Sulfonylurea compounds

Abstract

The present application relates to sulfonylurea compounds, in particular to compounds having both sulfonylurea and 2-(furan-2-yl)propan-2-ol, and to related salts, solvates, prodrugs, and compositions. The present application also relates to the use of the compounds as medicaments for the treatment and prevention of medical conditions and diseases by NLRP3 inhibition. The present application also relates to the use of the compounds as medicaments for the treatment and prevention of medical conditions and diseases by NLRP3 inhibition. The sulfonylurea compounds of the present application have strong NLRP3 inflammasome inhibitory activity.

Description

Technical Field

[0001] This application relates to sulfonylurea compounds, specifically compounds having both a sulfonylurea structure and a 2-(furan-2-yl)prop-2-ol structure, and to related salts, solvates, prodrugs, and compositions. This application also relates to the pharmaceutical use of said compounds as inhibitors of NLRP3 for the treatment and prevention of medical conditions and diseases. Background Technology

[0002] Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) combines with the adaptor protein ASC (apoptosis-associated speck-like protein containing caspaserecruitment domain) and the effector protein pro-caspase-1 to form a complex protein macromolecule, namely the NLRP3 inflammasome. The NLRP3 inflammasome mediates inflammatory responses by recognizing pathogen-associated molecules such as exogenous pathogens and bacteria, or endogenous damage-associated molecules. Its normal biological activity plays an important role in maintaining homeostasis within the body.

[0003] However, due to various pathological reasons, overactivation of the NLRP3 inflammasome can lead to excessive release of inflammatory mediators interleukin-1β and interleukin-18, causing severe cellular inflammation. Simultaneously, the cleavage of the perforator gasdermin D leads to pyroptosis, exacerbating the inflammation. Studies have shown that abnormal activation of the NLRP3 inflammasome is closely related to the occurrence and development of various diseases, such as autoimmune diseases like inflammatory bowel disease and rheumatoid arthritis, atherosclerosis, gout, type 2 diabetes, ischemic stroke, and neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, as well as other related conditions. The NLRP3 inflammasome plays a crucial role in inflammatory response-related diseases, and inhibiting its activity can have a therapeutic effect. Given the widespread and serious harm of NLRP3 inflammasome-related diseases, there is an urgent need for high-performance NLRP3 inflammasome inhibitors. Summary of the Invention

[0004] This application relates to sulfonylurea compounds, specifically compounds having both sulfonylurea and 2-(furan-2-yl)prop-2-ol, and to related salts, solvates, prodrugs, and compositions. This application also relates to the pharmaceutical use of said compounds for the treatment and prevention of medical conditions and diseases through NLRP3 inhibition. The sulfonylurea compounds of this application possess strong NLRP3 inflammasome inhibitory activity.

[0005] Therefore, the embodiments of this application disclose at least the following technical solutions:

[0006] In a first aspect, the embodiments disclose compounds of formula (I):

[0007]

[0008] Wherein, A is phenyl; B is a fused-ring aromatic group; R1 is independently selected from H, alkyl, halogen, haloalkyl, alkoxy; R2 is independently selected from H, alkyl, halogen, haloalkyl, alkoxy; R3 is independently selected from H or halogen.

[0009] Secondly, the embodiments disclose pharmaceutically acceptable salts, solvates, or prodrugs of the compounds described in the first aspect.

[0010] Thirdly, the embodiments disclose an NLRP3 inhibitor comprising the compound described in the first aspect, or a pharmaceutically acceptable salt described in the second aspect, or a solvent compound thereof or a prodrug thereof.

[0011] Fourthly, the embodiments disclose a composition. The composition comprises the compound described in the first aspect, or the optical isomer described in the second aspect, a labeled compound, a pharmaceutically acceptable salt, a tautomer, a solvate, or a prodrug, and a pharmaceutically acceptable excipient.

[0012] Fifthly, the embodiments disclose a composition. The composition comprises the compound described in the first aspect, the optical isomer described in the second aspect, a labeled compound, a pharmaceutically acceptable salt, a tautomer, a solvate, or a prodrug, wherein the compound, the pharmaceutically acceptable salt, the solvate, or the prodrug, or the composition, is used in a pharmaceutical preparation.

[0013] Sixthly, the embodiments disclose the use of the compound described in the first aspect, or the pharmaceutically acceptable salt described in the second aspect, or its solvent compound or prodrug, or the composition described in the fourth aspect for the preparation of a medicament for treating or preventing a disease, symptom, or ailment selected from:

[0014] (i) Inflammation;

[0015] (ii) Autoimmune diseases;

[0016] (iii) Cancer;

[0017] (iv) Infection;

[0018] (v) Central nervous system diseases;

[0019] (vi) Metabolic diseases;

[0020] (vii) Cardiovascular diseases;

[0021] (viii) Respiratory diseases;

[0022] (ix) Liver disease;

[0023] (x) Nephropathy;

[0024] (xi) Eye disease;

[0025] (xii) Skin diseases;

[0026] (xiii) Lymphatic disorders;

[0027] (xiv) Psychological disorder;

[0028] (xv) graft-versus-host disease;

[0029] (xvi) tactile pain; and

[0030] (xvii) Any disease in which an individual has been identified as carrying a germline or somatic non-silenced NLRP3 mutation.

