Sulfonylurea compound and use thereof

Abstract

A sulfonylurea compound and use thereof. The sulfonylurea compound is represented by formula (I), wherein the definition of each substituent is described in detail in the specification. The sulfonylurea compound, as an NLRP3 inhibitor, can be used for preparing a drug for treating diseases related to NLRP3 activity.

Description

A sulfonylurea compound and use thereof

[0001] The present application claims priority from the Chinese patent application No. 202410836339.9, filed on June 26, 2024, and entitled "A sulfonylurea compound and use thereof", the contents of which should be understood as incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to, but is not limited to, the field of pharmaceutical technology, and in particular to a sulfonylurea compound as an NLRP3 inhibitor and use thereof. BACKGROUND

[0003] Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a kind of multimeric protein complex, which can activate cysteine asparate protease-1 (caspase-1) and further induce the maturation of interleukin (IL) IL-1β and IL-18.

[0004] NLRP3 inhibitors directly target NLRP3, interact with NACHT or PYD domains of NLRP3, and the possible effects include inhibiting the enzymatic activity of NLRP3 and inhibiting the interaction between NLRP3, thereby affecting the NLRP3 inflammasome assembly process (i.e., the activation process).

[0005] Under normal physiological conditions, the activation of NLRP3 inflammasome leads to the release of pro-inflammatory factors IL-1β and IL-18, which play a crucial role in the response and defense of pathogens. However, abnormal activation of NLRP3 inflammasome leads to neuroinflammation, which is closely related to the occurrence and development of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

[0006] Initially, the sulfonylurea compound glibenclamide was discovered to be an effective NLRP3 inhibitor when screening a library of diaryl sulfonylureas for their phenotypes on interleukin 1 beta (IL-1b) secretion from human monocytes (J. Pharmacol. Experimental Therapeutics 2001, 299(1), 187-197.), but it was weakly active. Subsequently, these compounds were further optimized and their mechanism was initially investigated, with the initial hypothesis that they act by inhibiting GST omega 1-1. Further work found that these compounds act by inhibition of NLRP3 (J. Biol. Chem. 2003, 278, 16567-16578.). One of the glibenclamide derivatives, CRID3 or CP456,773, was renamed MCC950 and was found to be a potent inhibitor of the NLRP3 inflammasome (Nat. Med. 2015, 21(3), 248-255.). MCC950 was tested in the clinic for rheumatoid arthritis, but the trial was terminated possibly due to elevated liver enzymes in patient sera. MCC950 acts by binding to the Walker B motif in the NACHT domain of NLRP3 and blocking NLRP3-mediated ATP hydrolysis. Since then, MCC950 has been used as a tool compound and has been used extensively in a range of in vitro and in vivo studies involving NLRP3 diseases. This tool compound, used in conjunction with a range of target validation techniques, has demonstrated that NLRP3 is active in a number of diseases, including cryopyrin associated periodic syndrome (CAPS), inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), gout, multiple sclerosis, stroke, Alzheimer’s disease and Parkinson’s disease. SUMMARY

[0007] The following is a summary of the subject matter of the detailed description herein. This summary is not intended to limit the scope of protection of the present application.

[0008] A first aspect of the present application provides a sulfonylurea compound, isomer, solvate or pharmaceutically acceptable salt thereof, the structure of which is shown in formula (I):

[0009] wherein,

[0010] R1and R3are each independently hydrogen, C1-C6alkyl, amino, hydroxyl, halogen, C1-C6alkoxy, nitro or cyano;

[0011] Z1and Z2are each independently R2or -(CH2)-N(R4)CH3, wherein R2is hydrogen, C1-C6alkyl, amino, hydroxyl, halogen, C1-C6alkoxy, or cyano, and R4is C1-C6alkyl;

[0012] R5is C1-C6alkyl;

[0013] Optionally, R4is linked to R1, R2, or R5to form a ring through a single bond or C1-C6alkylene.

[0014] The second aspect of the present application provides a pharmaceutical composition comprising the above-mentioned sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] The third aspect of the present application provides the above-mentioned sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, for use as:

[0016] (i) an NLRP3 inflammasome inhibitor; and / or

[0017] (ii) a modulator of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33, and Th17 cells.

[0018] The fourth aspect of the present application provides use of the above-mentioned sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, in the manufacture of a medicament for treating or preventing a disease, disorder, or condition.

[0019] The fifth aspect of the present application provides a method of treating or preventing a disease, disorder, or condition, comprising administering to an individual in need thereof a therapeutically effective amount of the above-mentioned sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0020] The sixth aspect of the present application provides the above-mentioned sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, for use in treating or preventing a disease, disorder, or condition in an individual in need thereof.

[0021] Other aspects can become apparent after reading and understanding the detailed description.

[0022] SUMMARY

[0023] The accompanying drawings are intended to provide a better understanding of the technical solutions of the present application, and constitute a part of the specification, and together with the embodiments of the present application serve to explain the technical solutions of the present application, and do not constitute a limitation on the technical solutions of the present application.

[0024] Figure 1 shows the change in IL-1β release for Example 1 and Examples 3-5 of the present application versus MCC950;

[0025] Figure 2 shows the change in IL-1β release for Example 2 of the present application versus MCC950;

[0026] Figure 3 shows the change in IL-1β release for Example 6 of the present application versus MCC950;

[0027] Figure 4 shows the change in IL-1β release for Examples 7-10 of the present application versus MCC950;

[0028] Figure 5 shows the change in IL-1β release for Example 13 and Example 14 of the present application at a concentration of 1 μΜ;

[0029] Figure 6 shows the change in IL-1β release for Example 1 of the present application versus the concentration of MCC950;

[0030] Figure 7 shows the change in IL-1β release for Example 1 and Example 6 of the present application at a concentration of 1 μΜ;

[0031] Figure 8 shows the change in IL-1β release for Example 3, Example 6 and MCC950 at a concentration of 1 μΜ;

[0032] Figure 9 shows the change in IL-1β release for Example 2, Example 7 of the present application at a concentration of 1 μΜ;

[0033] Figure 10 shows the change in IL-1β release for Examples 8-10 of the present application at a concentration of 1 μΜ.

[0034] DETAILED DESCRIPTION

[0035] The first aspect of the present application provides a sulfonylurea compound, isomers, solvates or pharmaceutically acceptable salts thereof, the structure of the sulfonylurea compound is shown as formula (I):

[0036] wherein,

[0037] R1and R3are each independently hydrogen, C1-C6alkyl, amino, hydroxyl, halogen, C1-C6alkoxy, nitro or cyano;

[0038] Z1and Z2are each independently R2or -(CH2)-N(R4)CH3, wherein R2is hydrogen, C1-C6alkyl, amino, hydroxyl, halogen, C1-C6alkoxy or cyano, and R4is C1-C6alkyl;

[0039] R5is C1-C6alkyl;

[0040] Optionally, R4is linked to R1, R2, or R5in a ring through a single bond or C1-C6alkylene.

[0041] wherein "linked in a ring through a single bond or C1-C6alkylene" means that R4is linked to R1, R2, or R5in a ring either directly through a single bond or through an additional C1-C6alkylene.

[0042] In an exemplary embodiment, when Z1is one of R2or -(CH2)-N(R4)CH3, Z2is the other, wherein R2is hydrogen, C1-C6alkyl, amino, hydroxyl, halogen, C1-C6alkoxy, or cyano, and R4is C1-C6alkyl.

[0043] In an exemplary embodiment, when Z2is R2and Z1is -(CH2)-N(R4)CH3, the sulfonylurea compound has the structure:

[0044] In an exemplary embodiment, R4is linked to R1, R2, or R5in a ring through a single bond or C1-C6alkylene in the compound of formula (II).

[0045] In an exemplary embodiment, when Z1is R2and Z2is -(CH2)-N(R4)CH3, the sulfonylurea compound has the structure:

[0046] In an exemplary embodiment, R4is linked to R1, R2, or R5in a ring through a single bond or C1-C6alkylene in the compound of formula (III).

[0047] In an exemplary embodiment, the sulfonylurea compound is selected from any one of the following:

[0048] In an exemplary embodiment, in the compound of formula (II), R1is amino, R2and R3are hydrogen, and R4and R5are methyl.

[0049] In an exemplary embodiment, in the compound of formula (II), R1is hydrogen, R2is hydroxyl, R3is fluoro, and R4and R5are methyl.

[0050] In an exemplary embodiment, in the compound of formula (II), R1is fluoro, R2and R3are hydrogen, and R4and R5are methyl.

[0051] In an exemplary embodiment, in the compound of formula (II), R1and R3are fluoro, R2is hydrogen, and R4and R5are methyl.

[0052] In an exemplary embodiment, the compound of formula (II) is where R1is methyl, R2and R3are hydrogen, and R4and R5are methyl.

[0053] In an exemplary embodiment, the compound of formula (II) is where R1is chloro, R2and R3are hydrogen, and R4and R5are methyl.

[0054] In an exemplary embodiment, the compound of formula (II) is where R1and R3are hydrogen, R4and R2are connected by a single bond to form a ring, and R5is methyl.

[0055] In an exemplary embodiment, the compound of formula (II) is where R1, R2, and R3are hydrogen, and R4and R5are connected by a single bond to form a ring.

[0056] In an exemplary embodiment, the compound of formula (II) is where R1is nitro, R2and R3are hydrogen, and R4and R5are connected by a single bond to form a ring.

[0057] In an exemplary embodiment, the compound of formula (II) is where R1is amino, R2and R3are hydrogen, and R4and R5are connected by a single bond to form a ring.

[0058] In an exemplary embodiment, the compound of formula (II) is where R1is cyano, R2and R3are hydrogen, and R4and R5are methyl.

[0059] In an exemplary embodiment, the compound of formula (III) is where R1is amino, R2and R3are hydrogen, and R4and R5are methyl.

[0060] In an exemplary embodiment, the compound of formula (III) is where R2is amino, R1and R3are hydrogen, and R4and R5are methyl.

[0061] In an exemplary embodiment, the compound of formula (III) is where R1, R2, and R3are hydrogen, and R4and R5are connected by a single bond to form a ring.

[0062] In an exemplary embodiment, the compound of formula (III) is where R1is cyano, R2and R3are hydrogen, and R4and R5are methyl.

[0063] In an exemplary embodiment, the typical administration route of the sulfonylurea compound, isomers, solvates, or pharmaceutically acceptable salts thereof includes, but is not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0064] The second aspect of the present application provides a pharmaceutical composition comprising the above-mentioned sulfonylurea compound, isomers, solvates, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.

[0065] In an exemplary embodiment, the pharmaceutical composition can be prepared by combining the sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0066] In an exemplary embodiment, typical routes of administration of the pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0067] In an exemplary embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients can make the compounds of the present application formulated into tablets, pills, dragees, sugar-coated tablets, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0068] In an exemplary embodiment, solid oral compositions can be prepared by conventional mixing or compounding techniques. For instance, the active compound can be mixed with a solid excipient and optionally with a lubricant, and if desired, with other suitable excipients, and the mixture then processed into granules, with cores for tablets or sugar-coated tablets. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents, and the like.

[0069] In an exemplary embodiment, the pharmaceutical composition can also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0070] In an exemplary embodiment, the pharmaceutical composition can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying or lyophilizing processes.

[0071] The third aspect of the present application provides a sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, as described above, for use as:

[0072] (i) an NLRP3 inflammasome inhibitor; and / or

[0073] (ii) a modulator of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33, and Th17 cells.

[0074] ​The fourth aspect of the present application provides use of the above-mentioned sulfonylurea compound, isomer, solvate or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for treating or preventing a disease, disorder or condition.

[0075] In an exemplary embodiment, the disease, disorder or condition is selected from the group consisting of:

[0076] (i) an immune system disease, disorder or condition;

[0077] (ii) an inflammatory disease, disorder or condition or an autoimmune disease, disorder or condition;

[0078] (iii) a skin disease, disorder or condition;

[0079] (iv) a cardiovascular system disease, disorder or condition;

[0080] (v) a cancer, tumor or other malignant neoplasm;

[0081] (vi) a renal system disease, disorder or condition;

[0082] (vii) a gastrointestinal tract disease, disorder or condition;

[0083] (viii) a respiratory system disease, disorder or condition;

[0084] (ix) an endocrine system disease, disorder or condition;

[0085] (x) a central nervous system (CNS) disease, disorder or condition; and / or

[0086] (xi) a local or systemic infection.

[0087] In an exemplary embodiment, the disease, disorder or condition is selected from the group consisting of:

[0088] Autoinflammatory diseases including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjogren's syndrome, and Schnitzler syndrome;

[0089] Autoimmune diseases including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjogren's syndrome, and Schnitzler syndrome;

[0090] Macrophage activation syndrome;

[0091] Bull's syndrome;

[0092] Respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis;

[0093] Dermatitis including contact dermatitis;

[0094] Central nervous system diseases including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, brain damage caused by cerebral malaria and pneumococcal meningitis;

[0095] Metabolic diseases including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout;

[0096] Eye diseases including those of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infection, and dry eye;

[0097] Kidney diseases including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, and diabetic nephropathy;

[0098] Liver diseases including nonalcoholic steatohepatitis (NASH) and alcoholic liver disease;

[0099] Cutaneous inflammatory reactions including contact hypersensitivity and sunburn;

[0100] Arthritic responses, including osteoarthritis, systemic onset juvenile idiopathic arthritis, adult onset Still's disease, relapsing polychondritis;

[0101] Viral infections, including alphaviruses (including chikungunya virus, Ross River virus) and flaviviruses (including dengue virus, Zika virus), influenza, human immunodeficiency virus (HIV);

[0102] Hidradenitis suppurativa (HS) and other cyst-causing skin diseases;

[0103] Cancers, including lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;

[0104] Polymyositis;

[0105] Stroke, including ischemic stroke;

[0106] Myocardial infarction, including recurrent myocardial infarction;

[0107] Congestive heart failure;

[0108] Embolism;

[0109] Cardiovascular disease;

[0110] Graft versus host disease;

[0111] Hypertension;

[0112] Colitis;

[0113] Helminth infection;

[0114] Bacterial infection;

[0115] Sepsis;

[0116] Septic shock;

[0117] Abdominal aortic aneurysm;

[0118] Wound healing;

[0119] Depression, psychological stress;

[0120] Ischemia-reperfusion injury and any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0121] In an exemplary embodiment, the disease, disorder, or condition is selected from the group consisting of:

[0122] (i) autoinflammatory diseases, including cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, or pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA);

[0123] (ii) Parkinson’s disease or Huntington’s disease;

[0124] (iii) gout or juvenile idiopathic arthritis;

[0125] (iv) nonalcoholic steatohepatitis (NASH);

[0126] (v) oxalate nephropathy or nephrocalcinosis;

[0127] (vi) uveitis;

[0128] (vii) hidradenitis suppurativa (HS);

[0129] (viii) myelodysplastic syndrome, macrophage activation syndrome, Schnitzler syndrome, adult-onset Still’s disease, or Behcet’s disease; or

[0130] (ix) sepsis, septic shock.

