NLRP3 inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a compound shown as a formula (IV), or a stereoisomer, a tautomer, a deuterated compound or a pharmaceutical salt thereof, a preparation method of the compound, and application of the compound to medicines, and the compound can be used for treating or preventing NLRP3-related diseases or symptoms.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the compound shown in formula (IV) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts, their preparation methods and their applications in medicine. Background Technology

[0002] NLRP3 belongs to the NOD-like receptor protein family and is one of the most studied intracellular pattern recognition receptors in recent years. After recognizing pathogen-associated molecular patterns (PAMPs) or host-derived danger signaling molecular patterns (DAMPs), it recruits apoptosis-associated speckle-like protein (ASC) and caspase-1 to assemble into an inflammasome through two steps: initiation and activation. Simultaneously, it releases activated inflammatory cytokines IL-1β and IL-18, inducing an inflammatory response. Previous studies have shown that NLRP3 is widely expressed in immune cells such as monocytes and macrophages, and that the initiation step of NLRP3 in monocyte-derived macrophages is crucial for the activation of the inflammasome.

[0003] Inflammation is the body's defensive response to stimuli, including infectious and aseptic inflammation. Inflammation is mainly characterized by redness, swelling, heat, pain, and functional impairment, usually caused by increased permeability of vascular endothelial cells and the leakage of immune cells from the plasma. The inflammatory response usually ends rapidly after tissue repair, but excessive cytokine production can lead to a cytokine storm, causing damage to the body. Inflammatory dysregulation is an important pathogenic mechanism in many human diseases.

[0004] Abnormal NLRP3 inflammasome activation has been observed in numerous inflammatory diseases, and excessive production of IL-1β and IL-18 also participates in and promotes the occurrence and development of various diseases, including Cryopyrin-related periodic syndrome; sickle cell disease; autoimmune diseases such as systemic lupus erythematosus and psoriasis; liver diseases such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, and alcoholic liver disease; inflammatory arthritis-related diseases such as gout, osteocalcemia, osteoarthritis, and rheumatoid arthritis; and kidney diseases such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, and hematologic disorders. Dialysis-related inflammation and diabetic nephropathy; neuroinflammatory diseases such as brain infections, acute injuries, and neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease; cardiovascular and metabolic diseases such as atherosclerosis, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), peripheral artery disease, acute heart failure, and hypertension; wound healing and scar formation; inflammatory skin diseases such as acne and hidradenitis suppurativa; asthma; sarcoidosis; age-related macular degeneration; and cancer-related diseases such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes, myelofibrosis, lung cancer, and colon cancer.

[0005] Currently, there are no marketed NLRP3 inhibitors. The earliest compound to enter clinical trials, MCC950, had its trials terminated due to liver toxicity; however, it has been used as a tool molecule in numerous studies to explore different indications or mechanisms. Compounds such as OLT1177, Emlenoflast, RG6418, and DFV890 are currently in clinical trials for the treatment of acute gout attacks, knee osteoarthritis, Schnitzler syndrome, Cryopyrin-related periodic syndrome, ulcerative colitis, and Parkinson's disease. Diseases that are inherently inflammatory or immune-related are often difficult to diagnose or treat efficiently. Most treatments include symptom management, slowing disease progression, lifestyle modifications, and surgery as a last resort. There is an urgent need for more efficient and effective treatments for these diseases.

[0006] Neuroinflammation is key to central nervous system (CNS) diseases. Numerous clinical and neuropathological studies have shown that NLRP3 is overexpressed in microglia during the development of neuroinflammation. Activated microglia, equivalent to macrophages in the brain and spinal cord, serve as the first and most important line of immune defense in the CNS, playing a prominent role in the pathogenesis of neurodegenerative diseases. Abnormally activated NLRP3 inflammasomes mediate excessive neuroinflammation, leading to neuronal death and thus promoting the development of CNS diseases. Therefore, developing NLRP3 inflammasome inhibitors holds significant therapeutic potential for these diseases characterized by inflammatory pathology. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a novel nitrogen-containing derivative that can be used as an NLRP3 inhibitor for the treatment of diseases.

[0008] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0009] On the one hand, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0010]

[0011] in:

[0012] Selected from single or double bonds;

[0013] R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced;

[0014] Or, R 2 With R 3 And the atoms connected to it form C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl; the C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0015] Or, R 3 With R 4 And the atoms connected to it form C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl; the C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0016] R 5 Each is independently selected from -OC(O)-R 5a -C(O)OR 5a -OC(O)OR 5a -OR 5a -SC(O)OR 5a -SC(O)-R 5a -OC(O)NHR 5a -OC(O)NR 5a R 5b -SC(O)NR 5a R 5b -NHC(O)-R 5a -C(O)NH-R 5a -NHC(O)OR 5a -OC(O)-R 5a -OR 5c -OC(O)OR5a -O-R 5c 、-SC(O)O-R 5a -O-R 5c 、-SC(O)-R 5a -O-R 5c 、-B(OR 5a )(OR 5b )、-B(OR 5a )(O-CO-R 5b )、-OC(O)NH(AA)C(O)OR 5a 、-O(CR 5a1 R 5b1 ) n -OC(O)R 5a 、-OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OC(O)NR 5a R 5b 、-O(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 )n OC(O)R 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OCR 5a1 R 5b1 -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、O-(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -P(O)(OCR 5a1 R 5b1 OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a(O(CR)) 5a1 R 5b1 ) n OC(O)R 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OR 5a (O(CR)) 5a1 R 5b1 ) n OR 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OC(O)OR 5a )(OC(O)OR 5b );

[0017] R 5a R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-16 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further substituted with one or more R groups. a Replaced;

[0018] Or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0019] R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0020] AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration;

[0021] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0022] X is independently selected from C or N;

[0023] Ring A is selected from 3-12 membered heterocyclic groups, 5-14 membered heteroaryl groups, or C. 6-12 Aryl; the 3-12 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced;

[0024] B is selected from Alternatively, a 3-12 N-containing heterocyclic group may be optionally further modified by one or more R groups. a Replaced;

[0025] L is selected from covalent bonds, NR 7 O or C(R) 7 )2;

[0026] R 7 Each is independently selected from H, halogen or C 1-6 alkyl;

[0027] R a Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 Alkylamine, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl, the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 Alkylamine, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12The aryl group may be further selected by one or more groups chosen from deuterium, halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl or C 1-6 The substituents of the alkylamine group are replaced.

