Bicyclic substituted pyridazine derivative and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a bicyclic substituted pyridazine derivative and application thereof, in particular to a compound shown as a formula (I) and pharmaceutically acceptable salt and application thereof. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to a bicyclic substituted pyridazine derivative and uses thereof, and specifically to a compound of formula (I) and a pharmaceutically acceptable salt thereof and uses thereof. Background Art

[0002] As a component of the innate immune system, inflammasomes play a vital role in immune regulation. It is known that NOD-like receptors and AIM2-like receptors in cells can assemble into structurally common inflammasomes, among which NLRP3 inflammasome is the most well-studied inflammasome. It is a multi-protein macromolecular complex composed of NLRP3 protein, junction protein ASC and effector caspase-1, and is usually distributed in macrophages, dendritic cells, microglia and endothelial cells. The content of NLRP3 protein in normal cells is low. When cells are stimulated by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), the gene expression of NLRP3 and pro-inflammatory factors is upregulated through the NF-κB signaling pathway. After NLRP3 protein oligomerization, it recruits pro-caspase-1 through ASC to assemble into NLRP3 inflammasomes. Caspase-1 is converted from a precursor form to an active form, promoting the release of inflammatory factors and accompanied by inflammatory pyroptosis of cells.

[0003] NLRP3 inflammasome activation is accompanied by severe inflammatory responses and is involved in the pathology of a variety of diseases, such as immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases. Therefore, the rational design and synthesis of compounds with NLRP3 inflammasome inhibitory activity is of great value for the treatment of inflammatory diseases. Summary of the invention

[0004] The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0005]

[0006] in,

[0007] Structural unit is a fused bicyclic heteroaryl;

[0008] Q and Y are each independently selected from C, Si or N, and one of Q and Y is N;

[0009] Z 1 , Z 2 and Z 3 Each independently selected from C(R3 )、Si(R 3 ) or N;

[0010] 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 -;

[0011] Ring A is selected from phenyl or 5-6 membered heteroaryl, and the ring A is optionally independently substituted with one or more R a1 replace;

[0012] Ring B is selected from C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, wherein the ring B is optionally independently substituted by 1, 2, 3, 4, 5 or 6 R a2 replace;

[0013] 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 one or more deuterium, halogen, OH, SH, 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 with one or more R b replace;

[0014] Each R 3 Each independently selected from H, deuterium, OH, SH, CN, NH2, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -NH(C 1-3Alkyl), -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 is optionally substituted independently by one or more deuterium, halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R c replace;

[0015] R 4 Selected from H, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted independently with one or more deuterium, halogen, OH, SH, NH2 or CN;

[0016] Each R 5 and R 6 Each independently selected from H, deuterium, OH, SH, NH2, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0017] Each R a1 and R a2 Each independently selected from OH, SH, CN, NH2, halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2 is optionally substituted independently by one or more deuterium, halogen, OH, SH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R d replace;

[0018] Each R b Each independently selected from OH, SH, CN, NH2, halogen, =O, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2 is optionally substituted independently by one or more deuterium, halogen, OH, SH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R e replace;

[0019] Each R c Each independently selected from deuterium, halogen, OH, SH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0020] Each R d Each independently selected from deuterium, halogen, OH, SH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0021] Each R e Each independently selected from deuterium, halogen, OH, SH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0022] m is selected from 0, 1, 2 or 3;

[0023] i is selected from 0, 1 or 2;

[0024] Each R a1 , R a2 , R 5 , R 6 , R c , R d or R e each optionally independently substituted with one or more substituents;

[0025] Optionally, each R 2 , R 3 , R 4 , R a or R b Each is independently substituted with one or more other substituents.

[0026] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0027]

[0028] in,

[0029] Structural unit is a fused bicyclic heteroaryl;

[0030] Q and Y are each independently selected from C, Si or N, and one of Q and Y is N;

[0031] Z 1 , Z 2 and Z 3 Each independently selected from C(R 3 )、Si(R 3 ) or N;

[0032] 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 -;

[0033] Ring A is selected from phenyl or 5-6 membered heteroaryl, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 replace;

[0034] Ring B is selected from C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, wherein the ring B is optionally independently substituted by 1, 2, 3, 4, 5 or 6 R a2 replace;

[0035] 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 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally substituted independently by 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;

[0036] 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 is 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 with 1, 2 or 3 R c replace;

[0037] R 4 Selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN;

[0038] Each R 5 and R 6 Each independently selected from H, OH, NH2, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0039] Each R a1 and R a2 Each is independently selected from OH, CN, NH2, halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2 is 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 with 1, 2 or 3 R d replace;

[0040] Each R b Each is independently selected from OH, CN, NH2, halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2 is 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 with 1, 2 or 3 R e replace;

[0041] Each R c Each independently selected from halogen, OH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0042] Each R d Each independently selected from halogen, OH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0043] Each R e Each independently selected from halogen, OH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0044] m is selected from 0, 1, 2 or 3;

[0045] i is selected from 0, 1 or 2;

[0046] Each R a1 , R a2 , R 5 , R 6, R c , R d or R e each optionally independently substituted with one or more substituents;

[0047] Optionally, each R 2 , R 3 , R 4 , R a or R b Each is independently substituted with one or more other substituents.

[0048] In some embodiments of the present disclosure, each R a1 , R a2 , R 5 , R 6 , R c , R d or R e Each is independently optionally substituted with 1, 2 or 3 substituents.

[0049] In some embodiments of the present disclosure, each R 4 , R 2 , R 3 , R a or R b Each is independently optionally substituted with 1, 2 or 3 additional substituents.

[0050] In some embodiments of the present disclosure, each R a1 , R a2 , R 5 , R 6 , R c , R d or R e Each is optionally independently substituted by one or more substituents, or each R 2 , R 3 , R 4 , R a or R bEach is independently substituted by one or more other substituents, wherein the “substituent” or “other substituent” can be selected from the following groups: deuterium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, carboxaldehyde group, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl , halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc.

[0051] In some embodiments of the present disclosure, the heteroatom in the "heterocycloalkyl" described in the present disclosure is selected from boron, sulfur, oxygen, nitrogen and / or phosphorus.

[0052] In some embodiments of the present disclosure, the heteroatom in the "heterocycloalkyl" or "heteroaryl" described in the present disclosure is selected from nitrogen, oxygen or sulfur.

[0053] In some embodiments of the present disclosure, the "one or more" is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" is selected from 1, 2, or 3. In some embodiments, the "one or more" is selected from 1 or 2.

[0054] 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.

[0055] In some embodiments of the present disclosure, one and only one of Q and Y is N, and the other is Si or C.

[0056] In some embodiments of the present disclosure, one and only one of Q and Y is N, and the other is C.

[0057] In some embodiments of the present disclosure, Q is selected from N, and Y is selected from C.

[0058] In some embodiments of the present disclosure, Q is selected from C and Y is selected from N.

[0059] 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 , Z2 and Z 3 Each independently selected from C(R 3 ) or N.

[0060] In some embodiments of the present disclosure, Z 1 , Z 2 and Z 3 Each independently selected from C(R 3 ) or N.

