NLRP3 inhibitors

Abstract

This invention relates to an NLRP3 inhibitor represented by general formula (I), namely a NOD-like receptor family Pyrin domain protein 3 inhibitor, and its use in the preparation of medicaments for the prevention and / or treatment of NLRP3-related diseases. The compounds of this invention are ideal highly active NLRP3 inhibitors that can be used to treat and / or prevent diseases including autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, hereditary cold pyrine periodic syndrome (CAPS), neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, pain management, metabolic diseases such as diabetes and gout, cancer treatment, and other inflammatory diseases such as pulmonary fibrosis and kidney disease, and cardiovascular diseases such as stroke, heart failure, and atherosclerosis.

Description

[0001] This application claims priority to the prior application filed on January 27, 2022 with the China National Intellectual Property Office, and has the patent application number 202210100461.0. The entire contents of this application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical chemistry, and relates to a NLRP3 (NOD-like receptor family, Pyrin domain-containing protein 3) inhibitor, a pharmaceutical composition thereof, a preparation method thereof, and use thereof in the preparation of a drug for preventing and / or treating indications related to the NLRP3 signaling pathway. BACKGROUND

[0003] NOD-like receptor family, Pyrin domain-containing protein 3 (NLRP3) inflammasome is one of the components of the inflammatory process. NLRP3 inflammasome is mainly expressed in macrophages, and is also expressed in dendritic cells, B and T cells. It is less expressed in monocytes. Non-keratinized stratified squamous epithelial cells such as oral cavity, esophagus, cervix and thymus, epithelial cells of bladder and ureter, lung epithelial cells, and chondrocytes have expression. NLRP3 inflammasome is in an inhibited state in resting cells. When the body is infected by external microorganisms or stimulated by damage signals from itself, NLRP3 inflammasome is activated, causing the activation of caspase-1 and further cleaving interleukin IL-1β and IL-18 into active forms, and caspase-1 can also cleave gasdermin-D to trigger pyroptosis.

[0004] Studies have shown that the activation of NLRP3 inflammasome is related to various diseases. Hereditary cold urticaria periodic syndrome (CAPS) is an inflammatory disease caused by gain-of-function mutations in NLRP3. The activation of NLRP3 inflammasome is also found in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In addition, it has been pointed out that uric acid crystals can activate NLRP3 inflammasome, thereby causing inflammatory reactions and joint damage after gout attacks. Activation of NLRP3 has been found in adipose tissue of obese people, and the increase of IL-1β downstream of NLRP3 is a risk signal for type 2 diabetes. It is believed that IL-1β can produce insulin resistance by blocking the insulin signaling pathway, and long-term high blood sugar levels are toxic to pancreatic islet cells, leading to cell destruction and insulin secretion disorders. NLRP3 inflammasome is related to the occurrence and development of various autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis.

[0005] There is an urgent need to provide a NLRP3 inhibitor with better effect. SUMMARY

[0006] The present application aims to provide a NLRP3 (NOD-like receptor family, Pyrin domain-containing protein 3) inhibitor, a pharmaceutical composition thereof, a preparation method thereof, and use thereof in the preparation of a drug for preventing and / or treating a disease associated with the NLRP3 signaling pathway.

[0007] To achieve the object of the present application, the present application adopts the following technical solutions:

[0008] The present application provides a compound having the structure shown in general formula (I), a deuterated compound or a metabolite thereof, and a pharmaceutically acceptable salt thereof:

[0009]

[0010] wherein,

[0011] Ring A is a five or six-membered unsaturated ring, containing 0-3 heteroatoms selected from N, O, and S;

[0012] Ring B is a five or six-membered unsaturated ring, containing 0-3 heteroatoms selected from N, O, and S;

[0013] X is selected from a chemical bond, -O-, -NH-;

[0014] L is selected from a chemical bond, -O-, -OC(R7)2-, -OC(R7)2C(R7)2-, -C(R7)2-, alkyne, -NR7-;

[0015] R1 is selected from H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)aryl;

[0016] R2 is H, (C1-C6)alkyl, hydroxyl, halogen, cyano, amino;

[0017] R3 is (C1-C4)alkylene-R6;

[0018] R4, R 4a , and R 4b are independently selected from hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6 alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)heteroalkynyl, -CO(C1-C6)alkyl; or

[0019] R4 and R 4a form a (C4-C7)cycloalkyl or (C5-C7)heterocycloalkyl with the atom to which they are attached, the (C5-C7)heterocycloalkyl containing at least one heteroatom selected from O, N, and S;

[0020] R5is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, (C1-C6)alkoxy, -NH2, -NH(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)heteroalkynyl, (C3-C8)heterocycloalkyl;

[0021] R6is a five or six membered unsaturated ring containing 0-3 heteroatoms selected from N, O, S; wherein said R6is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHCO(C1-C6alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)-heteroalkynyl, -CO(C1-C6alkyl);

[0022] R7is selected from the group consisting of hydrogen, halogen, methyl, halomethyl, or a phenyl ring;

[0023] said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, amino, alkoxy, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)-heteroalkynyl, -CO(C1-C6alkyl).