[0131] A fifth aspect of the present application provides a method of treating or preventing a disease, disorder, or condition, comprising administering to an individual in need thereof a therapeutically effective amount of the above sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0132] In an exemplary embodiment, a therapeutically effective amount in the sulfonylurea compound, isomer, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition can be determined, for example, according to the particular use of the treatment, the manner in which the compound is administered, the health of the patient, and the judgment of the prescribing physician. The proportion or concentration of active ingredient in a pharmaceutical composition can not be fixed, and will vary with factors such as the dosage, chemical characteristics (e.g., hydrophobicity) and the route of administration. For example, a suitable dose can be provided by dissolution of the compound, isomer, solvate, or pharmaceutically acceptable salt thereof in a physiologically-acceptable buffer. Some typical dose ranges are about 1 g / kg body weight / day. In certain embodiments, the dose ranges from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage will likely depend on such variables as the type and extent of disease or disorder, the general health of the particular patient, the preferred mode of administration, and the relative biological efficacy of the compound selected. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0133] In an exemplary embodiment, the disease, disorder, or condition is selected from the group consisting of:

[0134] (i) an immune system disease, disorder, or condition;

[0135] (ii) an inflammatory disease, disorder, or condition or an autoimmune disease, disorder, or condition;

[0136] (iii) a skin disease, disorder, or condition;

[0137] (iv) a cardiovascular system disease, disorder, or condition;

[0138] (v) a cancer, tumor, or other malignancy;

[0139] (vi) a renal system disease, disorder, or condition;

[0140] (vii) a gastrointestinal tract disease, disorder, or condition;

[0141] (viii) a respiratory system disease, disorder, or condition;

[0142] (ix) an endocrine system disease, disorder, or condition;

[0143] (x) a central nervous system (CNS) disease, disorder, or condition; and / or

[0144] (xi) a local or systemic infection.

[0145] In an exemplary embodiment, the disease, disorder, or condition is selected from the group consisting of:

[0146] constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal onset multisystem inflammatory disease (NOMID), 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 antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency, and immune dysregulation (APLAID), and sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD);

[0147] autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet’s disease, Sjogren’s syndrome, and Schnitzler’s syndrome;

[0148] macrophage activation syndrome;

[0149] Brewer’s syndrome;

[0150] respiratory diseases, including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis;

[0151] dermatitis, including contact dermatitis;

[0152] central nervous system diseases, including Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, brain damage caused by cerebral malaria, and pneumococcal meningitis;

[0153] metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout;

[0154] ocular diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infection, and dry eye;

[0155] kidney diseases, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, and diabetic nephropathy;

[0156] liver diseases, including nonalcoholic steatohepatitis (NASH) and alcoholic liver disease;

[0157] cutaneous inflammatory reactions, including contact hypersensitivity and sunburn;

[0158] Arthritic responses, including osteoarthritis, systemic onset juvenile idiopathic arthritis, adult onset Still's disease, relapsing polychondritis;

[0159] Viral infections, including alphaviruses (including chikungunya virus, Ross River virus) and flaviviruses (including dengue virus, Zika virus), influenza, human immunodeficiency virus (HIV);

[0160] Hidradenitis suppurativa (HS) and other cyst-causing skin diseases;

[0161] Cancers, including lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;

[0162] Polymyositis;

[0163] Stroke, including ischemic stroke;

[0164] Myocardial infarction, including recurrent myocardial infarction;

[0165] Congestive heart failure;

[0166] Embolism;

[0167] Cardiovascular disease;

[0168] Graft versus host disease;

[0169] Hypertension;

[0170] Colitis;

[0171] Helminth infection;

[0172] Bacterial infection;

[0173] Sepsis;

[0174] Septic shock;

[0175] Abdominal aortic aneurysm;

[0176] Wound healing;

[0177] Depression, psychological stress;

[0178] Ischemia-reperfusion injury and any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0179] In an exemplary embodiment, the disease, disorder, or condition is selected from the group consisting of:

[0180] (i) autoinflammatory diseases, including cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, or pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA);

[0181] (ii) Parkinson’s disease or Huntington’s disease;

[0182] (iii) gout or juvenile idiopathic arthritis;

[0183] (iv) nonalcoholic steatohepatitis (NASH);

[0184] (v) oxalate nephropathy or nephrocalcinosis;

[0185] (vi) uveitis;

[0186] (vii) hidradenitis suppurativa (HS);

[0187] (viii) myelodysplastic syndrome, macrophage activation syndrome, Schnitzler syndrome, adult-onset Still’s disease, or Behcet’s disease; or

[0188] (ix) sepsis, septic shock.

[0189] The sixth aspect of the present application provides the above-mentioned sulfonylurea compound, isomer, solvate or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for use in treating or preventing a disease, disorder or condition in an individual in need thereof.

[0190] In an exemplary embodiment, the disease, disorder or condition is selected from the group consisting of:

[0191] (i) a disease, disorder or condition of the immune system;

[0192] (ii) an inflammatory disease, disorder or condition or an autoimmune disease, disorder or condition;

[0193] (iii) a disease, disorder or condition of the skin;

[0194] (iv) a disease, disorder or condition of the cardiovascular system;

[0195] (v) a cancer, tumor or other malignancy;

[0196] (vi) a disease, disorder or condition of the renal system;

[0197] (vii) a gastrointestinal disease, disorder or condition;

[0198] (viii) a respiratory disease, disorder or condition;

[0199] (ix) an endocrine system disease, disorder or condition;

[0200] (x) a central nervous system (CNS) disease, disorder or condition; and / or

[0201] (xi) a local or systemic infection.

[0202] In an exemplary embodiment, the disease, disorder or condition is selected from the group consisting of:

[0203] a constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID), 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 antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency, and immune dysregulation (APLAID), and sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD);

[0204] an autoimmune disease, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet’s disease, Sjogren’s syndrome, and Schnitzler syndrome;

[0205] a macrophage activation syndrome;

[0206] Brewer syndrome;

[0207] a respiratory disease, including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis;

[0208] a dermatitis, including contact dermatitis;

[0209] a central nervous system disease, including Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, and brain injury resulting from pneumococcal meningitis;

[0210] Metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, pseudogout;

[0211] Eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infections and dry eye;

[0212] Kidney diseases, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis and diabetic nephropathy;

[0213] Liver diseases, including non-alcoholic steatohepatitis (NASH) and alcoholic liver disease;

[0214] Skin inflammatory reactions, including contact hypersensitivity and sunburn;

[0215] Joint inflammatory reactions, including osteoarthritis, systemic onset juvenile idiopathic arthritis, adult onset Still's disease, relapsing polychondritis;

[0216] Viral infections, including alphaviruses (including chikungunya virus, Ross River virus) and flaviviruses (including dengue virus, Zika virus), influenza, human immunodeficiency virus (HIV);

[0217] Hidradenitis suppurativa (HS) and other cyst-causing skin diseases;

[0218] Cancers, including lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;

[0219] Polymyositis;

[0220] Stroke, including ischemic stroke;

[0221] Myocardial infarction, including recurrent myocardial infarction;

[0222] Congestive heart failure;

[0223] Embolism;

[0224] Cardiovascular diseases;

[0225] Graft versus host disease;

[0226] Hypertension;

[0227] Colitis;

[0228] Helminth infections;

[0229] Bacterial infections;

[0230] Sepsis;

[0231] Septic shock;

[0232] Abdominal aortic aneurysm;

[0233] wound healing;

[0234] depression, psychological stress;

[0235] ischemia-reperfusion injury and any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0236] In an exemplary embodiment, the disease, disorder or condition is selected from the group consisting of:

[0237] (i) an autoinflammatory disease, including cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, or pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA);

[0238] (ii) Parkinson’s disease or Huntington’s disease;

[0239] (iii) gout or juvenile idiopathic arthritis;

[0240] (iv) nonalcoholic steatohepatitis (NASH);

[0241] (v) oxalate nephropathy or nephrocalcinosis;

[0242] (vi) uveitis;

[0243] (vii) hidradenitis suppurativa (HS);

[0244] (viii) myelodysplastic syndrome, macrophage activation syndrome, Schnitzler syndrome, adult-onset Still’s disease, or Behcet’s disease; or

[0245] (ix) sepsis, septic shock.

[0246] The term

[0247] Herein, the halogen refers to a fluorine, chlorine, bromine or iodine atom.

[0248] The C1-C6 alkyl refers to an alkane radical having a number of carbon atoms of from 1 to 6 - C n H 2n+1 (n = 1-6), for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, neopentyl or n-hexyl.

[0249] C1-C6alkoxy means an -O-C1-C6alkyl group, for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, neopentoxy, or n-hexyloxy, and the like.

[0250] C1-C6alkylene means a straight or branched divalent alkyl group having from one to six carbon atoms, -CH2-, n H 2n -(n = 1-6), for example methylene (-CH2-), ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), isopropylene (-CH(CH3)-CH2-), and the like.

[0251] In this document, the sulfonylurea compounds of the application encompass all stereoisomers, geometric isomers, tautomers and isotopologues of the described structures. Unless otherwise specified, a compound named herein with a particular tautomer designation is intended to include other tautomers as well. Unless otherwise stated, the sulfonylurea compounds of the application can exist in enantiomeric, diastereomeric, or racemic forms, or as mixtures thereof. The stereoisomers of the sulfonylurea compounds of the application include cis- and trans- isomers, optical isomers (such as enantiomers), diastereomers, geometric isomers, rotational isomers, atropisomers, conformational isomers and tautomers of the sulfonylurea compounds of the application, as well as mixtures of isomers such as racemates and diastereomeric mixtures.

[0252] In this document, the atoms in the sulfonylurea compounds of the application can be present with their natural isotopic abundances, or one or more of the atoms can be present with artificially enhanced isotopic abundances in one or more specific isotopes having the same atomic number but an atomic mass different from the atomic mass that predominates in nature. The application encompasses all suitable isotopologues of the sulfonylurea compounds described herein, for example deuterium substitutions, where deuterium enrichment can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds useful as standards or probes in biological assays. Isotopologues of the sulfonylurea compounds of the application can be prepared according to known procedures, using appropriate isotopically enriched reagents or intermediates, according to the procedures described herein, or according to procedures known to those skilled in the art. Examples of isotopes that can be present in the sulfonylurea compounds of the application include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F,36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.

[0253] In the present context, the sulfonylurea compounds of the present application can exist in solvate or non-solvate form. The solvates described herein include hydrates, and the solvent or water in the solvates or hydrates can be in a stoichiometric or non-stoichiometric amount. The solvates refer to a complex formed by the sulfonylurea compounds of the present application with one or more molecules of a pharmaceutically acceptable solvent such as methanol, ethanol, acetone, dimethylformamide, water and the like. When the solvent is water, the solvate is a hydrate.

[0254] In the present context, the sulfonylurea compounds of the present application can exist in the form of their pharmaceutically acceptable salts, such as acid addition salts or base addition salts of the sulfonylurea compounds of the present application. The acids which can be present as the acid addition salts are inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, acid sulfate, sulfurous acid, acid sulfurous acid, phosphoric acid, acid phosphoric acid, carbonic acid, acid carbonic acid, and organic acids, such as formic acid, acetic acid, propionic acid, pantothenic acid, lactic acid, oxalic acid, salicylic acid, citric acid, acid citric acid, tartaric acid, acid tartaric acid, succinic acid, maleic acid, fumaric acid, glucuronic acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ascorbic acid, gentisic acid, pamoic acid, camphorsulfonic acid, mandelic acid, saccharic acid, amino acids such as natural amino acids, L-glycine, L-aspartic acid, L-glutamic acid, L-valine, and the like. The bases which can be present as the base addition salts are inorganic bases, such as sodium, potassium, calcium, magnesium, manganese, iron, zinc or aluminum containing bases, and organic bases, including basic amino acids (e.g., arginine, lysine, histidine), ammonia, primary, secondary, tertiary amines, cyclic amines such as piperidine, morpholine, piperazine.

[0255] In the present context, the term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0256] In the present text, the term "pharmaceutically acceptable adjuvant" refers to those adjuvants which do not cause an appreciable stimulation of the organism and which do not impair the biological activity and properties of the active compounds. Suitable adjuvants are well known to the person skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

[0257] In the present text, the word "comprise" or "comprising" and its English variants such as "comprises" or "comprising", are to be interpreted both as open and non-exclusive meaning, i.e. "including but not limited to".

[0258] In the present text, the term "pharmaceutical composition" refers to a mixture of one or more of the sulfonylurea compounds of the present application, isomers, solvates or salts thereof with a pharmaceutically acceptable adjuvant. The purpose of a pharmaceutical composition is to facilitate administration of the sulfonylurea compounds of the present application, isomers, solvates or salts thereof to an organism.

[0259] In the present text, the effective amount refers to an amount of the sulfonylurea compounds of the present application, isomers, solvates or salts thereof or pharmaceutical composition which is sufficient to affect any one or more beneficial or desired results with respect to the disease, including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presented during development of the disease. The therapeutically effective amount refers to the amount of the compound to be administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0260] In the present text, the term "treatment" means the administration of a compound or formulation described herein to improve or eliminate the disease or one or more symptoms associated with the disease, and includes:

[0261] (i) inhibiting the disease or condition, i.e. arresting its development;

[0262] (ii) relieving the disease or condition, i.e. causing regression of the disease or condition.

[0263] In the present text, the term "prevention" means the administration of a compound or formulation described herein to prevent the disease or one or more symptoms associated with the disease, and includes:

[0264] Preventing the disease or condition from occurring in a subject (e.g. a mammal), particularly when such subject is predisposed to the condition but has not yet been diagnosed as having it.

[0265] The compounds of the present application can be prepared by a variety of synthetic processes, including the specific embodiments set forth below, embodiments formed by the combination of the specific embodiments with other chemical synthetic processes known to one of ordinary skill in the art, and equivalents thereof, preferred embodiments including, but not limited to, the examples of the present application.

[0266] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the event that solvents are not specifically named, the most appropriate solvent or solvent combination known to one of ordinary skill in the art will be employed.

[0267] One important consideration in the planning of synthetic routes in the art is the selection of appropriate protecting groups for reactive functional groups, such as the amino groups in the present application, for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc., all references cited herein are incorporated by reference in their entirety.

[0268] Other features and advantages of the present application will be set forth in the following description, and in part will become apparent to those skilled in the art upon examination of the following or can be learned by practice of the present application. Other advantages of the present application can be realized and attained by means of the instrumentalities and combinations particularly pointed out in the following description. DETAILED DESCRIPTION

[0269] In order to make the purposes, technical solutions and advantages of the present application clearer, the following will describe the embodiments of the present application in detail. It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other in any manner without conflict.

[0270] The present application will be further described in the following with reference to specific examples, but the examples should not be understood as limiting the present application.

[0271] The following abbreviations are used in the present application:

[0272] Toluene: methylbenzene;

[0273] BnSH: benzyl mercaptan;

[0274] NCS: N-chlorosuccinimide;

[0275] HCl: hydrochloric acid;

[0276] ACN or MeCN: acetonitrile;

[0277] H2O: water;

[0278] NH3: ammonia;

[0279] BTC or triphosgene: triphosgene;

[0280] TFA: trifluoroacetic acid;

[0281] NH4HCO3: ammonium bicarbonate;

[0282] DMSO: dimethylsulfoxide;

[0283] EA: ethyl acetate;

[0284] THF: tetrahydrofuran;

[0285] DIEA: N,N-diisopropylethylamine;

[0286] DMF: N,N-dimethylformamide;

[0287] DCM: dichloromethane;

[0288] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0289] LCMS: liquid chromatography-mass spectrometry;

[0290] TLC: thin layer chromatography;

[0291] HPLC: high performance liquid chromatography;

[0292] RP-HPLC: reverse phase high performance liquid chromatography;

[0293] STAB or NaBH(OAc)3: sodium triacetoxyborohydride;

[0294] AcOH: acetic acid;

[0295] MeOH: methanol;

[0296] EtOH: ethanol;

[0297] PPh3: triphenylphosphine;

[0298] Pd(OAc)2: palladium acetate;

[0299] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium;

[0300] Pd(PPh3)4: tetrakis(triphenylphosphine)palladium;

[0301] TEA or Et3N: triethylamine;

[0302] Boc2O: di-tert-butyl dicarbonate;

[0303] DMAP: 4-dimethylaminopyridine;

[0304] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0305] PE: petroleum ether;

[0306] t-BuXphos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl;

[0307] TTC: 2,3,5-trichlorotriphenyl tetrazolium chloride;

[0308] HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid;

[0309] EGTA: ethylene glycol bis(2-aminoethylether) tetraacetic acid;

[0310] Na2-ATP: adenosine triphosphate disodium;

[0311] -OBn: benzyloxy;

[0312] 1,4-dioxane: 1,4-dioxane;

[0313] p-TsOH: p-toluenesulfonic acid;

[0314] t-BuOK or tBuOK: potassium tert-butoxide;

[0315] PMB: p-methoxybenzyl;

[0316] NaBH3CN: sodium cyanoborohydride;

[0317] flash: medium pressure preparation, flash column chromatography;

[0318] 2M in THF: 2 moles / liter solution in tetrahydrofuran.