[0031] In a seventh aspect, the embodiments disclose the use of the compound described in the first aspect, or a pharmaceutically acceptable salt described in the second aspect, or a solvent compound thereof or a prodrug thereof, or a composition described in the fourth aspect, in the preparation of a medicament for treating or preventing a disease, symptom, or ailment selected from:

[0032] (i) Cryoinflammatory-associated periodic syndrome (CAPS);

[0033] (ii) Markel-Wells syndrome (MWS);

[0034] (iii) Familial cold-cause autoinflammatory syndrome (FCAS);

[0035] (iv) Neonatal episodic multisystem inflammatory disease (NOMID);

[0036] (v) Familial Mediterranean fever (FMF);

[0037] (vi) Suppurative arthritis, pyoderma gangrenosa, and acne syndrome (PAPA);

[0038] (vii) Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS);

[0039] (viii) Tumor necrosis factor (TNF) receptor-related periodic syndrome (TRAPS);

[0040] (ix) Systemic juvenile idiopathic arthritis;

[0041] (x) Adult-onset Still's disease (AOSD);

[0042] (xi) Recurrent polychondritis;

[0043] (xii) Schönitzler syndrome;

[0044] (xiii) Sweet's syndrome;

[0045] (xiv) Behcet's disease;

[0046] (xv) Antisynergistic syndrome;

[0047] (xvi) Interleukin-1 receptor antagonist deficiency (DIRA); and

[0048] (xvii)A20 single dose insufficiency (HA20). Attached Figure Description

[0049] Figure 1 This is a schematic diagram of the synthesis step one of compound 1 provided in the example.

[0050] Figure 2 This is a schematic diagram of the synthesis step two of compound 1 provided in the example.

[0051] Figure 3 This is a schematic diagram of the synthesis step three of compound 1 provided in the example.

[0052] Figure 4 A schematic diagram of the synthesis step three of compound 15 provided in the examples.

[0053] Figure 5 A schematic diagram of the synthetic routes of compounds 1 to 15 provided in the examples.

[0054] Figure 6 The diagram shows the structures of compounds 1 to 15 provided in the examples. Detailed Implementation

[0055] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application. Reagents not specifically described in detail herein are all conventional reagents and are commercially available; methods not specifically described in detail are all conventional experimental methods and can be learned from the prior art.

[0056] Definitions and Terms

[0057] Throughout this specification, references to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in association with said embodiment is included in at least one embodiment. Therefore, the phrase "in one embodiment" appearing throughout this specification does not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any suitable manner in one or more embodiments. Additionally, unless otherwise expressly stated, the singular forms "a," "an," and "the" as used in this specification and the appended claims include plural indicators. It should also be noted that unless otherwise expressly stated, the term "or" is generally used in its meaning, including "and / or."

[0058] Unless otherwise indicated, the following terms as used herein have the following meanings:

[0059] "Phenyl" refers to a group that forms a bond with at least one carbon atom of the benzene ring.

[0060] "Fused ring aromatic group" refers to: phenyl, or at least two benzene rings sharing two adjacent carbon atoms to form a polycyclic aromatic hydrocarbon compound as a linking group, wherein "fused ring aromatic hydrocarbon" can be, for example, naphthalene, anthracene, or phenanthrene. "Fused ring aromatic group" can refer to phenyl, naphthyl, anthraceneyl, or phenanthrene.

[0061] "alkyl" refers to a monovalent group of a straight-chain or branched saturated hydrocarbon having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever used herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is C1-10 alkyl. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl.

[0062] "Halogen" or "halogen" refers to a bromine group, a chlorine group, a fluorine group, or an iodine group. In some embodiments, the halogen is a fluorine group or a chlorine group. In some embodiments, the halogen is a fluorine group.

[0063] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0064] "Alkoxy" refers to a group having the formula -ORa, where Ra is an alkyl group as defined. Unless otherwise specifically stated in the specification, alkoxy groups may optionally be substituted, for example, with oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc.

[0065] In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with a halogen.

[0066] The term “treatment” is used interchangeably with curative and palliative therapies. The term includes achieving a beneficial or desired physiological outcome, which may or may not be clinically determined. Beneficial or desired clinical outcomes include (but are not limited to) detectable or undetectable symptom relief, symptom prevention, reduction of disease severity, disease stabilization (i.e., no exacerbation), delay or slowing of disease / symptom progression / exacerbation, improvement or remission of disease / symptoms, and reduction (whether partial or complete). The term “remission” as used herein and its variations mean a reduction in the severity and / or undesirable manifestations of a physiological disorder or symptom and / or a slowing or prolonging of its progression compared to the absence of the compounds, salts, solvates, prodrugs, or pharmaceutical compositions of the present invention. The term “prevention” as used herein in relation to disease, condition, or disorder refers to prophylactic or preventative therapy and therapy that reduces the risk of developing a disease, condition, or disorder. The term “prevention” includes both avoiding the occurrence of a disease, condition, or disorder and delaying its onset. Any statistically significant (p≤0.05) avoidance of occurrence, delay of onset, or reduction of risk as measured by a controlled clinical trial may be considered prevention of a disease, condition, or disorder. Individual subjects suitable for prevention include those identified as having an increased risk of a disease, condition, or disorder by genetic or biochemical markers. Typically, genetic or biochemical markers are applicable to the disease, condition, or disorder under consideration and may include, for example, inflammatory biomarkers such as C-reactive protein (CRP) and monocyte chemoattractant 1 (MCP-1) in inflammatory cases; total cholesterol, triglycerides, insulin resistance, and C-peptides in NAFLD and NASH cases; and more generally, IL-1β and IL-18 in cases of disease, condition, or disorder that respond to NLRP3 inhibition.

[0067] compound

[0068] The examples disclose a compound of formula (I):

[0069]

[0070] Wherein, A is phenyl; B is a fused-ring aromatic group; R1 is independently selected from H, alkyl, halogen, haloalkyl, alkoxy; R2 is independently selected from H, alkyl, halogen, haloalkyl, alkoxy; R3 is independently selected from H or halogen.

[0071] In some embodiments, B is independently selected from phenyl, naphthyl, anthraceneyl, or phenanthrene.

[0072] In some embodiments, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, or octyl.

[0073] In some embodiments, the halogen group is selected from bromo, chloro, fluorine, or iodine groups.

[0074] In some embodiments, the alkyl halogroup is selected from trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0075] In some embodiments, the alkoxy group is selected from groups having the formula -ORa, and Ra is the alkyl group.

[0076] In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.

[0077] In some embodiments, the compound has the following structural formula: (Compound 1).

[0078] In some embodiments, the compound has the following structural formula: (Compound 2).

[0079] In some embodiments, the compound has the following structural formula: (compound) 3 ).