[0028] In some embodiments, the compound has the structure shown in formula (I'):

[0029]

[0030] in: Selected from single or double bonds;

[0031] R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced;

[0032] Or, R 2 With R 3 And the atoms connected to it form C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl; the C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0033] Or, R 3 With R 4 And the atoms connected to it form C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl; the C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0034] R 5 Each is independently selected from -OC(O)-R5a 、-C(O)O-R 5a 、-OC(O)O-R 5a 、-O-R 5a 、-SC(O)O-R 5a 、-SC(O)-R 5a 、-OC(O)NHR 5a 、-OC(O)NR 5a R 5b 、-SC(O)NR 5a R 5b 、-NHC(O)-R 5a 、-C(O)NH-R 5a 、-NHC(O)O-R 5a 、-OC(O)-R 5a -O-R 5c 、-OC(O)O-R 5a -O-R 5c 、-SC(O)O-R 5a -O-R 5c 、-SC(O)-R 5a -O-R 5c 、-B(OR 5a )(OR 5b )、-B(OR 5a )(O-CO-R 5b )、-OC(O)NH(AA)C(O)OR 5a 、-O(CR 5a1 R 5b1 ) n -OC(O)R 5a 、-OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OC(O)NR 5a R 5b 、-O(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR5a1 R 5b1 ) n OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OCR 5a1 R 5b1 -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、O-(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -P(O)(OCR 5a1 R 5b1 OC(O)R 5a )(O(CR 5a1 R5b1 ) n OC(O)R 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a (O(CR)) 5a1 R 5b1 ) n OC(O)OR 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a (O(CR)) 5a1 R 5b1 ) n OC(O)R 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OR 5a (O(CR)) 5a1 R 5b1 ) n OR 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OC(O)OR 5a )(OC(O)OR 5b );

[0035] R 5a R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-16 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 1-6 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups.a Replaced;

[0036] Or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0037] R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0038] AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration;

[0039] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0040] X is independently selected from C or N;

[0041] Ring A is selected from 3-12 membered heterocyclic groups, 5-14 membered heteroaryl groups, or C. 6-12 Aryl; the 3-12 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced;

[0042] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0043] L is selected from covalent bonds, NR 7 O or C(R) 7 )2;

[0044] R 7 Each is independently selected from H, halogen or C 1-6 alkyl;

[0045] R a Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkyl sulfone group, C 1-6 Alkylamine, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl, the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 Alkylamine, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may be further selected by one or more groups chosen from deuterium, halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl or C 1-6 The substituents of the alkylamine group are replaced.

[0046] In some embodiments, the compound has the structure shown in formula (IA):

[0047]

[0048] Among them, R 1 R 2 R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0049] R 5a Selected from hydrogen, C 1-16 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl; the C 1-16 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 The aryl or 5-14 heteroaryl group may optionally be further divided by one or more R groups. a Replaced;

[0050] L is selected from O and NR 7 or C(R) 7 )2;R 7 Selected from hydrogen or C 1-6alkyl;

[0051] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0052] R a Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Haloalkyl or 3-12 membered heterocyclic groups;

[0053] The ring A is defined as described in general formula (I).

[0054] In some embodiments, the compound has the structure shown in formula (IB):

[0055]

[0056] Among them, R 5 Selected from -OC(O)-R 5a or -OR 5a ;

[0057] R 5a Each is independently selected from hydrogen and C 1-16 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl; the C 1-16 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 The aryl or 5-14 heteroaryl group may optionally be further divided by one or more R groups. a Replaced;

[0058] R 1 R 2 R 3 R 4 Ring A, L, R a The definition is as stated in general formula (IA).

[0059] In some implementations, ring A is selected from...

[0060]

[0061] Wherein, Y is independently selected from CH or N;

[0062] R 6 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkylamine or C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 alkylamine or C 1-6 Alkoxy groups may optionally be further selected from one or more C 1-6 Substituted by alkyl, halogen, or hydroxyl substituents;

[0063] R 8 Selected from hydrogen, C 1-6 Alkyl, hydroxyl, cyano, amino, C 1-6 Alkoxy, C 2-6 alkynyl group, C 3-8 cycloalkyl or 5-10 heteroaryl; the C 1-6 Alkoxy, C 2-6 alkynyl group, C 3-8 Cycloalkyl or 5-10 heteroaryl groups optionally further selected from C10 and C20 are used. 1-6 Substituted by alkyl, halogen, carboxyl, or hydroxyl groups.

[0064] In some embodiments, the compound has the structure shown in formula (II):

[0065]

[0066] in, Selected from single or double bonds;

[0067] L is selected from NR 7 O or C(R) 7 )2;

[0068] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0069] X, R 1 R 2 R 3 R 4 R 5 R 7 R a The definition is as stated in general formula (I) or (I');

[0070] Y is independently selected from CH or N;

[0071] R 6 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C1-6 alkylamine or C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 alkylamine or C 1-6 Alkoxy groups may optionally be further selected from one or more C 1-6 Substituted by alkyl, halogen, or hydroxyl substituents;

[0072] R 8 Selected from hydrogen, C 1-6 Alkyl, hydroxyl, cyano, amino, C 1-6 Alkoxy, C 2-6 alkynyl group, C 3-8 cycloalkyl or 5-10 heteroaryl; the C 1-6 Alkoxy, C 2-6 alkynyl group, C 3-8 Cycloalkyl or 5-10 heteroaryl groups optionally further selected from C10 and C20 are used. 1-6 Substituted by alkyl, halogen, carboxyl, or hydroxyl groups.

[0073] In some embodiments, the compound has the structure shown in formula (IIA):

[0074]

[0075] in, Selected from single or double bonds;

[0076] L is selected from NR 7 O or C(R) 7 )2;

[0077] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0078] X, R 1 R 2 R 3 R 4 R 5 R 7 R a The definition is as stated in general formula (I) or (I');

[0079] R 6 R 8 The definition is as stated in general formula (II).

[0080] In some embodiments, the compound has the structure shown in formula (IIB):

[0081]

[0082] in, Selected from single or double bonds;

[0083] L is selected from NR 7 O or C(R) 7 )2;

[0084] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0085] X, R 1 R 2 R 3 R 4 R 5 R 7 R a The definition is as stated in general formula (I) or (I');

[0086] R 6 R 8 The definition is as stated in general formula (II).

[0087] In some embodiments, the compound has the structure shown in formula (III):

[0088]

[0089] in, Selected from single or double bonds;

[0090] L is selected from NR 7 O or C(R) 7 )2;

[0091] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0092] R 1 R 2 R 3 R 4 R 5 R 7 R a The definition is as stated in general formula (I) or (I');

[0093] R 6 R 8 The definition is as stated in general formula (II).

[0094] In some embodiments, the compound has the structure shown in formula (IV):

[0095]

[0096] in, Selected from single or double bonds;

[0097] L is selected from NR 7 O or C(R) 7 )2;

[0098] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0099] R 1 R 2 R 3 R 4 R 5 R 7 R a As described in general formula (I) or (I');

[0100] R 6 The definition is as stated in general formula (II).

[0101] In some embodiments, the compound has the structure shown in formula (V):

[0102]

[0103] in, Selected from single or double bonds;

[0104] B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced;

[0105] R 1 R 2 R 3 R 4 R 5 R 7 R a The definition is as stated in general formula (I) or (I');

[0106] R 6 The definition is as stated in general formula (II).

[0107] In some embodiments, the B is selected from 5-6 membered N-containing heterocyclic groups, which are further substituted by one or more methyl, ethyl, halogen, cyano, or hydroxyl groups.

[0108] In some embodiments, the compound has the structure shown in formula (VI):

[0109]

[0110] in, Selected from single or double bonds;

[0111] R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced;

[0112] L is selected from NR 7 Or O;

[0113] R 7 Each is independently selected from H, halogen or C 1-6 alkyl;

[0114] R 5 Each is independently selected from -OC(O)-R 5a -C(O)OR 5a -OC(O)OR 5a -OR 5a -SC(O)OR 5a -SC(O)-R 5a -OC(O)NHR 5a -OC(O)NR 5a R 5b -SC(O)NR 5a R 5b -NHC(O)-R 5a -C(O)NH-R 5a -NHC(O)OR 5a -OC(O)-R 5a -OR 5c -OC(O)OR 5a -OR 5c -SC(O)OR 5a -OR5c 、-SC(O)-R 5a -O-R 5c 、-B(OR 5a )(OR 5b )、-B(OR 5a )(O-CO-R 5b )、-OC(O)NH(AA)C(O)OR 5a 、-O(CR 5a1 R 5b1 ) n -OC(O)R 5a 、-OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OC(O)NR 5a R 5b 、-O(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OP(O)(O(CR 5a1R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OCR 5a1 R 5b1 -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、O-(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -P(O)(OCR 5a1 R 5b1 OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OR 5a (O(CR)) 5a1 R 5b1 ) n OR 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OC(O)OR 5a )(OC(O)OR 5b );

[0115] R 5a R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-16 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 1-6 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0116] Or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0117] R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 3-8 cycloalkyl;

[0118] AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration;

[0119] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0120] R a Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 Halogenated alkyl; the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 The haloalkyl group may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 Alkyl halogenates are substituted.

