI-, [MH] - )m / z:124.06.

[0256] Step B: Tetramethyl orthoformate (8.16 g, 59.9 mmol) and aluminum isopropoxide (1.632 g, 7.99 mmol) were added to a solution of 1-2 (5 g, 40 mmol) in acetonitrile (10 mL). After nitrogen displacement, the mixture was heated to 120°C for 18 hours. After completion of the reaction, the reaction solution was concentrated and dried, and the crude product was purified by silica gel column chromatography to obtain 1-3 (3.6 g). MS (ESI+, [M+H] + )m / z:165.92.

[0257] 1 H NMR (500MHz, DMSO-d6) δ11.29(s,1H),7.48(dd,J=2.8,1.4Hz,1H),7.03(dd,J=3.7,1.4Hz,1H),6.73(dd,J=3.7,3.0Hz,1H), 4.00(s,3H).

[0258] Step C: 1-3 (4 g, 24.22 mmol) was dissolved in toluene (100 mL), and N,N-diisopropylethylamine (DIPEA) (8.46 mL, 48.4 mmol), water (0.57 mL, 31.5 mmol) and phosphorus oxychloride (18.57 g, 121 mmol) were added. After nitrogen substitution, the mixture was heated to 110°C for 15 hours. After the reaction, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and water (50 mL) and 1M sodium hydroxide (20 mL) solution were added to the residue. The mixture was extracted with ethyl acetate (3 x 150 mL). The organic phases were combined, concentrated and dried, and the crude product was purified by silica gel column chromatography to give 1-4 (1.3 g). MS (ESI-, [MH] - )m / z:167.99.

[0259] 1 H NMR (500MHz, DMSO-d6) δ12.53 (s, 1H), 7.87 (dd, J = 3.0, 1.5Hz, 1H), 6.94–6.86 (m, 2H).

[0260] Step D: 1-4 (1.3 g, 7.67 mmol), toluene (20 mL) and Lawesson's reagent (3.1 g, 7.67 mmol) were added to a 100 mL single-necked bottle in sequence. The mixture was heated to 110°C and reacted for 18 hours. After the reaction, the reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, concentrated, and dried. The crude product was purified by silica gel column chromatography to obtain 1-5 (1.2 g). MS (ESI-, [MH] - )m / z:184.00.

[0261] 1 H NMR (500MHz, DMSO-d6) δ14.12(s,1H),8.22(dd,J=3.0,1.5Hz,1H),7.14(dd,J=3.9,1.5Hz,1H),7.11(dd,J=3.9,3.0Hz,1H).

[0262] Step E: 1-5 (1.2 g, 6.46 mmol), tetrahydrofuran (20 mL), cesium carbonate (2.11 g, 7.54 mmol), and iodomethane (1.84 g, 12.9 mmol) were added to a 100 mL single-necked bottle in sequence. The mixture was heated to 60°C and reacted for 12 hours. After the reaction, the reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3*100 mL). The organic phases were combined, concentrated, and dried. The crude product was purified by silica gel column chromatography to obtain 1-6 (1.2 g). MS (ESI+, [M+H] +)m / z:200.08.

[0263] Step F: 1-6 (400 mg, 2.00 mmol) and (R)-1-methylpiperidin-3-amine (4.57 g, 40.1 mmol) were added to a 25 mL single-necked bottle, and the mixture was heated to 110°C for 4 hours. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain 1-7 (380 mg). MS (ESI+, [M+H] + )m / z:278.01.

[0264] Step G: 1-7 (200 mg, 0.721 mmol), 1,4-dioxane (15 mL), 2-hydroxy-4-trifluoromethylphenylboronic acid (445 mg, 2.16 mmol), thiophene-2-carboxylic acid ketone (302 mg, 1.58 mmol), and tetrakistriphenylphosphine palladium (83 mg, 0.072 mmol) were added to a 35 mL microwave tube, and the reaction was placed in a microwave reactor and microwaved at 110 ° C for 8.0 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and dried. The crude product was purified by silica gel column chromatography to obtain 1 (55 mg).

[0265] 1 H NMR(500MHz,DMSO-d6)δ11.02(s,1H),7.64(d,J=7.8Hz,1H),7.31(d,J=8.2Hz,2H) ,7.06(dd,J=18.6,3.2Hz,2H),6.98(d,J=7.9Hz,1H),6.72(t,J=3.3Hz,1H),4.26( d,J=9.6Hz,1H),3.05–2.99(m,1H),2.72–2.66(m,1H),2.21(s,3H),1.98–1.86(m, 3H),1.74(dt,J=12.8,3.7Hz,1H),1.62–1.54(m,1H),1.38(td,J=11.7,4.0Hz,1H).

[0266] HRMS (ESI+, [M+H] + )m / z:392.1695.

[0267] Example 2

[0268] Reaction process:

[0269] Step A: To a 250 mL single-necked flask, add MeOH (80 mL), 2-1 (10 g, 55.2 mmol), and hydrazine hydrate (32.5 g, 552 mmol) sequentially. Heat the mixture to 90°C under nitrogen for 16 hours. After completion of the reaction, filter and dry the filter cake in vacuo to obtain 2-2 (9.55 g).

[0270] MS (ESI+, [M+H] + )m / z:182.05.

[0271] Step B: To a 100 mL single-necked flask were added 2-2 (1.0 g, 5.52 mmol), acetonitrile (30 mL), acetic acid (1.0 g, 27.6 mmol), and tetramethyl orthoformate (1.50 g, 11.04 mmol) in sequence. Under nitrogen, the mixture was heated to 70°C for 4 hours. After the reaction, the solvent was removed under reduced pressure on a rotary evaporator to obtain a residue. MeOH (50 mL) and potassium hydroxide (0.62 g, 11.04 mmol) were added to the above residue, and the mixture was heated to 70°C for 3 hours. After the reaction, methanol was removed under reduced pressure on a rotary evaporator. Water (40 mL) was added to the residue, and the pH was adjusted to 1 with 6N HCl solution (10 mL). The mixture was stirred for 1 hour, filtered, and the filter cake was dried under vacuum to obtain 2-3 (1.12 g).

[0272] 1 H NMR (500MHz, DMSO-d6) δ 11.34 (s, 1H), 7.75 (d, J = 5.4Hz, 1H), 7.45 (d, J = 5.3Hz, 1H), 7.42 (s, 1H), 4.07 (s, 3H).

[0273] MS (ESI+, [M+H] + )m / z:221.91.

[0274] Step C: To a 100 mL single-necked flask, toluene (50 mL), 2-3 (1.12 g, 5.06 mmol), DIPEA (1.31 g, 10.13 mmol), water (0.119 g, 6.58 mmol), and phosphorus oxychloride (3.88 g, 25.3 mmol) were added sequentially. Under nitrogen protection, the mixture was heated to 110°C for 16 hours. After the reaction, the solvent was evaporated under reduced pressure on a rotary evaporator, and water (30 mL) was added to the residue to precipitate a solid, which was filtered and the filter cake was dried under vacuum to obtain 2-4 (0.82 g).

[0275] MS (ESI-, [MH] - )m / z:223.96.

[0276] Step D: To a 50 mL single-necked flask, 2-4 (400 mg, 1.77 mmol), xylene (12 mL), and Lawesson's reagent (574 mg, 1.41 mmol) were added sequentially. Under nitrogen, the mixture was heated to 140°C for 5 hours. After the reaction, water (80 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DMC:MeOH = 50:1) to obtain 2-5 (85 mg).

[0277] MS (ESI-, [MH] - )m / z:240.04.

[0278] Step E: To a 50 mL single-necked flask were added 2-5 (170 mg, 0.703 mmol), THF (8 mL), iodomethane (200 mg, 1.407 mmol), and cesium carbonate (229 g, 0.703 mmol) in sequence. Under nitrogen, the mixture was heated to 60°C for 2 hours. After the reaction, ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution. The layers were separated, and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain 2-6 (72 mg).

[0279] 1 H NMR (500MHz, DMSO-d6) δ7.91 (d, J = 5.5 Hz, 1H), 7.77 (d, J = 5.5 Hz, 1H), 7.53 (s, 1H), 2.85 (s, 3H).

