A class of compounds containing indacen and their medical uses

Abstract

The present disclosure relates to a class of compounds containing indacenophane and their medical uses. Specifically, there are provided compounds represented by Formula I or their pharmaceutically acceptable salts. Such compounds or their pharmaceutically acceptable salts 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 a class of compounds containing indacen and their medical uses. 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 "pyogenic domain-containing protein 3" (Inoue et al, Immunology, 2013, 139, 11 - 18). This gene encodes a protein that contains a pyridine 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 associated with multiple types of diseases, including: inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Therefore, there is a need 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] n and m independently selected from integers of 0 - 3;

[0007] j selected from integers of 0 - 6;

[0008] X 1 selected from N or CR 6 ; R 6 selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6 - 10-membered aryl, 3 - 6-membered heteroalkyl, 5 - 6-membered heteroaryl, acyl, the C1-6 Alkyl, C 1-6 Alkoxy, 6-10 membered aryl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl optionally substituted by 1-3 R 5e ;

[0009] Ring A is selected from 4-6 membered nitrogen-containing heteroalkyl, 5-6 membered nitrogen-containing heteroaryl;

[0010] R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl, the C 1-6 alkyl, C 1-6 alkoxy, 6-10 membered aryl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl optionally substituted by 1-3 R 5a ;

[0011] R 2 and R 3 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl, -COOR 5b ; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 6-10 membered aryl, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl optionally substituted by 1-3 R 5c ;

[0012] R 4 is independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6A cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 6-membered heteroalkyl group, a 5- to 6-membered heteroaryl group, an acyl group optionally substituted with 1 to 3 R 5d substituted;

[0013] R 5a 、R 5c 、R 5d 、R 5e are independently selected from halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl, 6- to 10-membered aryl;

[0014] R 5b is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl; the C 1-6 alkyl, C 3-6 cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, hydroxy, cyano, amino, nitro.

[0015] In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, ring A is selected from 4- to 6-membered nitrogen-containing heteroalkyl; preferably ring A is selected from 4- to 6-membered nitrogen-containing heteroalkyl containing 1 to 3 heteroatoms, and the heteroatoms are selected from oxygen atoms or nitrogen atoms;

[0016] The following compound structures are not within the scope of protection:

[0017]

[0018] In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, ring A is selected from piperidine, pyrrolidine, azetidine, and preferably ring A is selected from azetidine.

[0019] In a second aspect, the present disclosure also provides a compound of formula I-a, I-b, I-c or a pharmaceutically acceptable salt thereof,

[0020]

[0021] R 1 、R 2 、R 3 、R 4 、X 1 、n, m, j are as defined in formula I.

[0022] In some embodiments, in the compound of formula I, I-a, I-b, I-c or a pharmaceutically acceptable salt thereof, R2 Selected from halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, acyl, -COOR 5b ; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl is optionally substituted by 1-3 R 5c ;

[0023] R 3 is selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, acyl, -COOR 5b ; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl is optionally substituted by 1-3 R 5c ;

[0024] R 5b is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl; the C 1-6 alkyl, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, cyano, amino, nitro.

[0025] In some embodiments, in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 2 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 6-10-membered aryl, 5-6-membered heteroaryl, acyl, -COOR 5b ; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6A cycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, optionally substituted by 1 to 3 Rs 5c ;

[0026] Preferably, R 2 is selected from methyl, methoxy, ethyl, cyano, propyl, ethoxy, nitro, benzyl, a 5- to 6-membered heteroaryl group, -COOR 5b ; the methyl, methoxy, ethyl, propyl, ethoxy, benzyl, and 5- to 6-membered heteroaryl group are optionally substituted by 1 to 3 Rs 5c ;

[0027] R 5b , R 5c is as defined in Formula 1.

[0028] In some embodiments, in the compounds of Formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 2 is selected from halogen, nitro, cyano, hydroxy, amino, -COOR 5b ; R 5b is as defined in Formula I.