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

[0062] In some embodiments of the present disclosure, Z 1 and Z 2 Selected from N, Z 3 Selected from C(R 3 ).

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

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

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

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

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

[0068] In some embodiments of the present disclosure, Z 1 , Z 2 and Z 3 All are selected from N.

[0069] 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 ).

[0070] 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 ).

[0071] 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 ).

[0072] 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 ).

[0073] 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 ).

[0074] 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 ).

[0075] 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 ).

[0076] 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.

[0077] 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 3Selected from C(R 3 ).

[0078] 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 ).

[0079] 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 ).

[0080] 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 ).

[0081] 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 ).

[0082] 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 ).

[0083] 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 ).

[0084] 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.

[0085] 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, thiirane or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 is optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane or azetidinyl is optionally independently substituted with 1, 2 or 3 R c replace.

[0086] In some embodiments of the present disclosure, each R c Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0087] In some embodiments of the present disclosure, each R c Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

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

[0089] In some embodiments of the present disclosure, R c Selected from OH.

[0090] In some embodiments of the present disclosure, R c Selected from methyl.

[0091] In some embodiments of the present disclosure, R c Does not exist.

[0092] 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 by 1, 2 or 3 halogen, OH, NH2 or CN.

[0093] 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.

[0094] In some embodiments of the present disclosure, each R 3 Each is independently selected from H, F, Cl, methyl or trifluoromethyl.

[0095] In some embodiments of the present disclosure, each R 3 Each is independently H.

[0096] In some embodiments of the present disclosure, the structural unit Selected from

[0097]

[0098] In some embodiments of the present disclosure, the structural unit Selected from

[0099] In some embodiments of the present disclosure, the structural unit Selected from

[0100] In some embodiments of the present disclosure, the structural unit Selected from

[0101] In some embodiments of the present disclosure, X is selected from -N(R 4 )-, -O-, -S-, or -(C(R 5 )(R 6 )) m -.

[0102] In some embodiments of the present disclosure, R 4 Selected from H, C 1-4 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 are optionally substituted independently with 1, 2 or 3 halogen, OH, NH2 or CN.

[0103] In some embodiments of the present disclosure, R 4 Selected from H, methyl, ethyl or isopropyl.

[0104] In some embodiments of the present disclosure, R 4 Selected from H.

[0105] In some embodiments of the present disclosure, each R 5 and R 6 Each independently selected from H, OH, NH2, CN, C1-3 Alkyl or halogenated C 1-3 alkyl.

[0106] In some embodiments of the present disclosure, each R 5 and R 6 Each is independently selected from H or OH.

[0107] In some embodiments of the present disclosure, each R 5 and R 6 are each independently selected from H.

[0108] In some embodiments of the present disclosure, X is selected from -NH-, -O-, -S-, -CH2-, or -CH2CH2-.

[0109] In some embodiments of the present disclosure, X is selected from -NH-.

[0110] In some embodiments of the present disclosure, ring A is selected from phenyl, or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 replace.

[0111] In some embodiments of the present disclosure, ring A is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 replace.

[0112] In some embodiments of the present disclosure, ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 replace.

[0113] In some embodiments of the present disclosure, ring A is selected from phenyl, wherein ring A is optionally independently substituted with 1, 2 or 3 R a1 replace.

[0114] In some embodiments of the present disclosure, the substituents of Ring B are optionally independently replaced by 1, 2, 3 or 4 R a2 replace.

[0115] In some embodiments of the present disclosure, the substituents of Ring B are optionally independently replaced by 1 or 2 R a2 replace.

[0116] In some embodiments of the disclosure, Ring B has one or two double bonds.

[0117] In some embodiments of the disclosure, Ring B has only one double bond.

[0118] In some embodiments of the present disclosure, Ring B is selected from C 5-6 Cycloalkenyl, 5-6 membered heterocycloalkenyl 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 ring B is optionally independently substituted by 1, 2, 3 or 4 R a2 replace.

[0119] In some embodiments of the present disclosure, ring B is selected from cyclopentenyl, cyclohexenyl, 2,3-dihydrofuranyl, 2,3-dihydrothienyl, 2,3-dihydro-1H-pyrrolyl, 1,3-dioxolyl, 1,4-dioxinyl, 1,2,3,4-tetrahydropyrazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the ring B is optionally independently substituted by 1, 2, 3 or 4 R a2 replace.

[0120] In some embodiments of the present disclosure, ring B is selected from cyclopentenyl, cyclohexenyl, 2,3-dihydrofuranyl, 1,3-dioxolyl, 1,4-dioxinyl, phenyl or thienyl, and the ring B is optionally independently substituted by 1, 2, 3 or 4 R a2 replace.

[0121] In some embodiments of the present disclosure, ring B is selected from cyclopentenyl, wherein ring B is optionally independently substituted with 1, 2, 3 or 4 R a2 replace.

[0122] In some embodiments of the present disclosure, the structural unit Selected from

[0123] In some embodiments of the present disclosure, the structural unit Selected from

[0124] In some embodiments of the present disclosure, the structural unit Selected from

[0125] In some embodiments of the present disclosure, the structural unit Selected from

[0126] In some embodiments of the present disclosure, each R a1 and R a2 Each is independently selected from OH, CN, NH2, halogen, =O, C 1-3Alkyl, 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 is 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 with 1, 2 or 3 R d replace.

[0127] In some embodiments of the present disclosure, each R a1 and R a2 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, thiirane or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 is optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane or azetidinyl is optionally independently substituted with 1, 2 or 3 R d replace.

[0128] In some embodiments of the present disclosure, each R a1 and R a2 Each is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl or methoxy, wherein the methyl or methoxy is optionally independently substituted with 1, 2 or 3 halogens, OH, NH2 or CN.

[0129] In some embodiments of the present disclosure, each R a1 and R a2 Each is independently selected from F, Cl, OH or trifluoromethyl.

[0130] In some embodiments of the present disclosure, each R a1 and R a2 Each is independently selected from OH or trifluoromethyl.

[0131] In some embodiments of the present disclosure, each R a1 and R a2are each independently selected from OH.

[0132] In some embodiments of the present disclosure, each R d Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0133] In some embodiments of the present disclosure, each R d Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

[0134] In some embodiments of the present disclosure, each R d are each independently selected from F.

[0135] In some embodiments of the present disclosure, the structural unit Selected from

[0136] In some embodiments of the present disclosure, the structural unit Selected from

[0137] In some embodiments of the present disclosure, the structural unit Selected from

[0138] 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), said 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 replace.

[0139] 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), said 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.

[0140] 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.

[0141] 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 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.

[0142] In some embodiments of the present disclosure, R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, thiirane, azirane, oxetanyl, thiinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, 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.

[0143] 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 replace.

[0144] In some embodiments of the present disclosure, R 2 is selected from piperidinyl, which is optionally independently substituted by 1, 2 or 3 R b replace.

[0145] In some embodiments of the present disclosure, 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, thiirane or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 is optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane or azetidinyl is optionally independently substituted with 1, 2 or 3 R e replace.

[0146] In some embodiments of the present disclosure, each R b Each is 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), -N(C 1-3 alkyl)2 is 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 with 1, 2 or 3 R e replace.

