NLRP3 inhibitor compound

Abstract

The present disclosure relates to NLRP3 inhibitor compounds. Specifically, the present disclosure provides compounds of formula I-a or pharmaceutically acceptable salts thereof, which have NLRP3 inflammasome inhibitory activity and can be used for treating or preventing NLRP3-related diseases.

Description

Technical Field

[0001] The present disclosure relates to the field of medicine, and particularly to an NLRP3 inhibitor. Background Art

[0002] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene. This protein belongs to the nucleotide-binding and oligomerization domain-like receptors (NLRs) family and is also known as "pyroptosis protein 3" (Inoue et al, Immunology, 2013, 139, 11-18). This gene encodes a protein that contains a pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. By responding to sterile inflammatory danger signals, NLRP3 interacts with an adaptor protein, apoptosis-associated speck-like protein (ASC), and caspase-1 to form the NLRP3 inflammasome. Subsequently, the activation of the NLRP3 inflammasome leads to the release of inflammatory cytokines IL-1β and IL-18, and when the activation of the NLRP3 inflammasome is dysregulated, it will drive the occurrence of many diseases.

[0003] Studies have shown that the activation of the NLRP3 inflammasome is related to multiple types of diseases, including: inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Therefore, it is necessary to provide new NLRP3 inflammasome pathway inhibitors to provide new alternative methods for the treatment of the above diseases. Summary of the Invention

[0004] In a first aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0005]

[0006] wherein X is selected from O or NH;

[0007] R1 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycloalkyl, -O-aryl, -O-heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycloalkyl, -O-aryl, -O-heteroaryl are optionally substituted by one or more R 1a substituents;

[0008] R2 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, alkylcycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycloalkyl, -O-aryl, -O-heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-heterocycloalkyl, -O-aryl, -O-heteroaryl are optionally substituted by one or more R 2a substituted;

[0009] or R1 and R2 are linked to form a 4-membered cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted by R5;

[0010] R3 is selected from alkyl, C 2-6 alkenyl, C 1-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl; the alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl are optionally substituted by one or more R 3a substituted;

[0011] R4 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl are optionally substituted by one or more R 4a substituted;

[0012] R5 is selected from hydrogen, halogen, cyano, nitro, amino, oxo, hydroxy, mesyl, alkyl, cycloalkyl, -C(=O)-NH2, -O-alkyl, -O-cycloalkyl, -O-heterocycloalkyl; the alkyl, cycloalkyl, -C(=O)-NH2, -O-alkyl, -O-cycloalkyl, -O-heterocycloalkyl are optionally substituted by one or more R 5a substituted;

[0013] R 1a 、R 2a 、R 3a 、R 4a 、R 5a are independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-C 3-8 cycloalkenyl, 6-10 membered aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, -O-C 1-6 alkyl, -O-C2-6 alkenyl, -O-C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, -O-3- to 6-membered cycloalkyl, -O-3- to 6-membered heteroalkyl, -O-C 3-8 cycloalkenyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, -O-3- to 6-membered cycloalkyl;

[0014] n is an integer selected from 0-5;

[0015] m is an integer selected from 0-3.

[0016] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl; the C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl is optionally substituted by 1-3 R 1a ;

[0017] R2 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl; the C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl is optionally substituted by 1-3 R 2a ;

[0018] or R1 and R2 are linked to form a 4-membered cycloalkyl or 4- to 6-membered heteroalkyl optionally substituted by R5.

[0019] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from hydrogen, halogen, cyano, nitro, amino, and hydroxy.

[0020] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heterocycloalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl; the C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heterocycloalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl is optionally substituted by 1 to 3 R 1a substituents.

[0021] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from C 1-6 alkyl, 5- to 10-membered heteroaryl; the C 1-6 alkyl, 5- to 10-membered heteroaryl is optionally substituted by 1 to 3 R 1a substituents.

[0022] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 12-membered aryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heterocycloalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl; the 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 12-membered aryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heterocycloalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl is optionally substituted by 1 to 3 R 1a substituents.

[0023] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from pyridine optionally substituted by 1 to 3 R 1a substituents.

[0024] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from C 1-6 alkyl, the C 1-6 alkyl is optionally substituted by 1 to 3 R 1a substituents.

[0025] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is selected from ethyl, and the ethyl is optionally substituted by 1-3 R 1a substituents.

[0026] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino.