[0280] MS (ESI+, [M+H] + )m / z:255.89.

[0281] Step F: To a 50 mL single-necked vial were added 2-6 (50 mg, 0.196 mmol), 1,4-dioxane (10 mL), 2-7 (86 mg, 0.391 mmol), XphosPdG3 (33 mg, 0.039 mmol), potassium carbonate (81 mg, 0.587 mmol), and water (3 mL) in sequence. Under nitrogen, the mixture was heated to 90°C for 5 hours. After completion of the reaction, the solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to afford 2-8 (52 mg).

[0282] 1H NMR (500MHz, DMSO-d6) δ7.81(dd,J=14.8,5.5Hz,2H),7.70(d,J=7.7Hz,1H),7.54(s,1H),7.50(d,J=7.8Hz,1H),7.02(s,1H),3.85(s,3H),2.90(s,3H).

[0283] MS (ESI+, [M+H] + )m / z:396.05.

[0284] Step G: To a 10 mL reaction vial were added 2-8 (240 mg, 0.607 mmol) and 2-9 (1.73 g, 15.17 mmol) sequentially under nitrogen. The mixture was heated to 120°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (DCM:MeOH = 25:1) to afford 1-10 (130 mg).

[0285] MS(ESI+,[M+H]+)m / z: 462.12.

[0286] Step H: 2-10 (130 mg, 0.282 mmol), dichloromethane (10 mL), and a dichloromethane solution of boron tribromide (2N, 1.408 mL, 2.82 mmol) were added to a 25 mL single-necked bottle in sequence under nitrogen protection and reacted at room temperature for 1 hour. After the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with DCM (50 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The resulting crude product was subjected to liquid phase preparation (CHIRALART Cellulose-SB column; 0.05% aqueous phosphoric acid-ethanol (60:40)) to obtain compound 2 (20 mg).

[0287] 1 H NMR(500MHz,DMSO-d6)δ12.37(s,1H),8.24–7.51(m,3H),7.46–7.15(m,3H),6.91–6.47(m,1H),4.59–4.07(m,1H),2.98– 2.84(m,1H),2.65–2.55(m,1H),2.41–2.28(m,1H),2.25(s,3H),2.20–2.04(m,1H),1.97–1.87(m,1H),1.80–1.57(m,3H).

[0288] HRMS(ESI+,[M+H]+)m / z: 448.1447.

[0289] Example 3

[0290] Reaction process:

[0291] Step A: To a 10 mL reaction vial were added 2-6 (200 mg, 0.782 mmol) and 2-9 (1.73 g, 15.17 mmol) sequentially under nitrogen. The mixture was heated to 100°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (DCM:MeOH = 25:1) to afford 3-1 (76 mg).

[0292] MS(ESI+,[M+H]+)m / z: 334.05.

[0293] Step B: To a 35 mL microwave tube were added 3-1 (76 mg, 0.228 mmol), copper 2-thiophenecarboxylate (192 mg, 1.002 mmol), Pd(Ph3P)4 (52 mg, 0.046 mmol), 3-2 (282 mg, 1.368 mmol), and 1,4-dioxane (7 mL) in sequence. The mixture was heated to 120°C in a microwave oven under nitrogen atmosphere for 4 hours. After completion of the reaction, the mixture was filtered and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by liquid chromatography (XB-C18 column; water (10 mM ammonium acetate + 0.1% glacial acetic acid) - acetonitrile (62:38)) to afford compound 3 (11 mg).

[0294] 1H NMR(500MHz,DMSO-d6)δ10.84(s,1H),7.67(s,1H),7.56–7.17(m,4H),7.07(s,1H),6.03(s,1H),4.30(s ,1H),3.06(s,1H),2.71(s,1H),2.22(s,3H),2.01–1.88(m,3H),1.75(s,1H),1.60(s,1H),1.42(s,1H).

[0295] HRMS (ESI+, [M+H] + )m / z:448.1408.

[0296] Example 4

[0297] Reaction process:

[0298] Step A: Referring to Example 2, 4-1 was used to replace 2-1 in step A to obtain 4-2.

[0299] 1H NMR (500MHz, DMSO-d6) δ10.77(s,1H),8.32(s,1H),6.50(d,J=2.5Hz,1H),4.27(s,2H),2.73(t,J =7.2Hz,2H),2.52(d,J=8.4Hz,2H),2.25(dd,J=14.3,7.2Hz,2H).

[0300] MS (ESI+, [M+H] + )m / z:165.95.

[0301] Step B: Referring to Example 2, 4-2 was used in place of 2-2 in step B to give 4-3.

[0302] 1 H NMR (500MHz, DMSO-d6) δ11.06(s,1H),7.08(s,1H),3.95(s,3H),2.84(t,J=7.2Hz,2H),2.69(t,J=7.2Hz,2H),2.35(p,J=7.3Hz,2H).

[0303] MS (ESI+, [MH] + )m / z:205.90.

[0304] Step C: Referring to Example 2, 4-3 was used to replace 2-3 in step C to obtain 4-4.

[0305] 1 H NMR (500MHz, DMSO-d6) δ12.25(s,1H),7.51(s,1H),2.91(t,J=7.3Hz,2H),2.74(t,J=7.2Hz,2H),2.39(p,J=7.3Hz,2H).

[0306] MS (ESI-, [MH] - )m / z:207.98.

[0307] Step D: Referring to Example 2, 4-4 was used to replace 2-4 in step D to obtain 4-5.

[0308] 1 H NMR (500MHz, DMSO-d6) δ13.80(s,1H),7.92(s,1H),2.99(t,J=7.3Hz,2H),2.81(t,J=7.2Hz,2H),2.41(p,J=7.3Hz,2H).

[0309] MS (ESI-, [MH] -)m / z:223.98.

[0310] Step E: Referring to Example 2, 4-5 was used to replace 2-5 in step E to obtain 4-6.

[0311] 1 H NMR (500MHz, DMSO-d6) δ7.49 (s, 1H), 3.01 (t, J = 7.3Hz, 2H), 2.84 (t, J = 7.3Hz, 2H), 2.76 (s, 3H), 2.47-2.40 (m, 2H).

[0312] MS (ESI+, [M+H] + )m / z:239.93.

[0313] Step F: Referring to Example 2, 4-6 was used in place of 2-6 in step F to obtain 4-7.

[0314] MS (ESI+, [M+H] + )m / z:380.08.

[0315] Step G: Referring to Example 2, 4-7 was used to replace 2-7 in step G to obtain 4-8.

[0316] 1 H NMR (500MHz, DMSO-d6) δ7.60(s,1H),7.50(d,J=8.0Hz,1H),7.41(s,2H),6.93(d,J=6.7Hz,1H),4.28(s,1H),3.79(s,3H),3.10( s,1H),2.75(s,3H),2.24(d,J=9.5Hz,7H),1.98(s,3H),1.77(d,J=11.4Hz,1H),1.60(d,J=11.9Hz,1H),1.42(d,J=10.7Hz,1H).

[0317] MS (ESI+, [M+H] + )m / z:446.19.

[0318] Step H: Referring to Example 2, 4-8 was used to replace 2-8 in step H to obtain 4.

[0319] 1H NMR (500MHz, DMSO-d6) δ11.78(s,1H),7.72(s,1H),7.68(d,J=7.9Hz,1H),7.27(d,J=8.2Hz,1H),7.25(s,1H),7.14(s,1H),4.31(s,1H),3.12(s ,1H),2.80(t,J=7.1Hz,3H),2.64(t,J=7.1Hz,2H),2.35-2.21(m,5H),2 .00(d,J=9.1Hz,3H),1.77(s,1H),1.62(d,J=11.2Hz,1H),1.46(s,1H).

[0320] HRMS (ESI+, [M+H] + )m / z:432.2007.

[0321] Example 5

[0322] Reaction process:

[0323] Step A: Referring to Example 3, 4-6 was used to replace 2-6 in step A to obtain 5-1.

[0324] MS (ESI+, [M+H] + )m / z:318.05.

[0325] Step B: Referring to Example 3, step B, 5-1 was used to replace 3-1 to obtain 5.