[0029] In some embodiments, in the compounds of Formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 3 is selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 6- to 10-membered aryl group, a 5- to 6-membered heteroaryl group, -COOR 5b ; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, a 6- to 10-membered aryl group, and a 5- to 6-membered heteroaryl group are optionally substituted by 1 to 3 Rs 5c ; R 5b , R 5c is as defined in Formula I.

[0030] In some embodiments, in the compounds of Formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 3 is selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, methyl, methoxy, ethyl, cyano, propyl, ethoxy, nitro, benzyl, a 5- to 6-membered heteroaryl group, -COOR 5b ; the methyl, methoxy, ethyl, propyl, ethoxy, benzyl, and 5- to 6-membered heteroaryl group are optionally substituted by 1 to 3 Rs 5c ; R 5b , R 5c is as defined in Formula I.

[0031] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts 3 is selected from hydrogen, methyl, methoxy, ethyl, cyano, propyl, ethoxy, nitro, benzyl, 5-6 membered heteroaryl, -COOR 5b ; the methyl, methoxy, ethyl, propyl, ethoxy, benzyl, 5-6 membered heteroaryl is optionally substituted with 1-3 R 5c ;

[0032] R 5b 、R 5c is as defined in formula I.

[0033] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts 3 is selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, -COOR 5b ; R 5b is as defined in formula I.

[0034] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts 5b is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; the C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl is optionally substituted with 1-3 substituents selected from halogen, hydroxy, cyano, amino, nitro;

[0035] Preferably, R 5b is selected from methyl, ethyl, propyl, methylenecyclopropyl, cyclopropyl, benzyl, and the methyl, ethyl, propyl, methylenecyclopropyl, cyclopropyl, benzyl is optionally substituted with 1-3 substituents selected from halogen, hydroxy, cyano, amino, nitro.

[0036] In some embodiments, in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 5c is selected from halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered aryl;

[0037] Preferably, R 5cSelected from halogen, hydroxy, cyano, amino, nitro, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl.

[0038] In some embodiments, in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 5c Selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, 6-10 membered aryl;

[0039] Preferably, R 5c Selected from methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl.

[0040] In some embodiments, in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 5c Selected from halogen, hydroxy, cyano, amino, nitro.

[0041] In some embodiments, in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 2 Selected from halogen, methyl, ethyl, cyano, methoxy, benzyl, pyridyl, benzyl, methylene pyrimidine, -COOEt, -COOPr; the methyl, ethyl, cyano, methoxy, benzyl, pyridyl, benzyl, methylene pyrimidine, -COOEt, -COOPr are optionally substituted by 1-2 groups selected from halogen, cyano, hydroxy, nitro;

[0042] Preferably, R 2 Selected from -COOEt, COOPr; the -COOEt, -COOPr are optionally substituted by 1-2 groups selected from halogen, cyano, hydroxy, nitro.

[0043] In some embodiments, in the compounds of formula I, I-a, I-b, I-c or their pharmaceutically acceptable salts, R 3 Selected from hydrogen, halogen, methyl, ethyl, cyano, methoxy, benzyl, pyridyl, benzyl, methylene pyrimidine, -COOEt, -COOPr; the methyl, ethyl, cyano, methoxy, benzyl, pyridyl, benzyl, methylene pyrimidine, -COOEt, -COOPr are optionally substituted by 1-2 groups selected from halogen, cyano, hydroxy, nitro.

[0044] In a third aspect, the present disclosure also provides a compound of formula I-d or a pharmaceutically acceptable salt thereof,

[0045]

[0046] R 1 、R 2 、R 3 、R 4 、X 1 、n, m, and j are defined as described in Formula I.

[0047] In a fourth aspect, the present disclosure also provides a compound as shown in I-e or a pharmaceutically acceptable salt thereof,

[0048]

[0049] R 1 、R 2 、R 3 、R 4 、X 1 、n, m, and j are defined as described in Formula I.

[0050] In some embodiments, X in the compounds or pharmaceutically acceptable salts thereof as shown in Formula I, I-a, I-b, I-c, I-d, and I-e 1 is selected from N.