[0319] Unless otherwise specified, the chemical reagents were purchased from Shanghai Jituo Biotechnology Co., Ltd.

[0320] The instrument model information involved in the experiment is as follows:

[0321] LCMS: Agilent 1260-G6125 liquid chromatography-mass spectrometer, the default ESI mode was used for reaction monitoring and compound identification; the SIM mode was used for DMPK test;

[0322] Detection HPLC: Agilent 1260 high performance liquid chromatograph;

[0323] Preparative-HPLC: Xg LC5100 preparative high performance liquid chromatograph;

[0324] NMR instrument: Oxford, China, Quantum-1 plus AS400 NMR instrument.

[0325] Medium pressure preparation instrument (flash, flash column chromatography): AP-200 medium pressure preparation instrument of Elsh.

[0326] Unless otherwise specified, the preparation HPLC uses gradient elution from 10% acetonitrile / water to 100% acetonitrile, with the addition of 0.05% trifluoroacetic acid to the mobile phase; LCMS uses gradient elution from 10% acetonitrile / water to 100% acetonitrile, with the addition of 0.1% (v / v) formic acid to the mobile phase; the medium pressure preparation uses acetonitrile / water as the mobile phase by default, gradient elution from 10% acetonitrile / water to 100% acetonitrile, and the rest will be listed as (one) and (two) solvents by default, gradient elution from 100% of the first solvent to 100% of the second solvent, such as the addition of trifluoroacetic acid, the proportion of trifluoroacetic acid is fixed at 0.05%, such as the addition of ammonium bicarbonate, the proportion of ammonium bicarbonate is fixed at 0.05%.

[0327] Unless otherwise specified, the proportion of solvents or liquid reagents mentioned in this paper is volume ratio.

[0328] Example 1: 2-amino-3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0329] Synthetic route:

[0330] Step 1: 1-(3-bromo-2-nitrophenyl)-N,N-dimethylmethanamine

[0331] Weigh 3-bromo-2-nitrobenzaldehyde (600 mg) into a 100 mL single-neck flask, then add DCM (25 mL), add dimethylamine (THF in 2M) (2 eq.), HOAc (0.2 eq.) with stirring, stir at room temperature for 2 h. After 2 h, NaBH(OAc)3 (3 eq.) is added to the reaction solution at room temperature in batches. Stir at room temperature for 2 h, LCMS shows that the target compound is generated.

[0332] Post-treatment and purification: pour the reaction solution into an appropriate amount of ice water, extract twice with DCM:MeOH=10:1(v / v)(30mL), combine the organic phases, wash with saturated brine, dry and rotary evaporate, and purify by flash column chromatography (DCM / MeOH) to obtain the target compound as a yellow oily liquid 520 mg.

[0333] Step 2: 1-(3-(benzylmercapto)-2-nitrophenyl)-N,N-dimethylmethanamine

[0334] Weigh 1-(3-bromo-2-nitrophenyl)-N,N-dimethylmethanamine (520 mg) into a 40 mL microwave tube, then add toulene (12 mL), benzyl mercaptan (2 eq.), DIEA (3 eq.), Pd2(dba)3(0.1 eq.), Xantphos (0.2 eq.) under nitrogen. Heat to 118 °C for 12 h, LCMS shows the target compound is generated.

[0335] Work-up and purification: The reaction solution is mixed with silica gel, rotary evaporated, and purified by flash column chromatography (DCM / MeOH) to give the target compound as a yellow oily liquid 420 mg.

[0336] Step 3: 3-((dimethylamino)methyl)-2-nitrobenzenesulfonamide

[0337] Weigh 6M HCl (1.0 mL) into a 50 mg vial, add MeCN (15 mL), stir to cool to 0 °C, add NCS (3 eq.), dissolve 1-(3-(benzylmercapto)-2-nitrophenyl)-N,N- dimethylmethanamine (420 mg) in 10 mL MeCN and add dropwise into the vial at 0 °C, stir for 0.5 h to give the reaction solution. Prepare another 100 mL vial, add NH3H2O (35 mL), add the reaction solution dropwise into NH3H2O under stirring at room temperature, stir for 0.5 h, LCMS confirms the generation of the target compound. Work-up and purification: remove MeCN by rotary evaporation, extract twice with DCM:MeOH = 10:1 (v / v) (50 mL). Dry and concentrate under reduced pressure to give the target compound as a yellow oily crude product 0.5 g.

[0338] Step 4: 3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-2-nitrobenzenesulfonamide

[0339] Weigh 3-((dimethylamino)methyl)-2-nitrobenzenesulfonamide (580 mg, 1 eq.) into a 100 mL vial, add phenyl (5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamate (725 mg, 0.9 eq.), add THF (10 mL), add LiOH (80 mg, 1.5 eq.) under stirring at room temperature, stir for 2 h at room temperature, LCMS confirms the generation of the target compound. Work-up and purification: filter the reaction solution, mix with silica gel, rotary evaporate, and purify by flash column chromatography on silica gel (DCM / MeOH) to give the target compound as a yellowish solid crude product 400 mg.

[0340] Step 5: 2-amino-3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1 H-inden-4-yl)carbamoyl)benzenesulfonamide

[0341] Weigh 2-amino-3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1 H-inden-4-yl)carbamoyl)benzenesulfonamide (200 mg, 1 eq.) into a 40 mL single neck flask and add THF (3 mL) / EtOH (3 mL) / H2O (3 mL) to form a milky white solution, add NH4Cl (180 mg, 8 eq.) under stirring at room temperature, after addition, add zinc powder (370 mg, 15 eq.) portion by portion under stirring at room temperature, after addition, warm up to 50 °C and stir for 4 h, confirm the formation of the target compound by LCMS.

[0342] Work-up and purification: filter the reaction solution with celite, rinse the filter cake with DCM / MeOH = 3 / 1 (v / v) (50 mL), spin the filtrate to only water left, add DMSO 2 mL and acetonitrile 2 mL to help solubilization, purify with C18 medium pressure column (0.05% NH4HCO3 / acetonitrile) and lyophilize to get the target compound as white solid 18 mg.

[0343] MS: 496 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.06 (d, J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 5.4 Hz, 1H), 6.70 (s, 1H), 6.63 (t, J = 7.6 Hz, 1H), 3.86 (s, 3H), 3.66 (s, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.54 (t, J = 7.4 Hz, 2H), 2.31 (s, 6H), 1.98 - 1.85 (m, 2H).

[0344] Example 2: 5-((dimethylamino)methyl)-2-fluoro-4-hydroxy-N-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1 H-inden-4-yl)carbamoyl)benzenesulfonamide

[0345] Synthetic route:

[0346] Step 1: 2-benzyloxy-5-bromo-4-fluorobenzaldehyde

[0347] Weigh 5-bromo-4-fluoro-2-hydroxybenzaldehyde (500 mg, 1 eq.) in a 20 mL single neck flask, add DMF (6 mL), add Cs2CO3(2.2 g, 3 eq.), add BnCl (430 mg, 1.5 eq.) with stirring at room temperature, react overnight at 50 °C, TLC shows that the target compound is generated.

[0348] Post-treatment and purification: pour the reaction solution into an appropriate amount of water, extract with EA (50 mL x 2), wash the organic phase with water twice, wash with saturated brine, dry, stir into silica gel and rotary evaporate, purify by flash column chromatography on silica gel column (PE / EA) to obtain the target compound 600 mg of yellow oily liquid.

[0349] Step 2: 2-benzyloxy-5-benzylmercapto-4-fluorobenzaldehyde

[0350] Weigh 2-benzyloxy-5-bromo-4-fluorobenzaldehyde (600 mg, 1 eq.) in a 20 mL microwave tube, then add toluene (6 mL) under nitrogen, benzyl mercaptan (365 mg, 1.5 eq.), DIEA (1.0 g, 4 eq.), Pd2(dba)3(175 mg, 0.1 eq.), Xantphos (225 mg, 0.2 eq.). Heat to 115 °C for 24 h, TLC shows that the target compound is generated.

[0351] Post-treatment and purification: stir the reaction solution into silica gel, rotary evaporate, and purify the crude product by flash column chromatography on silica gel column (PE / EA) to obtain the target compound 600 mg of yellow oily liquid.

[0352] Step 3: 1-(2-benzyloxy-5-benzylmercapto-4-fluorophenyl)-N,N-dimethylmethanamine

[0353] Weigh 2-benzyloxy-5-benzylmercapto-4-fluorobenzaldehyde (600 mg, 1 eq.) in a 100 mL single neck flask, then add DCM (20 mL), add dimethylamine (2M in THF) (1.7 mL, 2 eq.) with stirring, add HOAc (20 mg, 0.2 eq.), stir at room temperature for 2 h. After 2 h, add sodium triacetoxyborohydride (1.25 g, 3.5 eq.) to the reaction solution in batches at room temperature, stir at room temperature for 2 h, LCMS shows that the target compound is generated.

[0354] Work-up and purification: pour the reaction solution into ice water, extract twice with DCM:MeOH=10:1 (v / v) (50 mL), combine the organic phase, wash with saturated brine, dry and rotary evaporation, and purify by flash column chromatography on silica gel (DCM / MeOH) to give the target compound as a yellow oily liquid 380 mg.

[0355] Step 4: 4-benzyloxy-5-((dimethylamino)methyl)-2-fluorobenzenesulfonamide

[0356] Take 6M HCl (0.8 mL) into a 40 mL single-neck flask, add MeCN (6 mL), and stir to cool to 0°C. Add NCS (400 mg, 3 eq.), and dissolve 1-(2-benzyloxy-5-benzylmercapto-4-fluorophenyl)-N,N-dimethylmethanamine (380 mg, 1 eq.) in 4 mL MeCN. Drop the above reaction solution into the NH4OH at 0°C, and stir for 0.5 h to prepare a standby solution. Prepare another 100 mL single-neck flask, add NH4OH (10 mL), and drop the standby solution into the NH4OH at 0°C while stirring at room temperature. After dropping, raise the temperature to room temperature and stir for 0.5 h. LCMS confirms the generation of the target compound.

[0357] Work-up and purification: pour the reaction solution into ice water, extract twice with DCM:MeOH=10:1 (v / v) (50 mL), combine the organic phase, wash with saturated brine, dry and rotary evaporation, and purify by flash column chromatography on silica gel (DCM / MeOH) to give the target compound as a yellow oily liquid 380 mg.

[0358] Step 5: 4-benzyloxy-5-((dimethylamino)methyl)-2-fluoro-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0359] Take 4-benzyloxy-5-((dimethylamino)methyl)-2-fluorobenzenesulfonamide (200 mg) into a 25 mL single-neck flask, add THF (8 mL), and add phenyl (5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (170 mg, 0.8 eq.). Stir at room temperature, add LiOH (21 mg, 1.5 eq.), and stir at room temperature for 2 h. LCMS confirms the generation of the target compound. Work-up and purification: filter the reaction solution, rotary evaporation, and purify the crude product by preparative TLC (DCM / MeOH=10:1) to give the target compound as a yellow solid 90 mg.

[0360] Step 6: 5-((dimethylamino)methyl)-2-fluoro-4-hydroxy-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0361] A 25 mL single neck flask was charged with 4-benzyloxy-5-((dimethylamino)methyl)- 2-fluoro-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide (90 mg, 1 eq.) and EtOH (3 mL) was added. DCM (3 mL) was added and Pd / C (60% water, 60 mg) was added with stirring at room temperature. The reaction was stirred under H2at room temperature for 3 h. LCMS confirmed the formation of the desired compound.

[0362] Work-up and purification: The reaction was filtered through celite and the filter cake was washed with DCM:MeOH = 2:1 mixture 50 mL. The filtrate was evaporated and purified by C18 medium pressure column (0.05% TFA in water / acetonitrile) and lyophilized to give the desired compound as a white solid 54 mg.

[0363] MS: 515 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 11.06 (s, 1H), 9.43 (s, 1H), 8.12-8.05 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 11.8 Hz, 1H), 6.78-6.71 (m, 1H), 6.60 (s, 1H), 4.25 (s, 2H), 3.89 (s, 3H), 2.90 ((t, J = 6.8 Hz, 2H), 2.70 (s, 6H), 2.63 (t, J = 7.4 Hz, 2H), 2.02-1.92 (m, 2H)).

[0364] Example 3: 3-((dimethylamino)methyl)-2-fluoro-N-[(5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl]benzenesulfonamide

[0365] Synthetic route:

[0366] Step 1: 1-(3-bromo-2-fluorophenyl)-N,N-dimethylmethanamine

[0367] Into a 100 mL flask was placed 3-bromo-2-fluorobenzaldehyde (1.0 g), DCM (10 mL), dimethylamine (2 M in THF, 3.7 mL), acetic acid (0.1 mL), stirred at room temperature for 1 h, then added sodium triacetoxyborohydride (3.15 g). After addition, stirred at room temperature overnight. LCMS showed the formation of the desired compound and the starting material was consumed. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate for 3 times. The organic layers were combined and washed with saturated brine for 2 times. The organic layer was dried and concentrated. The residue was purified by column chromatography (PE / EA) to give the product as an oil (1.0 g).

[0368] Step 2: 1-(3-(benzylmercapto)-2-fluorophenyl)-N,N-dimethylmethanamine

[0369] Into a 100 mL flask was placed 1-(3-bromo-2-fluorophenyl)-N,N-dimethylmethanamine (600 mg), benzyl mercaptan (480 mg), Pd2(dba)3(475 mg), XantPhos (600 mg), DIEA (1.0 g), 1,4-dioxane (10 mL). The reaction was heated to 120 °C under nitrogen overnight. LCMS showed the formation of the desired compound and the starting material was consumed. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH) to give the product as an oil (450 mg).

[0370] Step 3: 3-((dimethylamino)methyl)-2-fluorobenzenesulfonamide

[0371] Into a 25 mL flask was placed ACN (5 mL), HCl (6 M, 0.8 mL), cooled to 0 °C, then added NCS (435 mg), stirred at this temperature for 15 min, then added 1-(3-(benzylmercapto)-2-fluorophenyl)-N,N-dimethylmethanamine (300 mg), stirred for 1 h. The reaction was then added dropwise to aqueous ammonia (10 mL), stirred for 15 min. LCMS showed the formation of the desired compound and the starting material was consumed. The reaction was quenched by adding water, and the aqueous layer was extracted with dichloromethane / methanol (20 / 1, v / v) for 3 times. The organic layers were combined and washed with water, saturated brine for 2 times. The organic layer was dried and concentrated to give the product as an oil (200 mg).

[0372] Step 4: 3-((dimethylamino)methyl)-2-fluoro-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0373] Into a 100 mL single neck flask was placed 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (200 mg), DCM (5 mL), triethylamine (255 mg), and triphosgene (100 mg). The mixture was stirred at room temperature for 1 h, then 3-((dimethylamino)methyl)-2-fluorobenzenesulfonamide (200 mg) was added and the stirring was continued at room temperature. LCMS showed the formation of the desired compound and the starting material was consumed. The mixture was concentrated and purified by column chromatography (DCM / MeOH) to give the crude product. The product was further purified by high pressure prep (H2O(NH4HCO3) / ACN). The white solid product was obtained after lyophilization, 50.32 mg.