[0024] As a preference, the compounds of the present application have the following structure:

[0025]

[0026] X is selected from the group consisting of -O-, -NH-;

[0027] R1is selected from the group consisting of H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)aryl;

[0028] R4, R 4a , R 4b are independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)heteroalkynyl, -CO(C1-C6)alkyl; or

[0029] R4and R 4a form a (C4-C7)cycloalkyl or (C5-C7)heterocycloalkyl with the atom that links them, said (C5-C7)heterocycloalkyl containing at least one heteroatom selected from O, N and S;

[0030] R6is a five or six membered unsaturated ring, containing 0-3 heteroatoms selected from N, O, S; wherein said R6is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHCO(C1-C6alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)-heteroalkynyl, -CO(C1-C6alkyl);

[0031] said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, amino, alkoxy, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)-heteroalkynyl, -CO(C1-C6alkyl).

[0032] As a preference, the compounds of the present application have the following structure:

[0033] R1is selected from H, (C1-C6)alkyl, (C3-C8)cycloalkyl;

[0034] R4and R 4a form a (C4-C7)cycloalkyl with the atom that links them;

[0035] R 4b selected from hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, (C1-C6)alkoxy, -NH2, (C1-C6)alkyl;

[0036] R6is a five or six membered unsaturated ring, containing 0-3 heteroatoms selected from N, O, S; wherein said R6is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, nitro, (C1-C6)alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHCO(C1-C6alkyl), (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)heteroalkenyl, (C1-C6)-heteroalkynyl, -CO(C1-C6alkyl).

[0037] As a preference, the compound has the following structure:

[0038]

[0039] R1is selected from H, methyl, ethyl, isopropyl, cyclopentyl;

[0040] R 4b selected from hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, methyl, -NH2, alkoxy;

[0041] R6is selected from and R6is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, methoxy, -NH2, -NHCO(C1-C6 alkyl), (C1-C6) alkyl.

[0042] In certain more specific embodiments, the compound further has the structure of general formula II:

[0043]

[0044] wherein X is selected from -O- or -NH-;

[0045] R1is selected from ethyl, isopropyl, cyclopentyl;

[0046] R6is selected from

[0047] As a preference, the compound includes its deuterated compound or metabolite, and pharmaceutically acceptable salt, which is specifically selected from:

[0048]

[0049]

[0050] The present application also provides a pharmaceutical composition containing the above-mentioned compound and a pharmaceutically acceptable carrier thereof.

[0051] The present application also provides a use of any of the above-mentioned compounds or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing NLRP3-related diseases.

[0052] In certain specific embodiments, the NLRP3-related diseases include autoimmune diseases, neurodegenerative diseases, pain treatment, metabolic diseases, tumor treatment and other inflammation-induced diseases, cardiovascular and cerebrovascular diseases, etc.

[0053] In some embodiments, the NLRP3-related diseases include autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, hereditary cold urticarial periodic syndrome (CAPS), etc., neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, pain treatment, metabolic diseases such as diabetes, gout, tumor treatment, and other inflammation-induced diseases such as pulmonary fibrosis, kidney disease, cardiovascular and cerebrovascular diseases such as stroke, heart failure, atherosclerosis, etc.

[0054] The compound provided by the present application has strong drug efficacy, good drug metabolism, and low side effects, and is an ideal NLRP3 inhibitor. The compound of the present application is an ideal high-activity NLRP3 inhibitor, and can be used for treating and / or preventing clinical diseases including hereditary cold urticarial periodic syndrome (CAPS), neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, gout, type 2 diabetes, autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, etc. DETAILED DESCRIPTION

[0055] The present application will be further described in detail below in combination with specific embodiments, but the present application is not limited to the following embodiments.

[0056] Intermediate 1: 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoic acid ethyl ester

[0057]

[0058] 4-cyano-1H-pyrazole (481 mg, 5.17 mmol) and 2,3-epoxypropionic acid ethyl ester (300 mg, 2.59 mmol) were dissolved in ethanol (3 mL), heated to 90°C and stirred overnight. After the reaction was completed, the reaction solution was directly rotary evaporated, and the crude product was purified by reverse column to obtain 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoic acid ethyl ester (350 mg, yield: 65%), colorless liquid. MS (ESI): m / z 210.1 [M+H] + .