[0326] 1 H NMR (500MHz, DMSO-d6) δ10.82(s,1H),7.60(d,J=8.1Hz,1H),7.30(d,J=6.7Hz,2H),6.71(s,1H),5.69(d,J=6.9Hz,1H),4.26(s,1H),3.00(dd,J=8.5, 5.4Hz,2H),2.85(s,1H),2.68(t,J=7.0Hz,2H),2.39(dd,J=14.1,7.0Hz,2 H),2.32-2.08(m,5H),1.91(s,1H),1.79(s,1H),1.72(s,1H),1.57(s,2H).

[0327] HRMS (ESI+, [M+H] + )m / z:432.2012.

[0328] Example 6

[0329] Reaction process:

[0330] Step A: Referring to Example 2, in step A, 6-1 was used instead of 2-1 to obtain 6-2.

[0331] MS (ESI+, [M+H] + )m / z:165.96.

[0332] Step B: Referring to Example 2, in step B, 6-2 was used instead of 2-2 to obtain 6-3.

[0333] 1 H NMR (500MHz, DMSO-d6) δ11.06(s,1H),6.78(s,1H),3.93(s,3H),2.95(t,J=7.2Hz,2H),2.67–2.63(m,2H),2.45–2.40(m,2H).

[0334] MS (ESI+, [M+H] + )m / z:206.00.

[0335] Step C: Referring to Example 2, in step C, 6-3 was used instead of 2-3 to obtain 6-4.

[0336] 1 H NMR (500MHz, DMSO-d6) δ12.25(s,1H),6.63(s,1H),3.10(t,J=7.2Hz,2H),2.67(t,J=7.1Hz,2H),2.45(dt,J=14.5,7.3Hz,2H).

[0337] MS (ESI-, [MH] - )m / z:208.09.

[0338] Step D: Referring to Example 2, in step D, 6-4 was used instead of 2-4 to obtain 6-5.

[0339] 1 H NMR (500MHz, DMSO-d6) δ13.68(s,1H),6.85(s,1H),3.47–3.43(m,2H),2.70(t,J=7.3Hz,2H),2.42(dd,J=14.6,7.3Hz,2H).

[0340] MS (ESI-, [MH] - )m / z:224.08.

[0341] Step E: Referring to Example 2, in step E, 6-5 is used instead of 2-5 to obtain 6-6.

[0342] 1 H NMR (500MHz, DMSO-d6) δ6.82(s,1H),3.28(t,J=7.3Hz,2H),2.77(t,J=7.2Hz,2H),2.71(s,3H),2.49(s,2H).

[0343] MS (ESI+, [M+H] + )m / z:239.96.

[0344] Step F: Referring to Example 2, in step F, 2-6 was replaced by 6-6 to obtain 6-7.

[0345] 1 H NMR(500MHz,DMSO-d6)δ7.60(d,J=7.8Hz,1H),7.48(s,1H),7.45(d,J=7.8Hz,1H),6.31(s,1H) ,3.82(s,3H),3.34(d,J=7.3Hz,2H),2.75(s,3H),2.72(t,J=7.1Hz,2H),2.47(d,J=7.3Hz,2H).

[0346] MS (ESI+, [M+H] + )m / z:380.09.

[0347] Step G: Referring to Example 2, in step F, 2-8 was replaced with 6-7 to obtain 6-8.

[0348] 1 H NMR (500MHz, DMSO-d6) δ7.54(d,J=7.7Hz,1H),7.48–7.38(m,2H),6.07(s,1H),5.90(d,J=7.6Hz,1H),4.20(s,1H),3.80(s,3H ),3.29(s,2H),2.68(t,J=7.0Hz,2H),2.53(s,2H),2.35(s,3H),2.23(s,3H),1.75(s,3H),1.65(d,J=8.6Hz,1H),1.56(s,1H).

[0349] MS(ESI+,[M+H]+)m / z: 446.41.

[0350] Step H: Referring to Example 2, in step F, 2-10 was replaced with 6-8 to obtain 6.

[0351] 1H NMR(500MHz, DMSO-d6)13.58(s,1H),8.08(d,J=8.3Hz,1H),7.25(d,J=6.6Hz,2H),6.95(s,1H),6.17(d,J=7.1Hz,1H),4.21(s,1H),3.35 (s,2H),2.78(t,J=7.0Hz,2H),2.67(s,1H),2.60–2.53(m,2H),2.33(s,3H),2.23(s,3H),1.73(d,J=13.0Hz,3H),1.56(d,J=5.5Hz,1H).

[0352] HRMS(ESI+,[M+H]+)m / z: 432.2002.

[0353] Example 7

[0354] Reaction process:

[0355] Step A: Referring to Example 3, in step A, 2-6 was replaced by 6-6 to obtain 7-1.

[0356] MS (ESI+, [M+H] + )m / z:318.05.

[0357] Step B: Referring to Example 3, in step B, 7-1 was used instead of 3-1 to obtain 7.

[0358] 1 H NMR(500MHz,DMSO-d6)13.56(s,1H),8.09(d,J=7.1Hz,1H),7.25(s,2H),6.95(s,1H),6.18(s,1H),4.21(s,1H),3 .36(s,2H),2.78(s,2H),2.68(s,1H),2.57(d,J=23.9Hz,2H),2.34(s,3H),2.24(s,3H),1.74(s,3H),1.56(s,1H).

[0359] HRMS (ESI+, [M+H] + )m / z:432.2012.

[0360] Example 8

[0361] Reaction process:

[0362] Step A: Referring to Example 5, 8-1 was used to replace 2-9 in step A to obtain 8-2.

[0363] MS (ESI+, [M+H] + )m / z:380.05.

[0364] Step B: Referring to Example 5, 8-2 was used to replace 5-1 in step B to obtain 8.

[0365] 1 H NMR(500MHz,DMSO-d6)10.87(s,1H),7.82–7.54(m,1H),7.49–7.19(m,2H),6.90–6.65(m,1H),5.98–5.58(m,1H),4.68–4.13(m,2H),3.60(s ,2H),3.17–2.99(m,2H),2.90(dd,J=29.1,8.6Hz,1H),2.74(t,J=14.5Hz,2H),2.52–2.32(m,5H),1.83–1.49(m,4H),1.34(d,J=32.1Hz,2H).

[0366] HRMS (ESI+, [M+H] + )m / z:462.2123.

[0367] Example 9

[0368] Step A: To a 250 mL single-necked flask were added 1,4-dioxane (100 mL), 1-7 (800 mg, 2.88 mmol), 4-formyl-2-methoxyphenylboronic acid (2.06 g, 11.54 mmol), copper 3-methylsalicylate (2.46 g, 11.54 mmol), and Pd(Ph3P)4 (1.66 g, 1.44 mmol) in sequence. Under nitrogen, the mixture was heated to 100°C for 7.0 hours. After completion of the reaction, the solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to afford 9-1 (364 mg).

[0369] 1H NMR (500MHz, DMSO-d6) δ10.12(s,1H),7.71(s,3H),7.14(s,1H),7.10(d,J=4.0Hz,1H),6.98(d,J=4.1Hz,1H),6.77–6.68(m,1H),4.35 (s,1H),3.83(s,3H),3.17(s,1H),2.89(s,1H),2.41(s,3H),1.98(d,J=9.8Hz,2H),1.82(s,1H),1.66(d,J=11.7Hz,2H),1.49(s,1H).

[0370] MS (ESI+, [M+H] + )m / z:366.28.

[0371] Step B: To a 50 mL single-necked bottle, methanol (15 mL), 9-1 (190 mg, 0.52 mmol), potassium carbonate (144 mg, 1.04 mmol), and dimethyl (1-diazo-2-oxopropyl)phosphonate (120 mg, 0.624 mmol) were added sequentially under nitrogen and allowed to react at room temperature for 16 hours. After the reaction, water (80 mL) was added and the mixture was extracted with dichloromethane (50 mL × 2). The organic layers were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to afford 9-2 (66 mg).

[0372] MS (ESI+, [M+H] + )m / z:362.30.