[0374] MS: 499 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.81 - 7.68 (m, 2H), 7.63 (t, J = 6.9 Hz, 1H), 7.31 - 7.23 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 6.72 (s, 1H), 4.00 - 3.82 (m, 5H), 2.92 - 2.83 (m, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.45 (d, J = 11.7 Hz, 6H), 1.94 (p, J = 7.4 Hz, 2H).

[0375] Example 4: 3-((dimethylamino)methyl)-2,6-difluoro-N-((5-(2-methoxypyridin-4-yl)- 2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0376] Synthetic Route:

[0377] Step 1: 1-(3-bromo-2,4-difluorophenyl)-N,N-dimethylmethanamine

[0378] Into a 25 mL flask was placed 3-bromo-2,4-difluorobenzaldehyde (1.0 g), DCM (10 mL), dimethylamine (2 M in THF, 3.4 mL), acetic acid (0.1 mL), and stirred at room temperature for 1 h, then added sodium triacetoxyborohydride (2.88 g). After addition, the mixture was stirred at room temperature overnight. LCMS showed the formation of the desired compound and the starting material was consumed. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate for 3 times. The organic layers were combined and washed with saturated brine for 2 times. The organic layer was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH) to give the product as an oil (1.0 g).

[0379] Step 2: 1-(3-(benzylmercapto)-2,4-difluorophenyl)-N,N-dimethylmethanamine

[0380] Into a 25 mL flask was placed 3-bromo-2,4-difluorobenzaldehyde (1.0 g), DCM (10 mL), dimethylamine (2 M in THF, 3.4 mL), acetic acid (0.1 mL), and stirred at room temperature for 1 h, then added sodium triacetoxyborohydride (2.88 g). After addition, the mixture was stirred at room temperature overnight. LCMS showed the formation of the desired compound and the starting material was consumed. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate for 3 times. The organic layers were combined and washed with saturated brine for 2 times. The organic layer was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH) to give the product as an oil (1.0 g).

[0381] Step 3: 3-((dimethylamino)methyl)-2,6-difluorobenzenesulfonamide

[0382] Into a 25 mL flask was placed 3-bromo-2,4-difluorobenzaldehyde (1.0 g), DCM (10 mL), dimethylamine (2 M in THF, 3.4 mL), acetic acid (0.1 mL), and stirred at room temperature for 1 h, then added sodium triacetoxyborohydride (2.88 g). After addition, the mixture was stirred at room temperature overnight. LCMS showed the formation of the desired compound and the starting material was consumed. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate for 3 times. The organic layers were combined and washed with saturated brine for 2 times. The organic layer was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH) to give the product as an oil (1.0 g).

[0383] Step 4: 3-((dimethylamino)methyl)-2,6-difluoro-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1 H-inden-4-yl)carbamoyl)benzenesulfonamide

[0384] Take 5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-amine (200 g) in a 100 mL single-neck flask, add DCM (5 mL), triethylamine (255 mg), triphosgene (100 mg). Stir at room temperature for 1 h, then add 3-((dimethylamino)methyl)-2,6-difluorobenzenesulfonamide (320 mg), continue stirring at room temperature. LCMS shows that the target compound is generated, and the raw material is completely reacted. Concentrate and purify by column chromatography (DCM / MeOH) to obtain the product crude. Further high-pressure preparation purification (H2O (TFA) / ACN). After freeze-drying, 28.43 mg of yellow solid product is obtained.

[0385] MS: 517 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.35 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.95-7.90 (m, 1H), 7.48 (t, J = 9.3 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.80-6.74 (m, 1H), 6.64 (s, 1H), 4.38 (s, 2H), 3.89 (d, J = 3.6 Hz, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.76 (s, 6H), 2.64 (t, J = 7.5 Hz, 2H), 2.02-1.95 (m, 2H).

[0386] Example 5: 3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-lH-inden-4-yl)carbamoyl)-2-methylbenzenesulfonamide

[0387] Synthetic route:

[0388] Step 1: (3-bromo-2-methylphenyl)-N,N-dimethylmethanamine

[0389] Take 3-bromo-2-methylbenzaldehyde (0.5 g) in a single-neck flask, then add dichloromethane (10 mL), dimethylamine tetrahydrofuran solution (2.5 mL, 2 eq.), acetic acid (1 drop) and stir at room temperature for 15 min. Add sodium triacetoxyborohydride (2.1 g, 4 eq.) and stir at room temperature for 2 h. LCMS shows that the target compound is generated, and the raw material is completely reacted. Post-processing and purification: dilute the reaction system with water, adjust the pH > 7 with saturated sodium bicarbonate, extract with dichloromethane, dry the organic phase, and concentrate to obtain the target compound crude 0.53 g.

[0390] Step 2: 1 -(3-(benzylmercapto)-2-methylphenyl)-N,N-dimethylmethanamine

[0391] Into a single neck flask was placed (3-bromo-2-methylphenyl)-N,N- dimethylmethanamine (0.5 g), followed by Pd2(dba)3(198 mg, 0.1 eq.), Xantphos (251 mg, 0.2 eq.), diisopropylethylamine (560 mg, 2 eq.), toluene (10 mL), benzyl mercaptan (400 mg, 1.5 eq.). The reaction mixture was stirred at 110 °C overnight under nitrogen protection. LCMS confirmed the formation of the target compound and the starting material was consumed completely. Work-up and purification: the reaction mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography (dichloromethane / methanol) to give the target compound as a pure product 0.3 g.

[0392] Step 3: 3-((dimethylamino)methyl)-2-methylbenzenesulfonamide

[0393] Into a single neck flask was placed NCS (648 mg, 4 eq.), followed by acetonitrile (2 mL), 6 M HC1 (2 mL) and stirred at 0 °C for 15 min. 1 -(3-(benzylmercapto)-2- methylphenyl)-N,N-dimethylmethanamine (0.3 g, 1 eq.) was added and stirred at 0 °C for 1 h. The reaction mixture was slowly added to ammonia water (30 mL) and stirred at room temperature for 1 h. LCMS confirmed the formation of the target compound. Work-up and purification: the reaction mixture was extracted with DCM for three times, the organic phases were combined and washed with saturated brine once, and concentrated to give the crude product 0.18 g.

[0394] Step 4: 3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1 H- inden-4-yl)carbamoyl)-2-methylbenzenesulfonamide

[0395] Into a single neck flask was placed 3-((dimethylamino)methyl)-2-methylbenzenesulfonamide (0.18 g), followed by THF (5 mL), LiOH (27 mg, 1.5 eq.) and stirred at room temperature for 5 min. (5-(2-methoxypyridin-4-yl)-2,3-dihydro-1 H-inden-4- yl)phenylcarbamate (197 mg, 0.7 eq.) was added and stirred at room temperature for 1 h. LCMS confirmed the formation of the target compound and the starting material was consumed completely.

[0396] Workup and purification: The crude product was purified by flash column chromatography (TFA-H2O / MeCN) to give a white solid product 161 mg.

[0397] MS: 495.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.61 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.95 (dd, J = 8.1, 1.3 Hz, 1H), 7.79 (dd, J = 7.8, 1.4 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.84 - 6.77 (m, 1H), 6.65 (d, J = 1.4 Hz, 1H), 4.49 (s, 2H), 3.89 (s, 3H), 2.89 (t, J = 7.4 Hz, 2H), 2.80 (s, 6H), 2.66 (d, J = 8.4 Hz, 3H), 2.57 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H).

[0398] Example 6: 2-chloro-3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0399] Synthetic route:

[0400] Step 1: 1-(3-bromo-2-chlorophenyl)-N,N-dimethylmethanamine

[0401] Into a 100 mL single necked flask, 3-bromo-2-chlorobenzaldehyde (600 mg) was weighed in, followed by DCM (10 mL), dimethylamine (2 M in THF, 2.0 mL), acetic acid (0.1 mL), and the mixture was stirred at room temperature for 1 h. Then sodium triacetoxyborohydride (1.7 g) was added. After addition, the mixture was stirred at room temperature overnight. LCMS showed the formation of the desired compound and the starting material was consumed completely. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate for 3 times. The organic phase was combined and washed with saturated brine for 2 times. The organic phase was dried and concentrated. The residue was purified by column chromatography (DCM / MeOH) to give 500 mg of the product as an oil.

[0402] Step 2: 1-(3-(benzylmercapto)-2-chlorophenyl)-N,N-dimethylmethanamine

[0403] Into a 100 mL single neck flask was placed 1-(3-bromo-2-chlorophenyl)-N,N- dimethylmethanamine (500 mg), benzyl mercaptan (380 mg), Pd2(dba)3(370 mg), Xantphos (470 mg), DIEA (780 mg), 1,4-dioxane (10 mL). It was heated to 120 °C under nitrogen overnight. LCMS showed the target compound was generated and the starting material was consumed completely. It was cooled to room temperature, filtered and the filtrate was concentrated. It was purified by column chromatography (DCM / MeOH) and concentrated to give the product 500 mg.

[0404] Step 3: 2-chloro-3-((dimethylamino)methyl)benzenesulfonamide

[0405] Into a 25 mL single neck flask was placed ACN (5 mL), HCl (6 M, 1.5 mL), cooled to 0 °C, then NCS (685 mg) was added. It was stirred at this temperature for 15 min, then 1-(3-(benzylmercapto)-2-chlorophenyl)-N,N-dimethylmethanamine (500 mg) was added and stirred for 1 h. Then the reaction was added dropwise to ammonia (10 mL) and stirred for 15 min. LCMS showed the target compound was generated and the starting material was consumed completely. The system was added with appropriate amount of water, the water layer was extracted with dichloromethane / methanol (20 / 1) mixture solvent for 3 times, the organic phase was combined, washed with water and saturated brine for 2 times, dried, concentrated to give the product crude.

[0406] Step 4: 2-chloro-3-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0407] Into a 50 mL single neck flask was placed 2-chloro-3-((dimethylamino)methyl)benzenesulfonamide (200 mg), phenyl (5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamate (290 mg), THF (5 mL), LiOH (60 mg). It was stirred at room temperature overnight. LCMS showed the target compound was generated and the starting material was consumed completely. It was concentrated, purified by column chromatography {DCM / MeOH} to give the product crude. It was further purified by high pressure preparation {H2O (NH4HCO3) / ACN}. It was lyophilized to give the product 14.24 mg as white solid.

[0408] MS: 515 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.14 (d, J = 5.3 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.84 - 7.69 (m, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.93 - 6.83 (m, 1H), 6.74 (s, 1H), 3.94 - 3.88 (m, 3H), 3.67 (d, J = 37.3 Hz, 2H), 2.94 - 2.85 (m, 2H), 2.75 - 2.59 (m, 2H), 2.33 (s, 6H), 2.04 - 1.88 (m, 2H).

[0409] Example 7: N-((5-(2-methoxy-pyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamoyl)-2- methyl-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide

[0410] Synthesis route:

[0411] Step 1: 7-bromo-2-methyl-l,2,3,4-tetrahydroisoquinoline

[0412] Step 1: 7-bromo-2-methyl-l,2,3,4-tetrahydroisoquinoline

[0413] Step 2: 7-benzylmercapto-2-methyl-l,2,3,4-tetrahydroisoquinoline

[0414] Into a 100 mL flask, 7-bromo-2-methyl-l,2,3,4-tetrahydroisoquinoline (1.0 g, 1.0 eq.) was weighed, then benzyl mercaptan (658 mg, 1.2 eq.), Pd2(dba)3(200 mg, 0.05 eq.), XantPhos (128 mg, 0.05 eq.), DIEA (1.14 g, 2.0 eq.) and toluene (50 mL) were added respectively. After warming to 105 °C, it was stirred overnight. TLC confirmed that the starting material was completely reacted. After cooling to room temperature, the reaction was diluted with an appropriate amount of water, 6N HCl solution was added and stirred for 30 min, extracted with ethyl acetate, separated, the organic phase was discarded, the aqueous phase was adjusted to pH≥10 with ammonia water, extracted with ethyl acetate for 3 times, and the organic phase was combined. Washed with saturated brine for 2 times, dried over anhydrous Na2SO4, concentrated to give 920 mg of the target compound as a yellow solid, with a yield of 78%.

[0415] Step 3, 4: 2-methyl-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide

[0416] Into a 50 mL flask, acetonitrile (10 mL) and 6N HCl aqueous solution (1.7 mL, 5.5 eq.) were added respectively, cooled to 0 °C, NCS (1.0 g, 4.0 eq.) was added in batches, then 7-benzylmercapto-2-methyl-l,2,3,4-tetrahydroisoquinoline (500 mg, 1.0 eq.) was added dropwise in acetonitrile solution. After stirring at room temperature for 1 h, the reaction solution was slowly added to ammonia water (30 mL), and stirred at room temperature for 1 h. TLC confirmed that the starting material was completely reacted. After concentration, column chromatography {dichloromethane / methanol} purification, 320 mg of white solid compound was obtained as the target product, with a two-step yield of 76%.

[0417] Step 5: N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamoyl)-2-methyl- 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

[0418] Into a 100 mL flask, 2-methyl-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide (100 mg, 1.0 eq.), phenyl (5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamate (159 mg, 1.0 eq.), TEA (268 mg, 2.0 eq.) and DCM (30 mL) were weighed, and stirred at room temperature for 12 h. LCMS confirmed the formation of the target compound and the complete reaction of the starting material. After concentration, preparative-HPLC preparation purification (acetonitrile / water + 0.05% TFA), and freeze-drying, 126 mg of white solid product trifluoroacetate salt was obtained.

[0419] MS: 493 [M+H] + . 1 H NMR (400 MHz, D20) δ 8.06 (s, 1H), 7.67 (s, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.31 (m, 2H), 7.22 (d, J = 11.2 Hz, 2H), 7.14 (s, 1H), 4.56 (d, J = 15.8 Hz, 1H), 4.31 (d, J = 15.7 Hz, 1H), 4.09 (d, J = 6.9 Hz, 1H), 4.02 (s, 3H), 3.80-3.72 (m, 1H), 3.45-3.34 (m, 1H), 3.28 (d, J = 13.0 Hz, 1H), 3.01 (s, 3H), 2.93 (d, J = 7.7 Hz, 2H), 2.83 (d, J = 6.2 Hz, 1H), 2.64 (d, J = 6.8 Hz, 1H), 1.99 (d, J = 4.0 Hz, 2H).

[0420] Example 8: 2-amino-4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0421] Synthetic route:

[0422] Step 1: 1-(4-bromo-3-nitrophenyl)-N,N-dimethylmethanamine

[0423] To a single neck flask was charged with 4-bromo-3-nitrobenzaldehyde (1 g, 1 eq.) followed by dichloromethane (30 mL), dimethylamine tetrahydrofuran solution (4.1 mL, 2 eq.), acetic acid (1 drop) and stirred at room temperature for 15 min. Sodium triacetoxyborohydride (3.5 g, 4 eq.) was added and stirred at room temperature for 2 h. LCMS showed the formation of the desired compound and the starting material was completely consumed. Work-up and purification: the reaction was diluted with water, the pH was adjusted to >7 with saturated sodium bicarbonate solution, the organic layer was extracted with dichloromethane, the organic phase was dried and concentrated to get the crude product 1.15 g.

[0424] Step 2: 1-(4-(benzylmercapto)-3-nitrophenyl)-N,N-dimethylmethanamine

[0425] Into a single neck flask, was placed 1-(4-bromo-3-nitrophenyl)-N,N- dimethylmethanamine (1.1 g, 1 eq.), followed by Pd2(dba)3(412 mg, 0.1 eq.), Xantphos (521 mg, 0.2 eq.), diisopropylethylamine (1.1 g, 2 eq.), toluene (20 mL), benzyl mercaptan (838 mg, 1.5 eq.). The reaction mixture was stirred at 110 °C overnight under nitrogen atmosphere. LCMS confirmed the formation of the desired compound and the starting material was consumed completely. Work-up and purification: the reaction mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography {dichloromethane / methanol} to give the pure product 0.85 g.