[0059] Intermediate 3: 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoic acid cyclopentyl ester

[0060]

[0061] (1) 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoic acid

[0062] Ethyl 3-(4-cyano-lH-pyrazol-l-yl)-2-hydroxypropanoate (200 mg, 0.95 mmol) was dissolved in a mixture of methanol and water (4 mL, 3: 1) and stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was directly spin dried to give 3-(4-cyano-lH-pyrazol-l-yl)-2-hydroxypropanoic acid (320 mg, crude product) as a brown oil. MS (ESI): m / z 182.0 [M+H] + .

[0063] (2) 3-(4-cyano-lH-pyrazol-l-yl)-2-hydroxypropanoic acid cyclopentyl ester

[0064] 3-(4-cyano-lH-pyrazol-l-yl)-2-hydroxypropanoic acid (320 mg, 1.76 mmol) was added to cyclopentanol (4 mL) and concentrated sulfuric acid (1 mL) was added. The reaction was stirred at 25 °C overnight. After the reaction was completed, water was added and the reaction was extracted with ethyl acetate (2 x 4 mL). The organic phase was combined and concentrated under reduced pressure to remove the solvent to give a crude product. The crude product was purified by reverse phase column to give 3-(4-cyano-lH-pyrazol-l-yl)-2-hydroxypropanoic acid cyclopentyl ester (120 mg, two-step yield: 27.4%) as a colorless oil. MS (ESI): m / z 250.1 [M+H] + .

[0065] Intermediate 5: Isopropyl 2-hydroxy-3-(pyrazin-2-yl)propanoate

[0066]

[0067] (1) Ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate

[0068] Ethyl 2-methylpyrazine (3 g, 31.9 mmol) was dissolved in dioxane (30 mL) and ethyl 2-oxoacetate (13 g, 63.8 mmol, 50% purity), ferrous acetate (167 mg, 0.9 mmol) were added. The reaction was stirred at 135 °C overnight. The reaction solution was filtered through celite and concentrated under reduced pressure. Purification by silica gel column and reverse phase column gave ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate (400 mg, yield: 6%) as a yellow oil. MS (ESI): m / z 197.0 [M+H] + .

[0069] (2) 2-hydroxy-3-(pyrazin-2-yl)propanoic acid

[0070] Ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate (770 mg, 3.9 mmol) was dissolved in ethanol (5 mL), 2M aqueous sodium hydroxide solution (10 mL) was added, and the reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered and concentrated, water (20 mL) was added, and ethyl acetate (20 mL) was extracted. The aqueous phase was directly concentrated by adjusting the pH to 2 to obtain 2-hydroxy-3-(pyrazin-2-yl)propanoic acid (660 mg) as a yellow solid.

[0071] (3) Isopropyl 2-hydroxy-3-(pyrazin-2-yl)propanoate

[0072] 2-hydroxy-3-(pyrazin-2-yl)propanoic acid (171 mg, 1.0 mmol) was dissolved in isopropanol (5 mL), 3 drops of concentrated sulfuric acid were added, and the reaction system was stirred at 45°C overnight. Sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase column chromatography to obtain isopropyl 2-hydroxy-3-(pyrazin-2-yl)propanoate (100 mg, yield: 47%) as a yellow oil. MS (ESI): m / z 211.0 [M+H] + .

[0073] Intermediate 6: Cyclopentyl 2-hydroxy-3-(pyrazin-2-yl)propanoate

[0074]

[0075] Referring to the method of step (3) of Intermediate 5, 2-hydroxy-3-(pyrazin-2-yl)propanoic acid (660 mg, 3.9 mmol) and cyclopentanol (5 mL) were used as raw materials to obtain cyclopentyl 2-hydroxy-3-(pyrazin-2-yl)propanoate (476 mg, yield: 51%) as a colorless oil. MS (ESI): m / z 237.1 [M+H] + .

[0076] Intermediate 7: Ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate

[0077]

[0078] Referring to the method of step (1) of Intermediate 5, 2-methylpyrimidine (3 g, 31.9 mmol) was used as a raw material to obtain ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate (1.6 g, yield: 26%) as a colorless oil. MS (ESI): m / z 196.9 [M+H] + .

[0079] Intermediate 9: 2-Hydroxy-3-(pyrimidin-2-yl)cyclopentyl propanoate

[0080]

[0081] (1) 2-Hydroxy-3-(pyrimidin-2-yl)propanoic acid

[0082] Following the procedure of Intermediate 5, step (2), 2-hydroxy-3-(pyrimidin-2- yl)propanoic acid ethyl ester (1.6 g, 8.2 mmol) was used as starting material to give 2- hydroxy-3-(pyrimidin-2-yl)propanoic acid (1.4 g) as yellow solid.

