NLRP3 micromolecular protein degradation agent as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an NLRP3 small-molecule protein degradation agent and a preparation method and application thereof.Experiments show that compounds in an inhibitor have the effect of degrading NLRP3, and Elisa experimental results of the prepared compounds show that compounds J-1-J-6 can have the effect of inhibiting IL-1beta generated by THP-1 cell lines; wherein the inhibition effect of the compound J-1 is relatively obvious; a Western Blot experiment result of the prepared compound J-1 shows that the compound J-1 can generate an effect of reducing NLRP3 from a protein level on a THP-1 cell line. The inhibitor can be used for preparing drugs for preventing or treating diseases related to inhibition of NLRP3 activity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a NLRP3 small molecule protein degrader and a preparation method thereof. Such compounds have the function of degrading NLRP3 and are expected to be used in the preparation of drugs for preventing or treating diseases related to the inhibition of NLRP3 activity. Background Art

[0002] NOD-like receptor pyrin domain-associated protein 3 (NLRP3) is a member of the nucleotide oligomerization domain-like receptor family. After exogenous or endogenous stimulation, NLRP3 protein oligomerizes with apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain focus and recruits pro-caspase-1 to form the NLRP3 inflammasome. The activated NLRP3 inflammasome cleaves and activates pro-caspase-1, releasing active caspase-1, leading to the maturation of IL-1β, IL-18 and Gasdermin D (GSDMD). The mature GSDMD protein will make holes in the cell membrane, leading to the diffusion of inflammatory factors IL-1β and IL-18 and cell pyroptosis. Studies have shown that inhibiting the activation of NLRP3 protein and blocking the formation of NLRP3 inflammasome can effectively reduce the excessive inflammatory response of the body's tissues, thereby treating gout, type 2 diabetes, atherosclerosis, neurodegenerative diseases and other inflammatory-related diseases.

[0003] The inherited CAPS disease Muckle-Wells syndrome (MWs), familial cold autoinflammatory syndrome, and neonatal onset multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, making NLRP3 an important therapeutic target for these diseases. NLRP3 is also involved in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, and gout. The role of NLRP3 in central nervous system diseases is also emerging, and lung diseases have also been shown to be affected by NLRP3. In addition, NLRP3 also plays a role in liver disease, kidney disease, and the development of aging.

[0004] A variety of NLRP3 inflammasome inhibitors have been developed. MCC950 has good NLRP3 inhibitory activity and good selectivity, but failed to pass the clinical phase Ib due to liver toxicity; OLT1177 is currently in clinical phase II and has excellent inhibitory activity, but does not show a significant dose-dependency. In addition, a large number of NLRP3 inflammasome inhibitors are under study.

[0005] At present, there are no NLRP3 inhibitor drugs approved for clinical use. Clinically, excessive inflammatory responses are mainly suppressed by biological drugs such as IL-1β receptor antagonist anakinra, monoclonal antibody canakinumab and IL-1β blocker rilonacept. These biological drugs often have disadvantages such as easy infection, inconvenient administration route and high treatment cost. Therefore, it is of great significance to develop NLRP3 inflammasome inhibitors with good selectivity and strong inhibitory activity. Summary of the invention

[0006] Problems to be solved by the invention:

[0007] The object of the present invention is to provide a sulfonylurea compound as a novel NLRP3 small molecule protein degrader for reducing NLRP3 levels, which can be used to prepare a drug for preventing or treating diseases related to inhibiting NLRP3 activity.

[0008] Means of solving the problem:

[0009] In order to solve the above technical problems, in the first aspect, the present invention provides a NLRP3 small molecule protein degrader, which is a benzenesulfonamide compound of the following chemical structure general formula I or a pharmaceutically acceptable salt or solvate thereof:

[0010] in,

[0011] The connecting group A is: C1-C 20 Alkyl chains, ether chains, oxygen chains, sulfur chains, nitrogen chains, C1-C 20 Alkenyl chain, C1-C 20 Alkynyl chain, -C(=O)NH(C1-C 19 Alkyl chains, ether chains, oxygen chains, sulfur chains, nitrogen chains, C1-C 19 Alkenyl, C1-C 19 Alkynyl);

[0012] R1, R2, R3 and R4 are independently selected from hydrogen, halogen, hydroxy, nitro, methoxy, amino, methylamino, dimethylamino, carboxyl, cyano, -CO2Me, -CO2Et, -CH3, -Et, -N3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more selected from -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl), -O(C 1-4 Alkylene-C 3-6 Cycloalkyl), -O(three-membered to seven-membered heterocyclic group), -O(C 1-4Alkylene-three to seven-membered heterocyclic group), -SH, -S(C 1-6 Alkyl), -S(C 3-6 Cycloalkyl), -S(C 1-4 Alkylene-C 3-6 Cycloalkyl), -S(three-membered to seven-membered heterocyclic group), -S(C 1-4 Alkylene-three to seven-membered heterocyclic group), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl), -N(C 3-6 Cycloalkyl)2, -NH(C 1-4 Alkylene-C 3-6 Cycloalkyl), -N(C 1-4 Alkylene-C 3-6 Cycloalkyl)2, -NH(three-membered to seven-membered heterocyclic group), -N(three-membered to seven-membered heterocyclic group), -NH(C 1-4 Alkylene-three to seven-membered heterocyclic group), -N(C 1-4 Alkylene-three-membered to seven-membered heterocyclic group)2;

[0013] Group B is:

[0014]

[0015] Where R 11 , R 12 and R 13 Independently selected from hydrogen, halogen, hydroxy, nitro, methoxy, amino, methylamino, dimethylamino, carboxyl, cyano, -CO2Me, -CO2Et, -CH3, -Et, -N3; ​​X is NH, S, O;

[0016] The group C is: pyrazole, furan, tetrahydrofuran, tetrahydropyran, pyran, pyrrolidine, pyrrole, triazole, tetrazole, imidazole, pyridine, morpholine, piperazine, piperidine, substituted phenyl, phenylheteroaryl, phenylheterocyclic group, biphenyl, quinoline, isoquinoline, naphthyl, pyrazine and pyrimidine, all of which may be optionally substituted where appropriate; the group C is bonded directly or via a substituent to the adjacent oxygen and directly to the adjacent sulfur via a carbon atom.

[0017] The group D is:

[0018]

[0019] wherein Y at each occurrence is independently selected from C, N, S and O, which may be optionally substituted where appropriate;

[0020] R5, R6, R7, R8, R9 and R 10are independently selected from: hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, all of which may be optionally substituted by halogen, cyano or C1-C6 alkoxy where appropriate; and

[0021] Among them, R6 and R7, R7 and R8, R9 and R 10 may combine to form a phenyl group, a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered oxygen heterocycle, or a 5- or 6-membered nitrogen heterocycle, each of which may be optionally substituted;

[0022] Preferably, the group D is

[0023] Preferably, the group C is

[0024] Preferably, the group B is R 11 , R 12 and R 13 Independently selected from halogen, hydroxy, methoxy.

[0025] In a second aspect, the present invention provides a pharmaceutical composition comprising the sulfonylurea compound as described above or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0026] In a third aspect, the present invention provides a use of the sulfonylurea compound as described above or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for preventing or treating a disease associated with inhibiting NLRP3 activity.

[0027] Preferably, the disease is selected from the group consisting of immune system diseases, inflammatory diseases, autoimmune diseases, cancer, tumors or other malignancies, diseases of the renal system, diseases of the gastrointestinal tract, diseases of the respiratory system and diseases of the endocrine system.

[0028] Preferably, the disease is selected from constitutive inflammation, including cryptopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal onset multisystem inflammatory disease (NOMID); including autoinflammatory diseases: familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin 1 receptor (DIRA) antagonist deficiency, Majeed syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), granulomatous arthritis of childhood inflammatory dysregulation (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia (SIFD) with B-cell immunodeficiency, periodic fever and developmental delay (SIFD); Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), chronic relapsing multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO); autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome and Schnitz syndrome; respiratory diseases, including chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; central nervous system diseases, including Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and brain damage due to pneumococcal meningitis; metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout; eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis, and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy, and diabetic nephropathy; liver diseases, including nonalcoholic steatohepatitis and alcoholic liver disease; skin inflammatory reactions, including contact hypersensitivity and sunburn; arthritic reactions, including osteoarthritis, systemic Juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis; viral infections including alphaviruses including chikungunya and Ross River, and flaviviruses including dengue and Zika, influenza, HIV; hidradenitis suppurativa (HS) and other cyst-causing skin diseases; cancer including lung metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; stroke; myocardial infarction; graft-versus-host disease; hypertension: colitis: helminth infections: bacterial infections; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis including Dressler's syndrome, local ischemia-reperfusion injury and any disease in which the individual has been determined to carry a germline or somatic non-silent mutation in NLRP3. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The Elisa test results of the compounds prepared according to the examples of the present invention are shown;

[0031] Figure 2 The Western Blot experimental results of compounds I-4, I-6, I-10, I-12, I-16, and I-18 prepared according to the embodiments of the present invention are shown;

[0032] Figure 3 The qPCR experimental results of compound I-18 prepared according to an embodiment of the present invention are shown;

[0033] Figure 4 The results of the MTT toxicity test of compound I-18 prepared according to an example of the present invention are shown; DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with the accompanying drawings and the following embodiments. It should be understood that the accompanying drawings and the following embodiments are only used to illustrate the present invention, rather than to limit the present invention. The same or corresponding reference numerals in the various figures represent the same components, and repeated descriptions are omitted.