[0373] Step I: To a 50 mL single-necked bottle, dichloromethane (15 mL), 9-2 (47 mg, 0.13 mmol), and a dichloromethane solution of boron tribromide (2N, 0.65 mL, 1.30 mmol) were added in sequence, protected by nitrogen, and reacted in an ice bath for 0.5 hours. After the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The resulting crude product was subjected to liquid phase preparation (CHIRALART Cellulose-SB column; 0.05% aqueous phosphoric acid-ethanol (60:40) to obtain compound 9 (23 mg).

[0374] 1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),7.41(d,J=7.7Hz,1H),7.07(ddd,J=11.2,3.4,1.4Hz, 3H),7.02(dd,J=2.8,1.3Hz,1H),6.93(d,J=8.0Hz,1H),6.71(dd,J=3.8,2.7Hz,1H),4.29(s ,1H),4.27–4.19(m,1H),3.12–2.91(m,1H),2.69(d,J=11.1Hz,1H),2.21(s,3H),1.97–1.82 (m,3H),1.74(dt,J=11.8,3.7Hz,1H),1.58(tdd,J=15.6,9.7,3.9Hz,1H),1.44–1.29(m,1H).

[0375] HRMS (ESI+, [M+H] + )m / z:348.1818.

[0376] Example 10

[0377] Step A: To a 250 mL two-necked reaction bottle, 10-1 (5 g, 23.25 mmol), methanol (100 mL), (1-diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (6.70 g, 34.90 mmol) and K2CO3 (6.43 g, 46.5 mmol) were added in sequence, protected by nitrogen, and reacted at room temperature for 5 hours. After the reaction, purified water (100 mL) was added to quench the reaction, and ethyl acetate was added for extraction (125 mL×2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain 10-2 (4.39 g).

[0378] 1 H NMR (500MHz, Chloroform-d) δ7.48(d,J=8.0Hz,1H),6.99(d,J=1.8Hz,1H),6.97(dd,J=8.1,1.8Hz,1H),3.89(s,3H),3.12(s,1H).

[0379] Step B: 10-2 (3.6 g, 17.06 mmol) and tetrahydrofuran (60 mL) were added to a 250 mL two-necked reaction bottle in sequence under nitrogen protection. After cooling to -30 ° C, sodium hexamethyldisilazane (7.88 g, 21.49 mL, 43.0 mmol) was slowly added dropwise through a syringe. After stirring at this temperature for 15 minutes, iodomethane (7.26 g, 3.20 mL, 51.2 mmol) was slowly added dropwise through a syringe. After the addition, the temperature was slowly raised to room temperature and the reaction was continued for 3 hours. After the reaction was completed, purified water (50 mL) was added to quench the reaction, and ethyl acetate was added for extraction (100 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain 10-3 (4.14 g).

[0380] 1 H NMR (500MHz, Chloroform-d) δ7.43(d,J=8.1Hz,1H),6.91(d,J=1.8Hz,1H),6.86(dd,J=8.1,1.8Hz,1H),3.87(s,3H),2.04(s,3H).

[0381] Step C: 10-3 (4 g, 17.77 mmol) and tetrahydrofuran (100 ml) were added to a 250 mL two-necked reaction bottle in sequence. The mixture was cooled at -78 ° C for 10 min under nitrogen protection. Then, n-butyl lithium (1.8 g, 17.56 mL, 28.1 mmol) was slowly added dropwise through a syringe. After the addition was completed, stirring was continued at this temperature for 20 min. Then, triethyl borate (7.78 g, 53.3 mmol) was slowly added dropwise through a syringe. After the addition was completed, stirring was continued at this temperature for 40 minutes, and then the temperature was slowly raised to room temperature and stirring was continued for 1.5 hours. After the reaction was completed, 20 ml of 4N The reaction was quenched with HCl and stirred for 1 hour. Ethyl acetate (150 mL) and water (50 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 10-4 (2.9 g).

[0382] Step D: To a 100 mL reaction flask, 10-4 (2.9 g, 15.26 mmol), dichloromethane (50 mL), and boron tribromide (12 g, 23.95 mL, 47.9 mmol) were added sequentially under nitrogen atmosphere in an ice-water bath for 1 hour. After completion of the reaction, the reaction solution was slowly poured into water (50 mL) and extracted with ethyl acetate (125 mL x 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain 10-5 (2.96 g).

[0383] MS (ESI-, [MH] - )m / z:175.04.

[0384] Step E: Referring to Example 9, in step G, 10 was obtained by replacing 4-formyl-2-methoxyphenylboronic acid with 10-5. 1 H NMR (500MHz, DMSO-d6) δ10.12(s,1H),7.26(d,J=7.9Hz,1H),7.05(d,J=3.8Hz,1H),7.00(d, J=2.7Hz,1H),6.95(s,1H),6.88(d,J=8.0Hz,1H),6.83–6.75(m,1H),6.67(t,J=3.3Hz,1H), 4.23(td,J=14.3,6.1Hz,1H),3.01(d,J=10.6Hz,1H),2.67(t,J=6.0Hz,1H),2.19(s,3H),2. 05(s,3H),1.90-1.86(m,3H),1.73-1.69(m,1H),1.57(d,J=12.7Hz,1H),1.39–1.33(m,1H).

[0385] HRMS (ESI+, [M+H] + )m / z:362.1979.

[0386] Example 11

[0387] Reaction process:

[0388] Step A: Referring to Example 9, 1-7 was replaced with 5-1 in step A to obtain 11-1.

[0389] MS (ESI+, [M+H] + )m / z:406.29.

[0390] Step A: Referring to Example 9, 11-1 was used to replace 9-1 in step B to obtain 11-2.

[0391] MS (ESI+, [M+H] + )m / z:402.14.

[0392] Step B: Referring to Example 9, 11-2 was used in place of 9-2 in step C to obtain 11.

[0393] 1 H NMR(500MHz,DMSO-d6)δ10.42(s,1H),7.38(d,1H),7.16–6.97(m,2H),6.70(s,1H),5.62(d,1H),4.28(s,1H),4.26–4.16(m,1H),3.07–2 .92(m,2H),2.78(s,1H),2.68(t,2H),2.46(s,1H),2.38(p,2H),2.21(s,3H),2.15(s,2H),1.77(s,1H),1.69(s,1H),1.61–1.45(m,2H).

[0394] HRMS (ESI+, [M+H] + )m / z:388.2139.

[0395] Example 12

[0396] Reaction process:

[0397] Step A: To a 100 mL single-necked bottle, 9-1 (500 mg, 1.36 mmol), 1,4-dioxane (50 mL), methyltriphenylphosphonium bromide (733 mg, 2.05 mmol), and potassium carbonate (567 mg, 4.10 mmol) were added sequentially under nitrogen. The mixture was heated to 100°C for 9 hours. After the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (80 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 12-1 (64 mg).

[0398] MS (ESI+, [M+H] + )m / z:364.31.

[0399] Step B: Referring to Example 9, 12-1 was used to replace 9-2 in step C to obtain 12.

[0400] 1H NMR(500MHz,DMSO-d6)δ10.21(s,1H),7.39(d,1H),7.18–6.97(m,4H),6.91(d,1H),6.81–6.59(m,2H),5.85(d,1H),5.35(d,1H) ,4.32–4.18(m,1H),3.08–2.99(m,1H),2.75–2.65(m,1H),2.22(s,3H),2.05–1.85(m,4H),1.80–1.70(m,1H),1.63–1.51(m,1H).

[0401] HRMS (ESI+, [M+H] + )m / z:350.1980.

[0402] Example 13

[0403] Reaction process:

[0404] Step A: Referring to Example 1, 13-1 was used in step G to replace 2-hydroxy-4-trifluoromethylphenylboronic acid to obtain 13.

[0405] 1 H NMR(500MHz,DMSO-d6)δ10.67(s,1H),7.43(d,1H),7.04(d,4H),6.92(d,1H),6.71(s,1H),4.25(s,1 H),3.02(d,1H),2.69(d,1H),2.21(s,3H),1.91(s,3H),1.74(d,1H),1.58(d,1H),1.41–1.32(m,1H).

[0406] HRMS(ESI+,[M+H]+)m / z: 358.1432.

[0407] Example 14

[0408] Reaction process:

[0409] Step A: Referring to Example 6, 8-1 was used to replace 2-9 in step G to obtain 14-1.