[0147] In some embodiments of the present disclosure, each R b Each is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl, ethyl or methoxy, wherein the methyl or methoxy is optionally independently substituted with 1, 2 or 3 halogens, OH, NH2 or CN.

[0148] In some embodiments of the present disclosure, each R bEach is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl, ethyl or trifluoromethyl.

[0149] In some embodiments of the present disclosure, each R b Each is independently selected from F, Cl, OH, methyl, ethyl or trifluoromethyl.

[0150] In some embodiments of the present disclosure, each R b Each is independently selected from methyl or ethyl.

[0151] In some specific embodiments of the present disclosure, R b It is methyl.

[0152] In some specific embodiments of the present disclosure, R b It is ethyl.

[0153] In some embodiments of the present disclosure, each R e Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0154] In some embodiments of the present disclosure, each R e Each is independently selected from F, Cl, OH, methyl or trifluoromethyl.

[0155] In some embodiments of the present disclosure, each R e are each independently selected from F.

[0156] In some embodiments of the present disclosure, R 2 Selected from

[0157] 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.

[0158] In some embodiments of the present disclosure, R 2 Selected from

[0159] In some other embodiments of the present disclosure, R 2 Selected from

[0160] In some embodiments of the present disclosure, m is selected from 0 or 1.

[0161] In some embodiments of the present disclosure, i is selected from 0 or 1.

[0162] 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,

[0163]

[0164] in,

[0165] Ring A, Ring B, R 2 , Z 1 , Z 2 and Z 3 As defined for compounds of formula (I).

[0166] 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,

[0167]

[0168]

[0169] in,

[0170] Ring B, R 2 , R a1 , R b , Z 1 , Z 2 and Z 3 As defined for 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-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,

[0172]

[0173] in,

[0174] Ring B, R a1 , R b , Z 1 , Z 2 and Z 3 As defined for compounds of formula (I).

[0175] 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,

[0176]

[0177] in,

[0178] Ring B, R a1 , R b , Z 1 , Z 2 and Z 3 As defined for compounds of formula (I).

[0179] 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,

[0180]

[0181] in,

[0182] Ring B, R a1 , R b , Z 1 , Z 2 and Z 3 As defined for compounds of formula (I).

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

[0184] The present disclosure also provides the following compounds or pharmaceutically acceptable salts thereof:

[0185]

[0186] 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 the racemic form.

[0187] The present disclosure also provides the following compounds or pharmaceutically acceptable salts thereof:

[0188]

[0189] The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further includes a pharmaceutically acceptable carrier.

[0190] The present disclosure also provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in preparing a drug for treating or preventing a disease.

[0191] The present disclosure also provides a method for treating or preventing a disease, comprising administering a therapeutically or preventively 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.

[0192] The present disclosure also provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in treating or preventing a disease.

[0193] 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.

[0194] In some embodiments of the present disclosure, the disease is selected from a disease mediated by NLRP3 inflammasome.

[0195] In some embodiments of the present disclosure, the NLRP3 inflammasome-mediated disease is selected from: an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

[0196] Technical Effects

[0197] The compounds disclosed in the present invention are novel NLRP3 inflammasome inhibitors, which have a good inhibitory effect on NLRP3 inflammasome-induced signal transduction, good anti-pyroptosis activity on J774A.1 cells, good inhibitory activity on IL-1β expression in THP-1 cells, and good in vivo inhibitory activity. The compounds disclosed in the present invention have high liver microsome stability and good pharmacokinetic properties, and can be developed into new NLRP3 inflammasome inhibitor drugs.

[0198] Related definitions

[0199] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0200] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0201] The term "pharmaceutically acceptable salt" refers to salts of compounds of the present disclosure, prepared from compounds with specific substituents discovered in 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 such compounds with a sufficient amount of base in a pure 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 such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present disclosure contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0202] The pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid to prepare.

[0203] 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 mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0204] 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 single enantiomeric forms, forms enriched in one enantiomer, or racemic forms of the compound.

[0205] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

[0206] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and 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 regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound, If they are connected, it means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.

[0207] 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 an imidazole moiety, in which a proton can migrate between two ring nitrogens. Tautomers include interconversions by reorganization of some bonding electrons.

[0208] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up 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, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure.

[0209] 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.

[0210] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, 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 not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0211] The term "one or more substitutions" means that any one or more hydrogen atoms on a particular atom are replaced by substituents, 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 what is chemically feasible.

[0212] The "substituents" described herein include, but are not limited to, the terms "alkyl", "alkoxy", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocycloalkyl", "heteroaryl", "aryl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituents" include deuterium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide, sulfoxide, sulfone, sulfonamide, carboxyl, carboxaldehyde, etc. , imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, 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.

[0213] In some embodiments herein, the “substituent” is selected from deuterium, hydroxyl, thiol, 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 2-12alkenyl, 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 1-12 Heteroalkyl, 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, the 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(C1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 alkylene, 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.

[0214] 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, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0215] 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.

[0216] When the listed linking group does not indicate 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 the reading order from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0217] 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 bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line 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; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the 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.

[0218] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to 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 may 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.

[0219] Unless otherwise specified, the term “C 1-4 "Alkoxy" refers to those alkyl groups containing 1 to 4 carbon atoms which are linked to the rest of the molecule via an oxygen atom. 1-4 Alkoxy includes C 1-4 and C 1-3 Alkoxy, etc. 1-3 Alkoxy includes 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.

[0220] Unless otherwise specified, the term “C 1-4 "Alkylthio" means those alkyl groups containing 1 to 4 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-4 Alkylthio includes C 1-4 and C 1-3 Alkylthio, etc. 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.

[0221] The term "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0222] 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 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0223] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a straight 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 The alkenyl group can be C 2-4 Alkenyl or C 2-3 The C 2-4 Alkenyl includes 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.

[0224] Unless otherwise specified, “C 2-6 "Alkynyl" is used to denote a straight 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.

[0225] 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 systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 Cycloalkyl; it may 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.

[0226] 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 system. 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0227] 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 B, O, S, N, P, Si or Se, and the rest are carbon atoms, wherein the nitrogen atoms are 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 systems, wherein bicyclic systems include spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl", a heteroatom may occupy the position where the heteroalkyl ring is connected 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.

[0228] 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 B, O, S, N, P, Si or Se, and the rest are carbon atoms, wherein the nitrogen atoms are 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 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, etc. 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.

[0229] Unless otherwise specified, the term “C 5-6 "Cycloalkenyl" refers to a partially saturated hydrocarbon cycloalkyl group consisting of 5 to 6 carbon atoms, including monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. It can be monovalent, divalent or polyvalent.

[0230] Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" means a partially saturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from B, O, S, N, P, Si or Se, and the rest are carbon atoms, wherein the nitrogen atoms are 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 systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. In addition, with respect to the "5-6 membered heterocycloalkenyl", a heteroatom may occupy the position at which the heteroalkane ring is connected to the rest of the molecule.

[0231] 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, 1, 2, 3 or 4 of which 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 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 a 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, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, 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.), benzothienyl, etc.