[0035] The present invention provides a novel NLRP3 small molecule targeted degradation agent, which has a sulfonylurea compound of the following structural formula I or a pharmaceutically acceptable salt or solvate thereof:

[0036] in,

[0037] The connecting group A is: C1-C 20 Alkyl chains, ether chains, oxygen chains, sulfur chains, nitrogen chains, C1-C 20 Alkenyl chain, C1-C 20 Alkynyl chain, -C(=O)NH(C1-C 19 Alkyl chains, ether chains, oxygen chains, sulfur chains, nitrogen chains, C1-C 19 Alkenyl, C1-C 19 Alkynyl);

[0038] R1, R2, R3 and R4 are independently selected from hydrogen, halogen, hydroxy, nitro, methoxy, amino, methylamino, dimethylamino, carboxyl, cyano, -CO2Me, -CO2Et, -CH3, -Et, -N3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more selected from -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl), -O(C1-4 Alkylene-C 3-6 Cycloalkyl), -O(three-membered to seven-membered heterocyclic group), -O(C 1-4 Alkylene-three to seven-membered heterocyclic group), -SH, -S(C 1-6 Alkyl), -S(C 3-6 Cycloalkyl), -S(C 1-4 Alkylene-C 3-6 Cycloalkyl), -S(three-membered to seven-membered heterocyclic group), -S(C 1-4 Alkylene-three to seven-membered heterocyclic group), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl), -N(C 3-6 Cycloalkyl)2, -NH(C 1-4 Alkylene-C 3-6 Cycloalkyl), -N(C 1-4 Alkylene-C 3-6 Cycloalkyl)2, -NH(three-membered to seven-membered heterocyclic group), -N(three-membered to seven-membered heterocyclic group), -NH(C 1-4 Alkylene-three to seven-membered heterocyclic group), -N(C 1-4 Alkylene-three-membered to seven-membered heterocyclic group)2;

[0039] Group B is:

[0040]

[0041] Where R 11 , R 12 and R 13 Independently selected from hydrogen, halogen, hydroxy, nitro, methoxy, amino, methylamino, dimethylamino, carboxyl, cyano, -CO2Me, -CO2Et, -CH3, -Et, -N3; ​​X is NH, S, O.

[0042] The group C is: pyrazole, furan, tetrahydrofuran, tetrahydropyran, pyran, pyrrolidine, pyrrole, triazole, tetrazole, imidazole, pyridine, morpholine, piperazine, piperidine, substituted phenyl, phenylheteroaryl, phenylheterocyclic group, biphenyl, quinoline, isoquinoline, naphthyl, pyrazine and pyrimidine, all of which may be optionally substituted where appropriate; the group C is bonded directly or via a substituent to the adjacent oxygen and directly to the adjacent sulfur via a carbon atom.

[0043] The group D is:

[0044]

[0045] wherein Y at each occurrence is independently selected from C, N, S and O, which may be optionally substituted where appropriate;

[0046] R5, R6, R7, R8, R9 and R 10 are independently selected from: hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, all of which may be optionally substituted by halogen, cyano or C1-C6 alkoxy where appropriate; and

[0047] Among them, R6 and R7, R7 and R8, R9 and R 10 may combine to form a phenyl group, a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered oxygen heterocycle, or a 5- or 6-membered nitrogen heterocycle, each of which may be optionally substituted;

[0048] In a preferred embodiment of the present invention, the group D is

[0049] In a preferred embodiment of the present invention, the group C is

[0050] In a preferred embodiment of the present invention, the group B is R 11 , R 12 and R 13 Independently selected from halogen, hydroxy, methoxy.

[0051] The above synthesis scheme only lists the preparation methods of some compounds in the present invention. With reference to the commonly used technical means and existing technologies in this field, those skilled in the art can synthesize the compounds of the present invention by similar methods based on the above synthesis scheme.

[0052] The expression mn used herein refers to a range from m to n and a subrange consisting of individual point values ​​therein and individual point values. For example, the expression "C1-C 20 " or "C 1—20 " covers a range of 1-20 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 " or "C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, 4, 5, 6, 7, 8, 9, 10Etc. Other similar expressions in this article should be understood in a similar manner.

[0053] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

[0054] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. An "alkyl" group may have 1 to 20 carbon atoms, i.e., a "C1-C 20 Alkyl", such as C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 1-6 Alkyl, C 3-6 Alkyl. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof. "Subunit" refers to a group having two attachment sites to the rest of the molecule obtained by removing a hydrogen atom from a carbon atom having free valence electrons. For example, "alkylene" or "alkyl subunit" refers to a saturated straight or branched divalent hydrocarbon radical.

[0055] The term "alkylene", when used herein alone or in combination with other groups, refers to a straight or branched chain saturated divalent hydrocarbon group. For example, the term "C 1-20 The term "alkylene" refers to an alkylene group having 1 to 20 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene or ethylpropylene. The term "cycloalkylene" refers to a cyclic, saturated, divalent hydrocarbon group. For example, the term "C 3-6 "Cycloalkylene" refers to a cycloalkylene group having 3 to 6 carbon atoms, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, etc. The term "alkoxyene" refers to "-O-alkylene" or "alkylene-O-". "C 1-8 Examples of "alkoxy" include, but are not limited to, -O-methylene, -O-ethylene, -O-propylene, -O-butylene, methylene-O-, ethylene-O-, propylene-O-, butylene-O-, and the like.

[0056] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may have 2 to 20 carbon atoms, i.e., "C 2-20 "Alkenyl", such as C2-4 alkenyl, C3-4 alkenyl. Non-limiting examples of alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, and the like.

[0057] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may have 2 to 20 carbon atoms, i.e., "C 2-8 Alkynyl", such as C 2-4 Alkynyl, C 3-4 Alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0058] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl group can have 3-10 carbon atoms, i.e., "C 3-10 Cycloalkyl", such as C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl and spiro[3.3]heptyl, etc. The term also encompasses situations where the C atoms may be substituted with oxo (=O).

[0059] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group.

[0060] The term "heterocyclyl" or "heterocycloalkyl" refers to a monocyclic or bicyclic ring system (three-membered to ten-membered, three-membered to eight-membered, three-membered to seven-membered, four-membered to six-membered) having, for example, 3-10 (suitably 3-8, more suitably 3-7, in particular 4-6) ring atoms, wherein at least one ring atom (e.g. 1 or 3) is a heteroatom selected from N, O, S and P, and the remaining ring atoms are C. The ring system may be saturated (also understood as the corresponding "heterocycloalkyl") or unsaturated (i.e. having one or more double bonds and / or triple bonds in the ring). "Heterocyclyl" or "heterocycloalkyl" does not have aromaticity. The term also encompasses the case where a C atom may be substituted by oxo (=O) and / or a S atom on the ring may be substituted by 1 or 2 oxo (=O) and / or a P atom on the ring may be substituted by 1 or 2 oxo (=O).

[0061] The heterocyclic group can be, for example, a four-membered ring, such as azetidinyl, oxetanyl; or a five-membered ring, such as tetrahydrofuranyl, dioxanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithianyl; or a seven-membered ring, such as diazepine, Optionally, the heterocyclic group may be benzo-fused.

[0062] The heterocyclic group may be bicyclic, without limitation, for example a five-membered and a five-membered ring, such as a hexahydrocyclopenta[C]pyrrol-2(1H)-yl) ring; or a five-membered and a six-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.

[0063] As mentioned above, the heterocycle may be unsaturated, i.e., it may contain one or more double bonds, without being limited thereto, for example, an unsaturated heterocycle containing a nitrogen atom may be a 1,6-dihydropyrimidine, a 1,2-dihydropyrimidine, a 1,4-dihydropyrimidine, a 1,6-dihydropyridine, a 1,2-dihydropyridine, a 1,4-dihydropyridine, a 2,3-dihydro-1H-pyrrole, a 3,4-dihydro-1H-pyrrole, a 2,5-dihydro-1H-pyrrolyl, a 4H-[1,3,4]thiadiazinyl, a 4,5-dihydrooxazolyl or a 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom may be a 2H-pyran, a 4H-pyran, a 2,3-dihydrofuran, an unsaturated heterocycle containing a sulfur atom may be a 2H-thiopyran, a 4H-thiopyran. The heterocycle may be benzo-fused, without being limited thereto, for example, a dihydroisoquinolinyl ring.

[0064] The term "hydrocarbon chain" refers to a chain group consisting of carbon atoms and hydrogen atoms, which can be straight or branched. The hydrocarbon chain can be saturated (i.e., alkylene) or unsaturated, i.e., can contain one or more carbon-carbon double bonds or triple bonds. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), 1,7-heptylene (-CH2CH2CH2CH2CH2CH2CH2-), etc.

[0065] The “compound” described in the present invention includes all stereoisomers, geometric isomers, tautomers and isotopes.

[0066] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all isomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form; optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0067] The "compounds" described in the present invention also include geometric isomers; the geometric isomers may exist as mixtures or in separated E or Z structural forms.

[0068] The "compounds" described in the present invention also include tautomeric forms; tautomeric forms are caused by the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0069] The "compounds" of the present invention also include all isotopic atoms, whether intermediates or final compounds; isotopic atoms include atoms with the same number of protons but different mass numbers, for example, hydrogen isotopes include deuterium and tritium. In addition, if necessary, for example for special treatment or diagnostic treatment, the compounds of the present invention can introduce isotopes or radioactive isotopes known in the prior art, such as 3 H. 15 O. 13 C or 15 N isotope.