[0027] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a is independently selected from C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-C 3-8 cycloalkenyl, 6-10 membered aryl or 5-6 membered heteroaryl, and the C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-C 3-8 cycloalkenyl, 6-10 membered aryl or 5-6 membered heteroaryl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl.

[0028] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a is independently selected from -O-C 1-6 alkyl, 3-6 membered cycloalkyl, and the -O-C 1-6 alkyl, 3-6 membered cycloalkyl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano.

[0029] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a is independently selected from -O-C 1-6 alkyl, and the -O-C 1-6 alkyl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano.

[0030] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1aIndependently selected from methoxy, ethoxy, methylenecyclopropyl, and the methoxy, ethoxy, and methylenecyclopropyl are optionally substituted with 1-3 substituents selected from halogen, hydroxyl, oxo, nitro, and cyano.

[0031] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a Independently selected from 3- to 6-membered cycloalkyl, and the 3- to 6-membered cycloalkyl is optionally substituted with 1-3 substituents selected from halogen, hydroxyl, oxo, nitro, and cyano.

[0032] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a Independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted with 1-3 substituents selected from halogen, hydroxyl, oxo, nitro, and cyano.

[0033] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a Independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0034] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from

[0035]

[0036] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from

[0037] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from

[0038] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl.

[0039] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen.

[0040] In some embodiments, for the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R2 is selected from C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heterocycloalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl; the C 1-6alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, 6- to 12-membered aryl, 5- to 10-membered heteroaryl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl, -O-6- to 12-membered aryl, -O-5- to 10-membered heteroaryl, optionally substituted by 1 to 3 R 2a substituents.

[0041] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R2 is selected from C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl; the C 1-6 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered heteroalkyl, optionally substituted by 1 to 3 R 2a substituents.

[0042] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R2 is selected from C 1-6 alkyl; the C 1-6 alkyl is optionally substituted by 1 to 3 R 2a substituents.

[0043] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 2a is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino.

[0044] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 2a is independently selected from C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, -O-3- to 6-membered cycloalkyl, -O-3- to 6-membered heteroalkyl, -O-C 3-8 cycloalkenyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heteroalkyl, -O-3- to 6-membered cycloalkyl, -O-3- to 6-membered heteroalkyl, -O-C 3-8 cycloalkenyl, 6- to 10-membered aryl or 5- to 6-membered heteroaryl, optionally substituted by 1 to 3 selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C1-6 substituted by an alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered hetero cycloalkyl group, or -O-3- to 6-membered cycloalkyl group.

[0045] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are linked to form a 4- to 6-membered hetero cycloalkyl group optionally substituted by R5.

[0046] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are linked to form a 4-membered cycloalkyl group optionally substituted by R5.

[0047] In a second aspect, the present disclosure also provides a compound of formula I-a, I-b, or I-c or a pharmaceutically acceptable salt thereof, which is

[0048]

[0049] R2, R3, R4, R5, X, n, and m are as defined in formula 1.

[0050] In some embodiments, a compound of formula I, I-a, I-b, or I-c or a pharmaceutically acceptable salt thereof, wherein R5 is selected from hydrogen, halogen, cyano, nitro, amino, oxo, hydroxy, methanesulfonyl, C 1-6 alkyl, 3- to 6-membered cycloalkyl, -C(=O)-NH2, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered hetero cycloalkyl; the C 1-6 alkyl, 3- to 6-membered cycloalkyl, -C(=O)-NH2, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered hetero cycloalkyl is optionally substituted by 1 to 3 R 5a substituents.

[0051] In some embodiments, a compound of formula I, I-a, I-b, or I-c or a pharmaceutically acceptable salt thereof, wherein R5 is selected from hydrogen, halogen, cyano, nitro, amino, oxo, hydroxy, methanesulfonyl.

[0052] In some embodiments, a compound of formula I, I-a, I-b, or I-c or a pharmaceutically acceptable salt thereof, wherein R5 is selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, -C(=O)-NH2, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered hetero cycloalkyl; the C 1-6 alkyl, 3- to 6-membered cycloalkyl, -C(=O)-NH2, -O-C 1-6 alkyl, -O-3- to 7-membered cycloalkyl, -O-3- to 7-membered hetero cycloalkyl is optionally substituted by 1 to 3 R 5a substituents.

[0053] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 5a is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino.

[0054] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 5a is independently selected from C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-C 3-8 cycloalkenyl, 6-10 membered aryl or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, -O-C 3-8 cycloalkenyl, 6-10 membered aryl or 5-6 membered heteroaryl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -O-3-6 membered cycloalkyl.