[0426] Step 3: 4-((dimethylamino)methyl)-2-nitrobenzenesulfonamide

[0427] Into a single neck flask, was placed NCS (1.4 g, 4 eq.), followed by acetonitrile (4 mL), 6 M HC1 (4 mL) and stirred at 0 °C for 15 min. 1-(4-(benzylmercapto)-3- nitrophenyl)-N,N-dimethylmethanamine (0.8 g, 1 eq.) was added and stirred at 0 °C for 1 h. The reaction mixture was added slowly into ammonia water (40 mL) and stirred at room temperature for 1 h. LCMS confirmed the formation of the desired compound. Work-up and purification: the reaction mixture was extracted with DCM for three times, the organic phases were combined and washed with saturated brine once, and concentrated to give the crude product 0.44 g.

[0428] Step 4: 4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-2-nitrobenzenesulfonamide

[0429] Into a single neck flask, was placed 4-((dimethylamino)methyl)-2-nitrobenzenesulfonamide (0.2 g, 1 eq.), followed by THF (5 mL), LiOH (30 mg, 1.5 eq.) and stirred at room temperature for 5 min. Phenyl (5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamate (205 mg, 0.7 eq.) was added and stirred at room temperature for 1 h. LCMS confirmed the formation of the desired compound and the starting material was consumed completely. Work-up and purification: the reaction mixture was concentrated and purified by flash column chromatography {dichloromethane / methanol} to give the product 109 mg.

[0430] Step 5: 2-amino-4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)benzenesulfonamide

[0431] Take 4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-2-nitrobenzenesulfonamide (0.1 g) in a single neck flask, add absolute ethanol (10 mL), add Pd / C (20 mg) into the system, replace hydrogen gas, stir at room temperature for 3 h. LCMS confirms the formation of the target compound, the starting material is completely reacted. Post-treatment and purification: filter the system, elute the filter cake with ethanol, concentrate the filtrate, purify by preparative HPLC, and freeze-dry to obtain 15 mg of solid product.

[0432] MS: 496.4. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.06 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 24.6 Hz, 2H), 6.75 (d, J = 33.7 Hz, 3H), 6.46 (d, J = 8.2 Hz, 1H), 5.83 (s, 1H), 3.86 (s, 3H), 3.33 (s, 2H), 2.87 (s, 2H), 2.61 (s, 2H), 2.19 (s, 6H), 1.92 (s, 2H).

[0433] Example 9: 3-amino-4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0434] Synthetic route:

[0435] Step 1: 1-(4-bromo-2-nitrophenyl)-N,N-dimethylmethanamine

[0436] Take 4-bromo-2-nitrobenzaldehyde (2 g, 1 eq.) in a single neck flask, then add dichloromethane (60 mL), dimethylamine tetrahydrofuran solution (8.2 mL, 2 eq.), acetic acid (1 drop) and stir at room temperature for 15 min. Add sodium triacetoxyborohydride (6.9 g, 4 eq.) and stir at room temperature for 2 h. LCMS shows that the target compound is generated and the starting material is completely reacted. Post-treatment and purification: dilute the reaction system with water, adjust the pH > 7 with saturated sodium bicarbonate, extract the system with dichloromethane, dry the organic phase, and concentrate to obtain 2.3 g of the target compound crude product.

[0437] Step 2: 1-(4-(benzylmercapto)-2-nitrophenyl)-N,N-dimethylmethanamine

[0438] Into a single neck flask was placed 1-(4-bromo-2-nitrophenyl)-N,N- dimethylmethanamine (1.1 g), followed by Pd2(dba)3(412 mg, 0.1 eq.), Xantphos (521 mg, 0.2 eq.), diisopropylethylamine (1.1 g, 2 eq.), toluene (30 mL), benzyl mercaptan (838 mg, 1.5 eq.). The reaction mixture was stirred at 110 °C overnight under nitrogen atmosphere. LCMS confirmed the formation of the desired compound and the starting material was consumed completely. Work-up and purification: the reaction mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography (dichloromethane / methanol) to give the desired compound as a crude 3.6 g.

[0439] Step 3: 4-((dimethylamino)methyl)-3-nitrobenzenesulfonamide

[0440] Into a single neck flask was placed NCS (1.4 g, 4 eq), followed by acetonitrile (6 mL), 6 M HC1 (6 mL) and stirred at 0 °C for 15 min. Into the reaction mixture was added 1-(4-(benzylmercapto)-2-nitrophenyl)-N,N-dimethylmethanamine (0.8 g) and stirred at 0 °C for 1 h. The reaction mixture was slowly added to ammonia water (60 mL) and stirred at room temperature for 1 h. LCMS confirmed the formation of the desired compound. Work-up and purification: the reaction mixture was extracted with DCM three times, the organic layers were combined and washed with saturated brine once, and concentrated to give the crude product 3.1 g.

[0441] Step 4: 4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)-3-nitrobenzenesulfonamide

[0442] Into a single neck flask was placed 4-((dimethylamino)methyl)-3-nitrobenzenesulfonamide (0.6 g, 1 eq.), followed by THF (20 mL), LiOH (87 mg, 1.5 eq.) and stirred at room temperature for 5 min. Into the reaction mixture was added phenyl (5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (610 mg, 0.7 eq.) and stirred at room temperature for 1 h. LCMS confirmed the formation of the desired compound and the starting material was consumed completely. Work-up and purification: the reaction mixture was concentrated and purified by flash column chromatography (dichloromethane / methanol) to give the product 605 mg.

[0443] Step 5: 3-amino-4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3- dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide

[0444] Take 4-((dimethylamino)methyl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamoyl)-3-nitrobenzenesulfonamide (0.6 g, 1 eq.) in a single neck flask, add absolute ethanol (30 mL), Pd / C (0.1 g) into the system, replace hydrogen gas, stir at room temperature for 3 h. LCMS confirms the formation of the target compound, the starting material is completely reacted. Post-treatment and purification: filter the system, elute the filter cake with ethanol, concentrate the filtrate, purify by preparative HPLC, and obtain 101 mg of solid product after lyophilization.

[0445] MS: 496.4. 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 5.3 Hz, 1H), 7.86 (s, 1H), 7.17 (q, J = 7.6 Hz, 3H), 7.09 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 5.5 Hz, 1H), 6.67 (s, 1H), 3.87 (s, 3H), 2.89 (t, J = 7.4 Hz, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.21 (s, 6H), 1.97 (dq, J = 21.8, 7.4 Hz, 4H).

[0446] Example 10: 9-methyl-2 2 ,2 3 - dihydro-2 1 H-12-oxa-6-thia-3,5,9-triaza-1(4,2)-pyridazocine-2(5,4)-indocine-7(1,4)- benzocyclododecaketone 6,6-dioxide

[0447] Synthesis route:

[0448] Step 1: 2-((4-bromobenzyl)(methyl)amino)ethan-1-ol

[0449] Into a 250 mL flask, was placed 4-bromobenzaldehyde (3.0 g, 1.0 eq.), 2-(methylamino)ethan-1-ol (1.2 g, 1.0 eq.), NaBH(OAc)3 (10.3 g, 3.0 eq.), 2 drops of acetic acid, and DCM (70 mL). The mixture was stirred at room temperature for 12 h. LCMS showed the formation of the desired compound and the starting material was consumed completely. Work-up and purification: the reaction mixture was diluted with water, 6N HC1 solution was added and stirred for 30 min, extracted with DCM, separated, the aqueous phase was adjusted to pH > 10 with ammonia water, extracted with DCM (500 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was obtained as a white solid 2.7 g in 68.2% yield, which was used in the next step without further purification.

[0450] Step 2: 2-((4-(benzylthio)benzyl)(methyl)amino)ethan-1-ol

[0451] Into a 100 mL flask, was placed 2-((4-bromobenzyl)(methyl)amino)ethan-1-ol (2.7 g, 1.0 eq.), benzyl mercaptan (1.65 g, 1.2 eq.), Pd2(dba)3 (500 mg, 0.05 eq.), XantPhos (578.6 mg, 0.05 eq.), DIEA (2.85 g, 2.0 eq.), and toluene (50 mL). The mixture was stirred at 105 °C overnight. TLC showed the starting material was consumed completely. Work-up and purification: the reaction mixture was diluted with water, 6N HC1 solution was added and stirred for 30 min, extracted with ethyl acetate, separated, the aqueous phase was adjusted to pH > 10 with ammonia water, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine for 2 times, dried over anhydrous sodium sulfate, and concentrated to give 2.5 g of the desired compound as a yellow solid in 78% yield.

[0452] Step 3: 4-(((2-hydroxyethyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0453] Into a 50 mL single necked flask, acetonitrile (20 mL) and 6N aqueous HC1 (4.7 mL, 5.5 eq.) were added, cooled to 0 °C, NCS (2.8 g, 4.0 eq.) was added in portions, then a solution of 2-((4-(benzylsulfanyl)benzyl)(methyl)amino)ethan-1-ol (1.5 g, 1.0 eq.) in acetonitrile was added dropwise. After stirring at room temperature for 1 h, the reaction mixture was added slowly dropwise to a reaction system containing dimethoxybenzylamine (2.7 g, 2.0 eq.), TEA (3.0 g, 5.5 eq.) and DCM (30 mL), and stirring was continued at room temperature for 1 h. TLC confirmed that the starting material was completely reacted. Work-up and purification: concentration, column chromatography {dichloromethane / methanol} purification, to give 1.1 g of white solid as the target product, 43.5% yield for two steps.

[0454] Step 4: 4-(((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0455] Into a 100 mL single necked flask, 4-(((2-hydroxyethyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 g, 1.0 eq.), potassium tert-butoxide (347 mg, 1.5 eq.) and THF (30 mL) were added, and stirring was continued at 60 °C for 1 h, 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (470 mg) was added, and stirring was continued at this temperature for 12 h, then the reaction mixture was cooled to room temperature, and slowly added dropwise to ice water, and after stirring for 30 min, white solid was precipitated, the solution was removed by filtration, the filter cake was washed with water, and dried to give 630 mg of white solid as the target product, 42% yield.

[0456] Step 5: 4-(((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)methyl)benzenesulfonamide

[0457] Into a 100 mL single necked flask, 4-(((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (500 mg, 1.0 eq.) and TFA (10 mL) were added, and stirring was continued at room temperature for 12 h. The reaction mixture was introduced into ice water, and stirred, and the pH was adjusted to basic with a Na2CO3 solution, and white solid was precipitated, the solution was removed by filtration, the filter cake was washed with water, and dried to give 290 mg of self-colored solid as the target product, 89% yield.

[0458] Step 6: 9-methyl-2 2 ,2 3 - dihydro-2 1 H- 12-oxa-6-thia-3,5,9-triaza- 1(4,2)-pyridazocine-2(5,4)-indocine-7(1,4)- benzocyclododecaphan-4-one 6,6-dioxide

[0459] Weigh 4-(((2-((4-(4-amino-2,3-dihydro-lH-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)methyl)benzenesulfonamide (200 mg, 1.0 eq.), DIEA (115 mg, 2.0 eq.) and DCM (12 mL) in a 25 mL single neck flask, slowly drop phenyl chloroformate (70 mg, 1.0 eq.) at room temperature, stir for 12 h at room temperature. LCMS confirm the target compound is generated, the starting material is reacted completely. Work-up and purification: concentrate, prepare and purify by HPLC (acetonitrile / water + 0.05% TFA), lyophilize to get 96 mg of trifluoroacetate salt of white solid product.

[0460] MS: 479 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.60 (s, 1H), 8.39 (s, 1H), 7.96 (d, J = 5.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.90 (dt, J = 16.5, 8.2 Hz, 1H), 6.34 (s, 1H), 4.58 (d, J = 12.8 Hz, 2H), 4.31 (s, 2H), 3.47 (s, 2H), 3.13 (s, 3H), 2.94 (t, J = 7.5 Hz, 2H), 2.86 (m, 2H), 2.07 (dd, J = 15.2, 7.6 Hz, 2H).

[0461] Example 11: Intermediate (5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4- yl)phenylcarbamate

[0462] Synthetic route:

[0463] Step 1: N-(2,3-dihydro-lH-inden-4-yl)acetamide

[0464] Into a 1000 mL flask, was placed 2,3-dihydro-1H-inden-4-amine (30 g, 1 eq.), followed by DCM (400 mL), TEA (68 g, 3 eq.), and the mixture was cooled to 0 °C. Ac2O (34 g, 1.5 eq.) was added dropwise with stirring. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 2 h. LCMS showed that the target compound was generated. Work-up and purification: The reaction solution was poured into a suitable amount of ice water, and extracted with DCM (300 mL x 2). The combined organic phase was washed with water (500 mL x 2), saturated brine, dried, and rotary evaporated to give the product 31.5 g of white solid.

[0465] Step 2: N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide

[0466] Into a 1000 mL flask, was placed N-(2,3-dihydro-1H-inden-4-yl)acetamide (31.5 g, 1 eq.), followed by toluene (400 mL), p-TsOH (19.2 g, 0.55 eq.), and Pd(OAc)2 (2.0 g, 0.05 eq.). After the addition was completed, the mixture was stirred at room temperature for 0.5 h, and then NBS (35.2 g, 1.1 eq.) was added portionwise at below 20 °C. After the addition was completed, the mixture was stirred at 20 °C for 2 h. LCMS showed that the target compound was generated. Work-up and purification: The reaction solution was poured into a suitable amount of ice water, and extracted with EA (300 mL x 2). The organic phase was washed with saturated brine, dried, mixed with silica gel, rotary evaporated, and purified by flash column chromatography (PE / EA) to give the target compound 36 g of white solid.

[0467] Step 3: 5-bromo-2,3-dihydro-1H-inden-4-amine

[0468] Into a 1 L flask, was placed N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (18 g, 1 eq.), followed by EtOH (120 mL), and concentrated HCl (150 mL). After the addition was completed, the mixture was heated to 80 °C and stirred for 48 h. LCMS confirmed that the target compound was generated. Work-up and purification: The reaction solution was cooled in an ice-salt bath and filtered. The filter cake was washed with 30 mL of water, and the filter cake was rotary evaporated under reduced pressure to give the target product 13.5 g of yellowish solid (HCl salt).

[0469] Step 4: 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0470] Into a 250 mL flask, 5-bromo-2,3-dihydro-lH-inden-4-amine (5 g, 1 eq.) was weighed, 1,4-dioxane (80 mL) was added, water (15 mL) was added, K2CO3 (11.2 g, 4 eq.) was added, stirred for 5 min, replaced with nitrogen for three times, (2-methoxypyridin-4-yl)boronic acid (4.0 g, 1.3 eq.) was added, Pd(dppf)Cl2 (1.6 g, 0.1 eq.) was added, replaced with nitrogen for three times, warmed to 80 °C for 6 h, LCMS confirmed the generation of the target compound. Work-up and purification: the reaction solution was poured into the appropriate amount of ice water, extracted with EA (100 mL x 2), the organic phase was dried, rotary evaporation, mixed with silica gel, purified by flash column chromatography (PE / EA) to obtain the target compound white solid 3.6 g.

[0471] Step 5: (5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamic acid phenyl ester

[0472] Into a 100 mL flask, 5-(2-methoxypyridin-4-yl)-2,3-dihydro-lH-inden-4-amine (1.5 g, 1 eq.) was weighed, THF (30 mL) was added, DIEA (2.4 g, 3 eq.) was added, cooled to 0 °C, phenyl chloroformate (1.2 g, 1.2 eq.) was dissolved in 8 mL THF, and the above reaction solution was added dropwise at 0 °C, and then warmed to room temperature for 2 h. LCMS confirmed the generation of the target compound, and the reaction of the raw material was complete. Work-up and purification: the reaction solution was poured into the appropriate amount of ice water, extracted with EA (100 mL x 2), washed with saturated brine, dried and rotary evaporated, purified by flash column chromatography (PE / EA) to obtain the target compound white solid 1.9 g.