[0232] Unless otherwise specified, the term “C 6-10 "Aryl" means 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 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.).

[0233] The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0234] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0235] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0236] 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.

[0237] The term "therapeutically 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. 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 those skilled in the art based on their own knowledge and the present disclosure.

[0238] The term "prophylactically effective amount" means an amount of a compound of the present disclosure that prevents or delays 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.

[0239] The therapeutic or preventive dose of the disclosed compounds may be based on, for example, the specific use of the treatment or prevention, the mode of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. In certain embodiments, the dosage range is about 0.001 mg / kg to about 1000 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and degree of development 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 extrapolating the dose-response curve derived from an in vitro or animal model test system.

[0240] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0241] "Pharmaceutical composition" means a composition containing one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thereby exert biological activity. Pharmaceutical compositions include pharmaceutical compositions with a single dose of 0.001 mg to 1000 mg.

[0242] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0243] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art.

[0244] 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 synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0245] The present disclosure provides a general preparation route, including:

[0246] Route 1:

[0247]

[0248] Route 2:

[0249]

[0250] Among them, ring B and Rb As described for the compound of formula (I).

[0251] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes 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 the synthesis steps or reaction processes based on the existing embodiments.

[0252] 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.

[0253] An important consideration in synthetic route planning in the art is to select a suitable protecting group for a reactive functional group (such as the amino group in the present disclosure), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0254] 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.

[0255] All reagents used in this disclosure were commercially available and used without further purification. DETAILED DESCRIPTION

[0256] The present disclosure is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof are also disclosed therein. 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.

[0257] Example 1

[0258]

[0259] Reaction process:

[0260]

[0261] Step A: 1-1 (8 g, 57.5 mmol) and hydrazine hydrate (71.5 g, 2.23 mol) were added to ethanol (70 mL), and the mixture was heated to 90°C 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).

[0262] MS (ESI-, [MH] - )m / z:124.06.

[0263] Step B: Add tetramethyl orthoformate (8.16 g, 59.9 mmol) and aluminum isopropoxide (1.632 g, 7.99 mmol) to a solution of 1-2 (5 g, 40 mmol) in acetonitrile (10 mL). After nitrogen substitution, the mixture was heated to 120 ° C for 18 hours. After 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.

[0264] 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).

[0265] 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 replacement, 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, water (50 mL) and 1M sodium hydroxide (20 mL) solution were added to the residue, and extracted with ethyl acetate (3x150 mL), the organic phases were combined, concentrated and dried, and the crude product was purified by silica gel column chromatography to obtain 1-4 (1.3 g). MS (ESI-, [MH] - )m / z:167.99.

[0266] 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).

[0267] 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-mouth bottle in sequence, and the mixture was heated to 110 ° C for 18 hours. After the reaction, the reaction solution was cooled to room temperature, 100 mL of water was added, and extracted with ethyl acetate (3x100 mL). The organic phases were combined, concentrated and dried, and the crude product was purified by silica gel column chromatography to obtain 1-5 (1.2 g). MS (ESI-, [MH] - )m / z:184.00.

[0268] 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).

[0269] 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-mouth bottle in sequence, and the mixture was heated to 60°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, 100 mL of water was added, and 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.

[0270] 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-mouth bottle, and the mixture was heated to 110°C for 4.0 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.

[0271] Step G: 1-8 (3 g, 14.08 mmol) and tetrahydrofuran (45 ml) were added to a 100 mL two-necked reaction bottle in sequence, with nitrogen protection, and after cooling at -78 ° C for 10 min, n-butyl lithium (2 g, 31.2 mmol, 12.49 ml) was slowly added dropwise through a syringe. After the addition was completed, the temperature was slowly raised to room temperature and stirring was continued for 2 h, then -78 ° C was cooled for 10 min, and triethyl borate (3.29 g, 22.53 mmol) was slowly added dropwise through a syringe. After the addition was completed, the temperature was slowly raised to room temperature and stirring was continued overnight. After the reaction was completed, 6 ml of 1N HCl was added to quench the reaction, and stirring was continued for 1 h. Ethyl acetate was added for extraction (100 ml × 2), the organic phases were combined, washed with saturated brine, 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 (PE: EA = 4: 1) to obtain 1-9 (1.18 g).

[0272] MS (ESI-, [MH] - )m / z:177.12.

[0273] Step H: 1-9 (385 mg, 2.163 mmol), 3-methylsalicylate copper (464 mg, 2.163 mmol), Pd(Ph3P)4 (208 mg, 0.180 mmol), 1-7 (200 mg, 0.721 mmol) and 1,4-dioxane (10 ml) were added to a 100 mL reaction bottle in sequence. The mixture was protected by nitrogen and heated to 100 °C for 16 hours. After the reaction was completed, the mixture was filtered and the solvent was removed by rotary evaporation under reduced pressure. The crude product was subjected to liquid phase preparation (XB-C18 column; water (10 mM ammonium acetate + 0.1% glacial acetic acid) - acetonitrile (62:38)) to give compound 1 (30 mg).

[0274] HRMS (ESI+, [M+H] + )m / z:364.2139.

[0275] 1H NMR (500MHz, DMSO-d6) δ9.71(s,1H),7.25(d,J=7.6Hz,1H),7.14(dd,J=2.8,1.3Hz,1H),7.07(dd,J=3.9,1.4 Hz,1H),6.88(t,J=7.5Hz,2H),6.72(dd,J=3.8,2.9Hz,1H),4.24(dtt,J=11.1,8.0,4.0Hz,1H),3.07–2.98(m, 1H),2.93(t,J=7.5Hz,2H),2.88(t,J=7.4Hz,2H),2.69(d,J=11.0Hz,1H),2.21(s,3H),2.07(p,J=7.5Hz,2H) ,1.98–1.83(m,3H),1.74(dt,J=12.4,3.4Hz,1H),1.59(tt,J=14.2,7.8Hz,1H),1.36(qd,J=11.9,4.0Hz,1H).

[0276] Example 2

[0277]

[0278] Reaction process:

[0279]

[0280] Step A: 2-1 (5.0 g, 22.41 mmol), acetonitrile (100 ml), potassium hydroxide (2.52 g, 44.80 mmol), and methyl iodide (9.54 g, 67.20 mmol) were added to a 500 mL two-necked reaction bottle in sequence, and the mixture was heated to 40°C for 3 hours under nitrogen protection. After the reaction, the reaction solution was concentrated and dried, and the crude product was purified by silica gel column chromatography (PE: EA = 100: 1) to obtain 2-2 (5.27 g).

[0281] 1 H NMR (500MHz, DMSO-d6) δ8.13–8.07(m,1H),8.02–7.97(m,1H),7.72–7.66(m,2H),7.66–7.58(m,2H),3.94(s,3H).

[0282] Step B: 2-2 (2.0 g, 8.44 mmol) and tetrahydrofuran (30 ml) were added to a 250 mL two-necked reaction bottle in sequence, nitrogen protection, -78 ° C cooling for 10 min, n-butyl lithium (540 mg, 8.44 mmol, 3.38 mL) was slowly injected through a syringe, and the addition was completed, and the stirring was continued for 1 h. Triethyl borate (1.58 g, 8.44 mmol) was slowly injected through a syringe, and the addition was completed, and the stirring reaction was continued for 2.0 h. After the reaction was completed, saturated ammonium chloride (80 mL) was added to quench the reaction, and ethyl acetate was extracted (2*100 mL), the organic phases were combined, washed with saturated brine, 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 (DCM: MeOH = 20: 1) to obtain 2-3 (0.7 g).