[0051] In some embodiments, X in the compounds or pharmaceutically acceptable salts thereof as shown in Formula I, I-a, I-b, I-c, I-d, and I-e 1 is selected from CR 6 ; R 6 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10-membered aryl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, acyl, and the C 1-6 alkyl, C 1-6 alkoxy, 6-10-membered aryl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, acyl are optionally substituted by 1-3 R 5e ;

[0052] Preferably, X 1 is selected from CR 6 ; R 6 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, methyl, methoxy, ethyl, ethoxy, phenyl, benzyl, and the methyl, methoxy, ethyl, ethoxy, phenyl, benzyl are optionally substituted by 1-3 R 5e ;

[0053] R 5e is defined as in Formula I.

[0054] In some embodiments, X in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts 1 is selected from CR 6 ; R 6 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy.

[0055] In some embodiments, X in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts 1 is selected from CR 6 ; R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, 6-10 membered aryl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, acyl is optionally substituted by 1-3 R 5e ;

[0056] Preferably X 1 is selected from CR 6 ; R 6 is selected from hydrogen, methyl, methoxy, ethyl, ethoxy, phenyl, benzyl, wherein the methyl, methoxy, ethyl, ethoxy, phenyl, benzyl is optionally substituted by 1-3 R 5e ;

[0057] R 5e is as defined in formula I.

[0058] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts 5e is independently selected from halogen, hydroxy, cyano, amino, nitro, methyl, ethyl, methoxy, ethoxy, phenyl;

[0059] Preferably R 5e is independently selected from halogen, hydroxy, cyano, amino, nitro.

[0060] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts 5e is independently selected from halogen, hydroxy, cyano, amino, nitro.

[0061] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts 5e is independently selected from methyl, ethyl, methoxy, ethoxy, phenyl.

[0062] In some embodiments, R in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, acyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, 6-10 membered aryl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, acyl is optionally substituted by 1-3 R 5a ;

[0063] Preferably, R 1 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl is optionally substituted by 1-3 R 5a ; More preferably, R 1 is selected from hydrogen;

[0064] R 5a is as defined in formula I.

[0065] In some embodiments, in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts, R 4 is independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, acyl; wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, acyl is optionally substituted by 1-3 R 5d ;

[0066] Preferably, R 4Independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, methylenecyclopropyl, phenyl, benzyl; the methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, methylenecyclopropyl, phenyl, benzyl are optionally substituted by 1-3 R 5d substituted;

[0067] R 5d as defined in formula I.

[0068] In some embodiments, in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts, R 4 is independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, acyl; the acyl is optionally substituted by 1-3 R 5d substituted;

[0069] R 5d as defined in formula I.

[0070] In some embodiments, in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts, R 4 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 6-10 membered aryl, 3-6 membered heteroalkyl, 5-6 membered heteroaryl are optionally substituted by 1-3 R 5d substituted;

[0071] R 5d as defined in formula I.

[0072] In some embodiments, in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts, n and m are independently selected from integers of 0-3; preferably n and m are independently selected from integers of 1-3; more preferably n and m are independently selected from integers of 1-2; most preferably n and m are independently selected from 1.

[0073] In some embodiments, in the compounds of formula I, I-a, I-b, I-c, I-d, I-e or their pharmaceutically acceptable salts, j is selected from integers of 0-6; preferably j is selected from integers of 0-4; more preferably j is selected from integers of 0-2.

[0074] Fifth aspect, the present disclosure provides a compound as shown below or a pharmaceutically acceptable salt thereof

[0075]

[0076] Sixth aspect, the present disclosure also discloses an isotope substitute of the compound as shown in the first aspect to the fifth aspect. Preferably, the isotope substitution is deuterium atom substitution.

[0077] Seventh aspect, the present disclosure also provides a pharmaceutical composition comprising the compound as described in the first aspect to the fifth aspect or a pharmaceutically acceptable salt thereof, or the isotope substitute as described in the sixth aspect and a pharmaceutically acceptable excipient.