[0070] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt that maintains the pharmacological activity of its parent compound while improving the physicochemical properties or metabolic properties. Such salts include acid addition salts or base addition salts prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, inorganic bases), or mixtures thereof. In the present invention, suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or similar acids; suitable organic acids include fumaric acid, tartaric acid, lactic acid, acetic acid, citric acid, trifluoromethanesulfonic acid, mandelic acid, salicylic acid or its analogs.

[0071] The compounds according to the present invention may also exist in the form of solvates, such as hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).

[0072] Administration and pharmaceutical compositions

[0073] In general, the compounds of the present invention can be administered in an effective amount by any acceptable mode of administration for other similar purposes. For example, the compounds of the present invention can be administered orally, parenterally, transdermally, topically, rectally, intraperitoneally or intranasally.

[0074] When used as a medicine, the compounds of the present invention are usually administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the field of pharmacy, and these compositions contain at least one active compound. When preparing the composition provided by the present invention, the active ingredient is usually mixed with an excipient, diluted by the excipient or wrapped in a capsule, a pouch, a paper or other form of container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid substance, which can be used as a carrier, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, sprays (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0075] Some typical excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, sterile water, syrup and methylcellulose. In addition, lubricants (such as talcum powder, magnesium stearate and mineral oil), wetting agents, emulsifying and suspending agents, preservatives (such as methylparaben and propylparaben), sweeteners and flavor enhancers may also be included. Pharmaceutical composition of the present invention can achieve rapid, continuous or delayed release of active pharmaceutical ingredients after administration to patients by specific excipient mode, which is also a widely used method in this area.

[0076] The amount of active ingredient, ie, the compound of the present invention, in the pharmaceutical composition and unit dosage form can be varied or substantially adjusted depending on the specific application, the activity of the particular compound and the desired concentration.

[0077] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, i.e., causing clinical symptoms of the disease not to develop; (2) inhibiting the disease, i.e., preventing the development of clinical symptoms; (3) alleviating the disease, i.e., causing the regression of clinical symptoms.

[0078] The present invention is further described in detail below in conjunction with specific examples. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention. The specific process parameters and the like in the following examples are also only examples within a suitable range, that is, those skilled in the art can make a selection within a suitable range through the description herein, and are not limited to the specific values ​​​​exemplified below.

[0079] Example 1: Preparation of Compound I-1

[0080] Synthesis of 4-(4-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolyl-1-yl)butoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0081] Step 1: Synthesis of 3-chloro-1-indan-5-yl-propan-1-one

[0082] Indane (2.50 g, 21.15 mmol) was dissolved in DCM (40 mL), 3-chloropropionyl chloride (3.22 g, 25.38 mmol) and AlCl3 (4.23 g, 31.73 mmol) were added at 0°C, and the reaction solution was stirred at room temperature for 8 h. After the reaction was completed, ice water was added to quench, and DCM was used for extraction, and the crude product was dried to obtain a crude product, which was purified by silica gel column chromatography (PE: EA = 5: 1) to obtain a light yellow solid M1 (3.80 g, 86%). 1 H NMR (400MHz, DMSO-d6) δ7.8(s,1H),7.8(d,J=7.9Hz,1H),7.4(d,J=7.6Hz,1H),4. 0–3.9(m,2H),3.5(t,J=6.0Hz,2H),2.9(t,J=7.3Hz,4H),2.1–2.0(m,2H).ESI-MS calculated for[M+H] + :208.1,found:208.1.

[0083] Step 2: Synthesis of 3,5,6,7-tetrahydro-2H-S-indacen-1-one

[0084] M1 (3.00 g, 14.4 mmol) was added to concentrated sulfuric acid (30 mL) in batches and stirred at 60°C for 48 h. After the reaction was completed, ice water was slowly added at 0°C to dilute, and then the pH was adjusted to 7 with saturated NaOH aqueous solution. After EA extraction, the compound M2 (1.21 g, 49%) was purified by silica gel column chromatography. 1 H NMR (400MHz, DMSO-d6) δ7.43(s,1H),7.39(s,1H),3.02(t,J=7.4Hz,2H),2.94–2.84(m,4H),2.61(t,J=7.4Hz,2H),2.05(p,J=7.5Hz,2H).ESI-MScalculated for[M+H] + :173.1,found:173.1.

[0085] Step 3: Synthesis of 1,2,3,5,6,7-hexahydro-S-indacen-4-amine

[0086] Compound M2 (1.00 g, 5.81 mmol) was dissolved in concentrated sulfuric acid at 0°C, and KNO3 solid powder (882 mg, 8.72 mmol) was slowly added in batches, and the reaction was continued at 0°C for 2 h. After the reaction was completed, 15% NaOH solution was slowly added under ice bath conditions to quench, EA was extracted, and black oil was obtained by spin drying. The oil was dissolved in anhydrous THF (15 mL), and then 1M LiAlH4 THF suspension (15 mL) was slowly added dropwise under ice bath conditions, and the reaction was carried out at 66°C under nitrogen protection for 12 h. After the reaction was completed by TLC detection, the reaction solution was quenched with a saturated Na2SO4 solution containing 15% NaOH, and then the solid was removed by filtration, EA was extracted, and the brown solid M3 (453 mg, 45%) was obtained by purification by silica gel column chromatography (PE: EA = 3: 1). 1 H NMR (400MHz, DMSO-d6) δ6.33(s,1H),4.51(s,2H),2.70(t,J=7.4Hz,4H),2.57(t,J=7.4Hz,4H),1.95(p,J=7.4Hz,4H).ESI-MScalculated for[M+H] + :174.1,found:174.1.

[0087] Step 4: Synthesis of 4-isocyanato-1,2,3,5,6,7-hexahydroxy-S-indenodiene

[0088] Under nitrogen protection, triphosgene (286 mg, 0.963 mmol) and triethylamine (0.161 mL) were dissolved in anhydrous THF (50 mL), and then the anhydrous THF solution of compound M3 (500 mg, 2.89 mmol) was slowly added dropwise under ice-salt water bath conditions. After the addition was completed, the mixture was stirred at room temperature for 24 h. After monitoring by TLC, the THF was dried after the reaction was completed, the crude product was dissolved in anhydrous DCM and the insoluble matter was removed by filtration, and the colorless oil M4 (466 mg, 81%) was purified by column chromatography (pure PE). 1 H NMR (400MHz, DMSO-d6) δ6.96(s,1H),2.82–2.79(m,4H),2.57–2.48(m,4H),2.16–1.89(m,4H).

[0089] Step 5: Synthesis of N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)-4-hydroxybenzenesulfonamide 4-Hydroxybenzenesulfonamide (174 mg, 1.0 mmol) was dissolved in anhydrous THF (50 mL), and NaH (120 mg, 5 mmol) was added. After stirring at room temperature for 0.5 h under nitrogen protection, a solution of compound M4 (120 mg, 1 mmol) in anhydrous THF was added, and stirred at room temperature for 5 h. After TLC detection, the pH was adjusted to 7 with a 2M dilute hydrochloric acid solution, and a large amount of off-white solid precipitated. After filtering, the filter cake was washed with methanol several times to obtain the product M5 (335 mg, 90%). 1 H NMR (400MHz, DMSO-d6) δ10.53(s,2H),8.01(s,1H),7.75(d,J=8.6Hz,2H),6.90(d,J=8 .5Hz,3H),2.76(t,J=7.4Hz,4H),2.53(d,J=7.3Hz,4H),1.91(p,J=7.4Hz,4H).ESI-MS calculated for[M+H] + :373.1,found:373.1.

[0090] Step 6: Synthesis of 5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)indol-2-one At room temperature, 5-bromoindole oxide and 5-bromovanillin are dissolved in acetic acid, and sodium acetate is added. The reaction solution is then moved to a 117°C oil bath for reaction. After the reaction is allowed to proceed overnight, ice cubes are directly added to the reaction solution to precipitate a light yellow solid. The residue obtained by filtration is the crude product. The crude product is dissolved in THF at 75°C until it becomes clear and transparent. The solution is then cooled to room temperature, and petroleum ether is slowly added dropwise until solids precipitate. After no more solids precipitate, pure AN-OCH3 can be obtained by filtration.1 HNMR(400MHz,DMSO-d6)δ10.76(s,2H),8.56(s,1H),8.34(s,1H),7.93(s,1H),7.88(s,1H),7.84(s,1H),7.63(s,1H),7.56(s ,1H),7.44(d,J=8.7Hz,2H),7.37(d,J=7.9Hz,1H),6.89(d,J=8.3Hz,1H),6.83(d,J=8.2Hz,1H),3.93(d,J=7.2Hz,6H).ESI-MS calculated for[M+H] + :423.9,found:423.9.