[0283] 1 H NMR (500MHz, DMSO-d6) δ8.15(s,2H),8.13–8.08(m,1H),7.92–7.85(m,1H),7.60(d,J=7.6Hz,1H),7.56–7.49(m,3H),3.95(s,3H).

[0284] Step C: 2-3 (480 mg, 2.163 mmol), 3-methylsalicylate copper (464 mg, 2.163 mmol), Pd(Ph3P)4 (208 mg, 0.180 mmol), 1-7 (200 mg, 0.721 mmol) and 1,4-dioxane (25 ml) were added to a 100 mL reaction bottle in sequence. The mixture was protected by nitrogen and heated to 100 °C for 16 hours. After the reaction was completed, the mixture was filtered and the solvent was evaporated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain 2-4 (120 mg).

[0285] MS (ESI+, [M+H] + )m / z:388.21.

[0286] Step D: 2-4 (90 mg, 0.232 mmol), DCM (15 mL), and boron tribromide (1.16 g, 4.65 mmol, 2.323 mL) were added to a 100 mL reaction bottle in sequence, and the mixture was protected by nitrogen and reacted in an ice-water bath for 2 hours. After the reaction, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (50 mL), extracted with DCM (2*50 mL), the organic layers were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was subjected to liquid phase preparation (XB-C18 column; water (10 mM ammonium acetate + 0.1% glacial acetic acid)-acetonitrile (60:40)) to obtain compound 2 (9 mg). HRMS (ESI+, [M+H]+ )m / z:374.1977.

[0287] 1 H NMR (500MHz, DMSO-d6) δ11.21(s,1H),8.33(d,J=9.0Hz,1H),7.94(d,J=7.6Hz,1H),7.62(d,J=9.2Hz,4H),7.35(s,1H),7.22–6.95(m, 2H),6.78(s,1H),4.29(s,1H),3.05(s,1H),2.79–2.62(m,1H),2.21(s,3H),2.04–1.84(m,3H),1.80–1.52(m,2H),1.46–1.33(m,1H).

[0288] Example 3

[0289]

[0290] Reaction process:

[0291]

[0292] Step A: Referring to Example 2, the raw material 3-1 was used to replace 2-2 to prepare the intermediate 3-2.

[0293] MS (ESI-, [MH] - )m / z:207.04.

[0294] Step B: Referring to Example 2, intermediate 3-2 was used to replace 2-3 to prepare intermediate 3-3.

[0295] MS (ESI+, [M+H] + )m / z:394.25.

[0296] Step C: Referring to Example 2, intermediate 3-3 was used to replace 2-4 to prepare compound 3.

[0297] HRMS (ESI+, [M+H] + )m / z:380.1537.

[0298] 1H NMR(500MHz,DMSO-d6)δ1H NMR (500MHz, DMSO) δ10.18(s,1H),8.21(s,1H),8.09(s,1H),7.44(d,J=8.0Hz,1H),7.24(ddd,J=28.6,20.2,7.8Hz,3H),6.96(t,J=3.4Hz,1H ),6.80(d,J=7.8Hz,1H),4.29(s,1H),3.05(s,1H),2.79–2.62(m,1H), 2.21(s,3H),2.04–1.84(m,3H),1.80–1.52(m,2H),1.46–1.33(m,1H).

[0299] Example 4

[0300]

[0301] Reaction process:

[0302]

[0303] Step A: Referring to step F of Example 1, (R)-1-ethylpiperidin-3-amine was used instead of (R)-1-methylpiperidin-3-amine to obtain 4-1.

[0304] MS(ESI+,[M+H]+)m / z: 292.42.

[0305] Step B: Referring to step B of Example 1, replace 1-7 with 4-1 to obtain compound 4.

[0306] HRMS (ESI+, [M+H] + )m / z:378.2298.

[0307] 1 H NMR(500MHz,DMSO-d6)δ9.70(s,1H),7.25(d,J=7.6Hz,1H),7.14(d,J=2.7Hz,1H),7.06( d,J=3.8Hz,1H),6.94(s,1H),6.88(d,J=7.6Hz,1H),6.72(t,J=3.3Hz,1H),4.27(s,1H), 3.19(s,1H),2.93(t,J=7.5Hz,2H),2.88(t,J=7.4Hz,3H),2.16–2.03(m,4H),2.03–1.88 (m,3H),1.81–1.74(m,1H),1.65–1.54(m,1H),1.48–1.38(m,1H),1.04(t,J=7.2Hz,3H).

[0308] Example 5

[0309]

[0310] Reaction process:

[0311]

[0312] Step A: Referring to step A of Example 1, replace 1-1 with 5-1 to obtain 5-2.

[0313] MS (ESI-, [MH] - )m / z:177.12.

[0314] Step B: Referring to step B of Example 1, replace 1-2 with 5-2 to obtain compound 5.

[0315] HRMS (ESI+, [M+H] + )m / z:364.2141.

[0316] 1 H NMR(500MHz,DMSO-d6)δ9.77(s,1H),7.20(s,1H),7.02(ddd,J=8.7,3.3,1.3Hz,2H),6.87(s,1H) ,6.83(d,J=8.0Hz,1H),6.68(dd,J=3.8,2.8Hz,1H),4.24(q,J=8.9Hz,1H),3.02(d,J=10.2Hz,1H ),2.88(t,J=7.4Hz,2H),2.81(t,J=7.3Hz,2H),2.68(d,J=10.9Hz,1H),2.20(s,3H),1.88(dt,J= 18.8,10.3Hz,3H),1.73(dt,J=13.2,3.7Hz,1H),1.41–1.31(m,2H),0.84(qd,J=7.2,4.7Hz,2H).

[0317] Example 6

[0318]

[0319] Reaction process:

[0320]

[0321] Step A: Referring to step B of Example 2, replace 2-2 with 6-1 to obtain 6-2.

[0322] 1H NMR (500MHz, DMSO-d6) δ7.80(s,2H),7.22(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),3.75(s,3H),2.67(dt,J=26.9,6.3Hz,4H),1.85–1.56(m,4H).

[0323] Step B: Referring to step C of Example 2, replace 2-3 with 6-2 to obtain 6-3.

[0324] MS (ESI+, [M+H] + )m / z:392.32.

[0325] Step C: Referring to step D of Example 2, compound 6 was obtained by replacing 2-4 with 6-3.

[0326] HRMS (ESI+, [M+H] + )m / z:378.2289.

[0327] 1 H NMR(500MHz,DMSO-d6)δ10.23(s,1H),7.44–7.23(m,2H),7.12(s,1H),6.98(s,1H),6.75(d,J=9.8Hz,2H) ,4.25(s,1H),3.02(s,1H),2.83–2.59(m,5H),2.21(s,3H),2.00–1.67(m,8H),1.59(s,1H),1.38(s,1H).