[0410] MS (ESI+, [M+H] + )m / z:476.21.

[0411] Step B: Referring to Example 6, 14-1 was used in place of 6-8 in step H to obtain 14.

[0412] 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),7.74–7.65(m,2H),7.26(s,1H),7.25( s,1H),7.07(d,1H),4.50–4.36(m,1H),4.35–4.17(m,1H),3.60–3.44(m,2H), 3.20–3.03(m,1H),2.80(t,3H),2.65(t,2H),2.49–2.37(m,2H),2.34–2.24( m,2H),2.19–1.92(m,3H),1.75(d,1H),1.65–1.52(m,1H),1.51–1.40(m,1H).

[0413] HRMS (ESI+, [M+H] + )m / z:462.2120.

[0414] Example 15

[0415] Reaction process:

[0416] Step A: Referring to Example 1, 15-1 was used in step F to replace (R)-1-methylpiperidin-3-amine to obtain 15-2.

[0417] MS (ESI+, [M+H] + )m / z:265.25.

[0418] Step B: Referring to Example 1, 15-2 was used to replace 1-7 in step G to obtain 15.

[0419] 1 H NMR(500MHz,DMSO-d6)δ10.90(s,1H),7.64(d,1H),7.43(d,1H),7.30(d,2H),7.05(dd,2H),6. 71(s,1H),5.02(s,1H),4.23–4.09(m,1H),2.47–2.39(m,2H),2.18–2.06(m,2H),1.31(s,3H).

[0420] HRMS (ESI+, [M+H] + )m / z:379.1386.

[0421] Example 16

[0422] Step A: To a 25 mL single-necked vial were added 4-6, 16-1, Pd2(dba)3 (19 mg, 0.021 mmol), BINAP (26 mg, 0.042 mmol), Cs2CO3 (136 mg, 0.417 mmol), and 1,4-Dioxane (2 ml) in sequence. Under nitrogen, the mixture was heated to 90°C for reaction. After completion of the reaction, the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to afford 16-2 (36 mg).

[0423] 1 H NMR(500MHz,DMSO-d6)δ7.15(s,1H),5.88(d,1H),5.36(d,1H),4.35–4.29(m,1H),4.25–4.19(m,1H),4.09(dd,1 H),3.92(dd,1H),3.71(dd,1H),3.54(dd,1H),3.06–2.93(m,2H),2.74(dd,2H),2.66(s,3H),2.40–2.34(m,2H).

[0424] MS (ESI+, [M+H] + )m / z:306.98.

[0425] Step B: Referring to Example 3, step B, 16-2 was used to replace 3-1 to obtain 16.

[0426] 1 H NMR(500MHz,DMSO-d6)δ10.84(s,1H),7.63(d,1H),7.31(d,2H),6.77(s,1H),6.24(s,1H),4.43–4.31(m,2H) ,4.13(dd,1H),3.97(dd,1H),3.76(dd,1H),3.57(dd,1H),3.11–2.96(m,2H),2.69(t,2H),2.40–2.34(m,2H).

[0427] HRMS (ESI+, [M+H] + )m / z:421.1494.

[0428] Example 17

[0429] Step A: Referring to Example 16, step A was carried out using 17-1 instead of 16-1 to obtain 17-2.

[0430] MS (ESI+, [M+H] +)m / z:306.98.

[0431] Step B: Referring to Example 3, step B, 17-2 was used to replace 3-1 to obtain 17.

[0432] 1 H NMR(500MHz,DMSO-d6)δ10.85(s,1H),7.66(d,1H),7.31(d,2H),6.75(s,1H),6.24(s,1H),5.61(s,1H),4.48–4.33( m,2H),4.17(dd,1H),3.94(dd,1H),3.76(dd,1H),3.55(dd,1H),3.14–2.92(m,2H),2.72(t,2H),2.42–2.35(m,2H).

[0433] HRMS (ESI+, [M+H] + )m / z:421.1482.

[0434] Example 18

[0435] Step A: Referring to Example 16, step B, 18-1 was used to replace 3-2 to obtain 18.

[0436] 1 H NMR(500MHz,DMSO-d6)δ10.84(s,1H),7.41(d,1H),7.07–6.98(m,2H),6.72(s,1H),6.02(d,1H),5.44(s,1H),4.42–4.2 6(m,2H),4.12(dd,1H),3.96(dd,1H),3.75(dd,,1H),3.56(dd,1H),3.11–2.95(m,2H),2.68(t,2H),2.40–2.34(m,2H).

[0437] HRMS (ESI+, [M+H] + )m / z:387.1233.

[0438] Example 19

[0439] Reaction process:

[0440] Step A: Referring to Example 17, 13-1 was used in place of 3-2 in step B to give 19.

[0441] HRMS (ESI+, [M+H] + )m / z:387.1224.

[0442] Example 20

[0443] Reaction process:

[0444] Step A: Referring to Example 5, in step A, 2-9 was replaced with 15-1 to obtain 20-1.

[0445] MS (ESI+, [M+H] + )m / z:305.17.

[0446] Step B: Referring to Example 5, in step B, 5-1 was replaced with 20-1 to obtain 20.

[0447] 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),7.69(d,2H),7.56(s,1H),7.27(dd,1H),7.24(s,1H),5.05(s,1H),4. 22–4.11(m,1H),2.81(t,2H),2.66(t,2H),2.47-2.44(m,2H),2.29(p,2H),2.18-2.15(m,2H),1.33(s,3H).

[0448] HRMS (ESI+, [M+H] + )m / z:419.1701.

[0449] Example 21

[0450] Reaction process:

[0451] Step A: Referring to Example 16, 21-1 was used in place of 16-1 in step A to give 21-2.

[0452] MS (ESI+, [M+H] + )m / z:319.19.

[0453] Step B: Referring to Example 16, 21-2 was used in place of 16-2 in step B to obtain 21.

[0454] 1H NMR(500MHz,DMSO-d6)δ10.83(s,1H),7.60(d,1H),7.30(d,2H),6.72(s,1H),5.56(d,1H),5.08(d,1H),3.82(d,1 H),3.52(d,1H),3.02(t,2H),2.69(t,2H),2.39(q,2H),2.19(d,1H),1.94(d,1H),1.67(d,2H),1.33–1.26(m,4H).

[0455] HRMS (ESI+, [M+H] + )m / z:433.1856.

[0456] Example 22

[0457] Reaction process:

[0458] Step A: To a 100 mL single-necked flask, 25-1 (300 mg, 1.0 mmol), dichloromethane (80 mL), TEA (388 mg, 3.0 mmol), and methanesulfonic anhydride (348 mg, 2.0 mmol) were added sequentially and allowed to react at room temperature for 2 hours. After the reaction, water (80 mL) was added and the mixture was extracted with dichloromethane (50 mL × 2). The organic layers were combined, washed with saturated sodium chloride water (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 22-1 (0.17 g).

[0459] MS (ESI+, [M+H] + )m / z:342.02.

[0460] Step B: Referring to Example 21, 22-1 was used instead of 21-2 in step B to obtain 22.

[0461] 1 H NMR(500MHz,DMSO-d6)δ10.82(s,1H),7.67(d,1H),7.32(d,2H),7.18(s,1H),7.09(d,2H),6.77–6.73(m,1H),4.30–4.22(m,1H) ,3.92(dd,1H),3.52(d,1H),2.90(s,3H),2.77(dd,1H),2.66–2.59(m,1H),2.07–2.01(m,1H),1.92(dd,1H),1.70–1.56(m,2H).

[0462] .HRMS(ESI+,[M+H] + )m / z:456.1321.

[0463] Example 23

[0464] Reaction process:

[0465] Step A: To a 250 mL single-necked flask were added 1,4-dioxane (20 mL), 23-1 (500 mg, 1.376 mmol), 2-7 (908 mg, 4.13 mmol), 3-methylsalicylate (886 mg, 4.13 mmol), and Pd(Ph3P)4 (397 mg, 0.344 mmol) in sequence. Under nitrogen, the mixture was heated to 100°C overnight. After completion of the reaction, the solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to afford 23-2 (646 mg).