[0080] In some embodiments, the compound has the following structural formula: (compound) 4) .

[0081] In some embodiments, the compound has the following structural formula: (Compound 5) 。

[0082] In some embodiments, the compound has the following structural formula: (Compound 6).

[0083] In some embodiments, the compound has the following structural formula: (Compound 7).

[0084] In some embodiments, the compound has the following structural formula: (Compound 8).

[0085] Some Implementation In the example, the structural formula of the compound is: (Compound 9).

[0086] In some embodiments, the compound has the following structural formula: (Compound 10).

[0087] In some embodiments, the compound has the following structural formula: (Compound 11).

[0088] In some embodiments, the compound has the following structural formula: (Compound 12).

[0089] In some embodiments, the compound has the following structural formula: (Compound 13).

[0090] In some embodiments, the compound has the following structural formula: (Compound 14).

[0091] In some embodiments, the compound has the following structural formula: (Compound 15).

[0092] Optical isomers of compounds

[0093] In some embodiments, the compounds of formula (I) are present in optical isomer form. The compounds of formula (I) include all diastereomers, enantiomers, and epimers, as well as corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used in the applications described herein. In some embodiments, the compounds of formula (I) are prepared as individual optical isomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomers, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these dissimilarity. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on differences in solubility.

[0094] Labeled compounds

[0095] In some embodiments, the compounds of formula (I) are present in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of formula (I) containing the aforementioned isotopes and / or other isotopes of other atoms, and their pharmaceutically acceptable salts, solvates, or optical isomers, are within the scope of this application. Certain isotopically labeled compounds, such as radioactive isotopes such as 3 H and 14 Those incorporating C can be used in drug and / or substrate tissue distribution assays. Tritiumization (i.e....) 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavy isotopes such as deuterium (i.e., 2 Substitution of H) can produce certain therapeutic advantages due to greater metabolic stability, such as increased half-life or reduced dose requirement.

[0096] In some embodiments, the compound of formula (I) is labeled by other means, including but not limited to the use of chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling.

[0097] Pharmaceutically acceptable salts

[0098] In some embodiments, the compounds of formula (I) are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0099] In some embodiments, the compound of formula (I) has an acidic or basic group and thus reacts with a number of inorganic or organic bases and any of inorganic and organic acids to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compound disclosed herein or its solvates or optical isomers, or by reacting the purified compound, in its free form alone, with a suitable acid or base, and isolating the resulting salt.

[0100] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds of formula (I) with mineral acids, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-heptanoates, glycerophosphates, glycolates, hemisulfates, heptasulfates, heptasulfates, hexyn-1,6-dicitates, hydroxybenzoates, and γ-hydroxybutyrates. Salts, hydrochlorides, hydrobromides, hydroiodates, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malonates, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, pyrates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pentanoates, propionates, pyrosulfates, pyrophosphates, propynates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, octanoates, sebacic acid salts, sulfonates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and xylenesulfonates.

[0101] Furthermore, the compound of formula (I) can be prepared into a pharmaceutically acceptable salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, wherein the pharmaceutically acceptable inorganic or organic acid includes, but is not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, etc. 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid, although not pharmaceutically acceptable on their own, are used to prepare salts that can be used as intermediates in obtaining the compounds disclosed herein, their solvates or optical isomers, and their pharmaceutically acceptable acid addition salts.

[0102] In some embodiments, those compounds described herein containing a free acid group react with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation; with ammonia; or with a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, etc.

[0103] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds of formula (I) also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization yields a water- or oil-soluble or dispersible product.

[0104] solvates

[0105] In some embodiments, the compound of formula (I) is present in the form of a solvate. This application provides a method for treating a disease by applying such a solvate. This application also provides a method for treating a disease by applying such a solvate in the form of a pharmaceutical composition.

[0106] The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. Solvates of the compounds of formula (I) can be readily prepared or formed during the processes described herein. By way of example only, hydrates of the compounds of formula (I) can be readily prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein can exist in both unsolvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.

[0107] tautomer

[0108] In some cases, compounds exist as tautomers. Compounds of formula (I) include all possible tautomers of the formulas described herein. Tautomers are compounds that can interconvert through the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. A chemical equilibrium of tautomers will exist in the bond arrangements in which tautomerism is possible. Consider all tautomer forms of the compounds disclosed herein. The precise ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0109] prodrug

[0110] Some embodiments provide prodrugs of the compounds of formula (I). A prodrug is a compound which is wholly or partially converted into the compound of this application when administered to a subject (e.g., a human). In most embodiments, the prodrug is a pharmacologically inert chemical derivative that can be converted in vivo into an active drug molecule to exert a therapeutic effect. Any of the compounds described herein may be administered in prodrug form to increase the activity, bioavailability, or stability of the compound or to otherwise modify the properties of the compound. Typical examples of prodrugs include compounds having a biologically unstable protecting group on the functional portion of an active compound. Prodrugs include (but are not limited to) compounds that can be oxidized, reduced, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydration, alkylation, dealkylation, acylation, deacylation, phosphorylation, and / or dephosphorylation to produce an active compound. This application also covers salts and solvates of the prodrugs described above.

[0111] The compounds, salts, solvates, and prodrugs of this application may contain at least one chiral center. Therefore, the compounds, salts, solvates, and prodrugs may exist in at least two isomeric forms. This application covers racemic mixtures of the compounds, salts, solvates, and prodrugs of this application, as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this application, the isomers of a compound that are “substantially enantiomers” comprise less than 5% by weight of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5%.

[0112] Pharmaceutically acceptable excipients

[0113] For example, “Aulton’s Pharmaceutics - The Design and Manufacture of Medicines”, MEAulton and KMG Taylor, Churchill Livingstone Elsevier, 4th edition, 2013, describes the routine procedures for selecting and preparing appropriate pharmaceutical formulations.

[0114] Pharmaceutically acceptable excipients (including adjuvants, diluents, or carriers) that can be used in the pharmaceutical compositions of this application are those pharmaceutically acceptable excipients commonly used in the field of pharmaceutical formulation, and include (but are not limited to) sugars, sugar alcohols, starches, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin).