[0328] Example 7

[0329]

[0330] Reaction process:

[0331]

[0332] Step A: Referring to step B of Example 2, 7-2 was obtained by replacing 2-2 with 7-1.

[0333] 1 H NMR (500MHz, DMSO-d6) δ7.37(d,J=7.9Hz,1H),7.05(t,J=8.5Hz,1H),6.47(dd,J=8.0,4.0 Hz,1H),6.39(d,J=7.9Hz,1H),3.77(s,3H),3.32(t,J=8.7Hz,2H),3.05(t,J=8.8Hz,2H).

[0334] Step B: Referring to step C of Example 2, replace 2-3 with 7-2 to obtain 7-3.

[0335] MS (ESI+, [M+H] + )m / z:380.25.

[0336] Step C: Referring to step D of Example 2, 7-3 was used to replace 2-4 to obtain 7.

[0337] HRMS (ESI+, [M+H] + )m / z:366.1935.

[0338] 1 H NMR(500MHz,DMSO-d6)δ10.16(s,1H),7.32–7.12(m,2H),7.06(s,1H),6.86(s,1H),6.71(s,1H),6.44(s,1H),4.61(s,2 H),4.23(s,1H),3.18(s,2H),3.02(s,1H),2.68(s,1H),2.20(s,3H),1.91(s,3H),1.65(d,J=73.4Hz,2H),1.34(s,1H).

[0339] Example 8

[0340]

[0341] Reaction process:

[0342]

[0343] Step A: Referring to step B of Example 2, 8-2 was obtained by replacing 2-2 with 8-1.

[0344] 1 H NMR (500MHz, DMSO-d6) δ7.44(s,2H),7.10(d,J=8.2Hz,1H),6.57(d,J=8.3Hz,1H),4.31–4.25(m,2H),4.23–4.16(m,2H),3.75(s,3H).

[0345] Step B: Referring to step C of Example 2, replace 2-3 with 8-2 ​​to obtain 8-3.

[0346] MS (ESI+, [M+H] + )m / z:395.20.

[0347] Step C: Referring to step D of Example 2, 8-3 was used to replace 2-4 to obtain 8.

[0348] HRMS (ESI+, [M+H] + )m / z:382.1822.

[0349] 1 H NMR (500MHz, DMSO-d6) δ9.63 (s, 1H), 7.07 (d, J = 2.7Hz, 1H), 7.02 (d, J = 3.9Hz, 1H), 6.86–6.77 (m, 2H), 6.68 (t, J = 3.3Hz, 1H), 6.54 (d, J = 8. 3Hz,1H),4.27–4.14(m,2H),3.16–2.95(m,2H),2.79–2.62(m,2H),2.21(s,3H),2.04–1.84(m,4H),1.80–1.52(m,2H),1.46–1.33(m,1H).

[0350] Example 9

[0351]

[0352] Reaction process:

[0353]

[0354] Step A: 9-1 (5 g, 36.2 mmol) and toluene (100 mL) were added to a 500 mL single-mouth reaction bottle in sequence, and N-bromosuccinimide (7.08 g, 39.81 mmol) was added in batches under an ice bath, and the mixture was stirred for 2 h. After the reaction was completed, water (200 mL) was added to the reaction solution, and ethyl acetate (3*100 mL) was used for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo to obtain 9-2 (6.16 g).

[0355] 1 H NMR (500MHz, DMSO-d6) δ10.19(s,1H),6.97(d,1H),6.44(d,1H),6.03(s,2H).

[0356] Step B: 9-2 (5.5 g, 25.3 mmol) and tetrahydrofuran (100 mL) were added to a 100 mL single-mouth reaction bottle in sequence, sodium hydride (2.03 g, 50.7 mmol) was added in batches under an ice bath, the mixture was stirred for 10 min, chloromethyl ether (3.22 mL, 32.9 mmol) was added dropwise, and the reaction solution was stirred for 3 h. After the reaction was completed, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (3*100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA=10:1) to obtain compound 9-3 (6.58 g).

[0357] 1 H NMR (500MHz, DMSO-d6) δ7.08(d,1H),6.68(d,1H),6.07(s,2H),5.27(s,2H),3.78(q,2H),1.13(t,3H).

[0358] Step C: 9-3 (6.58 g, 23.9 mmol) and tetrahydrofuran (100 mL) were added to a 250 mL two-necked reaction bottle in sequence, and n-butyl lithium (22.44 mL, 35.9 mmol) was added at -78 ° C. The mixture was stirred for 30 min, and triethyl borate (6.10 mL, 35.9 mmol) was added dropwise, and the reaction solution was stirred for 1 h. After the reaction was completed, ice water (100 mL) was added to the reaction solution, extracted with ethyl acetate (3*100 mL), washed with saturated sodium chloride (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9-4 (5.41 g).

[0359] MS (ESI - ,[MH] - )m / z:239.11.

[0360] Step D: 9-4 (5.41 g, 22.54 mmol) and 1,4-dioxane (25 mL) were added to a 100 mL single-mouth reaction bottle, and 4M hydrogen chloride-1,4-dioxane solution (56.3 mL, 225.0 mmol) was slowly added dropwise, and the reaction solution was stirred for 1 h. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to obtain 9-5 (2.2 g).

[0361] MS (ESI - ,[MH] - )m / z:181.05.

[0362] Step E: Referring to step C in Example 2, 9 was obtained by replacing 2-3 with 9-5.

[0363] HRMS(ESI + ,[M+H] + )m / z:368.1725.

[0364] 1 H NMR(500MHz,DMSO-d6)δ10.22(s,1H),7.07(dd,2H),6.96(d,1H),6.88(d,1H),6.71(t,1H),6.62(d,1H),6.10(s,2H),3. 04–2.98(m,1H),2.68(d,1H),2.20(s,3H),1.97–1.83(m,3H),1.73(t,1H),1.57(q,1H),1.36(t,1H),1.26–1.22(m,1H).

[0365] Example 10

[0366]

[0367] Reaction process:

[0368]

[0369] Step A: 10-1 (1.0 g, 4.61 mmol), DMF (20 mL), NaH (240 mg, 5.99 mmol) and benzyl bromide (1.18 g, 6.91 mmol) were added to a 100 mL single-mouth bottle in sequence and reacted at room temperature for 1.0 h. After the reaction was completed, saturated ammonium chloride (20 mL) was added to quench the reaction, extracted with ethyl acetate (2*100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator to obtain 10-2 (1.2 g).

[0370] MS (ESI + ,[M+H] + )m / z:306.99.

[0371] Step B: Referring to step B of Example 2, replace 2-2 with 10-2 to obtain 10-3.

[0372] MS (ESI-, [MH] - )m / z:270.74.

[0373] Step C: 10-3 (545 mg, 2.00 mmol), 1-6 (200 mg, 1.00 mmol), potassium carbonate (415 mg, 3.01 mmol), dioxane (15 mL), water (5 mL), Xphos Pd G3 (127 mg, 0.15 mmol) were added to a 100 mL single-mouth bottle in sequence, and the mixture was heated to 100 ° C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered and the solvent was evaporated under reduced pressure on a rotary evaporator. The crude product was purified by silica gel column chromatography (PE: EA = 3: 1) to obtain 10-4 (250 mg).