[0083] (2) 2-Hydroxy-3-(pyrimidin-2-yl)cyclopentyl propanoate

[0084] Following the procedure of Intermediate 5, step (3), 2-hydroxy-3-(pyrimidin-2- yl)propanoic acid (1.37 g, 8.2 mmol), cyclopentanol (10 mL) were used as starting materials to give 2-hydroxy-3-(pyrimidin-2-yl)cyclopentyl propanoate (600 mg, yield: 32%) as colorless oil. MS (ESI): m / z 237.9 [M+H] + .

[0085] Intermediate 12: 2-Amino-3-(3-hydroxyphenyl)cyclopentyl propanoate

[0086]

[0087] (1) Methyl 2-((tert-butoxycarbonyl)amino)-3-(3-methoxyphenyl)propanoate

[0088] Zinc powder (1.79 g, 27.5 mmol) was placed in N,N-dimethylformamide (20 mL) and stirred at room temperature for 5 minutes after adding iodine (348 mg, 1.4 mmol). Then, methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (3 g, 9.2 mmol) and iodine (348 mg, 1.4 mmol) were added to the reaction solution, and stirring was continued at room temperature for 20 minutes. Tris(dibenzylideneacetone)dipalladium (195 mg, 0.3 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (378 mg, 0.09 mmol), and 1-iodo-3-methoxybenzene (2.79 g, 11.9 mmol) were further added, and stirring was continued at room temperature overnight. After the completion of the reaction, the reaction solution was filtered, water (60 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gave methyl 2-((tert-butoxycarbonyl)amino)-3-(3-methoxyphenyl)propanoate (2.6 g, yield: 92%) as a yellow oil. MS (ESI): m / z 210.3 [M+H-100] + .

[0089] (2) Methyl 2-amino-3-(3-hydroxyphenyl)propanoate

[0090] Methyl 2-((tert-butoxycarbonyl)amino)-3-(3-methoxyphenyl)propanoate (1.5 g, 4.9 mmol) was dissolved in dichloromethane (15 mL). Boron tribromide (6 g, 24.3 mmol) was added dropwise at -78°C, and the reaction solution was stirred at 0°C for 1 hour. After the reaction solution was quenched with methanol, the pH was adjusted to 6 with an aqueous sodium bicarbonate solution, and the reaction solution was directly dried by rotary evaporation. Purification by reverse phase column chromatography gave methyl 2-amino-3-(3-hydroxyphenyl)propanoate (550 mg, yield: 58%) as a yellow oil. MS (ESI): m / z 196.2 [M+H] + .

[0091] (3) 2-Amino-3-(3-hydroxyphenyl)propanoic acid

[0092] Methyl 2-amino-3-(3-hydroxyphenyl)propanoate (300 mg, 1.5 mmol) was used as a starting material to obtain 2-amino-3-(3-hydroxyphenyl)propanoic acid (278 mg) as a yellow solid according to the method of Intermediate 5, step (2).

[0093] (4) Cyclopentyl 2-amino-3-(3-hydroxyphenyl)propanoate

[0094] Reference to the method of intermediate 5 step (3), with 2-amino-3-(3- hydroxyphenyl)propionic acid (278 mg, 1.5 mmol), cyclopentanol (10 mL) as raw material, 2-amino-3-(3-hydroxyphenyl)propionic acid cyclopentyl ester (70 mg, yield: 18%) was obtained as a white solid. MS (ESI): m / z 250.3 [M+H] + .

[0095] Intermediate 15: 2-amino-3-(pyrimidin-2-yl)propionic acid cyclopentyl ester

[0096]

[0097] (1) 2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester

[0098] Phosphorus tribenzene (18.3 g, 70 mmol), imidazole (4.7 g, 70 mmol) were dissolved in dichloromethane (240 mL) under nitrogen protection, stirred in ice water bath for 10 minutes, then iodine (18 g, 70 mmol) was added, and after stirring at room temperature for 10 minutes, N-tert-butoxycarbonyl-DL-serine methyl ester (10.0 g, 46 mmol) was added. After reaction at room temperature overnight, the reaction solution was washed with sodium sulfite solution, sodium bicarbonate solution, saturated brine in turn, and the organic phase was concentrated under reduced pressure to obtain the crude product. Purification by silica gel column to obtain 2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (10.8 g, yield: 72%) as a yellow oily liquid. MS (ESI): m / z 262 [M+H] + .