[0055] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, -O-C 1-6 alkyl, -O-3-7 membered cycloalkyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, -O-C 1-6 alkyl, -O-3-7 membered cycloalkyl is optionally substituted by 1-3 R 3a .

[0056] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R3 is selected from C 1-6 alkyl, wherein the C1-6 The alkyl group is optionally substituted by 1-3 R 3a .

[0057] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R3 is selected from C 1-4 alkyl, the C 1-4 alkyl group is optionally substituted by 1-3 R 3a ; preferably R3 is selected from methyl optionally substituted by 1-3 R 3a .

[0058] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 3a is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino.

[0059] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 3a is independently selected from C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered heteroalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heteroalkyl, 6-10 membered aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered heteroalkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heteroalkyl, 6-10 membered aryl or 5-6 membered heteroaryl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered heteroalkyl, -O-3-6 membered cycloalkyl.

[0060] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 3a is independently selected from 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered heteroalkyl, -O-3-6 membered cycloalkyl.

[0061] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 3a is independently selected from pyrimidinyl or pyrazolyl, the pyrimidinyl or pyrazolyl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano, C1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3 to 6 membered hetero cycloalkyl, substituted by substituents of -O-3-6 membered cycloalkyl.

[0062] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R3 is selected from

[0063]

[0064]

[0065] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, R3 is selected from

[0066] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R3 is selected from

[0067] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered hetero cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl; said C 1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered hetero cycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl is optionally substituted by one or more R 4a substituents.

[0068] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered hetero cycloalkyl; said C 1-6 alkyl, 3-7 membered cycloalkyl, 3-7 membered hetero cycloalkyl is optionally substituted by 1-3 R 4a substituents.

[0069] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 4a is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino.

[0070] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 4a is independently selected from C 1-6 alkyl, -O-C 1-6alkyl, 3-6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 6-10-membered aryl or 5-6-membered heteroaryl, said C 1-6 alkyl, -O-C 1-6 alkyl, 3-6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 6-10-membered aryl or 5-6-membered heteroaryl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-3-6-membered cycloalkyl is substituted by the substituents.

[0071] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R 4a is independently selected from C 1-6 alkyl, -O-C 1-6 alkyl, 3-6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-3-6-membered cycloalkyl, -O-3-6-membered heterocycloalkyl, 6-10-membered aryl or 5-6-membered heteroaryl.

[0072] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, methyl, ethyl, -CH2-CH2-O-CH3, cyclobutyl, methylenecyclopropyl, cyclopentyl, benzyl, propyl.

[0073] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein X is selected from O.

[0074] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein X is selected from NH.

[0075] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0-4; preferably n is an integer selected from 0-3; more preferably n is an integer selected from 0-2; most preferably n is an integer selected from 0-1.

[0076] In some embodiments, a compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, wherein m is an integer selected from 0-3; more preferably m is an integer selected from 1-2; most preferably m is 1.

[0077] In a third aspect, the present disclosure also provides a compound of formula I' or a pharmaceutically acceptable salt thereof, which is

[0078]

[0079] R1, R2, R3, R4, R5, X, n, and m are as defined in Formula I.

[0080] In a fourth aspect, the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is

[0081]

[0082] In a fifth aspect, the present disclosure also provides an isotopically substituted compound of the compound as described in the first to fourth aspects. Preferably, the isotopic substitution is deuterium atom substitution.

[0083] In a sixth aspect, the present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound as described in the first to fourth aspects or a pharmaceutically acceptable salt thereof, or the isotopically substituted compound as described in the fifth aspect, and a pharmaceutically acceptable excipient.

[0084] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0085] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted compound. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted compound. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted compound. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted compound. In certain embodiments, the pharmaceutical composition contains 2% - 98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted compound.

[0086] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.1% - 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% - 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% - 98% of a pharmaceutically acceptable excipient.

[0087] In a seventh aspect, the present disclosure also provides the use of the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect in the preparation of a medicament for treating a disease related to NLRP3 activity.

[0088] The present disclosure also provides a method for preventing and / or treating a patient suffering from a disease related to NLRP3 activity, which comprises administering to the patient a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect.

[0089] The present disclosure also provides the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect for preventing or treating a disease related to NLRP3 activity.

[0090] The present disclosure also provides a method for preventing and / or treating a patient suffering from a disease related to NLRP3 activity, which comprises administering to the patient a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect.