[0121] In some embodiments, the compound has the structure shown in formula (VII):

[0122]

[0123] Among them, R 1 R 2 R 3 R 4 R 5 The definition is as stated in general formula (VI).

[0124] In a further implementation, the R 5 Selected from -OC(O)-R 5a -OC(O)OR 5a -OC(O)NHR 5a -OC(O)NR 5a R 5b -OC(O)NH(AA)C(O)OR 5a -O(CR) 5a1 R 5b1 ) n -OC(O)R 5a -O(CR) 5a1 R 5b1 ) n -OP(O)(OR 5a (OR) 5b ), -O(CR 5a1 R 5b1 ) n -OC(O)NR 5a R 5b -OP(O)(O(CR) 5a1 R 5b1 ) nOC(O)R 5a (O(C)) R5a1 R 5b1 ) n OC(O)R 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a (O(CR5)) a1 R 5b1 ) n OC(O)OR 5b ), -OP(O)(O(CR) 5a1 R 5b1 ) n OC(O)OR 5a (O(CR)) 5a1 R 5b1 ) n OC(O)OR 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a (O(CR)) 5a1 R 5b1 ) n OC(O)R 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OR 5a (O(CR)) 5a1 R 5b1 ) n OR 5b ), -O(CR 5a1 R 5b1 ) n -P(O)(OC(O)OR 5a )(OC(O)OR 5b ).

[0125] In a further implementation, the R 5a R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-16 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0126] Or, the R 5a and R 5b Together with the atoms they are attached to, they form C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced;

[0127] R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 alkyl;

[0128] R a Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine group, C 1-6 Haloalkyl, C 6-10 Aryl or 3-12 membered heterocyclic groups; the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine group, C 1-6 Haloalkyl, C 6-10 The aryl or 3-12 membered heterocyclic group may be further selected by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 Substituted with haloalkyl groups;

[0129] n is selected from 1 or 2.

[0130] In some implementations, the R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0131] In some embodiments, the compound has the structure shown in formula (VIII):

[0132]

[0133] Among them, R 5 Selected from -OC(O)-R 5a -OC(O)NR 5a R 5b -OCR 5a1 R 5b1 -OC(O)R 5a -OCR 5a1 R 5b1 -OC(O)NR 5a R 5b -O(CR) 5a1 R 5b1 ) n P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a (O(CR)) 5a1 R 5b1 ) n OC(O)R 5b ), -O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a (OR) 5b ) or -O(CR 5a1 R 5b1 ) n -P(O)(OR 5a (O(CR)) 5a1 R 5b1 ) n OR 5b );

[0134] The R 5a and R 5b Each is independently selected from hydrogen and C. 1-16 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, 5-8 membered heterocyclic, C 6-8 Aryl or 5-6 heteroaryl; the C 1-16 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, 5-8 membered heterocyclic, C 6-8 Aryl or 5-6 heteroaryl groups may optionally be further substituted with one or more R groups. a Replaced;

[0135] Or, the R 5a and R 5b Together with the atoms they are attached to, they form a 5-7 membered heterocyclic group; the 5-7 membered heterocyclic group may optionally be further bonded by one or more R... a Replaced;

[0136] R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 alkyl;

[0137] R a Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylamine group or 5-7 membered heterocyclic group;

[0138] n is selected from 0, 1, 2 or 3.

[0139] In some implementations, the R 5 Selected from

[0140]

[0141] In some embodiments, the compound is selected from...

[0142]

[0143]

[0144]

[0145] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (I'), (IA), (IB), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VII) or (VIII), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof.

[0146] In another aspect, the present invention provides the use of compounds of formula (I), (I'), (IA), (IB), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VII) or (VIII) as described above, or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts, or the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to NLRP3.

[0147] The present invention also provides the use of compounds comprising formulas (I), (I'), (IA), (IB), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VII) or (VIII) as described above, or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts, or the above pharmaceutical compositions in the prevention or treatment of diseases associated with NLRP3.

[0148] The present invention provides a method for treating and / or preventing diseases, comprising administering to a therapeutically effective amount of a compound of formula (I), (I'), (IA), (IB), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VII) or (VIII) as described above, or a stereoisomer, tautomer, deuterated compound or pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0149] Furthermore, the cancers mentioned include, but are not limited to, myeloproliferative neoplasms, myeloid leukemia, lung cancer, nasopharyngeal carcinoma, laryngeal cancer, esophageal cancer, bile duct cancer, oral cancer, head and neck cancer, mesothelioma, adrenocortical carcinoma, kidney cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, bone cancer, brain cancer, breast cancer, melanoma, pancreatic cancer, skin cancer, lymphoma, bladder cancer, small intestine cancer, soft tissue sarcoma, endometrial cancer, cervical cancer, osteosarcoma, prostate cancer, or testicular cancer.

[0150] Furthermore, the inflammatory diseases or diseases accompanied by inflammatory responses include, but are not limited to, chronic liver disease, liver fibrosis, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease, inflammatory arthritis, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, myelodysplastic syndrome, myelofibrosis, sickle cell disease, thrombocytopenia, atherosclerosis, type I and type II diabetes and related complications (e.g., heart failure, retinopathy, diabetic foot), peripheral artery disease, acute heart failure and hypertension, hyperoxaluria, lupus nephritis, hypertensive nephropathy, acute kidney injury, chronic nephritis, hemodialysis-related inflammation, diabetic nephropathy, and interstitial bladder disease. Cystitis, colitis, polymyositis, dermatomyositis, brain infection, acute traumatic brain injury, chronic migraine, neuropathic pain, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, mechanical wound healing, burns, scarring, acne, hidradenitis suppurativa, pyoderma gangrenosa, seborrheic dermatitis, Schnitzler syndrome, systemic lupus erythematosus, psoriasis, dry eye disease, keratitis, uveitis, macular degeneration, glaucoma, novel coronavirus infection and cytokine release syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchitis, asthma, sarcoidosis, age-related macular degeneration or thermocrine-related periodic syndrome.

[0151] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0152] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0153] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0154] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0155] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0156] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0157] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0158] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, more preferably C 3-6 Yuan, of which "C" 3-12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0159] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0160] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0161] The term "aryl," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbide ring atom. Preferably C 6-12 aryl, more preferably aryl is C 6-10Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0162] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0163] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-6 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, aza-butyl, pyrrolidinyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. Spiroheterocycles can be 6- to 12-membered spiroheterocycles, including, but not limited to, 4-azaspiro[2,4]heptane and 4-azaspiro[2,4]heptane. The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0164] The term "amino acid residue" refers to the unit of amino acids that make up a polypeptide. When these amino acids are linked together, some of their groups participate in the formation of peptide bonds, resulting in the loss of a water molecule. Therefore, the amino acid unit in a polypeptide is called an amino acid residue; that is, the remaining part after the amino acids linked by peptide bonds lose water. For example, the glycine residue is: -NH-CH2-CO-.