[0099] (2) 2-((tert-butoxycarbonyl)amino)-3-(pyrimidin-2-yl)propionic acid methyl ester

[0100] Zinc powder (1.9 g, 30.1 mmol), iodine (400 mg, 1.5 mmol) were added to a three-necked flask, and a solution of 2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester (3.3 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was added under nitrogen protection, followed by iodine (400 mg, 1.5 mmol). After cooling to room temperature, 2-bromopyrimidine (2.1 g, 12.0 mmol), tris(dibenzylideneacetone)dipalladium (210 mg, 3.0 mmol), sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate (220 mg, 3.0 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After filtration, the filtrate was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed successively with sodium sulfite solution, sodium bicarbonate solution, and saturated brine, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2-((tert-butoxycarbonyl)amino)-3-(pyrimidin-2-yl)propionic acid methyl ester (1.4 g, yield: 51%) as a yellow solid. MS (ESI): m / z 282.0 [M+H] + .

[0101] (3) 2-Amino-3-(pyrimidin-2-yl)propionic acid methyl ester

[0102] (2-((tert-butoxycarbonyl)amino)-3-(pyrimidin-2-yl)propionic acid methyl ester (500 mg, 1.75 mmol) was added to ethyl acetate (5 mL), and hydrochloric acid ethyl acetate (20 mL) was added to the reaction solution. Concentration under reduced pressure gave 2-amino-3-(pyrimidin-2-yl)propionic acid methyl ester (427 mg, yield: 97%) as a yellow solid. MS (ESI): m / z 182.0 [M+H] + .

[0103] (4) 2-Amino-3-(pyrimidin-2-yl)propionic acid

[0104] Referring to the method of step (2) of Intermediate 5, 2-amino-3-(pyrimidin-2-yl)propionic acid methyl ester (270 mg of crude product, 1.07 mmol) was used as the starting material to obtain 2-amino-3-(pyrimidin-2-yl)propionic acid (620 mg of crude product) as a yellow solid.

[0105] (5) 2-Amino-3-(pyrimidin-2-yl)propionic acid cyclopentyl ester

[0106] Referring to the method of step (3) of Intermediate 5, 2-amino-3-(pyrimidin-2-yl)propionic acid (620 mg of crude product), cyclopentanol (10 mL) were used as the starting materials to obtain 2-amino-3-(pyrimidin-2-yl)propionic acid cyclopentyl ester (120 mg, yield: 40%) as a colorless oil. MS (ESI): m / z 236.1 [M+H]+ .

[0107] Intermediate 21: 2-Amino-3-(pyridin-3-yl)cyclopentyl propanoate

[0108]

[0109] (1) Methyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoate

[0110] Methyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoate (630 mg, 2.25 mmol) was dissolved in methanol / water (4 mL / 1 mL) and lithium hydroxide (472 mg, 11.25 mmol) was added. The reaction was stirred overnight. The solvent was evaporated and the residue was purified by reverse phase column to give 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoic acid (430 mg, yield: 72%) as a white solid. MS (ESI): m / z 267.2 [M+H] + .

[0111] (2) 2-((tert-Butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoic acid

[0112] Methyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoate (630 mg, 2.25 mmol) was dissolved in methanol / water (4 mL / 1 mL) and lithium hydroxide (472 mg, 11.25 mmol) was added. The reaction was stirred overnight. The solvent was evaporated and the residue was purified by reverse phase column to give 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoic acid (430 mg, yield: 72%) as a white solid. MS (ESI): m / z 267.2 [M+H] + .

[0113] (3) 2-((tert-Butoxycarbonyl)amino)-3-(pyridin-3-yl)cyclopentyl propanoate

[0114] Methyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoate (630 mg, 2.25 mmol) was dissolved in methanol / water (4 mL / 1 mL) and lithium hydroxide (472 mg, 11.25 mmol) was added. The reaction was stirred overnight. The solvent was evaporated and the residue was purified by reverse phase column to give 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoic acid (430 mg, yield: 72%) as a white solid. MS (ESI): m / z 267.2 [M+H] + .

[0115] (4) 2-Amino-3-(pyridin-3-yl)cyclopentyl propanoate

[0116] Cyclopentyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propanoate (100 mg, 0.30 mmol) was dissolved in dichloromethane (3 mL), stirred at room temperature overnight after adding trifluoroacetic acid (3 mL). Concentration under reduced pressure obtained a residue of cyclopentyl 2-amino-3-(pyridin-3-yl)propanoate (70 mg, yield: 99%) as a yellow liquid. MS (ESI): m / z 235.1 [M+H] + .