[0091] Diseases related to NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0092] The present disclosure also provides the use of the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect in the preparation of a medicament for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0093] The present disclosure also provides the use of the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect in the preparation of a medicament for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0094] The present disclosure also provides the compound or a pharmaceutically acceptable salt thereof described in the first to fourth aspects, or the isotope-substituted product described in the fifth aspect or the pharmaceutical composition described in the sixth aspect for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0095] The present disclosure also provides a method for treating and / or preventing a patient with an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease, and / or an autoinflammatory disease by administering to the patient a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to the first to fourth aspects, or the isotope substitute according to the fifth aspect, or the pharmaceutical composition according to the sixth aspect. The inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases may specifically be selected from: autoinflammatory fever syndromes (such as cryopyrin-associated periodic syndromes), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis-related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, type I or type II diabetes and its complications (such as nephropathy, retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases), cardiovascular and metabolic-related disorders or diseases (such as reducing cardiovascular disease risk (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure, and hypertension), wound healing, scar formation, inflammatory skin diseases (such as acne, hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, cancer-related diseases / conditions (such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, colon cancer).

[0096] The compound or a pharmaceutically acceptable salt or a pharmaceutical composition thereof according to the present disclosure has certain NLPR3 inflammasome inhibitory activity, and the IC50 value of the inhibitory activity against the NLPR3 inflammasome is from 0.01 to 10 μM. The IC50 value of the inhibitory activity against the NLPR3 inflammasome of some compounds is from 0.01 to 1000 nM, the IC50 value of the inhibitory activity against the NLPR3 inflammasome of some compounds is from 0.01 to 500 nM, the IC50 value of the inhibitory activity against the NLPR3 inflammasome of some compounds is from 0.01 to 300 nM, the IC50 value of the inhibitory activity against the NLPR3 inflammasome enzyme of some compounds is from 0.01 to 200 nM, the IC50 value of the inhibitory activity against the NLPR3 inflammasome enzyme of some compounds is from 0.01 to 100 nM, the IC50 value of the inhibitory activity against the NLPR3 inflammasome enzyme of some compounds < 100 nM, and the IC50 value of the inhibitory activity against the NLPR3 inflammasome enzyme of some compounds < 50 nM. The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0097] 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or as a racemate. The optically pure form may be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0098] The optically active (R)- and (S)- isomers and D and L isomers may be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and the pure enantiomer is then recovered. In addition, the separation of enantiomers and diastereomers is generally accomplished by using chromatography employing a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of carbamates from amines).

[0099] In the chemical structure of the compounds of the present disclosure, the bond represents an unspecified configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or or may contain both and configurations. In the chemical structure of the compounds of the present disclosure, the bond does not specify the configuration, i.e., the configuration of the bond may be E or Z, or may contain both E and Z configurations.

[0100] 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, lactam-lactim isomerization. An example of the lactam-lactim equilibrium is between A and B shown below.

[0101]

[0102] All compounds in the present invention can be drawn in the form of A or B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0103] The present disclosure also includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced with atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl etc.

[0104] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position is understood to have a deuterium abundance greater than the natural abundance of deuterium (which is 0.015%) by at least 1000-fold (i.e., at least 10% deuterium incorporation). The deuterium in the exemplified compounds can have an abundance greater than the natural abundance of deuterium by at least 1000-fold, at least 2000-fold, at least 3000-fold, at least 4000-fold, at least 5000-fold, at least 6000-fold, or a higher abundance of deuterium. The present disclosure also includes various deuterated forms of the compound of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated borane, tetrahydrofuran solution of trideuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc.

[0105] "Optionally" or "optional" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally substituted with halogen or cyano C 1-6 alkyl" means that halogen or cyano can but does not have to be present, and this description includes the cases where the alkyl is substituted with halogen or cyano and the cases where the alkyl is not substituted with halogen and cyano.

[0106] Term Explanation:

[0107] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert biological activity.

[0108] "Pharmaceutically acceptable excipient" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the US Food and Drug Administration for use in humans or domestic animals.

[0109] As used herein, the term "effective amount" or "effective therapeutic amount" includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the disorder to be treated, the overall health of the patient, the method of administration and dosage, and the severity of side effects. The effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0110] "Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups having from 1 to 20 carbon atoms. Alkyl groups having from 1 to 6 carbon atoms are included. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof, etc. The alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, preferably with one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with halogen, hydroxy, nitro, cyano, or amino.