[0115] Treatment

[0116] This article discloses methods for administering NLRP3 inflammasome inhibitors to subjects exhibiting increased NLRP3 inflammasome activity levels or identified as being at risk of exhibiting increased NLRP3 inflammasome activity levels. This article also discloses methods for administering NLRP3 inflammasome inhibitors to subjects diagnosed with NLRP3 inflammasome-related diseases or conditions, or exhibiting symptoms or signs of NLRP3 inflammasome-related diseases or conditions.

[0117] In some embodiments, inhibition of NLRP3 inflammasome activity is achieved using any method known to a skilled craftsman. Examples of methods for inhibiting NLRP3 inflammasome activity include, but are not limited to, directly blocking the assembly of the NLRP3 inflammasome complex by inhibiting the oligomerization of the inflammasome adaptor protein ASC (also known as PYCARD (containing PYD and CARD domains)), reducing the expression of endogenous NLRP3 inflammasome genes, reducing the expression of NLRP3 inflammasome mRNA, and inhibiting the activity of NLRP3 inflammasome proteins. Reducing the expression of endogenous NLRP3 inflammasome genes includes providing a specific inhibitor of NLRP3 inflammasome gene expression. Reducing the expression of NLRP3 inflammasome mRNA or NLRP3 inflammasome protein includes reducing the half-life or stability of NLRP3 inflammasome mRNA or reducing the expression of NLRP3 inflammasome mRNA. In some embodiments, the NLRP3 inflammasome inhibitor is a compound that reduces the expression of the NLRP3 inflammasome gene, reduces the half-life, stability, and / or expression of NLRP3 inflammasome mRNA, or inhibits the function of NLRP3 inflammasome protein. In some embodiments, the inhibitory effect of the therapeutic agent on the expression, function, or activity of the NLRP3 inflammasome is indirect.

[0118] This article provides a method for inhibiting the NLRP3 inflammasome, which can be used to treat, prevent or improve NLRP3 inflammasome-related diseases in subjects of need by administering the compounds or optical isomers disclosed herein, labeled compounds, pharmaceutically acceptable salts, tautomers, solvates or prodrugs.

[0119] In some embodiments, the disease responds to one or more of the following in Th17 cells: IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33, and Th17 cells.

[0120] In some embodiments, regulation is the inhibition of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, and IL-33.

[0121] In some embodiments, regulation of Th17 cells is achieved by inhibiting the production and / or secretion of IL-17.

[0122] In some embodiments, the disease is an immune system disease, an inflammatory disease, an autoimmune disease, a skin disease, a cardiovascular disease, cancer, a kidney disease, a gastrointestinal disease, a respiratory disease, an endocrine disease, a viral disease, or a central nervous system (CNS) disease.

[0123] In some embodiments, the disease is an immune system disease. In some embodiments, the disease is an inflammatory disease. In some embodiments, the disease is an autoimmune disease. In some embodiments, the disease is a skin disease. In some embodiments, the disease is a cardiovascular disease. In some embodiments, the disease is a viral disease. In some embodiments, the disease is a kidney disease. In some embodiments, the disease is a gastrointestinal disease. In some embodiments, the disease is a respiratory disease. In some embodiments, the disease is an endocrine system disease. In some embodiments, the disease is a viral disease. In some embodiments, the disease is a central nervous system (CNS) disease.

[0124] In some embodiments, the disease is cancer, tumor, or other malignant tumor. As described herein, cancer, tumor, and malignant tumor refer to a disease, condition, or disorder characterized by abnormal or anomalous cell proliferation, differentiation, and / or migration, or cells or tissues associated with said disease, condition, or disorder, typically accompanied by an abnormal or anomalous molecular phenotype, including one or more genetic mutations or other genetic changes associated with tumorigenesis, expression of tumor markers, loss of expression or activity of tumor suppressor factors, and / or abnormal or anomalous expression of cell surface markers. In general embodiments, cancer, tumor, and malignant tumor may include, but are not limited to, sarcomas, lymphomas, leukemias, solid tumors, blastomas, gliomas, epithelial carcinomas, melanomas, and metastatic cancers.

[0125] In some embodiments, the disease is caused by or associated with a pathogen. In some embodiments, the pathogen is a virus, bacteria, protozoa, worm, or fungus.

[0126] Non-limiting examples of viruses include influenza virus; cytomegalovirus; EpsteinBarr virus; human immunodeficiency virus (HIV); alpha viruses, such as chikungunya virus and Ross river virus; flaviviruses, such as dengue virus, Zika virus and papilloma virus; and coronaviruses, such as human coronavirus 229E, human coronavirus NL63, human coronavirus OC43, human coronavirus HKU1, human coronavirus MERS, severe acute respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus 2.

[0127] Non-limiting examples of pathogenic bacteria include Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, and Mycobacterium leprae. Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhimurium (Typhi), Borrelia burgdorferi, and Yersiniapestis.

[0128] Non-restricted examples of protozoa include Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, and Trypanosomes.

[0129] Non-limiting examples of worms include parasitic worms, including schistosomes, roundworms, tapeworms, and flukes.

[0130] Non-limiting examples of fungi include species of the genera *Candida* and *Aspergillus*.