[0091] Step 7: Synthesis of 5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-1-(4-bromobutyl)indolin-2-one

[0092] Under nitrogen protection, AN-OCH3 was dissolved in anhydrous DMF at room temperature. After reacting for 0.5 hours, 1,4-dibromobutane was added and the reaction was continued for 2 hours. After the reaction was completed, the reaction was quenched with ice water, the reaction solution was extracted with EA, and an orange-red oil was obtained by spin drying. Subsequently, Y-1 was obtained by purification with PE:EA. 1 H NMR (600MHz, DMSO-d6) δ10.50(s,5H),10.36(s,2H),8.51(d,J=1.9Hz,5H),8.36(d,J=1.9Hz,5H),7.94(d,J =2.0Hz,5H),7.89(s,5H),7.84(d,J=2.0Hz,2H),7.67(s,2H),7.53(d,J=1.8Hz,2H),7.49(dd,J=8.4,2.0Hz, 2H),7.42(dd,J=8.3,2.0Hz,5H),7.40(d,J=1.9Hz,2H),7.09(d,J=8.4Hz,2H),7.03(d,J=8.3Hz,5H),3.92(s ,15H),3.89(s,6H),3.82–3.72(m,14H),3.61–3.54(m,14H),1.87–1.79(m,14H),1.76–1.66(m,14H).ESI-MS calculated for[M+H] + :556.9,found:556.8.

[0093] Step 8: Synthesis of 4-(4-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolin-1-yl)butoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide Compound M5, compound Y-1 and cesium carbonate were dissolved in DMF (n / v=1:20) at a molar ratio of 1:1:5 and reacted at room temperature for 24 hours. After TLC detection, saturated ammonium chloride solution was added to adjust the pH to 7, and EA was extracted and then dried to obtain an orange-red oil, which was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the final product YK-ND-1. 1 H NMR (600MHz, DMSO-d6) δ8.53(d,J=2.0Hz,1H),8.37(d,J=1.9Hz,1H),8.10(d,J=3.5Hz,2H),8.00–7.93(m,2H),7 .91(s,1H),7.88–7.80(m,4H),7.69(s,1H),7.54(d,J=2.0Hz,1H),7.50(dt,J=8.4,3.0Hz,1H),7.46–7.38(m,2H) ,7.10(d,J=9.0Hz,4H),7.06(dd,J=8.5,3.9Hz,2H),6.90(s,2H),4.10(d,J=6.1Hz,4H),3.90(s,3H),3.89(s,3H) ,3.83(q,J=6.1,5.5Hz,4H),2.74(t,J=10.7Hz,8H),2.52(d,J=7.7Hz,8H),1.96–1.85(m,8H),1.84–1.71(m,8H). 13C NMR(151MHz,DMSO-d6)δ165.65(2C),162.55(2C),149.76(2C),148.09(2C),147.68(2C),143.49(4C),140.12( 2C),139.16(2C),137.55(4C),132.37,132.11,130.98(2C),130.84(2C),130.02(4C),129.20(2C),127.28(2C) ,127.15(2C),122.35(2C),122.25(2C),118.31(2C),115.52(2C),114.92(4C),114.14(2C),110.86(2C),109.4 0(2C),68.19(2C),56.77,56.63,40.50(2C),32.89(4C),30.54(4C),26.36(2C),25.47(4C),24.24(2C).ESI-MS calculated for[M+H] + :850.0787,found:850.0792.

[0094] Example 2: Preparation of Compound I-2

[0095] Synthesis of 4-((8-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolin-1-yl)octyl)oxy)-N-((1,2,3,5,6,7-hexahydro-S-indolson-4-yl)carbamic acid)benzenesulfonamide

[0096] Refer to the synthetic route of Example 1 I-1. I-2: 1H NMR (600MHz, DMSO-d6) δ8.53(d,J=1.9Hz,1H),8.37(d,J=1.9Hz,1H),8.11(s,2H),7.94(d,J=2.0Hz,1H),7.88(s,1H),7.86(d, J=9.0Hz,5H),7.67(s,1H),7.53(s,1H),7.45(dd,J=8.4,2.0Hz,1H),7.41–7.35(m,2H),7.07(d,J=9.1Hz,4H),7.03(d,J=8.4H z,1H),6.97(d,J=8.4Hz,1H),6.88(s,2H),4.09–3.98(m,4H),3.92(s,3H),3.89(s,3H),3.75–3.68(m,4H),2.75(t,J=7.4Hz,8 H),2.53(t,J=6.2Hz,8H),1.90(p,J=7.4Hz,8H),1.77–1.63(m,4H),1.62–1.53(m,4H),1.42–1.32(m,4H),1.33–1.26(m,12H). 13 C NMR(151MHz,DMSO-d6)δ167.29,165.53,162.75(2C),149.67(2C),148.58,148.05,147.60,146.59,143.48(4C),142.77,140.16,139 .01,138.05,137.54(4C),132.31(2C),131.90(2C),130.96,130.79,130.06(4C),129.14(2C),127.27,127.11,126.83,126.12,124. 91,124.39,123.03,122.30,118.33(2C),115.50,114.88(4C),114.06,113.49,112.77,111.33,110.71,109.91,109.40,68.47(2C), 56.75,56.61,40.39(2C),32.89(4C),30.55(4C),29.10(4C),28.83(2C),27.54,27.47,26.81,26.69,25.81(2C),25.47(4C).ESI-MS calculated for[M+H] + :906.1411,found:906.1443.

[0097] Example 3: Preparation of Compound I-3

[0098] Synthesis of 4-((12-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolyl-1-yl)dodecyl)oxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0099] Refer to the synthetic route of Example 1 I-1. I-3: 1 H NMR (600MHz, DMSO-d6) δ8.53(d,J=1.9Hz,1H),8.37(d,J=1.9Hz,1H),8.03(s,2H),7.95(d,J=2.0Hz,1H),7.90(s,1H),7.88–7.83( m,5H),7.67(s,1H),7.53(d,J=1.9Hz,1H),7.47(dd,J=8.4,2.0Hz,1H),7.44–7.37(m,2H),7.10(dd,J=8.9,1.9Hz,4H),7.05(d,J=8 .4Hz,1H),6.99(d,J=8.4Hz,1H),6.90(s,2H),4.07–4.01(m,4H),3.91(s,3H),3.89(s,3H),3.78–3.67(m,4H),2.76(t,J=7.4Hz,8 H),2.53(t,J=7.3Hz,8H),1.97–1.86(m,8H),1.74–1.63(m,4H),1.62–1.52(m,4H),1.35(p,J=7.7,7.3Hz,4H),1.31–1.20(m,28H). 13C NMR(151MHz,DMSO-d6)δ167.30,165.55,162.72(2C),149.56(2C),148.62,148.06,147.57,146.58,143.49(4C),142.94,140.20,1 38.98,138.00,137.55(4C),132.32,131.87,130.96(2C),130.79(2C),130.06(4C),129.11,127.22,127.12,126.87,126.16,124.9 3,124.45,123.05,122.38,122.30,118.34(2C),115.53,114.89(4C),114.04,113.47,112.81,111.33,110.69,109.89,109.37,68 .52(2C),56.75,56.61,40.42(2C),32.88(4C),30.53(4C),29.37(14C),27.48,27.40,26.70,26.66,25.86(2C),25.45(4C).ESI-MS calculated for[M+H] + :962.2035,found:962.1961.

[0100] Example 4: Preparation of Compound I-4

[0101] Synthesis of 4-(2-(2-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolin-1-yl)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indolson-4-yl)carbamoyl)benzenesulfonamide

[0102] Refer to the synthetic route of Example 1 I-1. I-4: 1H NMR (600MHz, DMSO-d6) δ8.52(d,J=1.9Hz,1H),8.36(d,J=1.9Hz,1H),8.03(s,2H),7.90(d,J=2.0Hz,1H),7.87(s,1H) ,7.86–7.82(m,5H),7.68(s,1H),7.53(d,J=1.9Hz,1H),7.41(dd,J=8.4,2.0Hz,1H),7.39(s,1H),7.34(dd,J=8.3,2. 0Hz,1H),7.12–7.08(m,2H),7.05(d,J=8.9Hz,4H),6.90(s,2H),4.17–4.09(m,4H),3.98–3.93(m,4H),3.92(s,3H),3 .89(s,3H),3.81–3.75(m,4H),3.75–3.69(m,4H),2.75(t,J=7.5Hz,8H),2.53(t,J=7.8Hz,8H),1.90(p,J=7.5Hz,8H). 13 C NMR(151MHz,DMSO-d6)δ167.50,165.74,162.47(2C),149.53(2C),148.62,148.07,147.55,146.58,143.52(4C),143.06,14 0.50,139.06,138.09,137.56(4C),132.21,132.10,130.92(2C),130.69(2C),130.00(4C),129.09,127.26,126.95,126.86 ,126.15,124.76,124.39,122.93,122.30,122.13,118.38(2C),115.53,114.97(4C),114.08,113.51,112.80,111.93,111. 34,109.91,109.38,69.04(2C),68.29(2C),68.15(2C),56.77,56.64,40.54(2C),32.89(4C),30.54(4C),25.46(4C).ESI-MS calculated for[M+H] + :866.0736,found:866.0744.