[0473] Example 12: Intermediate tert-butyl (5-(2-(2-(methylamino)ethoxy)pyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamate

[0474] Synthetic route:

[0475] Step 1: 5-(2-fluoropyridin-4-yl)-2,3-dihydro-lH-inden-4-amine

[0476] Into a 500 mL single-neck flask, 5-bromo-2,3-dihydro-1H-inden-4-amine hydrochloride (7 g, 1 eq.) was weighed, then 1,4-dioxane (150 mL) was added, H2O (30 mL) was added, K2CO3 (15.7 g, 4 eq.) was added, stirred for 5 min, replaced with nitrogen for three times, (2-fluoropyridin-4-yl)boronic acid (5 g, 1.2 eq.) was added, Pd(dppf)Cl2 (1.4 g, 0.06 eq.) was added, replaced with nitrogen for three times, warmed to 80 °C for 7 h, LCMS confirmed the generation of the target compound. Work-up and purification: the reaction solution was poured into appropriate amount of ice water, extracted with EA (100 mL x 2), the organic phase was dried, rotary evaporation, mixed with silica gel, purified by flash column chromatography (PE / EA) to obtain the target compound 5.7 g of white solid.

[0477] Step 2: tert-Butyl (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamate

[0478] Into a 100 mL single-neck flask, 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4- amine (1.2 g, 1 eq.) was weighed, pyridine 20 mL was added, TEA (3.7 g, 7 eq.) was added, DMAP (0.13 g, 0.2 eq.) was added, (Boc)2O (3.4 g, 3 eq.) was added under stirring at room temperature, after addition, stirred at room temperature for 6 h, LCMS showed that the target compound was generated. Work-up and purification: the reaction solution was poured into appropriate amount of ice water, extracted with EA (60 mL x 2), the organic phase was washed with saturated brine, dried, mixed with silica gel, rotary evaporation, purified by flash column chromatography (PE / EA) to obtain the target compound 1.4 g of light yellow solid.

[0479] Step 3: tert-Butyl (5-(2-(2-(methylamino)ethoxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamate

[0480] Into a 50 mL single-neck flask, tert-butyl (5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4- yl)carbamate (0.8 g, 1 eq.) was weighed, THF (20 mL) was added, 2-(methylamino)ethan-1-ol (0.91 g, 5 eq.) was added, t-BuOK (1.36 g, 5 eq.) was added under stirring at room temperature, after addition, stirred at room temperature overnight, LCMS confirmed the generation of the target compound. Work-up and purification: the reaction solution was poured into appropriate amount of ice water, saturated ammonium chloride 80 mL was added, DCM / MeOH = 10 / 1 (v / v) (60 mL x 2) was added for extraction, dried and rotary evaporation, purified by medium pressure preparation (0.5 ‰ HCOOH aqueous solution / acetonitrile) to obtain 600 mg of light yellow silk product.

[0481] Example 13: 9-methyl-7 2 -nitro-2 2 ,2 3 -dihydro-2 1 H-12-oxa-6-thia-3,5,9-triaza-1(4,2)-pyridazocina-2(5,4)-indolizina-7(1,3)- benzocyclododec-4-one 6,6-dioxide

[0482] Synthetic route:

[0483] Step 1: 3-(benzylmercapto)-2-nitrobenzaldehyde

[0484] Weigh 3-bromo-2-nitrobenzaldehyde (5 g, 1 eq.) in a 100 mL single-neck flask, then add toluene (50 mL), benzyl mercaptan (4.0 g, 1.5 eq.), DIEA (9.0 g, 3.2 eq.), Pd2(dba)3(1.0 g, 0.05 eq.), Xantphos (1.25 g, 0.1 eq.). Warm to 115°C for 8 h, LCMS shows that the target compound is generated (no signal to see the peak position). Post-treatment and purification: the reaction solution is mixed with silica gel, rotary evaporation, and purified by flash (PE / EA) to obtain the target compound 5.8 g of crude yellow solid.

[0485] Step 2: 3-formyl-N,N-bis(4-methoxybenzyl)-2-nitrobenzenesulfonamide

[0486] Measure 6M HCl (16 mL) in a 250 mL single-neck flask, add MeCN (90 mL), and stir to cool to 0°C. Add NCS (7.04 g, 2.1 eq.) to obtain the reaction solution. Dissolve 3-(benzylmercapto)-2-nitrobenzaldehyde (5.8 g, 1 eq.) in 30 mL MeCN, and drop into the above reaction solution at 0°C. Stir for 40 min to prepare a standby solution. Prepare another 500 mL single-neck flask, add NH(PMB)2(5.45 g, 1 eq.), add THF (100 mL), add TEA (25 mL), and drop the standby solution into the flask at 0°C with stirring. After dropping, warm to room temperature and stir for 1 h. LCMS confirms the generation of the target compound. Post-treatment and purification: add 100 mL saturated ammonium chloride solution, add an appropriate amount of water, extract with EA (200 mL x 2), dry and rotary evaporate, and purify by medium pressure preparation (0.5‰ HCOOH aqueous solution / acetonitrile) to obtain the product 2.4 g of orange oily liquid.

[0487] Step 3: (5-(2-(2-((3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-nitrobenzyl)(methyl)amino)ethoxy)pyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamic acid tert-butyl ester

[0488] Into a 100 mL flask, was placed 3-formyl-N,N-bis(4-methoxybenzyl)-2-nitrobenzenesulfonamide (1.2 g, 1 eq.), MeOH (30 mL), THF (5 mL), (5-(2-(2-(methylamino)ethoxy)pyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamic acid tert-butyl ester (0.6 g, 0.6 eq.), ZnCl2(2 M in THF) (1.3 mL, 0.5 eq.), and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to room temperature, and NaBH3CN (0.8 g, 5 eq.) was added. The reaction mixture was stirred at room temperature overnight. LCMS showed the formation of the desired compound. Work-up and purification: The reaction mixture was poured into ice water, and the mixture was extracted with EA (80 mL x 2). The combined organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / EA) to give the desired compound as a yellow solid (360 mg).

[0489] Step 4: 3-(((2-((4-(4-amino-2,3-dihydro-lH-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)methyl)-2-nitrobenzenesulfonamide

[0490] Into a 50 mL flask, was placed (5-(2-(2-((3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-nitrobenzyl)(methyl)amino)ethoxy)pyridin-4-yl)-2,3-dihydro-lH-inden-4-yl)carbamic acid tert-butyl ester (360 mg, 1 eq.), and TFA (10 mL). The reaction mixture was stirred at room temperature for 4 h. LCMS showed the formation of the desired compound. Work-up and purification: The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of ice water, and the mixture was stirred in an ice water bath. Na2CO3 was added to adjust the pH to 8. THF was added to dissolve the mixture. The mixture was purified by medium pressure prep (0.5% NH4HCO3 in water / acetonitrile) to give the product as a brown oily liquid (200 mg).

[0491] Step 5: 9-methyl-7 2 -nitro-2 2 ,2 3 -dihydro-2 1H-12-oxa-6-thia-3,5,9-triaza-1 (4, 2)-pyridina-2 (5, 4)-indina-7 (1, 3)- benzadodecaful-4-one 6, 6-dioxide

[0492] Weigh 3-(((2-((4-(4-amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)oxy)ethyl)(methyl)amino)methyl)-2-nitrobenzenesulfonamide (200 mg, 1 eq.) into a 25 mL single-necked flask, add THF (8 mL), add DIEA (780 mg, 15 eq.), and then lower the temperature to 0 °C under nitrogen protection to obtain a reaction solution. Dissolve phenyl chloroformate (76 mg, 1.2 eq.) in 1 mL of THF, and then slowly drop it into the above reaction solution at 0 °C. After dropping, stir for 15 min, and then raise the temperature to room temperature and stir for 1 h. After confirming the generation of an intermediate state by LCMS, raise the temperature to 60 °C and stir for 3 h. After confirming the generation of the target compound by LCMS, add an appropriate amount of water, extract with EA (50 mL x 2), dry, rotary evaporate, and purify by TLC (DCM / MeOH = 10:1) to obtain 120 mg of a crude product. Take 50 mg and purify by medium pressure preparation (0.5 ‰ NH4HCO3 aqueous solution / acetonitrile) to obtain the target compound as a white solid by freeze-drying, 27 mg.

[0493] MS: 524 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.12 (s, 1H), 8.06 (d, J = 5.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 5.6 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 5.2 Hz, 1H), 6.24 (s, 1H), 4.14-3.39 (m, 4H), 2.96 (t, J = 7.8 Hz, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.76-2.54 (m, 2H), 2.37 (s, 3H), 2.14-2.14 (m, 2H).

[0494] Example 14: 7 2 - amino-9-methyl-2 2 ,2 3 - dihydro-2 1 H-12-oxa-6-thia-3,5,9-triaza-1 (4, 2)-pyridina-2 (5, 4)-indina-7 (1, 3)- benzadodecaful-4-one 6, 6-dioxide

[0495] Synthesis route:

[0496] Weigh 9-methyl-72-nitro-22,23-dihydro-21H-12-oxa-6-thia-3,5,9-triaza-1(4,2)- pyridoza-2(5,4)-indolaza-7(1,3)-benzocyclododeca-4-one 6,6-dioxide (70 mg, 1 eq.) in a 20 mL single-neck flask, then add THF (2.5 mL), EtOH (2.5 mL), H2O (2.5 mL), add NH4Cl (57 mg, 8 eq.) under stirring at room temperature, continue to add zinc powder (140 mg, 16 eq.), after adding, stir at room temperature for 1 h, LCMS shows that the target compound is generated. Post-treatment and purification: filter the reaction solution with diatomite, rinse the filter cake with DCM / MeOH = 7:1 (v / v) (80 mL), separate the liquid, extract the aqueous phase with DCM / MeOH = 7:1 (v / v) (20 mL), combine the organic phases, wash the organic phase with 0.5 ‰ NH4HCO3 aqueous solution 30 mL, separate the liquid, dry the organic phase and rotary evaporate to obtain the crude product, purify the crude product by medium pressure preparation (0.5 ‰ NH4HCO3 aqueous solution / ethyl) to obtain the target compound white solid 27 mg.

[0497] MS: 494 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 8.0 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 5.6 Hz, 1H), 6.59 (t, J = 7.6 Hz, 1H), 6.49 (s, 1H), 4.21 (s, 2H), 3.53 (s, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.76-2.62 (m, 2H), 2.47 (s, 3H), 2.15-2.04 (m, 2H).

[0498] Test:

[0499] Biological evaluation: Study of the inhibition of NLRP3 activity of the compounds of the application

[0500] Experimental content

[0501] 1) Using human monocytic lymphoma cell line THP-1, NLRP3 is activated by LPS (lipopolysaccharide) as the first signal and nigericin as the second signal. After NLRP3 is activated, mature IL-1β is released, and the activation of NLRP3 can be judged by detecting IL-1β by ELISA. On this basis, the effect of adding compounds on the release of IL-1β can be observed.

[0502] 2) Using human monocytic lymphoma cell line THP-1, NLRP3 is activated by LPS as the first signal and nigericin as the second signal. After NLRP3 is activated, mature IL-1β is released, and the activation of NLRP3 can be judged by detecting IL-1β by ELISA. On this basis, the same compound at different concentrations can be added to draw an inhibition curve.

[0503] 3) Using human monocytic lymphoma cell line THP-1, NLRP3 is activated by transfection of LPS through a non-canonical pathway and releases mature IL-1β, and the activation of NLRP3 can be judged by detecting IL-1β by ELISA. On this basis, the effect of adding compounds on the release of IL-1β can be observed to determine the effect on the activation of NLRP3 through the non-canonical pathway.

[0504] 4) Isolate peripheral blood mononuclear cells (PBMCs) from healthy people, activate NLRP3 by LPS as the first signal and nigericin as the second signal. After NLRP3 is activated, mature IL-1β is released, and the activation of NLRP3 can be judged by detecting IL-1β by ELISA. On this basis, the effect of adding compounds on the release of IL-1β can be observed.

[0505] 5) Using human whole blood, NLRP3 is activated by LPS as the first signal and nigericin as the second signal. After NLRP3 is activated, mature IL-1β is released, and the activation of NLRP3 can be judged by detecting IL-1β by ELISA. On this basis, the same compound at different concentrations can be added to draw an inhibition curve.

[0506] 6) Using mouse macrophage cell line J774A.1, NLRP3 is activated by LPS as the first signal and nigericin as the second signal. After NLRP3 is activated, mature IL-1β is released, and the activation of NLRP3 can be judged by detecting IL-1β by ELISA. On this basis, the effect of adding compounds on the release of IL-1β can be observed.

[0507] 7) Using mouse macrophage cell line J774A.1, activating NLRP3 by LPS as the first signal and Nigericin as the second signal. After NLRP3 activation, mature IL-1β will be released. By detecting IL-1β through ELISA, NLRP3 activation can be determined. On this basis, adding different concentrations of the same compound can draw its inhibition curve.

[0508] 8) Injecting or orally gavaging the compound into the tail vein of rats, and by determining the concentration of the compound in plasma, liver and brain tissue, the pharmacokinetic properties of the compound can be analyzed.

[0509] Experimental Example 1: Inhibition of NLRP3 classical pathway activation by 1 μM compound on human monocytic lymphoma cell line

[0510] Human monocytic lymphoma cell line (THP-1) cells were plated in 96-well plates at a density of 1.0 x 10 6 100 μL. 100 ng / mL of phorbol 12-myristate 13-acetate (PMA) was added at the time of plating, and the cells were incubated for 24 h to differentiate into macrophage-like cells. After washing the plates with phosphate buffered saline (PBS) during this process, the differentiated cells were maintained for 24 h, and then activated NLRP3 with LPS + 5 μM Nigericin. The IL-1β level in the cell supernatant was detected. The cell culture medium consisted of: RPMI-1640 medium (brand: Gibco, reference number: C11875500BT) + 10% fetal bovine serum (brand: VISTECH, reference number: SE / 00-011) + 1% glutamine (brand: Gibco, reference number: 25030-081) + 1% penicillin-streptomycin mixture (brand: Solarbio, reference number: P1400).

[0511] Human monocytic lymphoma cell line (THP-1) was purchased from the Cell Resource Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; LPS was purchased from Sigma, catalog number: L2654; Nigericin was purchased from Shanghai Yuanye Bio, catalog number: S45490; PMA was purchased from Sigma, catalog number: P1585; PBS (1x) pH 7.4 was purchased from EallBio, catalog number: 03.15018C; human IL-1β ELISA detection kit was purchased from Thermo Invitrogen, catalog number: 88-7261-88.

[0512] Experimental groups: negative control group, LPS alone incubation control group, LPS combined with Nigericin positive control group, and example compound experimental group.

[0513] PMA incubation for 24 h, the cells changed from suspension to adherent state, the plates were washed with PBS for three times, and then the medium was replaced with normal maintenance medium (1640 medium, Gibco Cat# C11875500BT) for another 24 h. After 24 h, the medium of all groups except the negative control group was completely replaced with fresh medium containing 1 μg / mL LPS, and the medium of the negative control group was replaced without LPS. After overnight incubation, the medium of the Example Compound Test Group was completely replaced with fresh medium containing the specified 1 μM Example Compound, and the medium of the other groups was completely replaced. After 1 h, 5 μL of 100 μM Nigericin was added to the medium of the LPS combined Nigericin positive control group and the Example Compound Test Group to achieve a working concentration of 5 μM. Meanwhile, 5 μL of cell culture medium was added to the negative control group and the LPS incubation control group. After 1 h, the cell supernatant was collected, centrifuged at 1000 g for 20 min, and then the IL-1β in the supernatant was detected by enzyme-linked immunosorbent assay (ELISA) according to the kit instructions.