[0165] The term "α-amino acid" refers to any natural (encoded) and non-natural α-aminocarboxylic acid, including their D-isomers, which are called α-amino acids when the amino group is attached to a carbon atom (also called the α-carbon atom) directly bonded to the carboxyl carbon.

[0166] The term "β-amino acid" refers to any β-aminocarboxylic acid, that is, when the amino group is attached to a carbon atom (also called the β-carbon atom) that is one carbon atom away from the carboxyl carbon. Examples include β-alanine and isoserine.

[0167] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0168] The term "alkathioyl" refers to a straight-chain or branched alkyl group linked by sulfur atoms, i.e., -S-alkyl, such as C 1-6 Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), and hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio).

[0169] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0170] The term "cyano" refers to the -CN group.

[0171] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0172] The "compound" described in this invention includes, but is not limited to, the following forms of compounds: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, etc.

[0173] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0174] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0175] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0176] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0177] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0178] In addition to their salt forms, the compounds provided by this invention exist as phenolic esters. The compounds described in this invention readily undergo chemical changes under physiological conditions to transform into active metabolites with comparable or higher NLRP3 inhibitory activity. Furthermore, the compounds described in this invention can be converted into their corresponding active metabolites in the in vivo environment via chemical or biochemical methods.

[0179] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0180] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of deriving pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0181] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0182] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0183] Unless otherwise stated, this invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof, when the compounds represented by formulas (I), (I'), (IA), (IB), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VII) or (VIII) are present.

[0184] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0185] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0186] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0187] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0188] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0189] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0190] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0191] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0192] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0193] This invention, based on the target design of NLRP3 inhibitors, develops novel nitrogen-containing compounds that can serve as NLRP3 inhibitors. Related biological experiments have shown that these compounds exhibit significant IL-1β secretion inhibitory activity in THP-1 cells. Compared to the active metabolites, the compounds of this invention have a higher percentage of free concentration in plasma and higher concentrations of the active metabolites in rat sciatic nerve, spinal cord, and brain tissue. They can be effectively converted into the corresponding active metabolites in both rats and mice. In a mouse inflammation model, the compounds of this invention significantly reduce the levels of inflammatory factors IL-1β, IL-1α, and TNF-α in serum, as well as IL-1β levels in peritoneal lavage fluid, demonstrating significant clinical application potential. Furthermore, the synthetic route provided by this invention is novel, safe, environmentally friendly, and feasible for production. Attached Figure Description

[0194] Figure 1The effect of compound 27 in Example 6 on LPS-induced IL-1β cytokine in mouse serum.

[0195] Figure 2 The effect of compound 27 in Example 6 on LPS-induced IL-1α cytokine in mouse serum.

[0196] Figure 3 The effect of compound 27 in Example 6 on LPS-induced TNF-α cytokine in mouse serum.

[0197] Figure 4 The effect of compound 27 in Example 6 on the cytokine IL-1β in LPS-induced mouse peritoneal lavage fluid. Detailed Implementation

[0198] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0199] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0200] Compound M2: (R)-1-methylpiperidin-3-amine was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd. According to the quality inspection report provided by the raw material supplier, the purity (NMR) was 97% and the optical rotation was 9.8417° (c = 1.0 g / 100 mL, CHCl3).

[0201] This invention uses the following abbreviations:

[0202] TsOH·H2O: p-Toluenesulfonic acid monohydrate; NBS: N-bromosuccinimide; ACN: Acetonitrile; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; K2CO3: Potassium carbonate; MeB(OH)2: Methylboric acid; NaNO2: Sodium nitrite; SnCl2·2H2O: Stannous chloride dihydrate; TEA: Triethylamine; THF: Tetrahydrofuran; DIPEA: N,N-Diisopropylethylamine; n-BuOH: n-Butanol; BBr3: Boron tribromide; DCM: Dichloromethane; MeOH: Methanol; EA: Ethyl acetate; NaHCO3: Sodium bicarbonate; Na2SO4: Sodium sulfate; DMAP: 4-Dimethylaminopyridine; BTC: Triphosgene; PE: Petroleum ether; DMF: N,N-Dimethylformamide; Cs2CO3: Cesium carbonate; BzCl: Benzoyl chloride; In the embodiments of this invention, x mL×y: indicates y repetitions, x mL each time. For example, if DCM is used for extraction (10 mL×3), it means that 10 mL of dichloromethane is used for extraction each time, and the repetition is repeated 3 times. In the embodiments of this invention, the eluent is used in volume ratio. For example, EA:PE=1:5 means that the volume ratio of ethyl acetate and petroleum ether is 1:5.

[0203] Synthesis of intermediate (R)-3-methyl-2-(6-(1-methylpiperidin-3-yl)amino)-2H-pyrazol[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenol hydrochloride (IA)

[0204]

[0205] Step 1: Synthesis of 2,4-dichloro-5-(dimethoxymethyl)pyrimidine (M1)

[0206] Compound M0 was added sequentially to a flask: 2,4-dichloropyrimidin-5-carboxaldehyde (500.0 mg, 2.82 mmol), TsOH·H₂O (32.3 mg, 0.17 mmol), and trimethyl orthoformate (1.08 g, 10.18 mmol). MeOH (6 mL) was then added, and the mixture was reacted at 65 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 1:5) to give compound M1 (439.0 mg), with a yield of 73.5%.

[0207] LC-MS (ESI, m / z): 223.0 [M+H] + .

[0208] Step 2: Synthesis of 2-bromo-6-methoxy-4-(trifluoromethyl)aniline (I-2)

[0209] Compound I-1, 2-methoxy-4-(trifluoromethyl)aniline (1.00 g, 5.23 mmol), was dissolved in ACN (20 mL). While maintaining an internal temperature below 10 °C, NBS (977.5 mg, 5.49 mmol) was slowly added in an ice bath, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was diluted with EA (50 mL), washed with NaHCO3 solution (30 mL), water (20 mL), and saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (EA:PE = 7:93) to give compound I-2 (1.15 g), with a yield of 81.6%.

[0210] LC-MS(ESI,m / z):270.0 / 272.0[M+H] + .

[0211] Step 3: Synthesis of 2-methoxy-6-methyl-4-(trifluoromethyl)aniline (I-3)

[0212] Compound I-2 (1.14 g, 4.25 mmol), MeB(OH)2 (0.51 g, 8.50 mmol), K2CO3 (1.47 g, 10.62 mmol), and Pd(dppf)Cl2 (115.5 mg, 0.21 mmol) were added sequentially to a flask, followed by dioxane (20 mL) and water (2 mL). The reaction mixture was then incubated at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with EA (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (EA:PE = 1:9) to give compound I-3 (568.0 mg), with a yield of 65.1%.

[0213] LC-MS (ESI, m / z): 206.0 [M+H] + .

[0214] Step 4: Synthesis of 2-methoxy-6-methyl-4-(trifluoromethyl)phenylhydrazine (I-4)

[0215] Compound I-3 (568.0 mg, 2.77 mmol) was dissolved in concentrated hydrochloric acid (5 mL) under ice-salt bath conditions. While maintaining the internal temperature below 0°C, a solution of NaNO2 (286.5 mg, 4.15 mmol) in water (5 mL) was slowly added dropwise. The reaction was continued at this temperature for 40 minutes. Then, while maintaining the internal temperature below 0°C, a solution of SnCl2·2H2O (1.25 g, 5.34 mmol) in concentrated hydrochloric acid (3 mL) was slowly added dropwise, and the reaction was continued at this temperature for 1 hour. The reaction solution was filtered, and the filter cake was washed with a small amount of water, diluted with EA (20 mL), and adjusted to alkalinity with a saturated Na2CO3 aqueous solution. The mixture was separated, and the aqueous phase was extracted with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound I-4 (135.0 mg), with a yield of 22.1%.