[0078] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0079] 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. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutical composition contains 2% - 98% of the aforementioned compound or its pharmaceutically acceptable salt.

[0080] Eighth aspect, the present disclosure provides a method for preventing and / or treating a patient with an NLRP3-related disorder by administering to the patient a therapeutically effective amount of the compound as described in the first aspect to the fifth aspect or a pharmaceutically acceptable salt thereof, the isotope substitute as described in the sixth aspect, or the pharmaceutical composition as described in the seventh aspect.

[0081] Ninth aspect, the present disclosure provides a method for preventing and / or treating 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 as described in the first aspect to the fifth aspect or a pharmaceutically acceptable salt thereof, the isotope substitute as described in the sixth aspect, or the pharmaceutical composition as described in the seventh aspect.

[0082] The present disclosure also provides the use of the compound as described in the first aspect to the fifth aspect or a pharmaceutically acceptable salt thereof, the isotope substitute as described in the sixth aspect, or the pharmaceutical composition as described in the seventh aspect in the preparation of a drug for preventing and / or treating an NLRP3-related disorder.

[0083] The present disclosure also provides the use of the compound or its pharmaceutically acceptable salt as described in the first aspect to the fifth aspect, the isotope substitute as described in the sixth aspect, or the pharmaceutical composition as described in the seventh aspect in the preparation of a drug for preventing and / or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0084] The present disclosure also provides a method for treating and / or preventing a patient with an inflammasome-related disease, immune disease, inflammatory disease, autoimmune disease, and / or autoinflammatory disease, which comprises administering to the patient a therapeutically effective amount of the aforementioned compound or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition. 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 infections, acute injuries, 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 artery 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, diseases / conditions related to cancer (such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, colon cancer).

[0085] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0086] 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.

[0087] 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 recovered. In addition, the separation of enantiomers and diastereomers is generally accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (such as formation of carbamates from amines).

[0088] In the chemical structure of the compounds described in 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 may simultaneously include both configurations. In the chemical structure of the compounds described in the present disclosure, the bond does not specify a configuration, i.e., it may be the Z configuration or the E configuration, or may simultaneously include both configurations.

[0089] Although all of the above structural formulas are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotamers, geometric isomers, diastereoisomers, racemates, and enantiomers.

[0090] Tautomers are structural isomers of organic compounds that are readily interconvertible by a chemical reaction called tautomerization. Such reactions often result in the formal migration of a hydrogen atom or proton, accompanied by the conversion of a single bond and an adjacent double bond. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0091]

[0092] All compounds in the present disclosure can be drawn in the form of A or B. All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0093] The compounds described in the present disclosure, or their pharmaceutically acceptable salts, or any isotopically labeled derivatives of their isomers, are covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be respectively replaced by isotopes 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I, etc. Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood to have a deuterium abundance greater than 3000 times the natural abundance of deuterium (which is 0.015%), i.e., at least 45% deuterium incorporation.

[0094] 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 refer to relevant literature to synthesize the deuterated form of the compound of formula (I). 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 tri-deuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc.

[0095] "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 by halogen or cyano C 1 -C 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 by halogen or cyano and the cases where the alkyl is not substituted by halogen and cyano.

[0096] Glossary of Terms:

[0097] "Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and thereby exert biological activity.

[0098] "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.

[0099] "Effective amount" or "effective therapeutic amount" as described in the present disclosure includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. The effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may 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 may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0100] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having 1 to 20 carbon atoms. Alkyl groups having 1 to 6 carbon atoms. 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 may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8The cycloalkenyloxy group, 6- to 10-membered aryl or heteroaryl group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0101] "Alkenyl" includes branched and straight-chain alkenes having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups. For example, "C 2-6 alkenyl" represents an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0102] "Alkynyl" includes branched and straight-chain alkynyl groups having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups, or if a specific number of carbon atoms is specified, it means that particular number. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.

[0103] The term "cycloalkyl" or "carbocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls. The cycloalkyl can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.