[0131] In some embodiments, the disease is constitutive inflammation, including viral or pathogen-associated excessive inflammation, cytokine release syndrome, acute respiratory distress syndrome, acute lung injury, septic shock, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, and coronavirus disease; cold inflammatory cyclic syndrome (CAPS), Mucklerieve syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory disease (NOMID); autoinflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated cyclic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), and Majeed syndrome. Pulmonary arthritis, pyoderma gangrenosa, and acne syndrome (PAPA); A20 haploinadequacy (HA20); childhood granulomatous arthritis (PGA); PLACG2-related antibody deficiency and immune dysregulation (PLAID); PLACG2-related autoinflammation, antibody deficiency, and immune dysregulation (APLAID); and sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD); autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjogren's syndrome, and Schnitzler syndrome; macrophage activation syndrome; Blau syndrome. 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 injury caused by pneumococcal meningitis; metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout; eye diseases, including diseases of the ocular epithelium, age-related macular degeneration (AMD), uveitis, corneal infections, and dry eye; kidney diseases, including chronic kidney disease, oxalate nephropathy. Nephropathy, nephrocalcinosis, and diabetic nephropathy; liver diseases, including non-alcoholic steatohepatitis (NASH) and alcoholic liver disease; skin inflammatory reactions, including contact hypersensitivity and sunburn; joint inflammatory reactions, including osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and relapsing polychondritis;Viral infections, including alpha viruses (chikungunya virus, Ross River virus) and flaviviruses (dengue virus, Zika virus), influenza, HIV; hidradenitis suppurativa (HS) and other skin diseases that cause cysts; cancers, including metastatic lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndromes, leukemia; polymyositis; stroke, including ischemic stroke; myocardial infarction, including recurrent myocardial infarction; congestive heart failure; embolism; cardiovascular diseases; graft-versus-host disease; hypertension; colitis; parasitic helmintic infections; bacterial infections; abdominal aortic aneurysm; wound healing; depression, psychological stress; ischemia-reperfusion injury or diseases in which the individual has been identified as carrying germline or somatic non-silent mutations in NLRP3.

[0132] In some embodiments, the disease being treated is NASH. NLRP3 inflammasome activation is crucial for inflammatory recruitment in NASH, and inhibition of NLRP3 can prevent and reverse liver fibrosis. In some embodiments, the compounds disclosed herein cause histological reduction of liver inflammation, decreased recruitment of macrophages and neutrophils, and inhibition of NF-κB activation by blocking the function of the NLRP3 inflammasome in liver tissue.

[0133] In some embodiments, inhibiting NLRP3 reduces hepatic expression of IL-1β precursors and normalizes hepatic and circulating IL-1β, IL-6, and MCP-1 levels, thereby aiding in disease treatment.

[0134] In some embodiments, the disease is severe steroid-resistant (SSR) asthma. Respiratory infections induce the NLRP3 inflammasome / caspasesin-1 / IL-1β signaling axis in the lungs, which promotes SSR asthma. The NLRP3 inflammasome recruits and activates caspase-1 precursors to induce an IL-1β response. Therefore, the NLRP3 inflammasome-induced IL-1β response is important in infection control; however, overactivation leads to aberrant inflammation and has been associated with the pathogenesis of SSR asthma and COPD. Treatment with compounds described herein that target specific disease processes is more attractive than nonspecific inhibition of the inflammatory response with steroids or IL-1β. In some embodiments, targeting the NLRP3 inflammasome / caspasesin-1 / IL-1β signaling axis with compounds described herein can be used to treat SSR asthma and other steroid-resistant inflammatory disorders.

[0135] In some embodiments, the disease is Parkinson's disease. Parkinson's disease is the most common neurodegenerative motor disorder and is characterized by the selective loss of dopaminergic neurons, accompanied by the accumulation of misfolded α-synuclein (Syn) in the Lewy body, a pathological marker of the disease. Chronic microglial neuroinflammation is evident in the early stages of the disease and has been proposed to drive the pathology.

[0136] Dosage

[0137] In some embodiments, a composition containing one or more of the compounds described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or ailment in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or ailment. The effective amount for this purpose depends on the severity and course of the disease or ailment; prior therapy; the patient's health status, weight, and response to the drug; and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0138] In prophylactic applications, a composition containing the compounds described herein is administered to a patient who is susceptible to a particular disease, condition, or disorder, or otherwise at risk of such a disease, condition, or disorder. This amount is defined as a “preventative effective amount or dose.” In this application, the precise amount also depends on the patient’s health status, weight, etc. When used in a patient, the effective amount for this purpose will depend on the severity and course of the disease; prior treatment; the patient’s health status and response to the drug; and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering a pharmaceutical composition containing the compounds described herein or pharmaceutically acceptable salts thereof to a mammal who has previously experienced at least one symptom or risk factor of a treated disease and is currently in remission, to prevent recurrence of symptoms of the disease or disorder.

[0139] In some embodiments where the patient’s condition does not improve, the compound is administered for an extended period, i.e., for a prolonged period, including throughout the patient’s life, to improve or otherwise control or limit the symptoms of the patient’s disease or ailment, following the physician’s judgment.

[0140] In some embodiments where the patient's condition improves, the dosage of the administered drug is temporarily reduced or temporarily discontinued for a period of time (i.e., a "withdrawal period"). In specific embodiments, the duration of the withdrawal period is between 2 days and 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example, the dosage reduction during the withdrawal period is 10%-100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0141] Once the patient's condition has improved, a maintenance dose is administered as necessary. Subsequently, in specific embodiments, the dosage or frequency of administration, or both, is reduced to a level that maintains the improvement in the disease, condition, or ailment, depending on the symptoms. However, in some embodiments, the patient requires prolonged intermittent or daily treatment following any recurrence of symptoms.

[0142] The amount of a given drug corresponding to this quantity varies depending on factors such as the specific compound, the disease condition and its severity, the identity (e.g., weight, sex) of the person or host requiring treatment, but is determined based on the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the disease being treated, and the person or host being treated.

[0143] However, generally, the dosage for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In one aspect, the dosage for adult treatment is about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently provided as a single dose or in divided doses, which are administered simultaneously or at appropriate intervals, for example, as sub-dose twice, three, four or more times per day.

[0144] In one embodiment, a suitable daily dose of the compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the amount of active ingredient in the daily dose or dosage form may be lower or higher than the range indicated herein, based on a number of variables relating to a single treatment regimen. In various embodiments, the daily dose and unit dose may vary depending on a number of variables, including but not limited to the activity of the compound used, the disease or ailment to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or ailment being treated, and the practitioner's judgment.