[0466] MS (ESI+, [M+H] + )m / z:492.19.

[0467] Step B: To a 100 mL single-necked flask, 23-2 (646 mg, 1.314 mmol) and ethyl acetate (5 ml) were added sequentially. After cooling to 0°C, 4M HCl / dioxane (10 ml, 40.0 mmol) was slowly added dropwise via syringe. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was continued overnight. After the reaction was completed, the solvent was removed under reduced pressure on a rotary evaporator to obtain 23-3 (624 mg).

[0468] MS (ESI+, [M+H] + )m / z:392.13.

[0469] Step C: To a 100 mL single-necked flask were added 23-3 (624 mg, 1.458 mmol), dichloromethane (10 ml), Et3N (738 mg, 1.016 ml, 7.29 mmol), and tert-butyl chlorosulfonylcarbamate (1.88 7 g, 8.75 mmol) in sequence. The mixture was reacted at room temperature overnight. After the reaction, the solvent was removed under reduced pressure on a rotary evaporator. Ethyl acetate (150 ml) and water (50 ml) were then added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 ml × 2). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give 23-4 (320 mg).

[0470] MS (ESI+, [M+H]+ )m / z:571.26.

[0471] Step D: To a 50 mL two-necked reaction flask, 23-4 (150 g, 0.263 mmol) and DCM (5 mL) were added sequentially. The mixture was cooled in an ice-water bath for 10 min, followed by the addition of boron tribromide (330 mg, 0.659 ml, 1.317 mmol). After addition, the temperature was slowly raised to room temperature and the reaction was allowed to react for 2 h. After completion of the reaction, the reaction solution was slowly poured into water (50 mL) and extracted with ethyl acetate (2 x 125 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by liquid chromatography (CHIRALART Cellulose-SB column; water (10 mM ammonium acetate + 0.1% glacial acetic acid) - acetonitrile (62:38)) to afford compound 23 (15 mg).

[0472] 1 H NMR(500MHz,DMSO-d6)δ10.82(s,1H),7.66(d,1H),7.40–7.22(m,2H),7.11(d,1H),7.07(d,2H),6.86–6.62(m,3H),4.32(d ,1H),3.79(d,1H),3.41(d,1H),2.61–2.53(m,1H),2.47–2.39(m,1H),2.00(d,1H),1.90(d,1H),1.63(d,1H),1.52(q,1H).

[0473] HRMS (ESI+, [M+H] + )m / z:457.1277.

[0474] Example 24

[0475] Step A: To a 25 mL single-necked vial were added 25-1 (200 mg, 0.67 mmol), DCM (10 ml), DIPEA (259 mg, 2.00 mmol), and 24-1, sequentially. The reaction mixture was stirred at room temperature. Upon completion of the reaction, the solvent was removed under reduced pressure using a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford 24-2 (220 mg).

[0476] 1H NMR(500MHz,DMSO-d6)δ7.46(dd,1H),7.08(dd,1H),6.93(s,1H),6.84(dd,1H),4.20–4.08(m,1H),3.92(dd,1H),3.55(d,1H),3.35–3.31(m ,1H),2.93–2.79(m,1H),2.72–2.66(m,3H),2.63–2.50(m,1H),2.07– 2.00(m,1H),1.94–1.85(m,1H),1.69–1.52(m,2H),1.01–0.90(m,4H).

[0477] MS (ESI+, [M+H] + )m / z:368.09.

[0478] Step B: Referring to Example 3, step B, 24-2 was used to replace 3-1 to obtain 24.

[0479] 1 H NMR(500MHz,DMSO-d6)δ11.94(s,1H),10.83(s,1H),7.67(d,1H),7.32(d,2H),7.08(dd,2H),6.78–6.73(m,1H),4.27(d,1H),3.96(dd,1H),3 .59(d,1H),2.87(dd,1H),2.78–2.69(m,1H),2.67–2.59(m,1H),2.11– 2.02(m,1H),1.94–1.85(m,1H),1.72–1.55(m,2H),1.03–0.96(m,4H).

[0480] HRMS (ESI+, [M+H] + )m / z:482.1483.

[0481] Example 25

[0482] Reaction process:

[0483] Step A: To a 100 mL single-necked flask were added 23-1 (1.8 g, 4.95 mmol), 1,4-dioxane (20 mL), and a 4N 1,4-dioxane hydrogen chloride solution (18.57 mL, 74.3 mmol). The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure. The crude product was slurried with ethyl acetate (30 mL), filtered, and the filter cake dried to afford 25-1 (1.5 g).

[0484] MS (ESI+, [M+H] + )m / z:264.24.

[0485] Step B: To a 250 mL single-necked flask were added 25-2 (5.0 g, 52.6 mmol), dichloromethane (100 mL), TBSCl (10.3 g, 68.3 mmol), and TEA (10.64 g, 105 mmol) in sequence and reacted in an ice-water bath for 4 h. After the reaction, the reaction solution was evaporated under reduced pressure to remove the solvent. Water (150 mL) and ethyl acetate (150 mL) were added to the crude product. The layers were separated and the organic phase was washed with water (100 mL × 3) and saturated sodium chloride water (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator to obtain 25-3 (9.2 g).

[0486] 1 H NMR (500MHz, CDCl3) δ4.60(s,1H),3.01(s,3H),0.95(s,9H),0.29(s,6H).

[0487] Step C: To a 50 mL single-necked flask, dichlorotriphenylphosphine (1.07 g, 3.21 mmol), chloroform (8 mL), TEA (0.58 g, 5.73 mmol), and 25-3 (300 mg, 1.43 mmol) were added sequentially and reacted in an ice-water bath for 0.5 h. TEA (0.29 g, 2.87 mmol) and 25-1 (344 mg, 1.146 mmol) were added and reacted at room temperature for 0.5 h. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:3) to afford 25-4 (0.92 g).

[0488] MS (ESI+, [M+H] + )m / z:455.21.

[0489] Step D: To a 100 mL single-necked bottle were added 25-4 (900 mg, 3.21 mmol), 1,4-dioxane (60 mL), 3-2 (815 mg, 3.96 mmol), copper 3-methylsalicylate (850 mg, 3.96 mmol), and tetrakistriphenylphosphine palladium (572 mg, 0.49 mmol) in sequence. The mixture was heated to 100°C for 16 hours. After completion of the reaction, the mixture was filtered and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by liquid chromatography (XB-C18 column; water (10 mM ammonium acetate + 0.1% glacial acetic acid) - acetonitrile (65:35)) to give compound 25 (8 mg).

[0490] 1H NMR(500MHz,DMSO-d6)δ7.52(d,1H),7.24–7.11(m,1H),7.10–6.92(m,4H),6.77–6.58(m,1H),4.39–4.21(m,1H) ),4.05–3.95(m,1H),3.62-3.53(m,3H),2.75(s,3H),2.70–2.61(m,1H),2.08–1.86(m,2H),1.68–1.44(m,2H).

[0491] HRMS(ESI+,[M+H]+)m / z: 455.1490.

[0492] Example 26

[0493] Reaction process:

[0494] Step A: To a 100 mL single-necked bottle, 26-1 (500 mg, 2.78 mmol), methanol (50 mL), sodium carbonate (883 mg, 8.33 mmol), and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.60 g, 8.33 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen for 1.0 hour. After the reaction, water (80 mL) was added and the mixture was extracted with dichloromethane (50 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to afford 26-2 (260 mg).

[0495] 1 H NMR (500MHz, DMSO-d6) δ7.79(s,2H),7.50(d,1H),7.07–7.01(m,2H),4.23(s,1H),3.81(s,3H).

[0496] MS (ESI-, [MH] - )m / z:175.19.

[0497] Step B: To a 100 mL single-necked flask were added 1-6 (500 mg, 2.50 mmol), 1,4-dioxane (45 mL), 26-2 (881 mg, 5.01 mmol), XphosPdG3 (318 mg, 0.376 mmol), potassium carbonate (1.04 g, 7.51 mmol), and water (15 mL) in sequence. Under nitrogen, the mixture was heated to 90°C for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to afford 26-3 (445 mg).