[0117] Example 1: Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-((((6-methyl-5-(2-(((1- methylpiperidin-4-yl)oxy]pyridin-4-yl]-2,3-dihydro-1H-indan-4-yl)carbamoyl)oxy)propanoate (Compound 1)

[0118]

[0119] Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-((((6-methyl-5-(2-(((1- methylpiperidin-4-yl)oxy]pyridin-4-yl]-2,3-dihydro-1H-indan-4-yl)carbamoyl)oxy)propanoate (Compound 1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.04 - 8.79 (m, 1H), 8.43 - 7.91 (m, 3H), 7.11 (s, 1H), 6.68 (s, 1H), 6.51 - 6.47 (m, 1H), 5.31 - 5.26 (m, 1H), 5.08 - 4.99 (m, 1H), 4.57 (s, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.02 (s, 2H), 2.88 (d, J = 8.0, 3H), 2.22 - 2.18 (m, 5H), 1.99 (s, 8H), 1.68 (s, 3H), 1.16 - 1.12 (m, 3H).

[0120] Example 2: 3-(4-cyano-lH-pyrazol-l-yl)-2-((((6-methyl-5-(2-((l- methylpiperidin-4-yl)oxy]pyridin-4-yl]-2,3-dihydro-lH-indan-4-yl)carbamoyl)oxy)propanoic acid cyclopentyl ester (Compound 3)

[0121]

[0122] To 6-methyl-5-(2-(((l-methylpiperidin-4-yl)oxy]pyridin-4-yl)-2,3-dihydro-lH- indan-4-amine (57 mg, 0.17 mmol) in tetrahydrofuran (4 mL) was added triphosgene (33 mg, 0.11 mmol), stirred at 25 °C for 2 h, then 3-(4-cyano-lH-pyrazol-l-yl)-2- hydroxypropanoic acid cyclopentyl ester (40 mg, 0.16 mmol) and cuprous chloride (16 mg, 0.16 mmol) were added, stirred at 25 °C for 2 h, concentrated to dryness and purified by pre-HPLC to give the title compound (13.6 mg, yield: 13.8%) as a white solid. MS (ESI): m / z 613.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.24 (s, 1H), 8.11-8.05 (m, 2H), 7.11 (s, 1H), 6.64-6.61 (m, 1H), 6.47 (s, 1H), 5.18-4.98 (m, 3H), 4.56-4.50 (m, 2H), 2.91-2.87 (m, 2H), 2.71-2.64 (m, 4H), 2.19 (s, 5H), 19.8 (s, 7H), 1.77-1.56 (m, 9H).

[0123] Example 3: 2-(((6-methyl-5-(2-((l-methylpiperidin-4-yl)oxy]pyridin-4-yl)-2,3- dihydro-lH-indan-4-yl)carbamoyl)oxy)-3-(pyrazin-2-yl)propanoic acid isopropyl ester (Compound 5)

[0124]

[0125] Referring to the method of Example 1, 2-hydroxy-3-(pyrazin-2-yl)propanoic acid isopropyl ester (50 mg, 0.24 mmol) as a raw material, the title compound (58.0 mg, yield: 43%) was obtained as a white solid. MS (ESI): m / z 574.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 16 Hz, 1H), 8.55-8.52 (m, 3H), 8.07 (d, J = 4.4 Hz, 1H), 7.09 (s, 1H), 6.62-6.45 (m, 2H), 5.20-4.89 (m, 3H), 3.21-3.20 (m, 2H), 2.89-2.86 (m, 2H), 2.71-2.63 (m, 4H), 2.22-2.18 (m, 5H), 1.98 (s, 7H), 1.68-1.66 (m, 2H), 1.15-1.09 (m, 6H).

[0126] Example 4: 2-(((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3- dihydro-1H-indan-4-yl)carbamoyl)oxy)-3-(pyrazin-2-yl)propanoic acid cyclopentyl ester (Compound 6)

[0127]

[0128] Referring to the method of Example 1, using 2-hydroxy-3-(pyrazin-2-yl)propanoic acid cyclopentyl ester (250 mg, 1.1 mmol) as a raw material, the title compound (55 mg, yield: 9%) was obtained as a white solid. MS (ESI): m / z 600.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.81-8.52 (m, 3H), 8.18 (s, 1H), 8.07 (d, J = 4.8 Hz, 1H), 7.10 (s, 1H), 6.63-6.45 (m, 2H), 5.23-4.96 (m, 3H), 3.15 (d, J = 6.8 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.73-2.63 (m, 4H), 2.25-2.23 (m, 5H), 1.98 (s, 6H), 1.76-1.69 (m, 4H), 1.52 (s, 6H).