[0145] The toxicity and therapeutic efficacy of such treatment regimens are determined in cell cultures or laboratory animals using standard pharmaceutical procedures, including but not limited to determining LD10 and ED90. The dose ratio between toxic and therapeutic effects is a therapeutic index, and it is expressed as the ratio between LD10 and ED90. In some embodiments, data obtained from cell culture assays and animal studies are used to establish therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within a range of cyclic concentrations including ED50 with minimal toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form used and the route of administration employed.

[0146] Other embodiments mentioned above include the following: wherein an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered topically to a mammal; and / or (f) administered non-systemically or locally to a mammal.

[0147] Other embodiments of the compound that include a single effective dose in any of the foregoing aspects include the following other embodiments: wherein (i) the compound is administered once a day; or (ii) the compound is administered to mammals multiple times over a day.

[0148] Other embodiments of the compound that include multiple administrations of an effective amount, as mentioned above, include the following additional embodiments: wherein (i) the compound is administered continuously or intermittently, such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a subject every 12 hours; and (v) the compound is administered to a subject every 24 hours. In other or alternative embodiments, the method includes a withdrawal period in which administration of the compound is temporarily stopped or the dose of the administered compound is temporarily reduced; at the end of the withdrawal period, administration of the compound is restarted. In one embodiment, the duration of the withdrawal period varies from 2 days to 1 year.

[0149] Application route

[0150] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ocular, nasal, and topical application. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0151] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular implantation) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by it. In other embodiments, the compounds described herein are provided in a rapid-release formulation, an extended-release formulation, or an intermediate-release formulation. In other embodiments, the compounds described herein are applied topically.

[0152] Pharmaceutical Compositions / Formulations

[0153] The compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents according to standard pharmaceutical practice, to the recipient in the form of a pharmaceutical composition. In one embodiment, the compounds of the present invention may be administered to animals. The compounds may be administered orally or parenterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes.

[0154] On the other hand, this document provides pharmaceutical compositions comprising the compounds or optical isomers described herein, labeled compounds, pharmaceutically acceptable salts, tautomers, solvates or prodrugs, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into pharmaceutically usable formulations. Appropriate formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in the following: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for this disclosure.

[0155] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0156] The pharmaceutical compositions described herein are administered to the subject via appropriate routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly melting formulations, tablets, capsules, pills, powders, sugar-coated pills, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixtures of immediate-release and controlled-release formulations.

[0157] Pharmaceutical compositions including the compounds or optical isomers described herein, labeled compounds, pharmaceutically acceptable salts, tautomers, solvates, or prodrugs are manufactured in a conventional manner, such as, by way of conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsifying, encapsulating, embedding, or pressing processes, by way of example only.

[0158] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and, if necessary, processing the mixture into granules after adding suitable excipients to obtain a tablet or pill core. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant such as croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to the coating of the tablet or pill to identify or characterize different combinations of doses of the active compound.

[0159] Orally administered pharmaceutical compositions include push-in capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules contain an active ingredient blended with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0160] Pharmaceutical compositions intended for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise sterile aqueous solutions, dispersions, or sterile powders containing compounds or optical isomers described herein, labeled compounds, pharmaceutically acceptable salts, tautomers, solvates, or prodrugs. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition also comprises a preservative to prevent microbial growth.

[0161] combination

[0162] This article discloses methods for treating diseases using combinations of the compounds or optical isomers disclosed herein, labeled compounds, pharmaceutically acceptable salts, tautomers, solvates, or prodrugs with additional therapeutic agents.In some embodiments, additional therapeutic agents are anti-IL-1β drugs, such as anakinin, cannabidiol, or linacicept; antiviral drugs or nucleoside inhibitors, such as remdesivir; colchicine, hydroxychloroquine (an antimitotic agent used in cancer therapy); dermalin D inhibitors, such as dimethyl fumarate or disulfiram; multiple sclerosis drugs, such as ozanimod, fingolimod, or siponimod; other NLRP3 inhibitors, such as tranilast or dapansutrile; and melatonin. tonin); anti-IL-6 agents, such as the anti-IL-6R antibody tocilizumab (atlizumab) or the anti-IL-6 antibody siltuximab; steroids, such as dexamethasone, methylprednisolone, or prednisone; diabetes medications, such as metformin, DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, or limonene); Linagliptin, SGLT inhibitors (dapagliflozin, canaglifozin), pioglitazone, sulfonylureas (tolbutamide or glimepiride), glucagon-like peptide agonists (exenatide, liraglutide, or lixasenatide); gout medications, such as allopurinol or febuxostat; statins, for example... Such as atorvastatin, rosuvastatin, or pravastatin; JAK inhibitors, such as ruxolitinib; nonsteroidal anti-inflammatory drugs, such as ibuprofen, naproxen, celecoxib, indomethacin, diclofenac, aspirin, or salicylates; or caspase-1 inhibitors, such as belinacasan (VX-765); or any combination thereof.

[0163] Synthesis of compound (I)

[0164] 1. Synthesis of Compound 1

[0165] The examples provide the synthetic steps for compound 1. The synthetic method for compound 1 includes: reacting o-bromoaniline with 3-fluorophenylboronic acid in a solvent system of acetonitrile and water at 120°C for 4 h to obtain 3'-fluoro-[1,1'-biphenyl]-2-amine; reacting 3'-fluoro-[1,1'-biphenyl]-2-amine with triphosgene in a solvent system of xylene and triethylamine to obtain a substituted biphenyl isocyanate; and reacting 4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide with the substituted biphenyl isocyanate to obtain compound 1.