[0498] 1 H NMR(500MHz,DMSO-d6)δ7.70(dd,1H),7.44(d,1H),7.30(d,1H),7.25–7.20 (m,1H),7.06(dd,1H),6.61(d,1H),4.35(s,1H),3.76(s,3H),2.84(s,3H).

[0499] MS (ESI+, [M+H] + )m / z:296.04.

[0500] Step C: To a 100 mL single-necked bottle, 26-3 (520 mg, 1.76 mmol), dichloromethane (30 mL), and m-chloroperbenzoic acid (357 mg, 1.76 mmol) were added sequentially under nitrogen atmosphere at room temperature for 1.0 hour. After the reaction, dichloromethane (30 mL) was added, and the mixture was washed with saturated sodium bicarbonate aqueous solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to afford 26-4 (190 mg).

[0501] 1 H NMR (500MHz, DMSO-d6) δ8.38(dd,1H),7.47(d,1H),7.34(d,1H),7.25(dd,1H),7.19(dd,1H),6.81(dd,1H),4.39(s,1H),3.78(s,3H),3.28(s,3H).

[0502] MS (ESI+, [M+H] + )m / z:312.05.

[0503] Step D: To a 10 mL reaction vial were added 26-4 (160 mg, 0.514 mmol) and 2-9 (1.17 g, 10.28 mmol) sequentially under nitrogen. The mixture was heated to 100°C for 2.0 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 30:1) to afford 26-5 (100 mg).

[0504] 1H NMR(500MHz,DMSO-d6)δ7.91(dd,1H),7.36(d,1H),7.24(d,1H),7.21–7.11(m,2H),6.88(dd,1H),6.33(d,1H),4.36–4.20(m,2H) ,3.73(s,3H),3.07(d,1H),2.71(d,1H),2.22(s,3H),2.07–1.85(m,3H),1.83–1.71(m,1H),1.66–1.55(m,1H),1.48–1.37(m,1H).

[0505] MS(ESI+,[M+H]+)m / z: 362.26.

[0506] Step E: Referring to Example 2, 26-5 was used in place of 2-10 in step H to obtain 26.

[0507] 1 H NMR(500MHz,DMSO-d6)δ13.41(s,1H),8.16(s,1H),7.97(d,1H),7.64(s,1H),7.22(d,1H),7.13–7.02(m,3H),4.44-4.24(m,2 H),3.17(d,1H),2.89–2.74(m,1H),2.32(s,3H),2.18–1.92(m,3H),1.87-1.77(m,1H),1.70-1.60(m,1H),1.57-1.43(m,1H).

[0508] HRMS (ESI+, [M+H] + )m / z:348.1811.

[0509] Experimental Example 1: In vitro cell anti-pyroptosis activity assay

[0510] 1.1 Anti-pyroptosis activity assay in J774A.1 cells

[0511] Take J774A.1 cells in good growth state, wash with PBS, digest with trypsin, stop with complete culture medium, collect into centrifuge tube, and adjust the cell density to 8×10 5 / mL, inoculated into 96-well plates (100 μL / well), incubated overnight at 37℃5% CO2; discarded the supernatant, added serum lipase (manufacturer: Sigma, 50 μL / well) at a final concentration of 200 ng / mL, incubated at 37℃5% CO2 for 3 h; used a nanoliter pipette to add compounds to a final concentration of 10000 nM-4.57 nM, two replicates, incubated at 37℃5% CO2 for 1 h; added Nigericin (manufacturer: Millipore, 50 μL / well) at a final concentration of 10 μM, incubated at 37℃5% CO2 for 4 h; added detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well), incubated at 37℃5% CO2 for 1 h, and measured its absorbance at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the anti-pyroptosis activity (EC 50 ), where A stands for: EC 50 ≤100nM; B represents: 100nM<EC 50 ≤1000nM; C represents: 1000nM<EC 50 .

[0512] The test results are shown in Table 1.

[0513] Table 1

[0514] Experimental Example 2: In vitro cell (IL-1β) expression assay

[0515] 2.1 In vitro THP-1 cell (IL-1β) expression assay

[0516] Take THP-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 2×10 6 / mL, inoculated into 96-well plates (50μL / well), and LPS (manufacturer: Sigma, 50μL / well) was added at a final concentration of 100ng / mL, and incubated at 37℃5%CO2 for 3h; the compound was added to a final concentration of 1000nM, 100nM, and 10nM (50μL / well, 2 replicates), and incubated at 37℃5%CO2 for 1h; Nigericin (manufacturer: Millipore, 50μL / well) was added at a final concentration of 10μM, and incubated at 37℃5%CO2 for 1h; centrifuged at 1500rpm for 3min, the supernatant was collected, and stored at -20℃ for testing Human IL-1β;

[0517] Human IL-1β detection (manufacturer: R&D): In a high-adsorption 96-well plate, add Human IL-1βCapture Antibody coating antibody (100 μL / well) at a final concentration of 4 μg / mL and incubate at 4°C overnight; discard the supernatant, add PBST for washing (300 μL / well, 3 times in total), add 1% BSA-PBS blocking solution (200 μL / well), block at 25°C for 2 hours; discard the supernatant, add PBST for washing (300 μL / well, 3 times in total), add the standard curve and diluted samples to be tested (100 μL / well), incubate at 25°C for 2 hours; discard the supernatant, add PBST for washing (300 μL / well, 3 times in total), add Human IL-1βDetection at a final concentration of 200 ng / mL Antibody detection with secondary antibody (100 μL / well) was performed, followed by incubation at 25°C for 2 h. The supernatant was discarded, and the cells were washed with PBST (300 μL / well, three times). Streptavidin-HRP tertiary antibody (100 μL / well) was added, followed by incubation at 25°C for 20 min. The supernatant was discarded, and the cells were washed with PBST (300 μL / well, three times). TMB was added for color development (100 μL / well), and the cells were incubated at 25°C for 5 min. The reaction was terminated by addition of 1 M H2SO4 (50 μL / well). The absorbance was measured at 450 / 570 nm using a PerkinElmer Envision microplate reader. IL-1β expression and inhibition rate were calculated using a four-parameter analysis. The results are shown in Table 2; A represents % inhibition ≥ 50; B represents 10 ≤ % inhibition < 50; and C represents % inhibition < 10.

[0518] Table 2

[0519] Experimental Example 3: In vitro liver microsome stability evaluation

[0520] Liver microsomal incubation samples were prepared by mixing PBS buffer (pH 7.4), a liver microsomal solution (0.5 mg / ml), the test compound, and an NADPH+MgCl2 solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), a liver microsomal solution (0.5 mg / ml), and the test compound. The sample was added to an acetonitrile solution containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis. The experimental results are shown in Table 3, demonstrating that the disclosed compounds exhibit good stability in human liver microsomes.

[0521] Table 3

[0522] Experimental Example 4: Pharmacokinetic Evaluation in Mice

[0523] ICR mice weighing 18-22 g were randomly divided into groups after acclimation for 3-5 days, with 9 mice in each group. The oral administration group was given a 10 mg / kg dose of the test compound solution by oral administration.

[0524] After administration, blood was collected from the eye sockets at 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours to prepare plasma samples to be tested.

[0525] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0526] The non-compartmental model was used to fit the pharmacokinetic parameters.

[0527] The experimental results show that the disclosed compounds have good pharmacokinetics and high bioavailability.

[0528] Experimental Example 5: Pharmacokinetic Evaluation in Rats

[0529] SD rats weighing 180-220 g were randomly divided into groups of 3 after acclimation for 3-5 days. The test compound solution was orally administered at a dose of 10 mg / kg and intravenously injected at a dose of 1 mg / kg.

[0530] Blood was collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 30 h, and 48 h after oral administration;

[0531] The time points for blood sampling after intravenous administration are 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h.

[0532] Blood was collected from the eye socket to prepare plasma samples.

[0533] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0534] The experimental results show that the disclosed compounds have good pharmacokinetics and high bioavailability.