[0103] Example 5: Preparation of Compound I-5

[0104] Synthesis of 4-(2-(2-(2-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indolson-4-yl)carbamoyl)benzenesulfonamide

[0105] Refer to the synthetic route of Example 1 I-1. I-5: 1 H NMR (600MHz, DMSO-d6) δ8.52(d,J=1.9Hz,1H),8.36(d,J=1.9Hz,1H),8.02(s,2H),7.93(d,J=2.0Hz,1H),7.89(s,1H),7 .89–7.78(m,5H),7.68(s,1H),7.53(d,J=1.9Hz,1H),7.45(dd,J=8.4,2.0Hz,1H),7.38(dd,J=8.2,2.0Hz,2H),7.13(d, J=3.1Hz,1H),7.11(d,J=8.8Hz,1H),7.07(d,J=9.0Hz,4H),6.90(s,2H),4.09–4.06(m,4H),3.96–3.92(m,4H),3.91(s, 3H),3.87(s,3H),3.73–3.61(m,8H),3.59–3.48(m,8H),2.75(t,J=7.4Hz,8H),2.61–2.50(m,8H),1.90(p,J=7.3Hz,8H). 13C NMR(151MHz,DMSO-d6)δ167.47,165.74,162.48(2C),149.58(2C),148.63,148.09,147.60,146.59,143.52(4C),143.14,1 40.56,139.05,138.09,137.57(4C),132.18(2C),130.93(2C),130.71(2C),130.04(4C),129.12,127.26,126.97,126.84,1 26.15,124.75,124.42,122.93,122.33,122.13,118.37(2C),115.54,114.94(4C),114.05,113.49,112.82,112.05,111.4 5,109.93,109.40,70.32(4C),69.16(2C),68.16(4C),56.77,56.65,40.44(2C),32.89(4C),30.54(4C),25.46(4C).ESI-MS calculated for[M+H] + :910.0997,found:910.1014.

[0106] Example 6: Preparation of Compound I-6

[0107] Synthesis of 4-(2-(2-(2-(2-(5-bromo-3-(3-bromo-4-hydroxy-5-methoxybenzylidene)-2-oxoindolyl-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indolyl-4-yl)carbamoyl)benzenesulfonamide

[0108] Refer to the synthetic route of Example 1 I-1. I-6: 1H NMR(600MHz,Chloroform-d)δ8.64(d,J=1.9Hz,1H),7.84–7.78(m,5H),7.71(s,2H),7.65(s,1H),7.50(d,J=1.9Hz ,1H),7.34(s,1H),7.28(dd,J=8.4,2.0Hz,1H),7.27–7.22(m,2H),7.08(s,2H),6.95–6.88(m,6H),6.85(d,J=8.5Hz ,1H),6.82(d,J=8.3Hz,1H),4.12–4.07(m,4H),3.94(s,3H),3.92–3.85(m,4H),3.85(s,3H),3.79–3.72(m,3H),3.6 8–3.63(m,4H),3.62–3.53(m,2H),3.55–3.47(m,12H),2.83–2.72(m,8H),2.60–2.51(m,8H),1.95(p,J=7.4Hz,8H). 13 C NMR(151MHz,Chloroform-d)δ167.16,164.91,162.06(2C),146.11,145.77,144.04,143.33,141.88,139.57,136.70(2C),136.52(2C), 130.94(2C),130.00(2C),129.80(2C),128.42(2C),127.47(2C),126.17(2C),126.01(2C),125.31(2C),124.33(2C),124.00(2C),122.2 6(2C),121.80(2C),120.51(2C),114.06(2C),113.99,113.74,113.47,113.22(2C),112.43,110.08(2C),109.74(2C),109.65(2C),107. 68(2C),69.89(2C),69.61(6C),68.45(2C),67.91(2C),66.98(2C),55.64,55.55,39.38(2C),31.91(4C),29.48(4C),24.51(4C).ESI-MS calculated for[M+H] + :954.1258,found:954.1262.

[0109] Example 7: Preparation of Compound I-7

[0110] Synthesis of 4-(4-(5-bromo-3-(3,5-dibromo-4-hydroxybenzylidene)-2-oxoindolyl-1-yl)butoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0111] Refer to the synthetic route of Example 1 I-1. I-7: 1 H NMR(600MHz,DMSO-d6)δ8.82(s,4H),8.13(s,3H),7.91(s,2H),7.89–7.83(m,8H),7.75(s,2H),7 .72(s,1H),7.61(s,1H),7.46(dd,J=8.4,2.0Hz,1H),7.34(dd,J=8.3,2.0Hz,2H),7.11(d,J=8.9H z,6H),7.07(d,J=8.7Hz,1H),7.01(d,J=8.3Hz,2H),6.90(s,3H),4.09(q,J=5.8Hz,6H),3.85–3.7 9(m,6H),2.75(t,J=7.4Hz,12H),2.55–2.51(m,12H),1.89(q,J=7.4Hz,12H),1.78–1.73(m,12H). 13 CNMR(151MHz,DMSO-d6)δ167.44,165.73,162.64(2C),149.60(2C),143.51(4C),142.96(2C),139.42 (2C),138.12,137.65(4C),137.57(4C),137.11,134.31(2C),131.98(2C),130.05(6C),129.57,129. 14,128.13,127.76,124.45,121.57,118.36(2C),114.98(8C),113.85,113.57,113.40,113.13,111. 32,110.44,68.26(2C),40.56(2C),32.90(4C),30.55(4C),26.46(2C),25.47(4C),24.39(2C).ESI-MS calculated for[M+H] + :897.9787,found:897.9797.

[0112] Example 8: Preparation of Compound I-8

[0113] Synthesis of 4-((8-(5-bromo-3-(3,5-dibromo-4-hydroxybenzylidene)-2-oxoindolyl-1-yl)octyl)oxy)-N-((1,2,3,5,6,7-hexahydro-S-indolson-4-yl)carbamic acid)benzenesulfonamide

[0114] Refer to the synthetic route of Example 1 I-1. I-8: 1 H NMR (600MHz, DMSO-d6) δ8.82(s,10H),8.07(s,7H),7.92(s,4H),7.90(d,J=2.0Hz,5H),7.86(d,J=8.8Hz,14H),7.81(s,5H) ,7.67(d,J=2.0Hz,2H),7.62(s,2H),7.47(dd,J=8.3,2.0Hz,2H),7.38(dd,J=8.3,2.0Hz,5H),7.09(d,J=8.8Hz,14H),7.05 (d,J=8.5Hz,2H),6.98(d,J=8.3Hz,5H),6.89(s,7H),4.02–4.00(m,14H),3.75–3.70(m,14H),2.76(d,J=7.4Hz,28H),2.53 (d,J=7.2Hz,28H),1.90(p,J=7.5Hz,28H),1.72–1.67(m,14H),1.61–1.55(m,14H),1.40–1.35(m,14H),1.32–1.28(m,42H). 13 CNMR(151MHz,DMSO-d6)δ167.11,165.52,162.75(2C),149.54(2C),143.50(4C),142.96(2C),140.11(2C),137.56 (4C),137.27(5C),136.37,134.04(2C),132.47,131.83,130.60,130.20,130.06(4C),129.10,128.12,127.11,12 5.32,124.70,122.20,118.36(2C),114.92(8C),113.98,113.55,112.59,112.34,111.41,110.67,68.50(2C),40. 55(2C),32.88(4C),30.53(4C),29.06(4C),28.81(2C),27.55,27.43,26.72,26.65,25.76(2C),25.45(4C).ESI-MS calculated for[M+H] +:954.0411,found:954.0423.

[0115] Example 9: Preparation of Compound I-9

[0116] Synthesis of 4-((12-(5-bromo-3-(3,5-dibromo-4-hydroxybenzylidene)-2-oxoindolyl-1-yl)dodecyl)oxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0117] Refer to the synthetic route of Example 1 I-1. I-9: 1 H NMR(600MHz,DMSO-d6)δ8.82(s,4H),8.04(s,3H),7.93(s,2H),7.92(s,2H),7.86(d,J=8.8Hz,8H),7.65(s,1H),7 .63(s,1H),7.48(dd,J=8.4,2.1Hz,1H),7.41(dd,J=8.3,2.0Hz,2H),7.10(d,J=9.0Hz,6H),7.06(d,J=8.2Hz,1H) ,6.99(d,J=8.4Hz,2H),6.90(s,3H),4.02(d,J=7.1Hz,6H),3.76–3.70(m,6H),2.76(t,J=7.3Hz,12H),2.55–2.51 (m,12H),1.91(p,J=7.4Hz,12H),1.69(p,J=6.4Hz,6H),1.60–1.54(m,6H),1.39–1.33(m,6H),1.30–1.21(m,42H). 13C NMR(151MHz,DMSO-d6)δ167.04,165.47,163.36(2C),149.53(2C),144.03(4C),142.98(2C),140.41(2C),137.58(4C),1 37.10(4C),136.86,136.14,133.95(2C),132.70,131.81,131.13,130.07(5C),129.09,128.12,126.81,125.63,124.81 ,122.52,118.39(2C),114.95(8C),114.09,113.60,112.39,111.84,111.52,110.85,68.54(2C),40.55(2C),32.89(4C) ,30.52(4C),29.33(8C),29.15(2C),29.07(2C),28.87(2C),27.43,27.33,26.69,26.62,25.85(2C),25.46(4C).ESI-MS calculated for[M+H] + :1010.1035,found:1010.1040.