[0216] Step 5: Synthesis of 2-chloro-5-(dimethoxymethyl)-4-(2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)hydrazyl)pyrimidine (I-5)

[0217] Compound I-4 (135.0 mg, 0.61 mmol) and compound M1 (136.8 mg, 0.61 mmol) were dissolved in THF (50 mL), and TEA (0.25 mL, 1.84 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was then concentrated and purified by column chromatography (EA:PE = 35:65) to give compound I-5 (88.0 mg), in a yield of 35.3%.

[0218] LC-MS (ESI, m / z): 407.0 [M+H] + .

[0219] Step 6: Synthesis of 6-chloro-2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-2H-pyrazole[3,4-d]pyrimidine (I-6)

[0220] Compound I-5 (88.0 mg, 0.22 mmol) was dissolved in ACN (5 mL), and p-TsOH·H₂O (41.1 g, 0.22 mmol) was added. The reaction solution was placed at 70 °C for 1 hour. After the reaction solution cooled to room temperature, it was concentrated and purified by column chromatography (EA:PE = 30:70) to give compound I-6 (59.0 mg), with a yield of 79.7%.

[0221] LC-MS (ESI, m / z): 343.0 [M+H] + .

[0222] Step 7: Synthesis of (R)-2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)-2H-pyrazol[3,4-d]pyrimidine-6-amine (I-7)

[0223] Compound I-6 (59.0 mg, 0.17 mmol) and compound M2 (R)-1-methylpiperidin-3-amine (23.6 g, 0.21 mmol) were dissolved in n-butanol (3 mL), and DIPEA (0.09 mL, 0.52 mmol) was added. The mixture was reacted at 100 °C for 1 hour. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure and purified by column chromatography (MeOH:DCM = 5:95) to give compound I-7 (128.0 mg).

[0224] LC-MS (m / z): 421.0 [M+H] + .

[0225] Step 8: Synthesis of (R)-3-methyl-2-(6-(1-methylpiperidin-3-yl)amino)-2H-pyrazol[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenol (I-8)

[0226] Compound I-7 (128.0 mg, 0.17 mmol) was dissolved in DCM (5 mL), and a DCM solution of BBr3 (2.0 M, 0.5 mL) was added under ice-water bath conditions. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with MeOH, concentrated under reduced pressure, and purified by reverse reaction to give compound I-8 (41.3 mg), with a two-step yield of 47.0%.

[0227] LC-MS (ESI, m / z): 407.0 [M+H] + .

[0228] 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.48(s,1H),7.23(s,1H),7.20-7.13(m,2H),4.08-3.94(m,1H),3.06-2.98(m,1H),2.8 0-2.70(m,1H),2.30(s,3H),2.21-1.99(m,5H),1.91-1.82(m,1H),1.79-1.69(m,1H),1.65-1.50(m,1H),1.45-1.29(m,1H).

[0229] Step 9: Synthesis of (R)-3-methyl-2-(6-(1-methylpiperidin-3-yl)amino)-2H-pyrazol[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenol hydrochloride (IA)

[0230] Compound I-8 (3.22 g) was dissolved in MeOH (40 mL), and EA solution of HCl (4.0 M, 10 mL) was added. After reacting at room temperature for 1 hour, the solution was concentrated and dried to give compound IA (3.47 g), with a yield of 98.9%.

[0231] LC-MS (ESI, m / z): 407.0 [M+H] + .

[0232] 1 H NMR(600MHz,DMSO-d6)δ11.09(brs,1H),10.55-10.35(m,1H),9.30-9.15(m, 1H),8.72-8.56(m,1H),8.10-7.70(m,1H),7.31(d,J=2.0Hz,1H),7.25(d,J= 2.0Hz,1H),4.32-4.24(m,1H),3.65-3.54(m,1H),3.41-3.33(m,1H),2.92-2 .74(m,5H),2.08(s,3H),2.07-2.01(m,1H),1.95-1.76(m,2H),1.50(m,1H).

[0233] Example 11: Synthesis of (R)-3-methyl-2-(6-(1-methylpiperidin-3-yl)amino)-2H-pyrazol[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenol (compound 11)

[0234]

[0235] Compound I-8 (414.0 mg, 1.02 mmol) and potassium carbonate (281.6 mg, 2.04 mmol) were added to anhydrous DMF (10 mL), and M3: dimethylcarbamoyl chloride (0.11 mL, 1.22 mmol) was added dropwise under an ice-water bath. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was quenched with water (20 mL), extracted with EA (20 mL × 2), the organic phases were combined, washed with water (20 mL × 4) and saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 13:87) to give compound 11 (261.2 mg).

[0236] LC-MS (ESI, m / z): 478.0 [M+H] + .

[0237] 1H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.52(s,1H),7.77(s,1H),7.73(s,1H),7.22(s,1H),4.09–3.81(m,1H),3.05–2.85(m,1H),2.7 5(s,3H),2.69–2.58(m,4H),2.22(s,3H),2.18(s,3H),1.97–1.81(m,3H),1.75–1.68(m,1H),1.59–1.47(m,1H),1.42–1.29(m,1H).

[0238] Example 26: Synthesis of (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenyl[1,4'-bipiperidin]-1'-carboxylic acid ester (compound 26)

[0239]

[0240] Compound IA (100.0 mg, 0.23 mmol) and TEA (114.0 mg, 1.13 mmol) were dissolved in anhydrous DCM (2 mL) under ice-water bath conditions. BTC (76.0 mg, 0.45 mmol) was added, and the mixture was stirred for 30 minutes. Then, M4: 4-piperidinylpiperidine (67.0 mg, 0.23 mmol) was added, and the reaction was carried out at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was quenched with water (10 mL), extracted with DCM (10 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (eluent ACN: 10 mM NH4HCO3 aqueous solution = 0–100%) to give compound 26 (23.0 mg), with a yield of 17.0%.

[0241] LC-MS (ESI, m / z): 601.0 [M+H] + .

[0242] 1H NMR(600MHz,DMSO-d6)δ9.13(s,1H),8.48(s,1H),7.79(s,1H),7.71(s,1H),7.22(s,1H),4.00–3.72(m,3H),2.74–2.64(m,3H), 2.31–2.18(m,8H),2.14(s,3H),1.87–1.82(m,1H),1.74–1.67(m,1H),1.60–1.32(m,13H),1.05–0.94(m,1H),0.72–0.59(m,1H).

[0243] Example 27: Synthesis of (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenyl neopentanoate (compound 27)

[0244]

[0245] Compound IA (100.0 mg, 0.23 mmol) and TEA (114.0 mg, 1.13 mmol) were dissolved in DCM (2 mL) at room temperature. DMAP (2.8 mg, 0.02 mmol) and M5: pentanoyl chloride (81.7 mg, 0.68 mmol) were added sequentially, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH:DCM = 0–10%) to give compound 27 in 24.7% yield.

[0246] LC-MS (ESI, m / z): 491.0 [M+H] + .