[0535] Experimental Example 6: Pharmacodynamic evaluation of the compound on lipopolysaccharide (LPS)-induced mouse peritonitis model

[0536] Male C57BL / 6 mice (Source: Shanghai Lingchang Biotechnology Co., Ltd.) were randomly assigned to groups of 6 mice based on body weight. On days 1 and 2, mice were administered drugs by gavage once daily. On day 3, drugs were administered by gavage (0 h) as pretreatment. One hour later, the modeling agent, lipopolysaccharide (LPS), was administered intraperitoneally (15 mg / kg). LPS was dissolved in PBS and used immediately. Serum was collected 3 h afterward for IL-1β analysis.

[0537] The experimental results show that the disclosed compound has good anti-inflammatory efficacy in vivo, and the efficacy has a dose-effect relationship.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Structural unit including fused and bicyclic heteroaryls; Q and Y are each independently selected from C, Si or N, and one of Q and Y is N; Z 1 、Z 2 and Z 3 Each independently selected from C(R 3 )、Si(R 3 ) or N; X is selected from -N(R 4 )-(C(R 5 )(R 6 )) m -、-O-(C(R 5 )(R 6 )) m -、-S-(C(R 5 )(R 6 )) m -or-(C(R 5 )(R 6 )) m -; R 1 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace; R 2 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 3-8 Cycloalkyl, -(CH2) i -(3-8 membered heterocycloalkyl), -(CH2) i -(C 6-10 aryl) or -(CH2) i -(5-9 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R b replace; Each R 3 Each independently selected from H, OH, CN, NH2, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2 are optionally substituted independently by 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R c replace; Or, Z 1 、Z 2 Each independently selected from C(R 3 ) or Si(R 3 ), Z 1 and Z 2 R on 3 Together with the atoms to which they are attached, they form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace; Or, Z 2 、Z 3 Each independently selected from C(R 3 ) or Si(R 3 ), Z 2 and Z 3 R on 3 Together with the atoms to which they are attached, they form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a replace; R 4 Selected from H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl may be optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; Each R 5 and R 6 Each independently selected from H, OH, NH2, CN, C 1-3 Alkyl or halogenated C 1-3 alkyl; Each R a Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 2-6 Alkenyl, -(CH2) i C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) i C 2-6 Alkenyl or -(CH2) i C 2-6 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace; Each R b Each independently selected from OH, CN, NH2, halogen, =O, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-NH2, -S(=O)2-NH-C 1-3 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-NH-C 3-6 Cycloalkyl, -S(=O)(NH)-C 1-3 Alkyl, -S(=O)(NH)-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-NH-C 1-3 Alkyl or -S(=O)(NH)-C 1-3 The alkyl group is optionally substituted independently with 1, 2 or 3 halogens, OH, NH2 or CN; the -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-NH-C 3-6 Cycloalkyl, -S(=O)(NH)-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted by 1, 2 or 3 R d replace; Each R c Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide; Each R d Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide; Each R e Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 alkyl halide; m is selected from 0, 1, 2 or 3; i is selected from 0, 1 or 2; Each R 4 、R 5 、R 6 、R c 、R d or R e each optionally independently substituted with one or more substituents; Optionally, each R 1 、R 2 、R 3 、R a or R b are each independently substituted with one or more other substituents.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Q and Y are each independently selected from C or N, and one of Q and Y is N; Z 1 、Z 2 and Z 3 Each independently selected from C(R 3 ) or N.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, wherein Z 1 Selected from N, Z 2 and Z 3 Selected from C(R 3 ); or Z 1 and Z 2 Selected from N, Z 3 Selected from C(R 3 ); or Z 1 and Z 3 Selected from N, Z 2 Selected from C(R 3 ); or Z 2 Selected from N, Z 1 and Z 3 Selected from C(R 3 ); or Z 2 and Z 3 Selected from N, Z 1 Selected from C(R 3 ); or Z 3 Selected from N, Z 1 and Z 2 Selected from C(R 3 ); or Z 1 、Z 2 and Z 3 All selected from C(R 3 ); or Z 1 、Z 2 and Z 3 All are selected from N.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 3 Each is independently selected from H, OH, CN, NH2, halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl, the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 being optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether or azetidinyl being optionally independently substituted with 1, 2 or 3 R c Substituted; preferably, each R 3 Each is independently selected from H, OH, CN, NH2, F, Cl, Br, I, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy; further preferably, each R 3 are each independently selected from H.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z 1 、Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 Together with the atoms to which they are attached, they form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a Substituted; preferably, Z 1 、Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 Together with the atoms to which they are attached, they form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, or 5 membered heteroaryl containing 1 or 2 ring heteroatoms selected from N, O, S, wherein the C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl or 5 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a Substituted; more preferably, Z 1 、Z 2 Each independently selected from C(R 3 ), Z 1 and Z 2 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z 2 、Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 Together with the atoms to which they are attached, they form C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl, the C 3-8 Partially saturated cycloalkyl, 3-8 membered partially saturated heterocycloalkyl, C 6-10 Aryl or 5-9 membered heteroaryl is optionally independently substituted by 1, 2 or 3 R a Substituted; preferably, Z 2 、Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 Together with the atoms to which they are attached, they form C 5-6 partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, O, S, or 5 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, wherein the C 5-6 Partially saturated cycloalkyl, 5-6 membered partially saturated heterocycloalkyl or 5 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a Substituted; more preferably, Z 2 、Z 3 Each independently selected from C(R 3 ), Z 2 and Z 3 R on 3 and the atoms to which they are attached form described Optionally independently 1, 2 or 3 R a replace.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein each R c Each independently selected from F, Cl, OH, methyl or trifluoromethyl; preferably, each R c are each independently selected from OH or methyl.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit Selected from Preferably, the structural unit Selected from More preferably, the structural unit Selected from More preferably, the structural unit Selected from 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from -N(R 4 )-, -O-, -S-, or -(C(R 5 )(R 6 )) m -.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R a Substituted; preferably, R 1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl is optionally independently substituted by 1, 2 or 3 R a Substituted; further preferably, R 1 is selected from phenyl, said phenyl being optionally independently substituted by 1, 2 or 3 R a replace.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein each R a Each independently selected from OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or -(CH2) i C 2-4 Alkynyl, said, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl or -(CH2) i C 2-4 Alkynyl is optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN; preferably, each R a Each independently selected from F, Cl, =O, OH, trifluoromethyl, trifluoromethoxy, difluoromethoxy, CF3CH2-, CN, 12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -(CH2) i C 3-6 Cycloalkyl, -(CH2) i -(3-6 membered heterocycloalkyl), -(CH2) i -phenyl or -(CH2) i -(5-6 membered heteroaryl), the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R b Substituted; preferably, R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, thiirane, aziridine, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein R 2 Optionally independently 1, 2 or 3 R b Substituted; further preferably, R 2 is selected from piperidinyl, said piperidinyl being optionally independently substituted by 1, 2 or 3 R b replace.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein each R b Each is independently selected from OH, CN, NH2, halogen, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiether, azetidinyl, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-NH2, -S(=O)2-NH-CH3, -S(=O)2-NH-CH2CH3, -S(=O)2-cyclopropyl, -S(=O)2-NH-cyclopropyl, -S(=O)2-CH3, -S(=O)2(NH)-CH2CH3 or -S(=O)(NH)-cyclopropyl, or -S(=O) (NH)-CH3, or -S(=O) (NH)-CH2CH3, are optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane, azetidinyl, -S(=O)2-cyclopropyl, -S(=O)2-NH-cyclopropyl or -S(=O) (NH)-cyclopropyl are optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane, azetidinyl, -S(=O)2-cyclopropyl, -S(=O)2-NH-cyclopropyl or -S(=O) (NH)-cyclopropyl are optionally independently substituted with 1, 2 or 3 R e Substituted; preferably, each R b Each is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl, trifluoromethyl, ethyl, 2-hydroxyethyl, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-cyclopropyl or -S(=O)(NH)-CH3.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compound of formula (I-1a) or the compound of formula (I-1b), or a pharmaceutically acceptable salt thereof, in, R 1 、R 2 、Z 1 、Z 2 and Z 3 As defined in claim 1.

15. A compound of the formula: or a pharmaceutically acceptable salt thereof:

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. Use of the compound of claims 1-15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16 in the preparation of a medicament for treating or preventing NLRP3 inflammasome-mediated diseases.

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