[0129] Example 5: 2-(((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3- dihydro-1H-indan-4-yl)carbamoyl)oxy)-3-(pyrazin-2-yl)propanoic acid cyclopentyl ester (Compound 6)

[0130]

[0131] The title compound (115 mg, yield: 2.4%) was obtained as a white solid according to the method of Reference Example 1, using ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate (31 mg, 0.16 mmol) as a starting material. MS (ESI): m / z 560.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 3H), 8.13 (s, 1H), 8.10-8.07 (m, 1H), 7.39 (t, J = 4.8 Hz, 1H), 7.11-7.06 (m, 1H), 6.67-6.54 (m, 1H), 6.47-6.39 (m, 1H), 5.52-5.37 (m, 1H), 5.05-4.89 (m, 1H), 4.20-4.07 (m, 2H), 3.34 (overlapped, 3H), 2.91-2.83 (m, 2H), 2.68-2.50 (m, 3H), 2.22-2.17 (m, 5H), 2.06-1.91 (m, 6H), 1.72-1.58 (m, 3H), 1.18-1.01 (m, 3H).

[0132] Example 6: 2-(((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H- indan-4-yl)carbamoyl)oxy)-3-(pyrimidin-2-yl)propanoic acid cyclopentyl ester (Compound 9)

[0133]

[0134] The title compound (115 mg, yield: 2.4%) was obtained as a white solid according to the method of Reference Example 1, using ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate (31 mg, 0.16 mmol) as a starting material. MS (ESI): m / z 560.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 3H), 8.13 (s, 1H), 8.10-8.07 (m, 1H), 7.39 (t, J = 4.8 Hz, 1H), 7.11-7.06 (m, 1H), 6.67-6.54 (m, 1H), 6.47-6.39 (m, 1H), 5.52-5.37 (m, 1H), 5.05-4.89 (m, 1H), 4.20-4.07 (m, 2H), 3.34 (overlapped, 3H), 2.91-2.83 (m, 2H), 2.68-2.50 (m, 3H), 2.22-2.17 (m, 5H), 2.06-1.91 (m, 6H), 1.72-1.58 (m, 3H), 1.18-1.01 (m, 3H).

[0135] Example 7: 2-(3-(6-methyl-5-(2-(((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)- 2,3-dihydro-1H-indan-4-yl)ureido)-3-(3-hydroxyphenyl)propanoic acid cyclopentyl ester (Compound 12)

[0136]

[0137] To a solution of 6-methyl-5-(2-(((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3- dihydro-1H-indan-4-amine (50 mg, 0.1 mmol) and N,N-diisopropylethylamine (58 mg, 0.5 mmol) in THF (10 mL) was added triphosgene (17.6 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then 2-amino-3-(3- hydroxyphenyl)propanoic acid cyclopentyl ester (44.8 mg, 0.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column and prep-HPLC to give the title compound (20 mg, yield: 22%) as a white solid. MS (ESI): m / z 613.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (br s, 1H), 8.17 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.39 (s, 1H), 7.02 (d, J = 8 Hz, 2H), 6.65-6.59 (m, 2H), 6.49 (t, J = 10 Hz, 3H), 6.21 (s, 1H), 5.00-4.99 (m, 2H), 4.30 (d, J = 6.8 Hz, 1H), 2.86 (t, J = 7.2 Hz, 2H), 2.78-2.64 (m, 6H), 2.21 (s, 5H), 1.98-1.93 (m, 7H), 1.75-1.47 (m, 10H).

[0138] Example 8: 2-(3-(6-methyl-5-(2-(((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)- 2,3-dihydro-1H-indan-4-yl)ureido)-3-(pyrimidin-2-yl)propanoic acid cyclopentyl ester (Compound 15)

[0139]

[0140] To a solution of 6-methyl-5-(2-(((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3- dihydro-1H-indan-4-amine (86 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added triphosgene (30.3 mg, 0.10 mmol) and triethylamine (90.5 mg, 0.89 mmol) and stirred at room temperature for 30 min. Then 2-amino-3-(pyrimidin-2-yl)propanoic acid cyclopentyl ester (60 mg, 0.25 mmol) was added and stirred at room temperature for 2 h. The residue was purified by pre-HPLC to give the title compound (19.2 mg, yield: 13%) as a white solid. MS (ESI): m / z 599.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 2H), 8.22 (s, 1H), 8.08 (s, 1H), 7.45 (s, 1H), 7.36 (t, J = 4.8 Hz, 1H), 7.03 (s, 1H), 6.63 (d, J = 4.8 Hz, 1H), 6.48 (s, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.01 - 4.93 (m, 2H), 4.71 - 4.66 (m, 1H), 3.22 - 3.18 (m, 2H), 2.87 - 2.84 (m, 2H), 2.75 (s, 2H), 2.62 (s, 2H), 2.32 - 2.26 (m, 5H), 1.97 - 1.90 (m, 7H), 1.70 - 1.68 (m, 4H), 1.49 - 1.40 (m, 6H).