[0104] The cycloalkyl ring can be fused to an aryl or heteroaryl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl can be optionally substituted or unsubstituted, and 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 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C3-8 The cycloalkenyloxy group, 6- to 10-membered aryl or heteroaryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano.

[0105] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group 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, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, and the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxyl, oxo, nitro, and cyano.

[0106] The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, where 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), but does not include the ring moieties of -O-O-, -O-S-, or -S-S-. The remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl includes spiro, fused, and bridged heterocycloalkyl. Non-limiting examples of "heterocycloalkyl" include:

[0107]

[0108]

[0109] and so on.

[0110] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring connected to the parent structure is a heterocycloalkyl ring, and non-limiting examples thereof include:

[0111] etc.

[0112] 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, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, and the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl are optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.

[0113] The term "aryl" refers to a 6- to 14-membered all-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 may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0114]

[0115] The aryl may 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, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, and the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8The cycloalkenyloxy group, 6- to 10-membered aryl or heteroaryl group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0116] 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. The heteroaryl group 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, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, and the like.

[0117] The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples thereof include:

[0118]

[0119] The heteroaryl group 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, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl group, where the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl group is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, and cyano.

[0120] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where the alkyl is defined as above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group 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, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 6- to 10-membered aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are as defined for "alkoxy" above.

[0121] The term "hydroxy" refers to the -OH group.

[0122] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0123] The term "cyano" refers to -CN.

[0124] The term "nitro" refers to -NO 2 .

[0125] The term "oxo" refers to the ═O substituent.

[0126] "Optionally" or "optional" means that the subsequent described event or circumstance may but need not occur, and this description includes the case where the event or circumstance occurs or does not occur. For example, "optionally substituted by halogen or cyano C 1-6 alkyl" means that halogen or cyano may but need not be present, and this description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano. Detailed embodiments

[0127] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0128] Example

[0129] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic resonance instrument, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS).

[0130] For the determination of MS, a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer is used.

[0131] For the determination of HPLC, a Shimadzu LC-20A systems, a Shimadzu LC-2010HT series or an Agilent 1200LC high performance liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18

[0132] 2.1*30mm chromatographic column) is used.

[0133] For chiral HPLC analysis and determination, Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3

[0134] 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 chromatographic columns are used;

[0135] For thin layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used in thin layer chromatography (TLC) are 0.15mm - 0.2mm, and the specifications of the silica gel plates used for thin layer chromatography separation and purification of products are 0.4mm - 0.5mm.

[0136] For column chromatography, silica gels of 100 - 200 mesh, 200 - 300 mesh or 300 - 400 mesh from Yantai Huanghai are generally used as carriers.

[0137] For chiral preparative columns, DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um) are used.

[0138] For the CombiFlash rapid preparator, Combiflash Rf150 (TELEDYNE ISCO) is used.

[0139] Determination of the average kinase inhibition rate and IC 50 value was performed using a NovoStar microplate reader (BMG Labtech, Germany).

[0140] The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals, etc.

[0141] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0142] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0143] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0144] The pressure hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0145] The hydrogenation reaction usually involves evacuating, filling with hydrogen, and repeating the operation 3 times.

[0146] The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

[0147] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0148] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0149] The progress of the reactions in the examples was monitored by thin-layer chromatography (TLC). For the developing agent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing agent system of thin-layer chromatography, the volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0150] Example 1

[0151] Ethyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-2-carboxylate

[0152] ethyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-2-carboxylate

[0153]

[0154] At 10 °C, 1A (100 mg, 0.577 mmol), triethylamine (200 mg, 1.98 mmol) and tetrahydrofuran (10 mL) were successively added to a 25 mL three-necked flask. Stir until dissolved, and add triphosgene (59 mg, 0.20 mmol). Stir at 70 °C for 1 hour, cool to room temperature, and then add ethyl azetidine-2-carboxylate (212 mg, 0.646 mmol). Stir at 10 °C for 3 hours, add water (30 mL), and extract with ethyl acetate (20 mL × 2). Wash with saturated brine (15 mL × 1) and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and purify the residue by column chromatography (SiO2, 0 - 30% ethyl acetate / petroleum ether) to obtain Compound 1 (50 mg).