[0118] Example 10: Preparation of Compound I-10

[0119] Synthesis of 4-(2-(2-(5-bromo-3-(3,5-dibromo-4-hydroxybenzylidene)-2-oxoindolyl-1-yl)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indolson-4-yl)carbamoyl)benzenesulfonamide

[0120] Refer to the synthetic route of Example 1 I-1. 1H NMR(600MHz,DMSO-d6)δ8.81(s,4H),8.05(s,3H),7.93(s,2H),7.88(d,J=2.0Hz,2H),7.85–7.81(m,8H), 7.64(s,1H),7.63(d,J=2.0Hz,1H),7.42(dd,J=8.5,2.0Hz,1H),7.36(dd,J=8.3,2.0Hz,2H),7.11(d,J=8. 5Hz,1H),7.08(d,J=9.6Hz,2H),7.05(d,J=9.0Hz,6H),6.90(s,4H),4.13–4.10(m,6H),3.95–3.92(m,6H) ,3.77–3.75(m,6H),3.74–3.71(m,6H),2.75(t,J=7.4Hz,12H),2.53(t,J=7.4Hz,12H),1.92–1.88(m,12H) 13 C NMR(151MHz,DMSO-d6)δ167.23,165.66,162.47(2C),149.51(2C),143.52(4C),143.23,143.00,140.72(2C), 137.56(4C),137.08(4C),136.94,136.22,133.95(2C),132.57,132.08,130.99,130.10,130.00(4C),129.09, 128.10,126.67,125.46,124.64,122.34,118.38(2C),115.04(4C),114.98(4C),114.11,113.61,112.40,112. 10,111.86,111.45,69.04(2C),68.25(2C),68.14(2C),40.44(2C),32.90(4C),30.54(4C),25.46(4C).ESI-MS calculated for[M+H] + :913.9736,found:913.9753.

[0121] Example 11: Preparation of Compound I-11

[0122] Synthesis of 4-(2-(2-(2-(5-bromo-3-(3,5-dibromo-4-hydroxybenzylidene)-2-oxoindolyl-1-yl)ethoxy)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0123] Refer to the synthetic route of Example 1 I-1. I-11: 1 H NMR (600MHz, DMSO-d6) δ8.81 (s, 4H), 8.05 (s, 3H), 7.92 (s, 2H), 7.90 (d, J = 2.0Hz, 2H), 7.88–7.83 (m, 6H), 7.83 (s, 1H), 7.7 7–7.70(m,1H),7.64(s,2H),7.50(s,0H),7.48(s,0H),7.45(dd,J=8.4,2.0Hz,1H),7.59–7.40(m,0H),7.38(dd,J=8.4,2. 0Hz,2H),7.13(d,J=6.1Hz,1H),7.08(d,J=8.9Hz,6H),7.04(d,J=8.3Hz,2H),6.90(s,3H),4.09–4.07(m,6H),3.94–3.90( m,6H),3.71–3.63(m,12H),3.56–3.50(m,J=2.7Hz,12H),2.79–2.73(m,12H),2.56–2.51(m,12H),1.91(q,J=7.4Hz,12H). 13 C NMR(151MHz,DMSO-d6)δ165.67(2C),162.52(2C),149.51(2C),143.52(4C),142.98(2C),140. 65(2C),137.57(4C),137.16(6C),133.97(2C),132.12(2C),130.76(2C),130.04(4C),129.10 (2C),126.79(2C),122.20(2C),118.38(2C),114.96(8C),114.04(2C),112.07(2C),111.46(2 C),70.32(4C),69.16(2C),68.18(4C),40.57(2C),32.89(4C),30.54(4C),25.46(4C).ESI-MS calculated for[M+H] + :957.9997,found:958.0020.

[0124] Example 12: Preparation of Compound I-12

[0125] Synthesis of 4-(2-(2-(2-(2-(5-bromo-3-(3,5-dibromo-4-hydroxybenzylidene)-2-oxoindolyl-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indolson-4-yl)carbamoyl)benzenesulfonamide

[0126] Refer to the synthetic route of Example 1 I-1. I-12: 1 H NMR (600MHz, DMSO-d6) δ8.81(s,4H),8.06(s,3H),7.92(s,2H),7.89(d,J=2.0Hz,2H),7.87(d,J=8.5Hz,6H),7.83(s, 2H),7.65–7.62(m,2H),7.46(dd,J=8.5,2.0Hz,1H),7.39(dd,J=8.2,2.0Hz,2H),7.12(d,J=8.7Hz,6H),7.07(d,J=8. 8Hz,1H),7.03(d,J=8.3Hz,2H),6.89(s,3H),4.18–4.12(m,6H),3.92–3.89(m,6H),3.71–3.68(m,6H),3.65–3.63(m, 6H),3.50–3.48(m,12H),3.46–3.44(m,12H),2.75(t,J=7.4Hz,12H),2.53(t,J=7.4Hz,12H),1.90(p,J=7.4Hz,12H). 13 C NMR(151MHz,DMSO-d6)δ167.20,165.63,162.53(2C),149.52(2C),143.52(4C),143.00(2C),140.68(2C),13 7.57(4C),137.12(4C),136.95,136.19,133.95(2C),132.52,132.11,130.88(2C),130.04(4C),129.09,128 .13,126.74,125.44,124.58,122.25,118.39(2C),115.02(4C),114.92(4C),114.06,113.58,112.45,112.1 3,111.98,111.44,70.20(8C),69.11(2C),68.20(4C),40.56(2C),32.89(4C),30.55(4C),25.46(4C).ESI-MS calculated for[M+H] +:1002.0258,found:1002.0286.

[0127] Example 13: Preparation of Compound I-13

[0128] Synthesis of 4-(4-(3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-2-oxoindolyl-1-yl)butoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0129] Refer to the synthetic route of Example 1 I-1. I-13: 1 H NMR(600MHz,DMSO-d6)δ8.83(s,6H),8.08(s,3H),8.04(d,J=3.9Hz,5H),7.94(s,4H),7.89–7.84 (m,12H),7.83(s,3H),7.65(dd,J=8.3,1.7Hz,2H),7.63(s,2H),7.60(dd,J=8.1,1.7Hz,3H),7.1 1(d,J=9.0Hz,10H),7.01(d,J=8.3Hz,2H),6.95(d,J=8.2Hz,3H),6.91(s,5H),4.12–4.06(m,10H ),3.85–3.76(m,10H),2.82–2.72(m,20H),2.53(s,20H),1.95–1.86(m,20H),1.80–1.70(m,20H). 13 C NMR(151MHz,DMSO-d6)δ165.38(2C),162.64(2C),149.52(2C),143.53(6C),140.97(2C),138. 52(2C),137.59(4C),137.04(4C),136.63(2C),133.98(2C),131.92,130.74,130.07(4C),129. 09(2C),128.21(2C),127.18(2C),118.41(2C),114.99(8C),112.33(2C),111.70(2C),111.48( 2C),68.22(2C),40.55(2C),32.90(4C),30.52(4C),26.41(2C),25.47(4C),24.24(2C).ESI-MS calculated for[M+H] + :945.9649,found:945.9661.

[0130] Example 14: Preparation of Compound I-14

[0131] Synthesis of 4-((8-(3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-2-oxoindolyl-1-yl)octyl)oxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0132] Refer to the synthetic route of Example 1 I-1. I-14: 1 H NMR(600MHz, DMSO-d6)δ8.83(s,6H),8.06(d,J=1.7Hz,3H),8.04(d,J=2.4Hz,5H),7.92(s,4H),7.89–7.84(m,12H),7. 84(s,3H),7.62(d,J=1.7Hz,2H),7.61(s,2H),7.57(dd,J=8.1,1.7Hz,3H),7.09(d,J=8.8Hz,10H),6.92(d,J=8.3Hz,2 H),6.89(s,5H),6.87(d,J=8.2Hz,3H),4.03–3.99(m,10H),3.74–3.66(m,10H),2.78–2.74(m,20H),2.55–2.51(m,20H ),1.91(p,J=7.4Hz,20H),1.69(d,J=6.3Hz,10H),1.57(p,J=6.9Hz,10H),1.37(d,J=6.6Hz,10H),1.31–1.26(m,30H). 13C NMR(151MHz,DMSO-d6)δ166.80,165.24,162.71(2C),149.52(2C),143.50(4C),143.40(2C),140.98(2C),138.51, 137.55(4C),137.14,137.02(4C),136.47,135.74,133.94(2C),131.78,130.64,130.08(4C),129.07,128.61,128 .17,126.95,125.66,123.15,118.37(2C),114.92(8C),112.28(2C),111.96,111.62(2C),111.33,68.49(2C),40. 41(2C),32.89(4C),30.53(4C),29.07(4C),28.82(2C),27.49,27.41,26.73,26.66,25.80(2C),25.46(4C).ESI-MS calculated for[M+H] + :1002.0273,found:1002.0288.

[0133] Example 15: Preparation of Compound I-15

[0134] Synthesis of 4-((12-(3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-2-oxoindolyl-1-yl)dodecyl)oxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0135] Refer to the synthetic route of Example 1 I-1. I-15: 1H NMR (600MHz, DMSO-d6) δ8.83(s,6H),8.05(s,3H),8.05(s,5H),7.92(s,4H),7.86(d,J=8.8Hz,12H),7.82(s,3 H),7.64–7.61(m,2H),7.61(s,2H),7.56(dd,J=8.2,1.7Hz,3H),7.10(d,J=8.9Hz,10H),6.94(d,J=8.3Hz,2H) ,6.90(s,5H),6.87(d,J=8.2Hz,3H),4.03(s,10H),3.74–3.68(m,10H),2.76(t,J=7.3Hz,20H),2.55–2.51(m, 20H),1.93–1.87(m,20H),1.71–1.67(m,10H),1.56(q,J=6.7Hz,10H),1.38–1.34(m,10H),1.26–1.21(m,70H). 13 C NMR(151MHz,DMSO-d6)δ165.32(2C),162.74(2C),149.53(2C),143.50(6C),140.76(2C),138.35,137.58(4C),13 7.16(5C),136.80,135.88,134.02(2C),131.81,130.55,130.08(4C),129.10(2C),127.27(2C),123.49(2C),118. 38(2C),114.94(8C),112.45(2C),112.07(2C),111.27(2C),68.53(2C),40.42(2C),32.89(4C),30.52(4C),29.3 4(6C),29.16(2C),29.08(2C),28.95(2C),28.87(2C),27.55,27.45,26.69,26.62,25.86(2C),25.47(4C).ESI-MS calculated for[M+H] + :1058.0897,found:1058.09020.