[0514] Experimental results

[0515] Because LPS + Nigericin activates NLRP3 through the classic pathway, which releases mature IL-1β, and this release can be inhibited by NLRP3 inhibitors, the relative change in the amount of IL-1β release can directly reflect the inhibitory effect of NLRP3. The results are shown in Figures 1-5.

[0516] In the present experimental example, effective inhibition of IL-1β release refers to a decrease of more than 50% compared with the LPS combined Nigericin positive control, and weak inhibition refers to a decrease of between 20-50% compared with the positive control. The results show that MCC950, Example 1, Example 3, Example 4, Example 5 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 1). MCC950, Example 2 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 2); MCC950, Example 6 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 3). MCC950, Example 7, Example 8, Example 9, Example 10 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 4).

[0517] Example 13, Example 14 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 5).

[0518] Experimental Example 2: NLRP3 classic pathway activation inhibition curve of Example Compound on human monocytic lymphoma cell line

[0519] Human monocytic lymphoma cell line (THP-1) cells were plated at a density of 1.0 x 106 Cells were plated at a density of 5 x 104cells / ml in 100 μL per well of a 96-well plate. 100 ng / mL of phorbol 12-myristate 13-acetate (PMA) was added at the time of plating and the cells were allowed to differentiate into macrophage-like cells for 24 h. The cells were then washed with phosphate-buffered saline (PBS) and maintained in culture for 24 h. The cells were then activated with LPS + 5 μM Nigericin. The IL-1β levels in the cell supernatant were measured. The cell culture medium consisted of RPMI-1640 medium (brand: Gibco, reference number: C11875500BT) + 10% fetal bovine serum (brand: VISTECH, reference number: SE / 00-011) + 1% glutamine (brand: Gibco, reference number: 25030-081) + 1% penicillin-streptomycin mixture (brand: Solarbio, reference number: P1400).

[0520] The human monocytic lymphoma cell line (THP-1) was purchased from the Cell Resource Center of the Institute of Basic Medicine, Chinese Academy of Medical Sciences; LPS was purchased from Sigma, item number: L2654; Nigericin was purchased from Shanghai Yuanye Bio, item number: S45490; PMA was purchased from Sigma, item number: P1585; PBS (1x) pH 7.4 was purchased from EallBio, item number: 03.15018C; the human IL-1β ELISA detection kit was purchased from Thermo Invitrogen, item number: 88-7261-88.

[0521] Experimental groups: negative control group, LPS incubation alone control group, LPS + Nigericin positive control group, and different concentrations of the compound of the present application experimental groups.

[0522] The THP-1 cells were plated and 100 ng / mL of PMA was added at the same time. The cells were incubated for 24 h, during which time the cells changed from a suspended state to an adherent state. The cells were washed with PBS three times and the culture medium was replaced with normal maintenance medium for continued culture for 24 h. After 24 h, the culture medium of each group was completely replaced with fresh medium, except for the negative control group, which was not added with LPS. The cells were incubated overnight. After 18 h, the culture medium of the compound of the present application experimental groups was completely replaced with culture medium containing different concentrations of the compound (range: 1 nM-100 μM), and the culture medium of the other groups was completely replaced. After 1 h, 5 μL of 100 μM Nigericin was added to the culture medium of the LPS + Nigericin positive control group and the compound of the present application experimental groups to achieve a working concentration of 5 μM. The negative control group and the LPS incubation alone control group were simultaneously added with 5 μL of cell culture medium. After 1 h, the cell supernatant was collected and centrifuged at 1000 g for 20 min. The IL-1β levels in the supernatant were then detected by enzyme-linked immunosorbent assay (ELISA) according to the kit instructions.

[0523] Experimental results

[0524] Because the classic pathway activates NLRP3 after the release of mature IL-1β, and this release can be inhibited by NLRP3 inhibitors, the relative change in the amount of IL-1β release can directly reflect the inhibitory effect of NLRP3. Different concentrations of compounds have different inhibitory strengths, and an inhibition curve can be constructed accordingly. Through IC 50 The inhibitory effect of the compound was evaluated. The results are shown in Table 1.

[0525] The results show that the IC 50 of Example 1 is 32.42 nM; the IC 50 of Example 7 is 44.76 nM; the IC 50 of Example 8 is 12.92 nM; the IC 50 of Example 9 is 11.08 nM; the IC 50 of Example 10 is 18.58 nM; and the IC 50 of MCC950 is 90.47 nM.

[0526] Table 1 (IC 50 determination results of Example 2 in the NLRP3 classic pathway activation model)

[0527] Example 3: Inhibition of NLRP3 non-classic pathway activation by example compounds on human monocytic lymphoma cell lines

[0528] Human monocytic lymphoma cell line (THP-1) cells were plated in a 96-well plate at a density of 1.0 x 10 6 cells / ml, 100 μL per well. 100 ng / mL of phorbol 12-myristate 13-acetate (PMA) was added at the same time as plating, and the cells were incubated for 24 h to differentiate into macrophage-like cells. During this process, the cells were maintained for 24 h after washing the plate with phosphate buffered saline (PBS) after differentiation, and then 0.4 μL (1 mg / mL) of lipo2000 was used to transfect 100 ng of lipopolysaccharide (LPS) per well. The specified example compounds were added at the same time as transfection. After overnight transfection, the cell supernatant was collected and the IL-1β level was determined by ELISA. The cell culture medium composition was: RPMI-1640 medium (brand: Gibco, reference number: C11875500BT) + 10% fetal bovine serum (brand: VISTECH, reference number: SE / 00-011) + 1% glutamine (brand: Gibco, reference number: 25030-081) + 1% penicillin-streptomycin mixture (brand: Solarbio, reference number: P1400).

[0529] Human monocyte lymphoma cell line (THP-1) was purchased from the Cell Resource Center of Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; LPS was purchased from Sigma, item number: L2654; PMA was purchased from Sigma, item number: P1585; PBS (1x) pH7.4 was purchased from EallBio, item number: 03.15018C; Human IL-1β ELISA detection kit was purchased from Thermo Invitrogen, item number: 88-7261-88; Lipo2000 (1mg / ml) was purchased from Thermo Invitrogen, item number: LOT: CN2513601.

[0530] Experimental grouping: negative control group, empty lipo2000 transfection control group, lipo2000 transfection LPS positive control group, different concentrations of example compound experimental group.

[0531] THP-1 cells were plated and 100ng / mL PMA was added at the same time and incubated for 24h, the cells changed from suspension to adhesion, and after washing the plate three times with PBS, the culture medium was replaced with normal maintenance medium for continued culture for 24h. After 24h, 0.4μL (1mg / mL) of lipo2000 was added to each well of the lipo2000 transfection LPS positive control group and the different concentrations of example compound experimental group to transfect 100ng of lipopolysaccharide (LPS), and the empty lipo2000 transfection control group was only added with an equal amount of lipo2000, and the negative control group was changed with liquid but not transfected, and incubated overnight. The cell supernatant was collected after 18h, centrifuged at 1000g for 20min, and then according to the kit instructions, the supernatant was detected for IL-1β by enzyme-linked immunosorbent assay (ELISA).

[0532] Experimental results

[0533] Because the release of mature IL-1β after transfection of LPS non-classical pathway activation of NLRP3 can be inhibited by NLRP3 inhibitors, the relative change in the amount of IL-1β release can directly reflect the inhibitory effect of NLRP3. The results are shown in Figure 6.

[0534] In the present experimental example, effective inhibition of the release of IL-1β refers to a decrease of more than 50% in the amount of release compared with the lipo2000 transfection LPS positive control, weak inhibition refers to a decrease of between 20-50% in the amount of release compared with the positive control, and no inhibition refers to a change in the amount of release of not more than ±20% compared with the positive control.

[0535] The results show that 10 μM of MCC950 can effectively inhibit the release of IL-1β, 1 μM of MCC950 has a weak inhibitory effect, and 200 nM of MCC950 has no inhibitory effect; 10 μM, 1 μM, and 200 nM of Example 1 all have effective inhibitory effects.

[0536] Experimental Example 4: Inhibition of NLRP3 classical pathway activation by the example compounds on peripheral blood mononuclear cells (PBMC) of healthy people

[0537] 30 mL of healthy human blood was collected in a 50 mL centrifuge tube containing anticoagulant heparin sodium, and then PBMC was separated by density gradient centrifugation by Ficoll method. 96-well plates were plated with 200,000 cells per well. After 3 h of plating, LPS was directly added, and incubated for 4 h. Then 1 μm of the specified compound was added and incubated for 1 h. Then 10 μM of Nigericin was added and incubated for 45 min. The cell supernatant was collected and the IL-1β level was determined by ELISA. Heparin sodium injection was purchased from Changzhou Qianghong Biochemical Pharmaceutical Co., Ltd.; the culture medium composition was: RPMI-1640 medium (brand: Gibco, reference number: C11875500BT) + 10% fetal bovine serum (brand: Gibco, reference number: 10099-141) + 1% glutamine (brand: Gibco, reference number: 25030-081) + 1% penicillin-streptomycin mixture (brand: Solarbio, reference number: P1400); LPS was purchased from Sigma, catalog number: L2654; Nigericin was purchased from Shanghai Yuanye Biological, catalog number: S45490; PBS (1x) pH 7.4 was purchased from EallBio, catalog number: 03.15018C; human IL-1β ELISA detection kit was purchased from Thermo Invitrogen, catalog number: 88-7261-88; TBD human peripheral blood lymphocyte separation medium was purchased from Huayasichuang Biological, catalog number: LTS1077; red blood cell lysis solution was purchased from Solarbio, catalog number: R1010.

[0538] Experimental grouping: negative control group, LPS incubation alone control group, LPS combined with Nigericin positive control group, 1 μM example compound experimental group.

[0539] Venous collection of healthy human blood 30 mL into 50 mL centrifuge tube containing anticoagulant heparin sodium, 3000 r / min centrifugation for 10 min, then the upper plasma was sucked out, and an equal volume of normal saline was added, then the sample was taken with a pipette and added dropwise on the same amount of lymphocyte separation medium, centrifuged at 1800 r / min for 10 min, then the lymphocyte layer was taken out, and the cells were washed by red blood cell lysis and centrifugal sedimentation, and then plated with 100 μL of medium containing 200,000 cells per well. After 3 h, 1 μg / mL of LPS was added to the negative control group and the rest of the groups for 4 h. Then 1 μM of the example compound was added to the experimental group for 1 h. Then 10 μM of nigericin was added to the LPS combined nigericin positive control group and the 1 μM example compound experimental group for 45 min. The cell supernatant was collected and the IL-1β level was determined by ELISA.

[0540] Experimental results

[0541] Because LPS + nigericin activates NLRP3 through the classic pathway, it releases mature IL-1β, and this release can be inhibited by NLRP3 inhibitors. The relative change in the amount of IL-1β release can directly reflect the inhibition of NLRP3. The results are shown in Figure 7.

[0542] In this experimental example, effective inhibition of the release of IL-1β means that the release is reduced by more than 50% compared with the LPS combined nigericin positive control. The results show that Example 1 and Example 6 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 7).

[0543] Experimental Example 5: Inhibition curve of example compound on NLRP3 classic pathway activation in healthy human whole blood

[0544] Venous aseptic collection of human whole blood 15 mL, plated in a 96-well plate, 198 μL per well, then 2 μL of 100× example compound gradient dilution solution of the specified concentration was added, then 10 μL of 21 μg / mL LPS gradient dilution solution was immediately added, 3 h later, 5 μM of nigericin was added, and after 1 h of stimulation, the whole blood was collected, centrifuged to collect the supernatant, and then the IL-1β in the sample supernatant was detected by ELISA. Heparin sodium injection was purchased from Changzhou Qianghong Biochemical Pharmaceutical Co., Ltd.; LPS was purchased from Sigma, item number: L2654; nigericin was purchased from Shanghai Yuanye Bio, item number: S45490; PBS (1×) pH 7.4 was purchased from EallBio, item number: 03.15018C; human IL-1β ELISA detection kit was purchased from Thermo Invitrogen, item number: 88-7261-88.

[0545] Experimental grouping: negative control group, LPS alone incubation control group, LPS combined with Nigericin positive control group, 1 μM example compound experimental group.

[0546] Venous aseptic collection of human whole blood 15 mL, pre-adding anticoagulant heparin sodium in 50 mL centrifuge tube. The collected whole blood was directly plated in 96-well plates, 198 μL per well, then 2 μL of 100x example compound gradient dilution solution of the specified concentration was added, then 10 μL of 21 μg / mL LPS gradient dilution solution was immediately added, and 3 h later, Nigericin with a working concentration of 5 μM was added, and after 1 h of stimulation, the whole blood was collected, centrifuged to collect the supernatant, and then the sample supernatant was detected by ELISA method to detect IL-1β in the sample supernatant.

[0547] Experimental results

[0548] Because the classic pathway activates NLRP3 to release mature IL-1β, and this release can be inhibited by NLRP3 inhibitors, the relative change in the amount of IL-1β release can directly reflect the NLRP3 inhibition. Different concentrations of compounds have different inhibition strengths, and an inhibition curve can be constructed accordingly, and the IC 50 The inhibitory effect of the compound was evaluated. The results are shown in Table 2.

[0549] The results show that the IC 50 of MCC950 is 3499 nM; the IC 50 of Example 1 is 457 nM.

[0550] Table 2 (experimental example 5 NLRP3 classic pathway activation model IC 50 determination results)

[0551] Experimental example 6: 1 μM compound inhibits NLRP3 classic pathway activation on mouse monocyte cell line

[0552] The mouse monocyte cell line (J774A.1) cells were seeded at 1.0 x 10 6The cells were plated at a density of 1 x 105cells / mL in 100 μL in a 96-well plate. Then, LPS + 10 μM Nig was used to activate NLRP3. The cell culture medium was composed of: DMEM (brand: Gibco, reference number: C12430500) + 10% fetal bovine serum (brand: Gibco, reference number: 10099-141) + 1% sodium pyruvate (brand: Gibco, reference number: 11360-070) + 1% penicillin-streptomycin mixture (brand: Solarbio, reference number: P1400). The J774A.1 mouse monocyte macrophage cell line was purchased from the Cell Resource Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (resource number 1101MOU-PUMC000222). Nig was purchased from Shanghai Yuanye Bio, item number: S45490; and the mouse IL-1β ELISA kit was purchased from Thermo Invitrogen, item number: 88-7013.

[0553] Experimental groups: negative control group, LPS incubation alone control group, LPS + Nig positive control group, and example compound experimental group.

[0554] After the plated J774A.1 cells adhered, the medium was replaced, and the medium of the other groups except the negative control group was completely replaced with cell culture medium containing 1 μg / mL LPS, and the negative control group was replaced with cell culture medium, and then incubated overnight. After 18 h, the medium was replaced again, and the medium of the example compound experimental group was completely replaced with cell culture medium containing the compound; the medium of the negative control group, LPS incubation alone control group, and LPS + Nig control group was replaced with cell culture medium. After 1 h, the medium of the LPS + Nig positive control group and example compound experimental group was completely replaced with cell culture medium containing 10 μM Nig. After 1 h, the cell supernatant was collected for IL-1β detection by ELISA.

[0555] Experimental results

[0556] Because LPS + Nig activates NLRP3 to release mature IL-1β, and this release can be inhibited by NLRP3 inhibitors, the relative change in the amount of IL-1β release can directly reflect the NLRP3 inhibition. The results are shown in FIGS. 8-10.

[0557] In the present experimental example, effective inhibition of IL-1β release refers to a decrease of more than 50% in the release amount compared with the positive control, and weak inhibition refers to a decrease of between 20-50% in the release amount compared with the positive control.

[0558] The results show that MCC950, Example 3, Example 6 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 8). Example 2, Example 7 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 9). Example 8, Example 9, Example 10 can effectively inhibit the release of IL-1β at a concentration of 1 μM (Figure 10).