[0155] 1 H NMR(400MHz,CDCl 3 )δ7.07(br s,1H),6.95(s,1H),4.76(t,J=8.0Hz,1H),4.35 - 4.24(m,2H),4.04 - 3.98(m,1H),3.79 - 3.74(m,1H),2.91 - 2.75(m,8H),2.52 - 3.47(m,2H),2.14 - 2.00(m,4H),1.33(t,J=7.2Hz,3H).LC-MS:m / z:329.2(M + H) + .

[0156] Example 2

[0157] ethyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-3-carboxylate

[0158] ethyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-3-carboxylate

[0159]

[0160] Using a synthetic method similar to that of Example 1, ethyl azetidine-2-carboxylate was replaced with ethyl piperidine-3-carboxylate to obtain the title compound 2.

[0161] 1 H NMR(400MHz,CDCl 3 )δ6.92(s,1H),6.58(s,1H),4.24 - 4.15(m,2H),3.69 - 3.66(m,2H),3.58 - 3.53(m,1H),3.39 - 3.34(m,1H),2.89 - 2.70(m,8H),2.63 - 2.60(m,1H),2.10 - 1.94(m,6H),1.62 - 1.57(m,2H),1.28(t,J=7.2Hz,3H).LC - MS:m / z:357.3(M + H) + .

[0162] Example 3

[0163] ethyl 1 - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)azetidine - 3 - carboxylate

[0164] ethyl 1 - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)azetidine - 3 - carboxylate

[0165]

[0166] At 10 °C, compound 1A (100 mg, 0.577 mmol), triethylamine (234 mg, 2.31 mmol) and tetrahydrofuran (3 mL) were successively added to a 25 - mL three - necked flask. Stir until dissolved, and then phosgene (60 mg, 0.20 mmol) was added. Stir at 60 °C for 30 minutes, and then cool down to 10 °C. Ethyl azetidine - 3 - carboxylate hydrochloride (96 mg, 0.58 mmol) was added. Stir at 10 °C for 1 hour. Filter, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrates were combined and concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 3 (60 mg).

[0167] 1 H NMR(400MHz,DMSO - d6)δ7.93(s,1H),6.90(s,1H),4.14(q,J=7.2Hz,2H),4.07(t,J=8.4Hz,2H),3.92(t,J=6.0Hz,2H),3.49 - 3.42(m,1H),2.80(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),1.99 - 1.91(m,4H),1.21(t,J=7.2Hz,3H).LC - MS:m / z:329.2(M + H)+ .

[0168] Example 4

[0169] Isopropyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-carboxylate

[0170] Isopropyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)azetidine-3-carboxylate

[0171]

[0172]

[0173] first step:

[0174] At 25°C, compound 1A (500 mg, 2.89 mmol), triethylamine (1.2 mL, 8.7 mmol) and tetrahydrofuran (20 mL) were added to a 100 ml three-necked flask in sequence. Stir until dissolved and add triphosgene (342 mg, 1.15 mmol). Stir at 80°C for 4 hours under nitrogen protection. Cool to 25°C and add azetidine-3-carboxylic acid methyl ester hydrochloride (498 mg, 4.33 mmol). Stir overnight at 25°C. Concentrate under reduced pressure, add dichloromethane (20 mL) for slurry, and filter. The filtrate is concentrated under reduced pressure to obtain compound 2A (600 mg). The crude product does not need to be purified and is directly used in the next step. LC-MS: m / z 315.1 (M+H) + .