[0136] Example 16: Preparation of Compound I-16

[0137] Synthesis of 4-(2-(2-(3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-2-oxoindolyl-1-yl)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0138] Refer to the synthetic route of Example 1 I-1. I-16: 1 H NMR (600MHz, DMSO-d6) δ8.82(s,4H),8.07(s,3H),8.04(d,J=1.7Hz,2H),7.93(s,2H),7.84(d,J=2 .9Hz,7H),7.82(s,2H),7.62(s,1H),7.62–7.56(m,1H),7.56–7.52(m,2H),7.13–7.03(m,6H),7.00 (d,J=8.4Hz,1H),6.94(d,J=8.3Hz,2H),6.90(s,3H),4.17–4.07(m,6H),3.98–3.87(m,6H),3.76(p ,J=2.2Hz,6H),3.74–3.66(m,6H),2.80–2.72(m,12H),2.54–2.51(m,12H),1.90(p,J=7.4Hz,12H). 13 CNMR(151MHz,DMSO-d6)δ165.46(2C),162.46(2C),149.52(2C),143.52(6C),141.32(2C),138 .43,137.57(4C),137.00(5C),136.56,135.87,133.96(2C),132.02(2C),130.03(4C),129.08 (2C),128.03(2C),126.81(2C),118.40(2C),114.98(8C),112.29(2C),112.03(2C),111.63(2 C),69.00(2C),68.17(2C),68.11(2C),40.50(2C),32.90(4C),30.54(4C),25.48(4C).ESI-MS calculated for[M+H] + :961.9598,found:961.9609.

[0139] Example 17: Preparation of Compound I-17

[0140] Synthesis of 4-(2-(2-(2-(3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-2-oxoindolyl-1-yl)ethoxy)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide

[0141] Refer to the synthetic route of Example 1 I-1. I-17:1 H NMR(600MHz,DMSO-d6)δ8.82(s,4H),8.05(s,3H),8.04(d,J=1.7Hz,2H),7.92(s,2H),7.88–7.83(m, 7H),7.82(s,2H),7.63–7.58(m,2H),7.54(dd,J=8.2,1.7Hz,2H),7.09(dd,J=19.5,9.0Hz,6H),7.00 (d,J=8.3Hz,1H),6.93(d,J=8.2Hz,2H),6.90(s,3H),4.13–4.05(m,6H),3.94–3.85(m,6H),3.71–3. 59(m,12H),3.56–3.49(m,12H),2.75(t,J=7.4Hz,12H),2.55–2.49(m,12H),1.90(p,J=7.5Hz,12H). 13 C NMR(151MHz,DMSO-d6)δ163.37(2C),160.38(2C),147.40(2C),141.40(6C),139.18(2C),136. 49(2C),135.46(4C),135.03(4C),134.56(2C),131.90(2C),129.95(2C),127.95(4C),126.97 (2C),126.32(2C),125.79(2C),116.42(2C),116.29(2C),112.85(8C),110.70(2C),109.85(2 C),68.18(4C),67.02(2C),66.05(4C),38.41(2C),30.78(4C),28.43(4C),23.35(4C).ESI-MS calculated for[M+H] + :1005.9859,found:1005.9874.

[0142] Example 18: Preparation of Compound I-18

[0143] The synthesis of 4-(2-(2-(2-(2-(3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-2-oxoindolyl-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-N-((1,2,3,5,6,7-hexahydro-S-indan-4-yl)carbamoyl)benzenesulfonamide refers to the synthetic route of Example 1 I-1. I-18: 1H NMR(600MHz,DMSO-d6)δ8.82(s,6H),8.31(s,5H),8.03(d,J=1.7Hz,3H),7.91(s,4H),7.89–7.83(m,12H),7.8 1(s,3H),7.62–7.58(m,4H),7.56–7.51(m,3H),7.11(dd,J=8.8,4.4Hz,10H),6.99(d,J=8.3Hz,2H),6.92(d,J =8.2Hz,3H),6.89(s,5H),4.17–4.12(m,10H),3.92–3.85(m,10H),3.71–3.68(m,10H),3.63–3.60(m,10H),3. 50–3.48(m,20H),3.45–3.43(m,20H),2.75(t,J=7.5Hz,20H),2.53(t,J=7.3Hz,20H),1.90(p,J=7.5Hz,20H). 13 C NMR(151MHz,DMSO-d6)δ167.18,165.54,162.50(2C),149.58(2C),143.51(4C),143.40(2C),140.6 2(2C),137.87,137.56(4C),137.41(5C),136.39,135.88,134.16(2C),132.12,130.18,130.05(4C) ),129.12(2C),127.26(2C),123.37(2C),118.36(2C),115.00(8C),112.84(2C),112.49(2C),111. 68(2C),70.26(8C),69.12(2C),68.18(4C),41.21(2C),32.90(4C),30.57(4C),25.48(4C).ESI-MS calculatedfor[M+H] + :1050.0120,found:1050.0132.

[0144] Example 19: Test of the inhibitory activity of compounds on NLRP3 at the cell level. Elisa assay, i.e., enzyme-linked immunosorbent assay, was used to assay the inhibitory ability of compounds I-1 to I-18 of the present invention on IL-1β.

[0145] Cell culture and treatment:

[0146] THP-1 cells were cultured in RMPI 1640 medium (Hyclone) supplemented with 50 μM β-mercaptoethanol, 10% fetal bovine serum (BI) and 1% penicillin and streptomycin (Sigma), and the incubator temperature was set at 37°C and the environment was set to 95% air and 5% carbon dioxide. Drug solutions were stored in DMSO or PBS at 1000 times the actual use concentration.

[0147] 5×10 5 / mL THP-1 cells were plated in 96-well plates and incubated with PMA at a final concentration of 100ng / mL for 24h to promote cell differentiation and adhesion. The drug was co-incubated with 100ng / mL LPS-stimulated cells and cells for 24h, and then stimulated with 10μM Nigericin for 0.5h.

[0148] Experimental method: After THP-1 cells were treated with drugs, the supernatant was extracted and diluted 1-fold with PBS. The IL-1β concentration was detected by ELISA (ABclonal) kit according to the instructions.

[0149] Figure 1 The Elisa test results of the compounds prepared according to the examples of the present invention are shown. Figure 1 It can be seen that compounds I-1 to 18 can all inhibit the IL-1β produced by the THP-1 cell line; among them, the inhibitory effects of compounds I-4, I-6, I-10, I-12, I-16, and I-18 are more obvious.

[0150] Example 20: Cell level determination of the targeted degradation activity of compounds on NLRP3. Western Blot experiments, i.e., protein blotting experiments, were used to determine the targeted degradation ability of the compounds on NLRP3 for compounds I-4, I-6, I-10, I-12, I-16, and I-18 of the present invention. The targeted degradation ability is mainly represented by two indicators: the maximum degradation degree of NLRP3 protein and the optimal degradation concentration of the compound. At the same time, a timed quantitative PCR experiment was used to prove that the compounds of the present invention had no significant effect on the expression level of NLRP3 mRNA, and only had a degradation effect on NLRP3 at the protein level. In addition, an MTT experiment was used to prove that the compounds of the present invention had no effect on cell activity and did not reduce NLRP3 protein expression by affecting cell activity.

[0151] Cell culture and treatment:

[0152] THP-1 cells were cultured in RMPI 1640 medium (Hyclone) supplemented with 50 μM β-mercaptoethanol, 10% fetal bovine serum (BI) and 1% penicillin and streptomycin (Sigma), and the incubator temperature was set at 37°C and the environment was set to 95% air and 5% carbon dioxide. Drug solutions were stored in DMSO or PBS at 1000 times the actual use concentration.

[0153] 5×10 5 / mL THP-1 cells were plated in 12-well plates and incubated with PMA at a final concentration of 100ng / mL for 24h to promote cell differentiation and adherence. The drug was stimulated with 100ng / mL LPS and the cells were co-incubated for 24h.

[0154] NLRP3 antibody was purchased from Cell Signaling Technologies, GAPDH antibody was purchased from Bioworld, and all other reagents were purchased from SigmaAldrich.