[0111] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, wherein the cycloalkyl ring contains from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl includes spiro, fused, and bridged cycloalkyl. The cycloalkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, preferably with one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted with halogen, hydroxy, nitro, cyano, or amino.

[0112] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents that contain from 3 to 20 ring atoms, wherein one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), provided that the ring moiety does not include -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains from 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, it contains from 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:

[0113] and so on.

[0114] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, where the ring attached to the parent structure is heterocycloalkyl, and non-limiting examples thereof include:

[0115] etc.

[0116] The heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, and the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0117] The term "alkoxy" means -O-(alkyl), where the alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. The alkoxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, and the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0118] The "monovalent group" means that a compound "formally" eliminates a monovalent atom or group. The "subunit" means that a compound "formally" eliminates two monovalent or one divalent atom or atomic group formed.

[0119] The term "alkylene" represents the remaining part after removing 2 hydrogen atoms from an alkane molecule, including straight-chain and branched-chain alkylene groups having 1 to 20 carbon atoms. Non-limiting examples of alkylene having 1 to 6 carbon atoms include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-). Unless otherwise specified, the alkylene may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available connection point, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0120] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyloxy", "cycloalkylene", "heterocycloalkylene" are the same as those of "alkylene".

[0121] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring, and non-limiting examples thereof include:

[0122]

[0123] Aryl can be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 3- to 8-membered cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally substituted with one or more selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0124] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6- to 12-membered, more preferably 5- or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, etc.

[0125] The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring, and non-limiting examples thereof include:

[0126]

[0127] Heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0128] The term "spiro" refers to a compound in which two rings share a single atom. Non-limiting examples of spiroalkyl groups include:

[0129]

[0130] The term "fused ring" refers to a compound formed by the fusion of two or more rings through sharing of two adjacent atoms. Non-limiting examples of fused cycloalkyl groups include:

[0131]

[0132] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0133]

[0134] The term "hydroxy" refers to the -OH group.

[0135] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0136] The term "cyano" refers to -CN.

[0137] The term "amino" refers to -NH2.

[0138] The term "nitro" refers to -NO2.

[0139] The term "oxo" refers to the =O substituent.

[0140] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. When the substituent is a ketone or oxo (i.e., =O), then two (2) hydrogens on the atom are replaced. Detailed embodiments

[0141] The present disclosure will be further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0142] Example

[0143] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is in 10 -6Given in units of (ppm). The NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0144] The MS measurements were performed using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

[0145] The HPLC measurements were performed using a Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or an Agilent 1200 LC high performance liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column or Gilson-281 Waters Xbridge 150*25mm column or Gilson-281 Waters Xbridge 150*25mm column or Gilson-281 Phenomenex luna C18 250*50mm column).

[0146] The chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um columns;

[0147] The thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15mm - 0.2mm, and the specifications of the silica gel plates used for thin layer chromatography separation and purification of products were 0.4mm - 0.5mm.

[0148] Column chromatography generally uses silica gel with a mesh size of 100 - 200, 200 - 300, or 300 - 400 from Yantai Huanghai Silica Gel as the carrier.

[0149] For chiral preparative columns, DAICEL CHIRALPAK IC (250mm * 30mm, 10um) or Phenomenex - Amylose - 1 (250mm * 30mm, 5um) is used.

[0150] The CombiFlash rapid preparative instrument uses Combiflash Rf150 (TELEDYNE ISCO).

[0151] The average inhibitory rate of kinases and the IC 50 value is measured using a NovoStar microplate reader (manufactured by BMG Labtech GmbH, Germany).

[0152] The known starting materials of the present disclosure can be synthesized by adopting or following methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, etc.

[0153] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0154] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

[0155] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

[0156] For the catalytic hydrogenation reaction, a Parr 3916EKX hydrogenator and a Qinglan QL - 500 hydrogen generator or an HC2 - SS hydrogenator are used.

[0157] For the hydrogenation reaction, it is usually evacuated, filled with hydrogen, and this operation is repeated 3 times.

[0158] The microwave reaction uses a CEM Discover - S 908860 microwave reactor.

[0159] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0160] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃ - 30℃.