[0175] Step 2:

[0176] At 25°C, add compound 2A (600 mg, 1.91 mmol), methanol (20 mL) and water (2 mL) to a 100 mL single-mouth bottle. Stir until dissolved and add lithium hydroxide solution (0.2 mL, 6.0 mmol). Stir at 75°C for 2 hours. Concentrate under reduced pressure, dilute with water (10 mL), and adjust pH to 6 with 2M hydrochloric acid. Extract with dichloromethane (20 mL × 3), wash with saturated brine (20 mL × 1), and dry with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain compound 3A (350 mg). The crude product does not need to be purified and is directly used in the next step. LC-MS: m / z 301.1 (M+H) + .

[0177] Step 3:

[0178] At 25 °C, compound 3A (100 mg, 0.333 mmol), isopropanol (40 mg, 0.666 mmol) and dichloromethane (10 mL) were added to a 50 mL single-necked flask. Stir until dissolved, and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (64 mg, 0.333 mmol). Stir for 16 hours, then add saturated aqueous sodium bicarbonate solution (20 mL). Extract with dichloromethane (20 mL × 3), wash with saturated brine (20 mL × 1), and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 4 (29.45 mg).

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 6.90 (s, 1H), 4.99 - 4.93 (m, 1H), 4.04 (t, J = 8.6 Hz, 2H), 3.90 (dd, J = 8.2, 5.8 Hz, 2H), 3.43 - 3.32 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.96 - 1.91 (m, 4H), 1.22 (d, J = 6.4 Hz, 6H). LC-MS: m / z: 343.2 (M + H) +

[0180] Example 5

[0181] Ethyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylazetidine-3-carboxylate

[0182] ethyl 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylazetidine-3-carboxylate

[0183]

[0184]

[0185] The first step:

[0186] At room temperature, add compound 1B (0.17 mL, 0.93 mmol) and N,N-dimethylformamide (6 mL) to a 40 mL reaction flask. Stir until dissolved, then sequentially add iodoethane (0.1 mL, 1.4 mmol) and potassium carbonate (193 mg, 1.40 mmol). Stir at room temperature for 2 hours and filter. Add water (20 mL) to the filtrate, and extract with ethyl acetate (50 mL × 3). Wash with saturated brine (25 mL × 1) and dry over anhydrous sodium sulfate. Concentrate under reduced pressure at 40 °C to obtain compound 2 (226 mg). The crude product is used directly in the next reaction without purification.

[0187] 1 H NMR(400MHz,CDCl 3 )δ4.22-4.17(m,4H),3.66(d,J=8.8Hz,2H)1.53(s,3H)1.44(s,9H)1.28(t,J=7.2Hz,3H).LC-MS:m / z:188.1(M+H-56) + .

[0188] The second step:

[0189] At room temperature, add compound 2B (226 mg, 0.929 mmol) and dichloromethane (4 mL) to a 50 mL single-necked flask. Stir until dissolved, then add trifluoroacetic acid (4 mL). Stir at room temperature for 2 hours. Concentrate under reduced pressure at 40 °C to obtain compound 3B (383 mg). The crude product is used directly in the next reaction without purification.

[0190] 1 H NMR(400MHz,CD 3 OD)δ4.36(d,J=11.6Hz,2H),4.26(q,J=7.2Hz,2H),3.91(d,J=11.2Hz,2H),1.59(s,3H),1.31(t,J=7.2Hz,3H).LC-MS:m / z:144.2(M+H) + .

[0191] The third step:

[0192] At room temperature, add compound 3B (155 mg, 0.603 mmol) and acetonitrile (4 mL) to a 10 mL single-necked flask. Stir until dissolved, then sequentially add 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (100 mg, 0.502 mmol) and triethylamine (0.2 mL, 1.5 mmol). Stir at room temperature for 2 hours, concentrate under reduced pressure, and purify the residue by high performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 5 (95.5 mg).

[0193] 1 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 6.91 (s, 1H), 4.07 - 4.21 (m, 4H), 3.65 (d, J = 8.0 Hz, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 1.98 - 1.94 (m, 4H), 1.48 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). LC-MS: m / z: 343.1 (M + H) + .