[0155] Experimental methods:

[0156] After THP-1 cells were treated with drugs, the culture medium was removed and the cells were washed with pre-cooled PBS. After adding an appropriate amount of RIPA (Beyotime), the cells were scraped off with a scraper, and the RIPA with cell fragments was transferred to a centrifuge tube and lysed on ice for 30 minutes. The lysed RIPA solution was then placed in a 4°C centrifuge and centrifuged at 12000rpm for 15 minutes to extract the supernatant. The total protein concentration in the supernatant was determined according to the BCA method (Beyotime), and then 5×SDS loading buffer was added and boiled at 100°C for 10 minutes to prepare a protein sample. The cell lysate was added to the corresponding lanes of SDS-PAGE with the same total protein as the standard. The protein was separated by running at 85V for 0.5h and then at 105V for 1.5h. The separated protein was treated with 320mA current for 1.5h and transferred to a 0.45μm or 0.22μm PVDF membrane. The PVDF membrane was subsequently blocked with a TBST solution containing 5% skim milk powder for 1h. Wash with TBST solution 3 times, 6 minutes each time. Dilute the corresponding primary antibody with TBST solution in proportion and incubate with PVDF membrane at 4°C overnight. Wash again with TBST solution 3 times, 6 minutes each time. Then incubate with secondary antibody diluted with TBST and PVDF membrane at room temperature for 1 hour. Finally, wash with TBST solution 3 times, 6 minutes each time. Develop the PVDF membrane with developer (Millipore) and record for semi-quantitative analysis and statistics.

[0157] Figure 2The Western Blot results of compounds I-4, I-6, I-10, I-12, I-16, and I-18 prepared according to the embodiments of the present invention are shown. Figure 2 It can be seen that compounds I-4, I-6, I-16, and I-18 can all reduce NLRP3 at the protein level in the THP-1 cell line, among which I-18 drug has a relatively better effect.

[0158] Experimental methods:

[0159] Timed quantitative PCR experiment:

[0160] The primers used for real-time quantitative PCR were synthesized by Sangon Inc, TRIZOL was purchased from TAKARA, and the other real-time quantitative PCR-related reagents were purchased from Yeason. The real-time quantitative PCR results were normalized according to GAPDH. The primer sequences are as follows:

[0161] NLRP3-F 5'-AACATTCGGAGATTGTGGTTGGG-3';

[0162] NLRP3-R 5'-GTGCGTGAGATTCTGATTAGTGCTG-3';

[0163] GAPDH-F 5'-ATGGGGAAGGTGAAGGTCG-3';

[0164] GAPDH-R 5'-GGGGTCATTGATGGCAACAATA-3';

[0165] Figure 3 The qPCR experimental results of compound I-18 prepared according to the embodiment of the present invention are shown. Figure 3 It can be seen that compound I-3 has no significant effect on the expression level of NLRP3 mRNA and only has an effect on NLRP3 at the protein level.

[0166] Figure 4 The results of the MTT toxicity test of compound I-18 prepared according to the embodiment of the present invention are shown. Figure 4 It can be seen that compound I-18 has no obvious cytotoxicity.

[0167] The above specific implementations further describe the purpose, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above is only a specific implementation of the present invention and is not limited to the protection scope of the present invention. Without departing from the purpose of the basic characteristics of the present invention, the present invention can be embodied in various forms. Therefore, the implementation forms in the present invention are used for illustration rather than limitation. Since the scope of the present invention is limited by the claims rather than the specification, and all changes within the scope defined by the claims or within the equivalent scope of the scope defined by the claims should be understood to be included in the claims. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A NLRP3 small molecule protein degrader, characterized in that: It is a sulfonylurea compound of the following chemical structure general formula I or a pharmaceutically acceptable salt or solvate thereof: in, The connecting group A is: C1-C 20 Alkyl chains, ether chains, oxygen chains, sulfur chains, nitrogen chains, C1-C 20 Alkenyl chain, C1-C 20 Alkynyl chain, -C(=O)NH(C1-C 19 Alkyl chains, ether chains, oxygen chains, sulfur chains, nitrogen chains, C1-C 19 Alkenyl, C1-C 19 Alkynyl); R1, R2, R3 and R4 are independently selected from hydrogen, halogen, hydroxy, nitro, methoxy, amino, methylamino, dimethylamino, carboxyl, cyano, -CO2Me, -CO2Et, -CH3, -Et, -N3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more selected from -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl), -O(C 1-4 Alkylene-C 3-6 Cycloalkyl), -O(three-membered to seven-membered heterocyclic group), -O(C 1-4 Alkylene-three to seven-membered heterocyclic group), -SH, -S(C 1-6 Alkyl), -S(C 3-6 Cycloalkyl), -S(C 1-4 Alkylene-C 3-6 Cycloalkyl), -S(three-membered to seven-membered heterocyclic group), -S(C 1-4 Alkylene-three to seven-membered heterocyclic group), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl), -N(C 3-6 Cycloalkyl)2, -NH(C 1-4 Alkylene-C 3-6 Cycloalkyl), -N(C 1-4 Alkylene-C 3-6 Cycloalkyl)2, -NH(three-membered to seven-membered heterocyclic group), -N(three-membered to seven-membered heterocyclic group), -NH(C 1-4 Alkylene-three to seven-membered heterocyclic group), -N(C 1-4 Alkylene-three-membered to seven-membered heterocyclic group)2; Group B is: Where R 11 , R 12 and R 13 Independently selected from hydrogen, halogen, hydroxy, nitro, methoxy, amino, methylamino, dimethylamino, carboxyl, cyano, -CO2Me, -CO2Et, -CH3, -Et, -N3; ​​X is NH, S, O. The group C is: pyrazole, furan, tetrahydrofuran, tetrahydropyran, pyran, pyrrolidine, pyrrole, triazole, tetrazole, imidazole, pyridine, morpholine, piperazine, piperidine, substituted phenyl, phenylheteroaryl, phenylheterocyclic group, biphenyl, quinoline, isoquinoline, naphthyl, pyrazine and pyrimidine, all of which may be optionally substituted where appropriate; the group C is bonded directly or via a substituent to the adjacent oxygen and directly to the adjacent sulfur via a carbon atom. The group D is: wherein Y at each occurrence is independently selected from C, N, S and O, which may be optionally substituted where appropriate; R5, R6, R7, R8, R9 and R 10 are independently selected from: hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, all of which may be optionally substituted by halogen, cyano or C1-C6 alkoxy where appropriate; and Among them, R6 and R7, R7 and R8, R9 and R 10 May combine to form a phenyl group, a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered oxygen heterocycle, or a 5- or 6-membered nitrogen heterocycle, each of which may be optionally substituted.

2. The NLRP3 small molecule protein degrader according to claim 1, characterized in that The group D is 3. The NLRP3 small molecule protein degrader according to claim 1 or 2, characterized in that The group C is 4. The NLRP3 small molecule protein degrader according to any one of claims 1 to 3, characterized in that The group B is R 11 , R 12 and R 13 Independently selected from halogen, hydroxy, methoxy.

5. The NLRP3 small molecule protein degrader according to any one of claims 1 to 4, characterized in that The compound is selected from the following compounds:

6. A method for preparing a NLRP3 small molecule protein degrader according to any one of claims 1 to 5, characterized in that: The steps include: in, R2, R 11 , R 13 As defined in claim 1.

7. A pharmaceutical composition, characterized in that It comprises the NLRP3 small molecule protein degrader as described in any one of claims 1 to 5, and a pharmaceutically acceptable carrier.

8. Use of the NLRP3 small molecule protein degrader according to any one of claims 1 to 5 in the preparation of a medicament for preventing or treating a disease associated with the inhibition of NLRP3 activity.

9. Use of the NLRP3 small molecule protein degrader according to any one of claims 1 to 5 in the preparation of a medicament for preventing or treating a disease associated with inhibiting the activity of IL-1β, IL-17, IL-18, IL-1α, IL-37, or IL-33.

10. The use according to any one of claims 8 or 9, wherein the disease, disorder or condition is a disease, disorder or condition of the immune system; The disease, disorder or condition is an inflammatory disease, disorder or condition or an autoimmune disease, disorder or condition; The disease, disorder or condition is a disease, disorder or condition of the skin; The disease, disorder or condition is a disease, disorder or condition of the cardiovascular system; The disease, disorder or condition is cancer, tumor or other malignancy; The disease, disorder or condition is a disease, disorder or condition of the renal system; The disease, disorder or condition is a disease, disorder or condition of the gastrointestinal tract; the disease, disorder or condition is a disease, disorder or condition of the respiratory system; The disease, disorder or condition is a disease, disorder or condition of the endocrine system.

11. The use according to any one of claims 8 or 9, characterized in that: The disease is selected from constitutive inflammation, including cryptopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID); including autoinflammatory diseases: familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin-1 receptor (DIRA) antagonist deficiency, Majeed syndrome, septic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia (SIFD) with B cell immunodeficiency, periodic fever and developmental delay (SIFD); Sweet's syndrome, chronic nonbacterial bone myelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, impetigo, hyperostosis, osteitis syndrome (SAPHO); autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome and Schnitz's syndrome; respiratory diseases, including chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis and cystic fibrosis; central nervous system diseases, including Parkinson's disease, Alzheimer's disease, Brain damage from Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and pneumococcal meningitis; metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout; eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis, and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy, and diabetic nephropathy; liver diseases, including nonalcoholic steatohepatitis and alcoholic liver disease; inflammatory skin reactions, including contact hypersensitivity and sunburn; Arthritic reactions, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis; viral infections, including alphaviruses including chikungunya and Ross River, and flaviviruses including dengue and Zika, influenza, HIV; Hidradenitis suppurativa (HS) and other skin diseases that cause cysts; cancer including lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; stroke; myocardial infarction; graft-versus-host disease; hypertension: Colitis: helminth infections: bacterial infections; abdominal aortic aneurysms; wound healing; depression, psychological stress; pericarditis including Dressler's syndrome, ischemia-reperfusion injury and any disease in which the individual has been identified to carry a germline or somatic non-silent mutation in NLRP3.

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