[0166] In some embodiments, the synthesis steps of compound 1 include:

[0167] Step 1: As Figure 1 As shown, 5 mmol of o-bromoaniline, 7.5 mmol of 3-fluorophenylboronic acid, 15 mL of MeCN / H₂O (9:1), 2.07 g (15 mmol) of anhydrous potassium carbonate, and 0.29 g (0.25 mmol) of tetrakis(triphenylphosphine)palladium were added sequentially to a 50 mL round-bottom flask. After stirring and dissolving, the mixture was reacted at 120 °C for 4 h. TLC monitoring was performed until the o-bromoaniline starting material reacted completely. After cooling the mixture to room temperature, 50 mL of ethyl acetate was added for dilution, and the mixture was washed with water (100 mL × 3). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Column chromatography was performed using petroleum ether / ethyl acetate (v / v) = 20:1 to 10:1 as the mobile phase to obtain 3'-fluoro-[1,1'-biphenyl]-2-amine. The resulting product was a yellow oily liquid with a yield of 75%. 1 HNMR (600MHz, DMSO-d6) δ: 7.40 (dd, J=14.1, 7.8Hz, 1H, ArH), 7.25 (d, J=7.2Hz, 1H, ArH), 7.18 (t, J=7.9Hz, 2H, ArH), 7.12 (d, J=7.5Hz,1H,ArH),7.04(td,J=8.4,2.1Hz,1H,ArH),6.84(t,J=7.4Hz,1H,ArH),6.78(d,J=8.0Hz,1H,ArH),3.63(s,2H,NH2).

[0168] Step Two: As Figure 2As shown, 297 mg (1 mmol) of triphosgene was added to a 100 mL round-bottom flask, followed by 40 mL of xylene. The mixture was stirred and dissolved in an ice bath. 2.2 mmol of 3'-fluoro-[1,1'-biphenyl]-2-amine and 0.3 mL (2 mmol) of triethylamine were dissolved in 10 mL of xylene. The mixture was slowly added dropwise to the triphosgene using a constant-pressure titration funnel under ice bath conditions, completing the addition over 1 hour. The resulting system was a milky white suspension. After reacting in an ice bath for 0.5 hours, the mixture was heated to reflux at 100 °C until the system became clear, then cooled to room temperature. The mixture was filtered, and the solvent was removed under reduced pressure to obtain substituted biphenyl isocyanates. The product was directly added to the next reaction step.

[0169] Step 3: As Figure 3 As shown, 410 mg (2 mmol) of 4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide was added to a 50 mL round-bottom flask, followed by 20 mL of anhydrous tetrahydrofuran. After stirring to dissolve, 216 mg (4 mmol) of sodium methoxide was added, and the mixture was heated to reflux at 75 °C for 0.5 h, at which point the system was a pale yellow suspension. The substituted biphenyl isocyanate synthesized in step two was added, and the mixture was heated to reflux again. TLC monitoring was maintained until the sulfonamide starting material reacted completely. Heating was stopped, and the mixture was cooled to room temperature. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The aqueous phase was separated, the solvent was removed under reduced pressure, and the residue was recrystallized from the residue using a mixed solvent of n-hexane / ethyl acetate to give compound 1.

[0170] The structural characteristics of compound 1 (chemical name: N-{[3'-fluoro-(1,1'-biphenyl)-2-yl]carbamoyl}-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide) are as follows: 1 H-NMR (600MHz, DMSO-d6) δ: 8.08 (d, J=8.28Hz, 1H, ArH), 7.51 (dd, J=11.13, 7.9Hz, 1H, ArH), 7.36 (s, 1H, NH), 7.21 (t, J=7.38Hz, 2H), 7.15 (t, J=7.08H z,2H,ArH),7.10(d,J=7.38Hz,1HArH),7.00(s,1H,furan-H),6.94(t,J=7.38Hz,1H,ArH),6.59(s,1H,furan-H),4.94(s,1H,OH),1.36(s,6H,2CH3); 13C-NMR (151MHz, DMSO-d6) δ: 163.31, 161.69, 158.38, 155.04, 141.43, 137.98, 137.69, 135.94, 13 1.02,129.81,128.24,125.40,121.86,121.28,116.03,114.37,110.00,66.71,31.26;IR(KBr,cm -1 ): 3425, 2973, 1629, 1587, 1517, 1443, 1261; ESI-MS: 441.1[M+Na]+.

[0171] 2. Synthesis of Compound 15

[0172] The examples provide the synthetic steps for compound 15. The synthetic method for compound 15 includes: reacting o-bromoaniline with 2-naphthoic acid in a solvent system of acetonitrile and water at 120°C for 4 h to obtain 2-(naphthyl-2-yl)aniline; reacting 2-(naphthyl-2-yl)aniline with triphosgene in a solvent system of xylene and triethylamine to obtain a substituted biphenyl isocyanate; and reacting 4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide with the substituted naphthylphenyl isocyanate to obtain compound 15.

[0173] In some embodiments, the synthesis steps of compound 15 include:

[0174] Step 1: Same as step 1 in the synthesis of compound 1, except that 2-naphthoboric acid is used instead of 3-fluorophenylboronic acid.

[0175] Step 2: Similar to step 2 of the synthesis of compound 1, 2-(naphthyl-2-yl)aniline replaces 3'-fluoro-[1,1'-biphenyl]-2-amine.

[0176] Step 3: As Figure 4 As shown, 410 mg (2 mmol) of 4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide was added to a 50 mL round-bottom flask, followed by 20 mL of anhydrous tetrahydrofuran. After stirring to dissolve, 216 mg (4 mmol) of sodium methoxide was added, and the mixture was heated to reflux at 75 °C for 0.5 h, at which point the system was a pale yellow suspension. The substituted naphthylbenzene isocyanate synthesized in step two was added, and the mixture was heated to reflux again. TLC monitoring was maintained until the sulfonamide starting material reacted completely. Heating was stopped, and the mixture was cooled to room temperature. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The aqueous phase was separated, the solvent was removed under reduced pressure, and the residue was recrystallized from the residue using a mixed solvent of n-hexane / ethyl acetate to give compound 15.