[0161] The reaction process in the examples was monitored by thin-layer chromatography (TLC). The eluent used for the reaction, the eluent system for column chromatography for purifying the compound, and the eluent system for thin-layer chromatography were adjusted according to the polarity of the compound by adjusting the volume ratio of the solvents. A small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0162] Example 1

[0163] (R)-Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-((((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)oxy)propionate

[0164]

[0165] First step:

[0166] At room temperature, compound 1a (23.5 g, 176.4 mmol), triethylamine (31.9 mL, 229.4 mmol), and dichloromethane (150 mL) were added to a 250 mL reaction flask. Stir until dissolved, and acetic anhydride (19.1 mL, 202.9 mmol) was added dropwise at 0 °C. The reaction solution was stirred at 0 °C for 0.1 h and then at room temperature for 1.4 h. Water (25 mL) was added to the reaction solution, and it was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an elution system (SiO2, 20 - 40% ethyl acetate / petroleum ether) to obtain the title product 1b (24.2 g, yield: 78.3%).

[0167] 1 1H NMR (400 MHz, CDCl3) δ 7.73 (d, 1H), 7.15 (t, 1H), 7.03 (d, 1H), 2.96 (t, 2H), 2.82 (t, 2H), 2.19 (s, 3H) 2.08 - 2.15 (m, 2H).

[0168] LC-MS m / z (ESI): 176.3 (M + H) + .

[0169] Second step:

[0170] At room temperature, compound 1b (5 g, 28.5 mmol) and toluene (40 mL), p-toluenesulfonic acid (3.0 g, 15.7 mmol), and a suspension of palladium acetate (0.30 g, 1.3 mmol) were added to a 100-mL single-necked flask and stirred for 0.5 h. N-Bromosuccinimide (4.3 g, 24.3 mmol) was added. Stirring was continued for 2 h. A saturated aqueous solution of sodium thiosulfate (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3), washed with saturated brine (20 mL×1), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure at 40 °C, and the residue was purified by silica gel chromatography using an elution system (SiO2, 10%-50% ethyl acetate / petroleum ether) to obtain compound 1c (4 g, yield: 78.3%).

[0171] 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, 1H), 7.09 (s, 1H), 7.00 (d, 1H), 2.85 - 2.92 (m, 4H), 2.22 (s, 3H), 2.03 - 2.11 (m, 2H).

[0172] LC-MS m / z (ESI): 254.1 (M + H) + 。

[0173] Step 3:

[0174] At room temperature, compound 1c (16 g, 62.96 mmol), ethanol (60 mL), and concentrated hydrochloric acid (36%-38%) (90 mL, 1080 mmol) were added to a 500-mL reaction flask. The mixture was stirred until dissolved and then stirred at 80 °C for 36 h. The reaction mixture was concentrated under reduced pressure at 60 °C to obtain compound 1d (18 g). The crude product was used directly in the next step without purification.

[0175] LC-MS m / z (ESI): 212.2 (M + H) + 。

[0176] Step 4:

[0177] At room temperature, compound 1d (6 g, 19.8 mmol), 1e (3.6 g, 23.8 mmol), potassium carbonate (8.8 g, 63.4 mmol), dioxane (10 mL) and water (10 mL) were added to a 250 mL single-necked flask, and the mixture was stirred for 15 minutes under nitrogen protection. [1,1-Bis(diphenylphosphino)ferrocene] dichloropalladium (0.8 g, 1.0 mmol) was added, and the reaction solution was stirred at 80 °C for 36 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3), washed with saturated brine (20 mL × 1), and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure at 40 °C. The residue was purified by silica gel chromatography with an elution system (SiO2, 15% ethyl acetate / petroleum ether) to obtain compound 1f (3.1 g, yield: 45.5%).

[0178] 1 H NMR (400 MHz, CDCl3) δ 8.22 (dd, 1H), 7.01 (dd, 1H), 6.98 (d, 1H), 6.87 - 6.86 (m, 1H), 6.77 (d, 1H), 3.99 (s, 3H), 3.50 - 3.91 (m, 2H), 2.97 (t, 2H), 2.77 (t, 2H), 2.13 - 2.21 (m, 2H).

[0179] LC-MS m / z (ESI): 241.3 (M + H) + 。

[0180] Step 5:

[0181] At room temperature, compound 1f (1 g, 4.2 mmol) and tetrahydrofuran (15 mL) were added to a 50 mL single-necked flask. The mixture was stirred until dissolved, cooled to 0 °C in an ice-water bath, and triethylamine (1.2 g, 11.9 mmol) and triphosgene (1.2 g, 4.0 mmol) were added. The mixture was stirred at room temperature for 0.5 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1g (0.8 g). The crude product was used directly in the next step without purification.