[0141] Example 9: 2-(3-(6-methyl-5-(2-(((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3- dihydro-1H-indan-4-yl)ureido)-3-(pyridin-3-yl)propanoic acid cyclopentyl ester (Compound 21)

[0142]

[0143] The title compound (20.5 mg, yield: 23%) was obtained as a white solid by the method of Reference Example 8, using 2-amino-3-(pyridin-3-yl)propanoic acid cyclopentyl ester (34.6 mg, 0.15 mmol) as a starting material. MS (ESI): m / z 598.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 3.6 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J = 5.2, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 7.29 - 7.26 (m, 1H), 7.02 (s, 1H), 6.65 (s, 1H), 6.50 (s, 1H), 6.35 (d, J = 8.0 Hz, 1H), 5.0 (s, 2H), 4.38 (d, J = 7.6, 1H), 2.90 - 2.84 (m, 4H), 2.76 (s, 2H), 2.62 - 2.58 (m, 2H), 2.32 - 2.28 (m, 5H), 1.97 - 1.92 (m, 7H), 1.77 - 1.67 (m, 4H), 1.55 - 1.44 (m, 6H).

[0144] Experimental Example 1: Evaluation of NLRP3 inflammasome activity

[0145] Human monocyte cell line THP-1 (ATCC) was cultured in RPMI1640 complete medium (containing 10% FBS, 50U / ml penicillin, 100 pg / ml streptomycin and 2mM L-glutamine). THP-1 cells were seeded into 96-well plates at a density of 7.5 x 105cells / mL and treated with 500nM PMA (Phorbol ester, purchased from MCE, HY-18739) for 18 hours. The adherent cells were washed with PBS and cultured in RPMI1640 medium for 24 hours. 5 / mL of PMA (Phorbol ester, purchased from MCE, HY-18739) for 18 hours. The adherent cells were washed with PBS and cultured in RPMI1640 medium for 24 hours.

[0146] The cell medium was changed to fresh RPMI1640 (containing 5% FBS without phenol red) on the third day and incubated for 1 hour before adding 1 pg / mL LPS (purchased from Invivogen, tlrl-pb5lps) and test compounds for 3 hours. The maximum final concentration of test compounds was 10 pM, 3-fold dilution, 9 concentration points. Then 5mM ATP was added and incubated for 4 hours. The supernatant was collected and the content of IL-1b was measured by ELISA, and the IC 50 .

[0147] The NLRP3 body inhibition activity of the compounds is shown in Table 1.

[0148] Wherein the IC50is represented by letters: ≤1 pM = ‘A’, ≤10 pM = ‘B’.

[0149] Table 1

[0150] Compounds IC 50 (μM) 1 B 3 B 5 A 6 A 7 A 9 A 12 B 15 A 21 B .

Claims

1. A compound having the structure of general formula (Ib) and pharmaceutically acceptable salts thereof: wherein X is selected from -O- or -NH-; R 1 is selected from H, methyl, ethyl, isopropyl, cyclopentyl; and R 2 is selected from H, methyl, ethyl, isopropyl, cyclopentyl. ， 2.A compound having the structure of general formula II: wherein X is selected from -O- or -NH-; R 1 is selected from ethyl, isopropyl, cyclopentyl. 3.The compound of claim 1, comprising the following specific compounds and pharmaceutically acceptable salts thereof: wherein X is selected from -O- or -NH-; R 1 is selected from ethyl, isopropyl, cyclopentyl. R 4b selected from hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, methyl, -NH2, methoxy; R6is selected from the group consisting of , , and R6is optionally substituted with 0, 1 or 2 hydrogen, halogen, hydroxyl, cyano, trifluoromethyl, methoxy, -NH2, -NHCO(Ci-C6alkyl), (Ci-C6)alkyl.

2. The compound of claim 1, wherein 4.A pharmaceutical composition comprising the compound of any one of claims 1-3 and a pharmaceutically acceptable carrier thereof. ； 5.Use of the compound of any one of claims 1-3 or the pharmaceutical composition of claim 4 in the preparation of a medicament for treating and / or preventing NLRP3-related diseases. The NLRP3-related diseases include autoimmune diseases, neurodegenerative diseases, pain, metabolic diseases, tumor and other inflammation-induced diseases, and cardiovascular and cerebrovascular diseases. R6is selected from , . The NLRP3-related diseases include inflammatory bowel disease, rheumatoid arthritis, hereditary cold urticaria periodic syndrome, Alzheimer's disease and Parkinson's disease, pain, diabetes, gout, tumor, pulmonary fibrosis, nephropathy, stroke, heart failure, and atherosclerosis. ， ， 。 ​ ​ 6. Use according to claim 5, characterized in that: ​ 7. Use according to claim 6, characterized in that: ​

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