[0247] 1 H NMR(600MHz,DMSO-d6)δ9.17–9.06(m,1H),8.52–8.46(m,1H),7.84(s,1H),7.76(s,1H),7.26–7.13(m,1H),4.02–3.87(m,1H),3.00–2.8 2(m,1H),2.72–2.58(m,1H),2.25–2.11(m,7H),1.90–1.81(m,2H),1.74–1.66(m,1H),1.58–1.50(m,1H),1.37–1.28(m,1H),0.96(s,9H).

[0248] Example 47: Synthesis of (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenethyl(methyl)carbamate (compound 47)

[0249]

[0250] Compound IA (100.0 mg, 0.23 mmol) was dissolved in DMF (2 mL) at room temperature, followed by the addition of K2CO3 (62.4 mg, 0.45 mmol) and M6:N-ethyl-N-methylcarbamoyl chloride (32.9 mg, 0.27 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH:DCM = 0–10%) to give compound 47 (75.3 mg), with a yield of 67.8%.

[0251] LC-MS (ESI, m / z): 492.0 [M+H] + .

[0252] 1 H NMR(600MHz,DMSO-d6)δ9.12(s,1H),8.50(s,1H),7.80–7.75(m,1H),7.7 5–7.70(m,1H),7.18(s,1H),4.04–3.88(m,1H),3.13–3.03(m,2H),2.99– 2.83(m,1H),2.78–2.57(m,4H),2.24–2.13(m,6H),2.04–1.80(m,3H),1. 74–1.64(m,1H),1.60–1.48(m,1H),1.39–1.28(m,1H),0.90–0.62(m,3H).

[0253] Example 48: Synthesis of (R)-((3-methyl-2-(6-(1-methylpiperidin-3-yl)amino)-2H-pyrazol[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenoxy)methyl)phosphonate diethyl ester (compound 48)

[0254]

[0255] Compounds I-8 and M7: diethyl p-toluenesulfonyloxymethylphosphonate (483.5 mg, 1.50 mmol) were dissolved in anhydrous DMF (10 mL), and Cs₂CO₃ (977.4 mg, 3.00 mmol) was added. The mixture was reacted at 80 °C for 4 hours. After cooling to room temperature, the reaction solution was diluted with EA (50 mL), washed with water (50 mL × 4) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 0–10%) to give compound 48 (319.0 mg), with a yield of 57.3%.

[0256] LC-MS (ESI, m / z): 557.0 [M+H] + .

[0257] 1 H NMR(600MHz,DMSO-d6)δ9.11(s,1H),8.47(s,1H),7.62(s,1H),7.50(s,1H), 7.11(s,1H),4.61(d,J=9.8Hz,2H),3.96(s,1H),3.82(h,J=7.2Hz,4H),2.89 (s,1H),2.68–2.56(m,1H),2.18(s,3H),2.11(s,3H),1.97–1.79(m,3H),1.7 2–1.65(m,1H),1.58–1.48(m,1H),1.36–1.26(m,1H),1.04(t,J=7.1Hz,6H).

[0258] Example 59: Synthesis of (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-5-(trifluoromethyl)phenylbenzoate

[0259]

[0260] I-8 (300.0 mg, 0.74 mmol) and DIPEA (190.7 mg, 1.48 mmol) were added to anhydrous DCM (5 mL). The reaction mixture was cooled to 0 °C, and a DCM solution of benzoyl chloride (103.8 mg, 0.74 mmol) in 2 mL was added dropwise. The mixture was then allowed to rise to room temperature for 5 minutes. The reaction mixture was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give compound 59 (289.0 mg), with a yield of 76.7%.

[0261] LC-MS (m / z): 511.0 [M+H] + .

[0262] 1H NMR(600MHz,DMSO-d6)δ9.08(s,1H),8.66(s,1H),8.02–7.99(m,1H),7.92–7.89(m,1H),7.83–7.79(m,2H),7.70–7.64(m,1H), 7.50–7.44(m,2H),7.34(s,1H),4.05–3.92(m,1H),3.66–3.55(m,1H),3.23–3.00(m,2H),2.45–2.17(m,7H),1.86–1.53(m,4H).

[0263] Bioactivity test

[0264] Example 1: Detection of plasma protein binding rate of compounds

[0265] Reagent preparation:

[0266] The test compound was prepared as a 1 mM dimethyl sulfoxide (DMSO) working solution, and the reference compound Warfarin was prepared as a 200 μM DMSO working solution.

[0267] Experimental methods:

[0268] 1. Blank matrix preparation: Freshly collected blood is centrifuged at 2000g / min for 10min at 4℃ to obtain blank plasma; or plasma stored at -70℃ is taken out, thawed in a 37℃ water bath, and the pH is adjusted to about 7.4±0.03 with dilute phosphoric acid.

[0269] 2. Preparation of PB buffer: Weigh a certain amount of NaH2PO4 and dissolve it in deionized water to prepare a 0.1M (12.0 g / L) solution A; weigh a certain amount of Na2HPO4 and dissolve it in deionized water to prepare a 0.1M (14.2 g / L) solution B. Mix solutions A and B in a ratio of 19:81, and adjust the pH to 7.4 ± 0.03 using H3PO4 and NaOH according to the pH value.

[0270] 3. According to the table below, take 4.00 μL of working solution and mix it with 796 μL of the corresponding plasma. After mixing thoroughly, take 50.0 μL and add 50.0 μL of LPB buffer and 400 μL of methanol (containing 1.00 ng / mL ramelteamide) as the zero point sample (T0) to investigate the recovery rate.

[0271] 4. The protein binding rate of the compounds was determined using a RED rapid equilibrium dialysis apparatus. 200 μL of drug-containing matrix was added to the test chamber (red well, plasma side, i.e., P side), and 400 μL of PB solution was added to the receiving chamber (white well, buffer side, i.e., B side). The plate was sealed with a sealing membrane and placed on a 37°C constant temperature shaker at 100 rpm for 6 h of dialysis.

[0272] 5. The remaining drug-containing system was incubated together on a 37°C constant temperature shaker to assess drug stability;

[0273] 6. After equilibration dialysis for 6 hours, take 50.0 μL of the test chamber sample (P side) and the stability sample (T6), add 50.0 μL of LPB solution and 400 μL of methanol (containing 1.00 ng / mL ramelteinamide); take 50.0 μL of the receiving chamber sample (B side), add 50.0 μL of blank matrix solution and 400 μL of methanol (containing 1.00 ng / mL ramelteinamide);

[0274] 7. After vortexing all samples for 1 min, centrifuge at 17000g for 10 min at 4℃, and take 180.0 μL for LC-MS detection.

[0275] Results analysis:

[0276] An LC-MS / MS analytical method for determining compound concentrations was established, and the ratio of analyte / internal standard peak area (Aanalyte / AIS) in the measured sample was used as the surrogate concentration for data processing.

[0277] The formulas for calculating the free fraction of the compound in plasma, plasma protein binding rate, recovery rate, and stability are as follows:

[0278]

[0279] Bound (%) = 100% - Fu (%)

[0280]

[0281] Table 1. Detection of plasma protein binding rate of compounds.

[0282]

[0283] Experimental results showed that compounds 11, 26, and 47 had higher percentages of free concentration in plasma than IA.