[0177] The structural characteristics of compound 15 (chemical name: N-{[2-(naphth-2-yl)phenyl]carbamoyl}-4-(2-hydroxypropyl-2-yl)-furan-2-sulfonamide) are as follows: 1H-NMR (600MHz, DMSO-d6) δ: 8.32 (d, J=8.34Hz, 1H, ArH), 8.00 (dd, J=11.58, 3.36Hz, 2H, ArH), 7.61 (t, J =7.14Hz,1H,ArH),7.53(t,J=14.70Hz,1H,ArH),7.44(t,J=7.50Hz,1H,ArH),7.37(d,J=6.78Hz,1H,Ar H),7.34(d,J=8.46Hz,1H,ArH),7.29-7.28(m,2H,furan-H&NH),7.06(dd,J=8.82,1.32Hz,1H,ArH),6. 95(t,J=7.44Hz,1H,ArH),6.47(s,1H,ArH),6.18(s,1H,furan-H),4.89(s,1H,OH),1.30(s,6H,2CH3); 13 C-NMR (151MHz, DMSO-d6) δ: 158.11, 155.05, 139.11, 138.14, 136.13, 136.07, 133.84, 131.63, 130.67, 128.94, 12 8.77,128.54,128.08,127.89,127.12,126.70,126.36,125.48,121.04,118.75,110.30,66.92,31.46; IR(KBr,cm -1 ): 3421,2972,1630,1512,1442,1387,1263,1145,778,650; ESI-MS: 473.1[M+Na] + .

[0178] like Figure 5 Synthetic routes for other compounds in compounds 1–15 are also shown.

[0179] Test of the inhibitory activity of the compound on the NLRP3 inflammasome

[0180] Active mouse J774a.1 macrophages (Shangen Biotechnology, T25 type) and RAW264.7 macrophages (Pronosei Biotechnology, CL-0190) passaged for more than 3 generations were collected in a clean bench. When the cell density reached 80%, the cells were gently pipetted to completely suspend them in the culture medium. The cells were then transferred to 15 mL centrifuge tubes and centrifuged at 1300 rpm for 5 min. After centrifugation, the supernatant was discarded, and 3 mL of cell culture medium was added to resuspend the cells. 1 mL of the cell suspension was diluted to 10 mL, and the cells were counted and their concentration adjusted to 3 × 10⁻⁶. 5Cells / mL. After thorough resuscitation, seed 100 μL of each of the two cell lines into a 96-well plate. The experiment included a blank control group, a normal control group, and a drug control group, with three replicates per group.

[0181] The blank group was given 100 μL of serum-free DMEM high glucose medium.

[0182] The control group was given a final concentration of 1 μg / mL of lipopolysaccharide (LPS) solution, 0.1% DMSO solution, and 5 mM ATP solution.

[0183] The drug groups were respectively added with LPS solution at a final concentration of 1 μg / mL, compound 1-15 solution at a final concentration of 1 μM, and ATP solution at 5 mM.

[0184] After overnight growth to approximately 80% confluence, post-treatment was performed. The supernatant culture medium from each well was discarded, and LPS solution was added for 6 hours, followed by drug treatment for 1 hour, and finally ATP solution for 1 hour. After culturing in a CO2 cell incubator, the supernatant from each well was transferred to sterile centrifuge tubes in a clean bench. The tubes were centrifuged at 3000 rpm for 10 minutes. The IL-1β content in each group of cell culture medium was measured according to the instructions of the Mouse IL-1β ELISA Kit (Abcam, ab197742).

[0185] The results are shown in Table 1 below. In Table 1, the inhibition rate = (control group IL-1β - compound group IL-1β) / (control group IL-1β - blank group IL-1β) × 100%

[0186] Table 1. Inhibition rate of each compound on activated NLRP3 inflammasome (n=3)

[0187]

[0188] Compounds 12 and 15 exhibited strong inhibitory activity against NLRP3 inflammasomes in mouse J774a.1 macrophages and RAW264.7 macrophages activated by lipopolysaccharide (LPS) and ATP.

[0189] IC50 of compounds 12 and 15 50

[0190] The IC50 of compounds 12 and 15 on the NLRP3 inflammasome in both cell lines was further determined. 50 value.

[0191] Actively growing mouse J774a.1 macrophages and mouse RAW264.7 macrophages (passaged 3 or higher) were collected. When the cell density reached 80%, the cells were gently pipetted to completely suspend them in the culture medium. The cells were then transferred to 15 mL centrifuge tubes and centrifuged at 1300 rpm for 5 minutes. After centrifugation, the supernatant was discarded, and 3 mL of cell culture medium was added to resuspend the cells. 1 mL of the cell suspension was diluted to 10 mL, and the cells were counted and their concentration adjusted to 3 × 10⁻⁶ cells / mL. 5 Cells / mL. After thorough resuscitation, 100 μL of each of the two cell lines was seeded into 96-well plates. Five groups were set up: a blank control group, a normal control group, and groups for compound 12 and compound 15, with three replicates per group. Each well contained 1 μg / mL LPS solution, 1000 nM, 400 nM, 160 nM, 64 nM, 25 nM, 10 nM, and 0 nM solutions of target compound 12 and compound 15, and 5 mM ATP solution. After overnight growth to approximately 80% confluence, post-treatment was performed: the supernatant culture medium was discarded, LPS solution was added for 6 hours, followed by drug treatment for 1 hour, and finally ATP solution was added for 1 hour. After cell culture in a CO2 incubator, the supernatant from each well was transferred to sterile centrifuge tubes in a clean bench. The tubes were centrifuged at 3000 rpm for 10 minutes. Following the instructions of the Mouse IL-1β ELISA Kit, the IL-1β content in the cell culture medium was measured, and the inhibition rates of the three compounds at different concentrations were calculated. Finally, the IC50 was plotted and the IC50 was calculated. 50 Value. The results showed that compound 15 had an IC50 effect on the inflammasomes of mouse J774a.1 macrophages and RAW264.7 macrophages. 50 The values ​​were 100.7 nM and 110.4 nM. Compound 12 showed an IC50 value against the inflammasomes of mouse J774a.1 macrophages and RAW264.7 macrophages. 50 The values ​​were 125.1 nM and 140.7 nM. Furthermore, testing revealed that the sulfonylurea compounds provided in this application have advantages in pharmacokinetics, facilitating their absorption in vivo.

[0192] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the compound is: 。 2. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the compound is: 。 3. Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of NLRP3 inflammasome-related diseases.

Images