[0182] LC-MS m / z (ESI): 267.2 (M + H) + 。

[0183] Step 6:

[0184] Add compound 1i (1.5 g, 16.1 mmol), compound 1j (0.8 g, 8.1 mmol) and ethanol (6 mL) into a 20 mL microwave tube, then tighten the bottle cap for sealing. Place the reaction on a microwave instrument and carry out microwave reaction at 100 °C for 3 hours. Concentrate the reaction solution at 40 °C. Purify the crude product by reverse-phase column (system: 0.2% formic acid / acetonitrile / water) to obtain product 1h (0.7 g, yield: 22.8%), which is a yellow oily liquid.

[0185] 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.78 (s, 1H), 4.54 - 4.49 (m, 3H), 4.31 - 4.25 (m, 2H), 1.33 - 1.29 (m, 3H).

[0186] LC-MS m / z (ESI): 210.0 (M + H) + 。

[0187] Step 7:

[0188] At room temperature, add compound 1g (87 mg, 0.41 mmol) and N,N-dimethylformamide (2 mL) into a 9 mL single-neck flask. Stir until dissolved. Add cuprous chloride (37 mg, 0.38 mmol) and 1j (100 mg, 0.38 mmol) in sequence. Stir at room temperature for 16 hours, filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the obtained crude product by high performance liquid chromatography (chromatographic column: Gilson-281, Xbridge 150*25 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: 0 - 10 min 50 - 70% B; flow 25 ml / min) to obtain compound 1 (9.6 mg, yield: 6.2%).

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 - 8.94 (m, 1H) 8.12 (d, 1H), 7.99 (s, 1H), 7.26 (d, 1H), 7.15 (d, 1H), 6.91 (d, 1H), 6.73 (s, 1H), 5.28 (s, 1H), 4.59 (s, 2H), 4.13 (q, 2H), 3.90 (s, 4H), 2.97 (t, 2H), 2.73 - 2.79 (m, 2H) 2.04 (m, 2H), 1.17 (t, 3H).

[0190] LC-MS m / z (ESI): 476.1 (M + H) + 。

[0191] Example 2

[0192] (R)-Ethyl 2-(3-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)ureido)-3-(pyrimidin-2-yl)propionate

[0193]

[0194] Step 1:

[0195] Add zinc powder (3.0 g, 45.6 mmol) into a 250 mL three-necked flask, then add a piece of iodine (23 mg), and then add N,N-dimethylformamide (30 mL). Dropwise add a solution of compound 2a (10 g, 30.4 mmol) in N,N-dimethylformamide (30 mL). The dropping takes 5 minutes. After dropping, no obvious phenomenon is observed. The temperature of the system drops from 28 °C to 25 °C. After stirring for another 10 minutes, the temperature of the system starts to rise and naturally warms up to 45 °C within 5 minutes, and then the temperature starts to slowly drop to 28 °C. The system is stirred at this temperature for 3 hours. The crude title product 2b (73 mL) is obtained, and the product is directly used for the next reaction without purification.

[0196] Step 2:

[0197] Add a magnetic stir bar into a 100 mL three-necked flask, change nitrogen three times, add 2b (73.1 mL, 31.4 mmol) with a syringe, a solution of compound 2-bromopyrimidine (5000 mg, 31.4 mmol) in N,N-dimethylformamide (10 mL), tris(dibenzylideneacetone)dipalladium(0) (500 mg, 0.55 mmol), and 2-(dicyclohexylphosphino)-2',6'-dimethoxybiphenyl (500 mg, 1.2 mmol) with a syringe as well. Heat to 80 °C and react overnight (~16 hours). Concentrate to dryness under a vacuum pump. Dissolve with methanol and filter. The filtrate is evaporated to dryness. The filtered solid is the palladium catalyst and salts. The residue after evaporation is purified by column chromatography (ethyl acetate:petroleum ether 0 to 100%) to obtain compound 2c (2000 mg, 22.6%).

[0198] 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, 2H), 7.91 (s, 1H), 7.19 (t, 1H), 5.87 (d, 1H), 4.87 - 4.82 (m, 1H), 3.71 (s, 3H), 3.61 - 3.57 (m, 1H), 3.48 - 3.44 (m, 1H), 1.41 (s, 9H).

[0199] LC-MS m / z (ESI): 226.0 (M + H) + 。

[0200] Step 3:

[0201] At room temperature, add compound 2c (300 mg, 1.1 mmol) and ethanol (22.5 mL) to a 50-mL single-necked flask. Stir until dissolved, then add concentrated hydrochloric acid (36%-38%) (4.5 mL, 145.6 mmol). Stir the reaction mixture at 100 °C for 24 hours. Concentrate under reduced pressure at 40 °C to obtain the hydrochloride salt of compound 2d (150 mg). The crude product can be directly used in the next step without purification.