[0284] Example 2: Inhibitory effect of the compound on IL-1β secretion by THP-1 cells

[0285] THP-1 cells were purchased from Wuhan Pronosei Biotechnology Co., Ltd. (catalog number CL-0233). The complete culture medium used was RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-strep antibiotics (Pen-Strep), and a final concentration of 0.05 mM β-mercaptoethanol. Cells were cultured according to the supplier's instructions, and the cell density was maintained in the logarithmic growth phase before the experiment. The cell density was then adjusted to 5 × 10⁶ cells / year. 4 For each well, phorbol-12-tetradecanoyl-13-acetate (PMA) was added to a final concentration of 100 ng / mL for induction for 16 h. After removing the PMA medium, 90 μL of complete medium containing 10 ng / mL lipopolysaccharide (LPS) was added for stimulation for 3 h. The compound of this invention was dissolved in dimethyl sulfoxide (DMSO), diluted 3-fold with medium to the desired concentration, and added to each well of a 96-well plate. After incubation for 1 h, 10 μL of nigra sodium (final concentration of 10 μM) was added to the treated plate for stimulation for 1 h. Cell-free supernatant was collected, and IL-1β levels were evaluated according to the ELISA kit instructions (Hangzhou Lianke Biotechnology Co., Ltd.). The medium group served as a negative control, and the DMSO group served as a positive control. Inhibition rate (%) = (1 - (experimental group value - negative control) / (positive control - negative control)) × 100%, IC50 50 The slope was fitted using the four-parameter method of log(agonist) vs. response-variable slope in GraphPad software. The results are shown in Table 2.

[0286] Table 2 shows the inhibitory effects of the compounds on IL-1β secretion from THP-1 cells.

[0287] compound <![CDATA[IC 50 (nM)]]> IA 14.9 27 51.2

[0288] Example 3: Detection of I-8 concentration in sciatic nerve, spinal cord, and brain tissue of SD rats after a single oral administration

[0289] Eight male SD rats were randomly divided into four groups of two rats each. Two groups were administered compounds 27 and 59 (3 mg / kg as I-8) by gavage, while the other two groups were administered I-8 at a dose of 3 mg / kg. The administration volume for each group was 10 mL / kg. Rats in the same compound group were euthanized by cervical dislocation and exsanguination at 2 h and 6 h post-administration. Tissues from the brain, spinal cord, and sciatic nerve were collected. The tissues were washed with physiological saline, blotted dry with filter paper, and homogenized using a 1 g:4 mL 50% methanol-water solution with a small steel ball. The homogenate was then centrifuged within one hour (1500 g / min, 5 min, 4℃). The tissue supernatant was stored at -80℃ before analysis. The samples were analyzed by LC-MS / MS with an injection volume of 1.00 μL. The results are shown in Table 3.

[0290] Table 3 shows the drug concentrations of compound I-8 in the sciatic nerve, spinal cord, and brain tissue after administration of the compounds.

[0291]

[0292] The results showed that, compared with the administered I-8, the administered compounds 27 and 59 had higher concentrations of the active metabolite I-8 in the sciatic nerve, spinal cord, and brain tissue.

[0293] Example 4: Concentration detection of compound conversion to I-8 in SD rats

[0294] Male SD rats (n=3) were fasted overnight (with free access to water). Blood samples of 0.3 mL were collected from the orbital venous plexus at 5 min, 15 min, and 240 min after oral administration of the drug (PO). Disodium EDTA-2Na was used for anticoagulation. After collection, the samples were placed on ice and centrifuged at 4℃ (2000 g / min, 10 min) within 1 hour to separate the plasma. The plasma was stored at -20℃ for analysis. The plasma concentration of the parent drug was determined by LC-MS / MS. The results of the plasma drug concentration data at different time points are shown in Table 4.

[0295] Table 4. Concentrations of the parent compound and I-8 in SD rats after administration of 11 and 27 doses.

[0296]

[0297] " / " indicates a concentration below the detection limit.

[0298] The results showed that after administration of compounds 11 and 27, the parent compounds were effectively converted into the active metabolite I-8 in SD rats.

[0299] Example 5: Determination of the concentration of the compound converted to I-8 in Balb / c mice

[0300] Female Balb / c mice (n=3) were fasted overnight (with free access to water). Blood samples of 0.1 mL were collected from the orbital venous plexus at 5 min, 15 min, and 240 min after oral administration of the drug (PO). Anticoagulation was performed using dipotassium ethylenediaminetetraacetate (EDTA-2K). The collected samples were placed on ice and centrifuged at 4°C (2000 g / min, 10 min) within 1 hour to separate the plasma. The plasma was stored at -20°C for analysis. The plasma concentration of the parent drug was determined by LC-MS / MS. The results of the plasma drug concentration data at different time points are shown in Table 5.

[0301] Table 5. Concentrations of the parent compound and I-8 in Balb / c mice after 47 days of drug administration.

[0302]

[0303]

[0304] The results showed that after administration of compound 47, the parent compound was effectively converted into the active metabolite I-8 in Balb / c mice.

[0305] Example 6: Inhibitory effect of compound 27 on inflammatory factors in a mouse model of LPS combined with adenosine triphosphate (ATP)-induced inflammation.

[0306] Eight-week-old male C57BL / 6 mice were randomly divided into three groups of eight: a Control group, a Model group, and a Compound 27 administration group (3.6 mg / kg, equivalent to 3 mg / kg I-8). The Compound 27 administration group received the compound once daily via gavage for three consecutive days, while the Control and Model groups received the corresponding volume of solvent daily. One hour after gavage administration on the third day, the Model and Compound 27 administration groups were intraperitoneally injected with LPS (5 mg / kg). Two hours later, ATP at a concentration of 20 mM was injected intraperitoneally at a dose of 0.1 mL / 10 g. The Control group received the corresponding volume of physiological saline intraperitoneally. Thirty minutes after the ATP intraperitoneal injection, blood and peritoneal lavage fluid were collected from each group. The blood was anticoagulated with 3% EDTA-2K and centrifuged at 4°C (2000 × g, 10 min). Serum was separated and stored at -65°C for later use. The levels of serum inflammatory factors IL-1β, IL-1α, and TNF-α, as well as IL-1β in peritoneal lavage fluid, were detected using flow cytometry microsphere array (CBA) multifactor detection technology. The experimental results are shown below. Figure 1 , Figure 2 , Figure 3 and Figure 4 .

[0307] The results showed that compound 27 significantly reduced the levels of inflammatory factors IL-1β, IL-1α, and TNF-α in mouse serum and peritoneal lavage fluid induced by LPS combined with ATP.

Claims

1. A compound having the following general structural formula (IV), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof: in, Selected from single or double bonds; R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced; Or, R 2 With R 3 And the atoms connected to it form C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl; the C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced; Or, R 3 With R 4 And the atoms connected to it form C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl; the C 3-8 Cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced; R 5 each independently selected from -OC(O)-R 5a 、-C(O)O-R 5a 、-OC(O)O-R 5a 、-O-R 5a 、-SC(O)O-R 5a 、-SC(O)-R 5a 、-OC(O)NHR 5a 、-OC(O)NR 5a R 5b 、-SC(O)NR 5a R 5b 、-NHC(O)-R 5a 、-C(O)NH-R 5a 、-NHC(O)O-R 5a 、-OC(O)-R 5a -O-R 5c 、-OC(O)O-R 5a -O-R 5c 、-SC(O)O-R 5a -O-R 5c 、-SC(O)-R 5a -O-R 5c 、-B(OR 5a )(OR 5b )、-B(OR 5a )(O-CO-R 5b )、-OC(O)NH(AA)C(O)OR 5a 、-O(CR 5a1 R 5b1 ) n -OC(O)R 5a 、-OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OC(O)NR 5a R 5b 、-O(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OCR 5a1 R 5b1 -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、O-(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -P(O)(OCR 5a1 R 5b1 OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(OC(O)OR 5a )(OC(O)OR 5b ); R 5a R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-16 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further substituted with one or more R groups. a Replaced; Or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced; R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 3-8 cycloalkyl; AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration; n is selected from 0, 1, 2, 3, 4, 5, or 6; R 6 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkylamine or C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 alkylamine or C 1-6 Alkoxy groups may optionally be further selected from one or more C 1-6 Substituted by alkyl, halogen, or hydroxyl substituents; B is selected from 3-12 N-containing heterocyclic groups, which may optionally be further divided by one or more R groups. a Replaced; L is selected from NR 7 O or C(R) 7 )2; R 7 Each is independently selected from H, halogen or C 1-6 alkyl; R a Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 Alkylamine, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl, the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 Alkylamine, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may be further selected by one or more groups chosen from deuterium, halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl or C 1-6 The substituents of the alkylamine group are replaced.