[0559] Experimental Example 7: Inhibition curve of compounds on mouse monocyte cell line for inhibiting activation of NLRP3 classical pathway

[0560] The mouse monocyte cell line (J774A.1) cells were plated in a 96-well plate at a density of 1.0 x 10 6 The cells were plated at a density of 1.0 x 10

[0561] Experimental grouping: negative control group, LPS incubation alone control group, LPS combined with Nig positive control group, and example compound experimental group.

[0562] After the plated J774A.1 cells adhered, the medium was changed, and the medium of the other groups except the negative control group was completely changed to cell culture medium containing 1 μg / mL LPS, and the negative control group was changed to cell culture medium, and then incubated overnight. After 18 h, the medium was changed again, and the medium of the example compound experimental group was completely changed to cell culture medium containing different concentrations of compounds; the negative control group, LPS incubation alone control group, and LPS combined with Nig positive control group were changed to cell culture medium. After 1 h, the medium of the LPS combined with Nig positive control group and the example compound experimental group was completely changed to cell culture medium containing 10 μM Nig. After 1 h, the cell supernatant was collected for IL-1β detection by ELISA.

[0563] Experimental results

[0564] Because the classic pathway activates NLRP3 to release mature IL-1β, and this release can be inhibited by NLRP3 inhibitors, the relative change in the amount of IL-1β release can directly reflect the inhibitory effect of NLRP3. Different concentrations of compounds have different inhibitory strengths, and an inhibition curve can be constructed accordingly. The IC 50 of the compound is evaluated. The results are shown in Table 3.

[0565] The results show that the IC 50 of Example 1 is 23.8 nM; the IC 50 of Example 2 is 163.6 nM; the IC 50 of Example 8 is 148.4 nM; the IC 50 of Example 9 is 68.0 nM; the IC 50 of Example 10 is 89.0 nM; and the IC 50 of MCC950 is 174.0 nM.

[0566] Table 3 (Experimental Example 7 IC 50 determination results of NLRP3 classic pathway activation model)

[0567] Experimental Example 8: Analysis of the pharmacokinetic properties of the compound

[0568] Adult Sprague dawley (SD) male rats were orally gavaged and intravenously administered, and each group was administered at a dose of 2.5 mg / kg. The rats were eye bled at 1 min, 30 min, 1 h, and 2 h after drug administration, and then the blood plasma was centrifuged at 4°C and 3000 rpm for 10 min. Acetonitrile was added to the blood plasma at a volume ratio of 1:3 to precipitate the protein, and the supernatant was taken after centrifugation, filtration, and detection of the compound concentration by LC-MS (Agilent 1260-G6125, SIM mode).

[0569] Experimental grouping: solvent control group, administration group.

[0570] Experimental results

[0571] Table 4 Half-life and blood concentration of the compound

[0572] As shown in Table 4, the half-life and blood concentration of Example 1 are significantly better than those of the control drug MCC950.

[0573] Although the embodiments of the present application have been shown and described above, it will be understood that the above embodiments are exemplary and should not be construed as limiting the present application, and those of ordinary skill in the art can make changes, modifications, replacements, and variations to the above embodiments within the scope of the present application.

Claims

1. A sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt, said sulfonylurea compound having the structure shown in formula (I): in, R1 and R3 are each independently hydrogen, C1-C6 alkyl, amino, hydroxyl, halogen, C1-C6 alkoxy, nitro or cyano; Z1 and Z2 are each independently R2 or -(CH2)-N(R4)CH3, wherein R2 is hydrogen, C1-C6 alkyl, amino, hydroxyl, halogen, C1-C6 alkoxy or cyano, and R4 is C1-C6 alkyl. R5 is a C1-C6 alkyl group; Optionally, R4 is cyclically linked to R1, R2, or R5 via a single chemical bond or a C1-C6 alkylene group.

2. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein, When Z2 is R2 and Z1 is -(CH2)-N(R4)CH3, the structural formula of the sulfonylurea compound is:

3. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt according to claim 2, wherein, In compounds of formula (II), R4 is cyclically linked to R1, R2 or R5 by a single chemical bond or a C1-C6 alkylene group.

4. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein, When Z1 is R2 and Z2 is -(CH2)-N(R4)CH3, the structural formula of the sulfonylurea compound is:

5. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt according to claim 4, wherein, In the compound of formula (iii), R4 is cyclically linked to R1, R2 or R5 by a single chemical bond or a C1-C6 alkylene group.

6. The compound, its isomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein, The sulfonylurea compound is selected from any one of the following:

7. A pharmaceutical composition comprising any one of the sulfonylurea compounds, isomers thereof, solvates or pharmaceutically acceptable salts and pharmaceutically acceptable excipients according to any one of claims 1-6.

8. A sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt according to any one of claims 1-6, used as: (i) NLRP3 inflammasome inhibitors; and / or (ii) One or more regulators of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33 and Th17 cells.

9. Use of any sulfonylurea compound, isomer thereof, solvate or pharmaceutically acceptable salt of any one of claims 1-6, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating or preventing a disease, symptom or condition.

10. The use according to claim 9, wherein, The disease, symptom, or condition is selected from the following groups: (i) Immune system diseases, symptoms, or conditions; (ii) Inflammatory diseases, symptoms or conditions or autoimmune diseases, symptoms or conditions; (iii) Skin diseases, conditions or illnesses; (iv) Cardiovascular diseases, conditions, or illnesses; (v) Cancer, tumor, or other malignant tumor; (vi) Diseases, symptoms or conditions of the kidney system; (vii) Gastrointestinal diseases, symptoms, or conditions; (viii) Respiratory diseases, symptoms, or conditions; (ix) Endocrine system disorders, symptoms, or conditions; (x) Diseases, symptoms, or conditions of the central nervous system (CNS); and / or (xi) Local or systemic infection.

11. The use according to claim 9 or 10, wherein, The disease, symptom, or condition is selected from the following groups: Constitutive inflammation includes cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory disease (NOMID), autoinflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated cycle syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia (D) and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome, septic arthritis, pyoderma gangrenosa and acne syndrome (PAPA), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLAID (PLCG2-associated antibody deficiency and immune dysregulation), PLAID (PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation), and sideroblastic anemia with B-cell immunodeficiency, periodic fever and developmental retardation (SIFD). Autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome, and Schnitz's syndrome; Macrophage activation syndrome; Blau syndrome; Respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; Dermatitis, including contact dermatitis; Central nervous system diseases, including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, and brain damage caused by pneumococcal meningitis; Metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout; Eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infections, and dry eye syndrome; Kidney diseases, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, and diabetic nephropathy; Liver diseases, including non-alcoholic steatohepatitis (NASH) and alcoholic liver disease; Inflammatory skin reactions, including contact hypersensitivity and sunburn; Joint inflammatory responses, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Stiebel disease, and relapsing polychondritis; Viral infections, including alpha viruses (Chekungunya virus, Ross River virus) and flaviviruses (dengue virus, Zika virus), influenza, and human immunodeficiency virus (HIV); Hidradenitis suppurativa (HS) and other skin diseases that cause cysts; Cancer, including metastatic lung cancer, pancreatic cancer, stomach cancer, myelodysplastic syndrome, and leukemia; Polymyositis; Stroke, including ischemic stroke; Myocardial infarction, including recurrent myocardial infarction; Congestive heart failure; embolism; Cardiovascular diseases; Graft-host disease; hypertension; colitis; worm infection; Bacterial infection; septicemia; Septic shock; Abdominal aortic aneurysm; Wound healing; Depression, psychological stress; Local ischemia-reperfusion injury and any disease in which an individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

12. The use as described in claim 9, 10, or 11, wherein, The disease, symptom, or condition is selected from the following groups: (i) Autoinflammatory diseases, including cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal multisystem inflammatory disease (NOMID), tumor necrosis factor-TNF receptor-associated cycle syndrome (TRAPS), hyperimmunoglobulinemia (D) and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome or pyogenic arthritis, pyoderma gangrenosa and acne PAPA; (ii) Parkinson's disease or Huntington's disease; (iii) Gout or juvenile idiopathic arthritis; (iv) Nonalcoholic steatohepatitis (NASH); (v) Oxalate nephropathy or nephrocalcinosis; (vi) uveitis; (vii) Hidradenitis suppurativa (HS); (viii) Myelodysplastic syndrome, macrophage activation syndrome, Schnitz syndrome, adult-onset Stiebel syndrome, or Behcet's disease; or (ix) Sepsis, septic shock.

13. A method for treating or preventing a disease, symptom, or condition, the method comprising administering to an individual with a therapeutically effective amount of any one of claims 1-6, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7.

14. The method according to claim 13, wherein, The disease, symptom, or condition is selected from the following groups: (i) Immune system diseases, symptoms, or conditions; (ii) Inflammatory diseases, symptoms or conditions or autoimmune diseases, symptoms or conditions; (iii) Skin diseases, conditions or illnesses; (iv) Cardiovascular diseases, conditions, or illnesses; (v) Cancer, tumor, or other malignant tumor; (vi) Diseases, symptoms or conditions of the kidney system; (vii) Gastrointestinal diseases, symptoms, or conditions; (viii) Respiratory diseases, symptoms, or conditions; (ix) Endocrine system disorders, symptoms, or conditions; (x) Diseases, symptoms, or conditions of the central nervous system (CNS); and / or (xi) Local or systemic infection.

15. The method according to claim 13 or 14, wherein, The disease, symptom, or condition is selected from the following groups: Constitutive inflammation includes cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory disease (NOMID), autoinflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated cycle syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia (D) and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome, septic arthritis, pyoderma gangrenosa and acne syndrome (PAPA), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLAID (PLCG2-associated antibody deficiency and immune dysregulation), PLAID (PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation), and sideroblastic anemia with B-cell immunodeficiency, periodic fever and developmental retardation (SIFD). Autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome, and Schnitz's syndrome; Macrophage activation syndrome; Blau syndrome; Respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; Dermatitis, including contact dermatitis: Central nervous system diseases, including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, and brain damage caused by pneumococcal meningitis; Metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout; Eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infections, and dry eye syndrome; Kidney diseases, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, and diabetic nephropathy; Liver diseases, including non-alcoholic steatohepatitis (NASH) and alcoholic liver disease; Inflammatory skin reactions, including contact hypersensitivity and sunburn; Joint inflammatory responses, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Stiebel disease, and relapsing polychondritis; Viral infections, including alpha viruses (Chekungunya virus, Ross River virus) and flaviviruses (dengue virus, Zika virus), influenza, and human immunodeficiency virus (HIV); Hidradenitis suppurativa (HS) and other skin diseases that cause cysts; Cancer, including metastatic lung cancer, pancreatic cancer, stomach cancer, myelodysplastic syndrome, and leukemia; Polymyositis; Stroke, including ischemic stroke; Myocardial infarction, including recurrent myocardial infarction; Congestive heart failure; embolism; Cardiovascular diseases; Graft-host disease; hypertension; colitis; worm infection; Bacterial infection; septicemia; Septic shock; Abdominal aortic aneurysm; Wound healing; Depression, psychological stress; Local ischemia-reperfusion injury and any disease in which an individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

16. The method according to claim 13, 14, or 15, wherein, The disease, symptom, or condition is selected from the following groups: (i) Autoinflammatory diseases, including cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal multisystem inflammatory disease (NOMID), tumor necrosis factor-TNF receptor-associated cycle syndrome (TRAPS), hyperimmunoglobulinemia (D) and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome or pyogenic arthritis, pyoderma gangrenosa and acne PAPA; (ii) Parkinson's disease or Huntington's disease; (iii) Gout or juvenile idiopathic arthritis; (iv) Nonalcoholic steatohepatitis (NASH); (v) Oxalate nephropathy or nephrocalcinosis; (vi) uveitis; (vii) Hidradenitis suppurativa (HS); (viii) Myelodysplastic syndrome, macrophage activation syndrome, Schnitz syndrome, adult-onset Stiebel syndrome, or Behcet's disease; or (ix) Sepsis, septic shock.

17. A sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt according to any one of claims 1-6, or a pharmaceutical composition according to claim 7, for use in the treatment or prevention of a disease, symptom, or condition in an individual with a corresponding need.

18. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to claim 17, wherein, The disease, symptom, or condition is selected from the following groups: (i) Immune system diseases, symptoms, or conditions; (ii) Inflammatory diseases, symptoms or conditions or autoimmune diseases, symptoms or conditions; (iii) Skin diseases, conditions or illnesses; (iv) Cardiovascular diseases, conditions, or illnesses; (v) Cancer, tumor, or other malignant tumor; (vi) Diseases, symptoms or conditions of the kidney system; (vii) Gastrointestinal diseases, symptoms, or conditions; (viii) Respiratory diseases, symptoms, or conditions; (ix) Endocrine system disorders, symptoms, or conditions; (x) Diseases, symptoms, or conditions of the central nervous system (CNS); and / or (xi) Local or systemic infection.

19. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to claim 17 or 18, wherein, The disease, symptom, or condition is selected from the following groups: Constitutive inflammation includes cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory disease (NOMID), autoinflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated cycle syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia (D) and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome, septic arthritis, pyoderma gangrenosa and acne syndrome (PAPA), A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), PLAID (PLCG2-associated antibody deficiency and immune dysregulation), PLAID (PLCG2-associated autoinflammatory disease, antibody deficiency and immune dysregulation), and sideroblastic anemia with B-cell immunodeficiency, periodic fever and developmental retardation (SIFD). Autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome, and Schnitz's syndrome; Macrophage activation syndrome; Blau syndrome; Respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; Dermatitis, including contact dermatitis; Central nervous system diseases, including Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, and brain damage caused by pneumococcal meningitis; Metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout; Eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infections, and dry eye syndrome; Kidney diseases, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, and diabetic nephropathy; Liver diseases, including non-alcoholic steatohepatitis (NASH) and alcoholic liver disease; Inflammatory skin reactions, including contact hypersensitivity and sunburn; Joint inflammatory responses, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Stiebel disease, and relapsing polychondritis; Viral infections, including alpha viruses (Chekungunya virus, Ross River virus) and flaviviruses (dengue virus, Zika virus), influenza, and human immunodeficiency virus (HIV); Hidradenitis suppurativa (HS) and other skin diseases that cause cysts; Cancer, including metastatic lung cancer, pancreatic cancer, stomach cancer, myelodysplastic syndrome, and leukemia; Polymyositis; Stroke, including ischemic stroke; Myocardial infarction, including recurrent myocardial infarction; Congestive heart failure; embolism; Cardiovascular diseases; Graft-host disease; hypertension; colitis; worm infection; Bacterial infection; septicemia; Septic shock; Abdominal aortic aneurysm; Wound healing; Depression, psychological stress; Local ischemia-reperfusion injury and any disease in which an individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

20. The sulfonylurea compound, its isomer, solvate, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to claim 17, 18, or 19, wherein, The disease, symptom, or condition is selected from the following groups: (i) Autoinflammatory diseases, including cryptothermal protein-associated cycle syndrome (CAPS), Mukel-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal multisystem inflammatory disease (NOMID), tumor necrosis factor-TNF receptor-associated cycle syndrome (TRAPS), hyperimmunoglobulinemia (D) and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome or pyogenic arthritis, pyoderma gangrenosa and acne PAPA; (ii) Parkinson's disease or Huntington's disease; (iii) Gout or juvenile idiopathic arthritis; (iv) Nonalcoholic steatohepatitis (NASH); (v) Oxalate nephropathy or nephrocalcinosis; (vi) uveitis; (vii) Hidradenitis suppurativa (HS); (viii) Myelodysplastic syndrome, macrophage activation syndrome, Schnitz syndrome, adult-onset Stiebel syndrome, or Behcet's disease; or (ix) Sepsis, septic shock.

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