[0202] LC-MS m / z (ESI): 196.1 (M+H) + 。

[0203] Step 4:

[0204] At room temperature, add compound 2d (50 mg, 0.26 mmol) and tetrahydrofuran (1.5 mL) to a 9-mL single-necked flask. Stir until dissolved, then successively add 1g (68 mg, 0.26 mmol) and triethylamine (0.07 mL, 0.5 mmol). Stir at room temperature for 16 hours, filter the reaction mixture, concentrate the filtrate under reduced pressure, and purify the obtained crude product by high-performance liquid chromatography (column: Gilson-281, Phenomenex luna C18 150*25 mm, 5 μm; mobile phase: aqueous phase (10 mM 0.225% formic acid) and acetonitrile, gradient ratio: 0-10 min 35-65% B; flow rate 25 mL / min) to obtain compound 2 (19.8 mg, yield: 16.8%).

[0205] 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 2H), 8.07 (d, 1H), 7.83 (s, 1H), 7.39 (t, 1H), 7.17 (d, 1H), 7.09 (d, 1H), 6.86 (d, 1H), 6.70 (s, 1H), 6.52 (d, 1H), 4.73-4.90 (m, 1H), 4.05 (q, 2H), 3.84 (s, 3H), 3.27 (d, 2H), 2.90 (t, 2H), 2.67-2.72 (m, 2H), 1.97 (m, 2H), 1.09 (t, 3H).

[0206] LC-MS m / z (ESI): 462.2 (M+H) + 。

[0207] Biological evaluation

[0208] The following test examples are used to further describe and explain the present disclosure, but these test examples do not mean to limit the scope of the present disclosure.

[0209] Test Example 1 Inhibitory Experiment on NLRP3 Inflammasome Activity in THP-1 Cells

[0210] 1. Experimental Materials

[0211]

[0212]

[0213] 2. Experimental Procedures

[0214] Resuspend THP-1 cells in cell culture medium containing RPMI1640, 10% FBS, and 1% P / S, and adjust the cell density to 1×10 6 / mL. Spread 10 mL of THP-1 cells in a 10-cm-diameter cell culture dish, and add PMA for differentiation treatment. The final concentration of PMA is 10 ng / mL. After incubating the cells in a cell culture incubator at 37°C and 5% carbon dioxide for 24 hours, take out the culture dish, remove the supernatant and non-adherent cells, digest the cells and resuspend them, and inoculate them in a 96-well plate at a density of 10 5 cells / well. Place the cell plate in the incubator and incubate overnight. After 12 hours, take it out, remove the culture medium, add 50 μL of fresh medium containing 200 ng / mL LPS, and incubate it in a cell culture incubator at 37°C and 5% carbon dioxide for 3.5 hours. Meanwhile, prepare a compound stock solution with a concentration of 30 mM in DMSO in a test tube, then use DMSO as the solvent, dilute the sample according to the need in a gradient manner, and finally dilute it 333 times in the medium. Transfer 50 μL of the sample to be tested into each well of the 96-well plate, and incubate it in a cell culture incubator at 37°C and 5% carbon dioxide for 0.5 hour. Take out the 96-well plate, and then add 50 μL of medium containing 15 μM Nigericin to each well, and incubate it in a cell culture incubator at 37°C and 5% carbon dioxide for 1 hour. Take out the cell plate, centrifuge it and take the supernatant, and operate according to the instructions of the ELISA Kit to detect IL-1β. Add reagents to the cells in the cell plate, and operate according to the instructions of the CellTiter-Glo Luminescent Cell Viability Assay Kit to detect cell viability.

[0215] Table 1

[0216] Number <![CDATA[IC 50 > Example 1 B Example 2 A

[0217] Note: A < 10 μM; 10 μM

Claims

1. A compound or a pharmaceutically acceptable salt thereof, 2. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable excipient.

3. Use of the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, or the pharmaceutical composition as claimed in claim 2, in the manufacture of a medicament for treating a disease associated with NLRP3 activity.

4. The use according to claim 3, wherein the disease associated with NLRP3 activity is selected from inflammasome-related diseases, immune diseases and inflammatory diseases.

5. The use according to claim 3, wherein the disease associated with NLRP3 activity is selected from autoimmune diseases and autoinflammatory diseases.

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