[0374] MS (ESI+, [M+H] + )m / z:392.20.

[0375] Step D: 10-4 (230 mg, 0.588 mmol), n-butanol (15 mL), (R)-1-methylpiperidin-3-amine (268 mg, 2.35 mmol) and DIEA (228 mg, 1.76 mmol) were added to a 35 mL microwave tube in sequence and reacted at 180 ° C for 8.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure on a rotary evaporator, and the crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain 10-5 (165 mg).

[0376] MS (ESI+, [M+H] + )m / z:458.25.

[0377] Step E: 10-5 (160 mg, 0.350 mmol), palladium carbon (20 mg), and acetic acid (8 mL) were added to a 25 mL single-mouth bottle in sequence, and heated to 50 ° C under H2 atmosphere for 10.0 h. After the reaction was completed, suction filtration was performed, and saturated sodium bicarbonate solution was added to the filtrate to adjust the pH to 7-8, and ethyl acetate was used for extraction (2*50 mL). The organic phases were combined, washed with saturated brine, 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 (DCM: MeOH = 20: 1) to obtain 10 (15 mg).

[0378] HRMS (ESI+, [M+H] + )m / z:368.1722.

[0379] 1H NMR(500MHz,DMSO-d6)δ13.97(s,1H),8.10(s,1H),7.62(d,1H),7.43(d,1H),7.34–7.22(m,1H),7.08(s,1H),6.61(d,1H), 6.07(s,2H),4.28(s,1H),3.09(d,1H),2.74(d,1H),2.25(s,3H),2.01-1.96(m,3H),1.77(d,1H),1.62(t,1H),1.45(t,1H).

[0380] Embodiment 11

[0381]

[0382] Reaction process:

[0383]

[0384] Step A: 11-1 (15.0 g, 110 mmol) and toluene (250 mL) were added to a 100 mL single-mouth bottle in sequence, and NBS (19.61 g, 110 mmol) was added after cooling to 0°C in an ice bath, and the mixture was reacted at room temperature for 2.0 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3*150 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator to obtain 11-2 (26 g).

[0385] MS (ESI-, [MH] - )m / z:212.95.

[0386] Step B: Referring to step A of Example 10, replace 10-1 with 11-2 to obtain 11-3.

[0387] MS (ESI+, [M+H] + )m / z:305.02.

[0388] Step C: Referring to step B of Example 2, replace 2-2 with 11-3 to obtain 11-4.

[0389] MS (ESI-, [MH] - )m / z:269.19.

[0390] Step D: Referring to step C of Example 10, replace 10-3 with 11-4 to obtain 11-5.

[0391] MS (ESI+, [M+H] + )m / z:390.15.

[0392] Step E: Referring to step D of Example 10, replace 10-4 with 11-5 to obtain 11-6.

[0393] MS (ESI+, [M+H] + )m / z:456.31.

[0394] Step F: Referring to step E of example 10, 11-6 was used instead of 10-5 to obtain 11.

[0395] MS (ESI+, [M+H] + )m / z:366.1935.

[0396] 1 H NMR(500MHz,DMSO-d6)δ14.28(s,1H),8.08(d,1H),7.88(d,1H),7.33(d,1 H),7.30(d,1H),7.07(t,1H),6.44(d,1H),4.62(t,2H),4.32–4.19(m,1H), 3.15(t,2H),3.05(dd,1H),2.71(d,1H),2.21(s,3H),2.05–1.97(m,1H),1 .96–1.84(m,2H),1.80–1.72(m,1H),1.66–1.54(m,1H),1.49–1.35(m,1H).

[0397] Experimental Example 1: In vitro cell anti-pyroptosis activity assay

[0398] 1.1 Determination of anti-pyroptosis activity of J774A.1 cells

[0399] Take J774A.1 cells in good growth state, wash with PBS, digest with trypsin, terminate with complete culture medium, collect into centrifuge tube, and adjust the cell density to 8×10 5 / mL, inoculated in 96-well plates (100μL / well), incubated overnight at 37℃5% CO2; discarded the supernatant, added serum lipase (manufacturer: Sigma, 50μL / well) with a final concentration of 200ng / mL, incubated for 3h at 37℃5% CO2; used a nanoliter pipette to add compounds to a final concentration of 10000nM-4.57nM, 2 replicates, incubated for 1h at 37℃5% CO2; added Nigericin (manufacturer: Millipore, 50μL / well) with a final concentration of 10μM, incubated for 4h at 37℃5% CO2; added detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10μL / well), incubated for 1h at 37℃5% CO2, detected its absorbance at 450nm with PerkinElmer Envision microplate reader, four-parameter analysis, fitted dose-effect curve, calculated anti-pyroptosis activity (EC 50 ), some of the compounds disclosed in the present invention have good anti-pyroptosis activity.

[0400] The test results are shown in Table 1, where A represents EC 50 ≤30nM.

[0401] Table 1

[0402] Example <![CDATA[EC 50 nM]]> 1 A 4 A 7 A 9 A 10 A 11 A

[0403] Experimental Example 2: In vitro cell (IL-1β) expression assay

[0404] 2.1 In vitro THP-1 cell (IL-1β) expression assay

[0405] 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 in a 96-well plate (50μL / well), and added LPS with a final concentration of 100ng / mL (manufacturer: Sigma, 50μL / well), incubated at 37℃5% CO2 for 3h; compound was added to make the final concentration of the compound 1000nM, 100nM, 10nM (50μL / well, 2 replicates), incubated at 37℃5% CO2 for 1h; Nigericin with a final concentration of 10μM (manufacturer: Millipore 50μL / well), incubated at 37℃5% CO2 for 1h; centrifuged at 1500rpm for 3min, collected the supernatant, and stored at -20℃ for Human IL-1β to be tested;

[0406] Human IL-1β detection (manufacturer: R&D): In a high-absorption 96-well plate, add Human IL-1β Capture Antibody coated antibody (100 μL / well) with a final concentration of 4 μg / mL, incubate at 4°C overnight; discard the supernatant, add PBST to wash (300 μL / well, 3 times in total), add 1% BSA-PBS blocking solution (200 μL / well), block at 25°C for 2h; discard the supernatant, add PBST to wash (300 μL / well, 3 times in total), add the standard curve and the diluted sample to be tested (100 μL / well), incubate at 25°C for 2h; discard the supernatant, add PBST to wash (300 μL / well, 3 times in total), add Human IL-1βDetectionAntibody detects secondary antibody (100μL / well), incubates at 25°C for 2h; discards supernatant, adds PBST to wash (300μL / well, 3 times in total), adds Streptavidin-HRP to detect tertiary antibody (100μL / well), incubates at 25°C for 20min; discards supernatant, adds PBST to wash (300μL / well, 3 times in total), adds TMB to develop color (100μL / well), incubates at 25°C for 5min, adds 1M H2SO4 to terminate the reaction (50μL / well), and detects its absorbance at 450 / 570nm using PerkinElmer Envision microplate reader. Four-parameter analysis is used to calculate IL-1β expression and inhibition rate. Some compounds disclosed herein have good inhibitory activity against IL-1β.