2. The compound as claimed in claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound has the structure shown in formula (VI): in, Selected from single or double bonds; R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may optionally be further reacted with one or more R groups. a Replaced; L is selected from NR 7 Or O; R 7 Each is independently selected from H, halogen or C 1-6 alkyl; R 5 each independently selected from -OC(O)-R 5a 、-C(O)O-R 5a 、-OC(O)O-R 5a 、-O-R 5a 、-SC(O)O-R 5a 、-SC(O)-R 5a 、-OC(O)NHR 5a 、-OC(O)NR 5a R 5b 、-SC(O)NR 5a R 5b 、-NHC(O)-R 5a 、-C(O)NH-R 5a 、-NHC(O)O-R 5a 、-OC(O)-R 5a -O-R 5c 、-OC(O)O-R 5a -O-R 5c 、-SC(O)O-R 5a -O-R 5c 、-SC(O)-R 5a -O-R 5c 、-B(OR 5a )(OR 5b )、-B(OR 5a )(O-CO-R 5b )、-OC(O)NH(AA)C(O)OR 5a 、-O(CR 5a1 R 5b1 ) n -OC(O)R 5a 、-OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a )(OR 5b )、-O(CR 5a1 R 5b1 ) n -OC(O)NR 5a R 5b 、-O(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-OCR 5a1 R 5b1 -OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-OP(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、O-(CR 5a1 R 5b1 ) n -O(CR 5a1 R 5b1 ) n -P(O)(OCR 5a1 R 5b1 OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)OR 5a )(O(CR 5a1 R 5b1 ) n OC(O)OR 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b )、-O(CR 5a1 R 5b1 ) n -P(O)(OC(O)OR 5a )(OC(O)OR 5b ); R 5a R 5b and R 5c Each is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C 1-16 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 1-6 Alkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced; Or, R 5a and R 5b Together with the atoms they are attached to, they form C 3-12 Cycloalkyl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; the C 3-12 Cycloalkyl, 3-12-membered heterocyclic or 5-10-membered heteroaryl groups may optionally be further coupled with one or more R groups. a Replaced; R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 3-8 cycloalkyl; AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration; n is selected from 0, 1, 2, 3, 4, 5, or 6; R a Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 Halogenated alkyl; the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 The haloalkyl group may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkylamine or C 1-6 Alkyl halogenates are substituted.

3. The compound as described in claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound has the structure shown in formula (VII): Among them, R 1 R 2 R 3 R 4 R 5 The definition is as described in claim 2.

4. The compound according to any one of claims 1 to 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 1 R 2 R 3 R 4 Each is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

5. The compound according to any one of claims 1 to 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound has the structure shown in formula (VIII): wherein, R 5 is selected from -OC(O)-R 5a 、-OC(O)NR 5a R 5b 、-OCR 5a1 R 5b1 -OC(O)R 5a 、-OCR 5a1 R 5b1 -OC(O)NR 5a R 5b 、-O(CR 5a1 R 5b1 ) n P(O)(O(CR 5a1 R 5b1 ) n OC(O)R 5a )(O(CR 5a1 R 5b1 ) n OC(O)R 5b 、-O(CR 5a1 R 5b1 ) n -OP(O)(OR 5a )(OR 5b ) or -O(CR 5a1 R 5b1 ) n -P(O)(OR 5a )(O(CR 5a1 R 5b1 ) n OR 5b ); The R 5a and R 5b Each is independently selected from hydrogen and C. 1-16 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, 5-8 membered heterocyclic, C 6-8 Aryl or 5-6 heteroaryl; the C 1-16 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, 5-8 membered heterocyclic, C 6-8 Aryl or 5-6 heteroaryl groups may optionally be further substituted with one or more R groups. a Replaced; Or, the R 5a and R 5b Together with the atoms they are attached to, they form a 5-7 membered heterocyclic group; the 5-7 membered heterocyclic group may optionally be further bonded by one or more R... a Replaced; R 5a1 and R 5b1 Each is independently selected from hydrogen, halogen, and C. 1-6 alkyl; R a Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylamine group or 5-7 membered heterocyclic group; n is selected from 0, 1, 2 or 3.

6. The compound according to any one of claims 1 to 5, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 5 Selected from 7. The compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound is selected from 8. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 7, or a stereoisomer, tautomer, deuterated compound, or pharmaceutical salt thereof.

9. The use of the compound of any one of claims 1 to 7, or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for the prevention or treatment of diseases associated with NLRP3.

10. The application according to claim 9, characterized in that, The diseases mentioned are selected from cancer, inflammatory diseases, or diseases accompanied by inflammatory responses; The cancers mentioned include, but are not limited to, myeloproliferative neoplasms, myeloid leukemia, lung cancer, nasopharyngeal carcinoma, laryngeal cancer, esophageal cancer, bile duct cancer, oral cancer, head and neck cancer, mesothelioma, adrenocortical carcinoma, kidney cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, bone cancer, brain cancer, breast cancer, melanoma, pancreatic cancer, skin cancer, lymphoma, bladder cancer, small intestine cancer, soft tissue sarcoma, endometrial cancer, cervical cancer, osteosarcoma, prostate cancer, or testicular cancer. The inflammatory diseases or diseases accompanied by inflammatory responses mentioned include, but are not limited to, chronic liver disease, liver fibrosis, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease, inflammatory arthritis, gout, chondrocyte calcification, osteoarthritis, rheumatoid arthritis, myelodysplastic syndrome, myelofibrosis, sickle cell disease, thrombocytopenia, atherosclerosis, type I and type II diabetes and related complications (e.g., heart failure, retinopathy, diabetic foot), peripheral artery disease, acute heart failure and hypertension, hyperoxaluria, lupus nephritis, hypertensive nephropathy, acute kidney injury, chronic nephritis, hemodialysis-related inflammation, diabetic nephropathy, interstitial cystitis, colitis, and multiple inflammatory diseases. Myositis, dermatomyositis, brain infection, acute traumatic brain injury, chronic pain, chronic migraine, neuropathic pain, nerve injury, neuropathy, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, mechanical wound healing, burns, scarring, acne, hidradenitis suppurativa, pyoderma gangrenosa, seborrheic dermatitis, Schnitzler syndrome, systemic lupus erythematosus, psoriasis, dry eye disease, keratitis, uveitis, macular degeneration, glaucoma, novel coronavirus infection and cytokine release syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchitis, asthma, sarcoidosis, age-related macular degeneration or thermocrine-related periodic syndrome.

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