[0194] Example 6

[0195] Ethyl 1 - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)pyrrolidine - 3 - carboxylate

[0196] ethyl 1 - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)pyrrolidine - 3 - carboxylate

[0197]

[0198] Using a synthetic method similar to that of Example 1, ethyl azetidine - 2 - carboxylate was replaced with ethyl pyrrolidine - 3 - carboxylate to obtain the title compound 6.

[0199] 1 1H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H), 5.68 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.73 - 3.69 (m, 2H), 3.64 - 3.58 (m, 1H), 3.50 - 3.44 (m, 1H), 3.21 - 3.11 (m, 1H), 2.89 (t, J = 8.4 Hz, 4H), 2.79 (t, J = 8.4 Hz, 4H), 2.30 - 2.21 (m, 1H), 2.09 - 1.98 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). LC-MS: m / z: 343.2 (M + H) + .

[0200] Biological evaluation

[0201] The following further describes and explains the present disclosure in combination with test examples, but these test examples do not mean to limit the scope of the present disclosure.

[0202] Test Example 1 Inhibitory experiment on NLRP3 inflammasome activity in THP - 1 cells

[0203] 1. Experimental materials

[0204]

[0205] 2. Experimental procedures

[0206] 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, add PMA for differentiation treatment, and 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. Take it out after 12 hours, 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. At the same time, 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, add 50 μL of medium containing 15 μM Negericin 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, 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.

[0207] Table 1

[0208] Number <![CDATA[IC 50 > Example 1 B Example 2 C Example 3 A Example 4 A Example 5 A Example 6 B

[0209] Note: A < 10 μM; 10 μM

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein, n, m are 1; j is selected from integers from 0 - 2; X 1 is CR 6 ; R 6 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1 to 3 R 5e ; ring A is selected from pyrrolidine, azetidine; R 1 selected from hydrogen, C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by 1-3 R 5a groups; R 2 selected from -COOR 5b ; R 3 Selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted by 1-3 R 5c ; R 4 Independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy; the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1-3 R 5d ; R 5a 、R 5c 、R 5d 、R 5e are independently selected from halogen, hydroxy, cyano; R 5b selected from C 1-6 alkyl; said C 1-6 alkyl is optionally substituted by 1-3 substituents selected from halogen, hydroxy, cyano, amino, nitro.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from azetidine.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is R 1 、R 2 、R 3 、R 4 、X 1 、n, m, and j are defined as described in claim 1.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 selected from hydrogen, halogen, hydroxyl, amino, methyl, methoxy, ethyl, cyano, propyl, ethoxy; the methyl, methoxy, ethyl, propyl, ethoxy are optionally substituted by 1-3 R 5c substituted; R 5c As defined in claim 1.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5b selected from methyl, ethyl, propyl, wherein the methyl, ethyl, propyl are optionally substituted by 1-3 groups selected from halogen, hydroxyl, cyano, amino, nitro.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Selected from -COOEt, -COOPr; the -COOEt and -COOPr are optionally substituted by 1-2 groups selected from halogen, cyano, hydroxy, nitro.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 、R 2 、R 3 、R 4 、X 1 、The definitions of n, m, and j are as described in claim 1.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 、R 2 、R 3 、R 4 、X 1 、n, m, and j are defined as described in claim 1.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 selected from CR 6 ; R 6 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, methyl, methoxy, ethyl, ethoxy, wherein the methyl, methoxy, ethyl, ethoxy are optionally substituted by 1-3 R 5e as defined in claim 1. 5e as defined in claim 1.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 is selected from CR 6 ; R 6 is selected from hydrogen.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from hydrogen.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 independently selected from hydrogen, halogen, methyl, methoxy, ethyl, ethoxy, propyl; the methyl, methoxy, ethyl, ethoxy, propyl are optionally substituted by 1-3 R 5d substituted; R 5d As defined in claim 1.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 is independently selected from hydrogen.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, is selected from 15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 14 and a pharmaceutically acceptable excipient.

16. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and / or treating NLRP3 - related disorders.

17. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and / or treating immune diseases, inflammatory diseases.

18. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and / or treating autoimmune diseases and / or autoinflammatory diseases.

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