[0407] The test results are shown in Table 2.

[0408] Table 2

[0409] Example <![CDATA[EC 50 nM]]> 7 0.63

[0410] Experimental Example 3: In vitro liver microsome stability evaluation

[0411] The sample for incubation of liver microsomes was prepared by mixing PBS buffer (PH7.4), liver microsome solution (0.5 mg / ml), test compound and NADPH+MgCl2 solution at 37°C and 300 rpm for 1 hour. The sample for 0 hours was prepared by mixing PBS buffer (PH7.4), liver microsome solution (0.5 mg / ml), test compound. The sample was added with acetonitrile solution containing internal standard to prepare supernatant by protein precipitation, and diluted for LC / MS / MS determination. Some compounds disclosed in the present invention have good liver microsomal stability.

[0412] The test results are shown in Table 3.

[0413] Table 3

[0414]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Structural unit is a fused bicyclic heteroaryl; 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 -; Ring A is selected from phenyl or 5-6 membered heteroaryl, and the ring A is optionally independently substituted with one or more R a1 replace; Ring B is selected from C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, wherein the ring B is optionally independently substituted by 1, 2, 3, 4, 5 or 6 R a2 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 one or more deuterium, halogen, OH, SH, 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 with one or more R b replace; Each R 3 Each independently selected from H, deuterium, OH, SH, 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 is optionally substituted independently by one or more deuterium, halogen, OH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R c replace; R 4 Selected from H, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted independently with one or more deuterium, halogen, OH, SH, NH2 or CN; Each R 5 and R 6 Each independently selected from H, deuterium, OH, SH, NH2, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl; Each R a1 and R a2 Each independently selected from OH, SH, CN, NH2, halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2 is optionally substituted independently by one or more deuterium, halogen, OH, SH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R d replace; Each R b Each independently selected from OH, SH, CN, NH2, halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2 is optionally substituted independently by one or more deuterium, halogen, OH, SH, NH2 or CN; said C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally independently substituted with one or more R e replace; Each R c Each independently selected from deuterium, halogen, OH, SH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl; Each R d Each independently selected from deuterium, halogen, OH, SH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl; Each R e Each independently selected from deuterium, halogen, OH, SH, CN, NH2, C 1-4 Alkyl or C 1-4 Haloalkyl; m is selected from 0, 1, 2 or 3; i is selected from 0, 1 or 2; Each R a1 , R a2 , R 5 , R 6 , R c , R d or R e each optionally independently substituted with one or more substituents; Optionally, each R 2 , R 3 , R 4 , R a or R b Each is 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; Or, 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 selected from N; Or, 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, thiirane or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 is optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane or azetidinyl is 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; Or, each R c Each independently selected from halogen, OH, CN, NH2, C 1-3 Alkyl or C 1-3 Preferably, each R c Each is independently selected from F, Cl, OH, methyl or trifluoromethyl; further preferably, each R c Each independently selected from OH or methyl; Alternatively, the structural unit Selected from Preferably, the structural unit Selected from Further preferably, the structural unit Selected from Or further preferably, the structural unit Selected from 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2, wherein X is selected from -N(R 4 )-, -O-, -S-, or -(C(R 5 )(R 6 )) m -; preferably, X is selected from -NH-, -O-, -S-, -CH2- or -CH2CH2-; further preferably, X is selected from -NH-.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is selected from phenyl, or a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 Preferably, ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 Further preferably, ring A is selected from phenyl, and the ring A is optionally independently substituted by 1, 2 or 3 R a1 replace; Alternatively, ring B is selected from C 5-6 Cycloalkenyl, 5-6 membered heterocycloalkenyl 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 ring B is optionally independently substituted by 1, 2, 3 or 4 R a2 Preferably, ring B is selected from cyclopentenyl, cyclohexenyl, 2,3-dihydrofuranyl, 1,3-dioxolyl, 1,4-dioxinyl, phenyl or thienyl, and the ring B is optionally independently substituted by 1, 2, 3 or 4 R a2 Further preferably, ring B is selected from cyclopentenyl, and the ring B is optionally independently substituted by 1, 2, 3 or 4 R a2 replace; Or, each R a1 and R a2 Each is 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), -N(C 1-3 alkyl)2 is 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 with 1, 2 or 3 R d Substituted; preferably, each R a1 and R a2 Each is independently selected from F, Cl, Br, I, OH, CN, NH2, methyl or methoxy, wherein the methyl or methoxy is optionally independently substituted by 1, 2 or 3 halogens, OH, NH2 or CN; further preferably, each R a1 and R a2 Each is independently selected from F, Cl, OH or trifluoromethyl; further preferably, each R a1 and R a2 are each independently selected from OH.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the structural unit Selected from Preferably, the structural unit Selected from Further preferably, the structural unit Selected from Alternatively, the structural unit Selected from Alternatively, the structural unit Selected from 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 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), said 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 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 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 Substitution; further preferably, 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 Substitution; More preferably, R 2 is selected from piperidinyl, which is optionally independently substituted by 1, 2 or 3 R b replace; Or, 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, thiirane or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, -NHCH3, -N(CH3)2 is optionally independently substituted with 1, 2 or 3 halogen, OH, NH2 or CN; the cyclopropyl, cyclobutyl, oxirane, thiirane, aziridine, oxetanyl, thiirane or azetidinyl is optionally independently substituted with 1, 2 or 3 R e Substituted; preferably, each R b Each is 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), -N(C 1-3 alkyl)2 is 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 with 1, 2 or 3 R e Substituted; further preferably, each R b Each is independently selected from F, Cl, OH, methyl, ethyl or trifluoromethyl; further preferably, each R b Each is independently selected from methyl or ethyl.

7. 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), an isomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A, Ring B, R 2 , Z 1 , Z 2 and Z 3 As defined in the compound of formula (I); Alternatively, 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), an isomer thereof or a pharmaceutically acceptable salt thereof, in, Ring B, R 2 , R a1 , R b , Z 1 , Z 2 and Z 3 As defined in the compound of formula (I); Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (I-2c-1), the compound of formula (I-2c-2), the compound of formula (I-2d-1) or the compound of formula (I-2d-2), an isomer thereof or a pharmaceutically acceptable salt thereof, in, Ring B, R a1 , R b , Z 1 , Z 2 and Z 3 As defined in the compound of formula (I); Alternatively, the compound of formula (I) or its isomer, or its pharmaceutically acceptable salt, is selected from the compound of formula (I-3a) or the compound of formula (I-3b), its isomer or its pharmaceutically acceptable salt, in, Ring B, R a1 , R b , Z 1 , Z 2 and Z 3 As defined in the compound of formula (I); Alternatively, 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), an isomer thereof or a pharmaceutically acceptable salt thereof, in, Ring B, R a1 , R b , Z 1 , Z 2 and Z 3 As defined for compounds of formula (I).

8. A compound of the formula below or a pharmaceutically acceptable salt thereof: Or a compound of the formula below or a pharmaceutically acceptable salt thereof, 9. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. Use of the compound according to claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating a disease.

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