Heterocyclic compound and pharmaceutical composition thereof

Abstract

Provided are a heterocyclic compound and a pharmaceutical composition thereof. The compound has a structure as shown in formula I, is an efficient NLRP3 inhibitor, and can be used for treating various diseases mediated by NLRP3.

Description

Heterocyclic compound and pharmaceutical composition thereof Technical Field

[0001] The present invention provides a heterocyclic compound and its pharmaceutical composition and application. The heterocyclic compound is an NLRP3 inhibitor and can be used to regulate various diseases mediated by NLRP3. Background Art

[0002] Inflammation is a common physiological and pathological activity in the body, and inflammasomes play a crucial regulatory role in this response. Currently, five major inflammasomes have been discovered: the NLRP1 inflammasome, the NLRP3 inflammasome, the NLRC4 inflammasome, the IPAF inflammasome, and the AIM2 inflammasome. Of these, the NLRP3 inflammasome has been the most extensively studied and thoroughly investigated.

[0003] NLRP3, a protein of the NLR (NOD-like receptor) family, is a core member of the inflammasome. It is composed of multiple proteins, including NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), and pro-caspase 1. NLRP3 is the inflammasome sensor, interacting with other proteins through its NACHT and LRR domains to form the activated inflammasome. ASC is an adaptor protein that interacts with NLRP3 through its CARD (caspase activation and recruitment domain) structure to promote inflammasome formation. Pro-caspase 1 is a proenzyme that, upon inflammasome formation, is activated into mature caspase 1, further regulating intracellular inflammatory responses.

[0004] The activation of NLRP3 involves multiple signaling pathways. Generally speaking, NLRP3 activation requires two signals: the first, through induction of NLRP3 transcription and protein expression, such as through activation of the Tol-like receptor (TLR) signaling pathway; and the second, typically from intracellular damage signals or other stimuli, such as intracellular oxidative stress, potassium ion efflux, or mitochondrial dysfunction. When these two signals are present simultaneously, NLRP3 is activated and forms the inflammasome, which in turn promotes the onset of an inflammatory response.

[0005] NLRP3 plays an important regulatory role in the inflammatory process. When the body is damaged, infected, or otherwise stimulated, NLRP3 is activated and forms the inflammasome. The NLRP3 inflammasome primarily participates in the development and progression of disease by promoting the massive release of downstream inflammatory cytokines, inducing acute and chronic inflammatory responses. Its downstream cytokines can participate in the development and progression of immune or parasitic diseases by regulating the function of immune cells. For example, IL-1β can promote the aggregation of Th2 cells and the differentiation of Th17 cells, IL-18 can simultaneously enhance the immune response involving both Th1 and Th2 cells, and IL-33 can mediate the response of Th2 cells.

[0006] NLRP3 is a core member of the inflammasome. Its activation and inflammasome formation play a crucial regulatory role in the inflammatory response. NLRP3 activation is closely associated with the development and progression of numerous diseases, including inflammatory diseases, autoimmune diseases, and tumors. Excessive NLRP3 activation is implicated in the development and progression of numerous inflammatory conditions, including gout, obesity, diabetes, and acute coronary syndrome (ACS). Therefore, as a core component of the inflammatory response, the NLRP3 inflammasome may offer new therapeutic approaches for various inflammatory diseases. Summary of the Invention

[0007] The present application provides a novel heterocyclic compound, which is a highly effective NLRP3 inhibitor and can be used to treat various NLRP3-mediated diseases.

[0008] This application relates to a compound as shown in formula I

[0009] or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof.

[0010] In some particularly preferred embodiments, the compound of formula I of the present invention is selected from:

[0011] Another aspect of the present invention is to provide the use of a compound as shown in Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled form, isomer, or prodrug thereof, in the preparation of a medicament for treating NLRP3-mediated diseases. DETAILED DESCRIPTION

[0012] The present invention will be further described in detail below through the following examples, through which the features and advantages of the present invention will become more clearly understood.

[0013] The word “exemplary” is used exclusively herein to mean “serving as an example, example, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0014] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0015] definition

[0016] The chemical naming schemes and structure diagrams used herein are modified versions of the IUPAC nomenclature system, which use ACD / named software program version 9.07 and / or ChemDraw Professional version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, the substituent is typically named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Unless described below, all bonds are identified in the chemical structure diagrams herein, but it is assumed that all bonds on some carbon atoms are bonded to enough hydrogen atoms to complete the valence.

[0017] Unless the context requires otherwise, throughout the specification and claims, the word "comprise" and variations thereof (e.g., "comprises" and "comprising") are to be construed in an open, inclusive sense, that is, to mean "including, but not limited to."

[0018] In this specification, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include its fraction (such as one tenth and one hundredth of an integer), unless otherwise stated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the range, value or structure shown, unless otherwise stated. It should be understood that the terms "one / a kind (a)" and "an" as used herein refer to "one / a kind or more / a variety" of the enumerated components. The use of alternatives (e.g., "or") should be understood to mean one or both of the alternatives or any combination thereof.

[0019] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0021] "Cyano" refers to a -CN group.

[0022] "Hydroxy" or "hydroxyl" refers to an -OH group.

[0023] "Oxo" refers to a =0 substituent.

[0024] "Mercapto" refers to a -SH substituent.

[0025] "Thio" refers to a =S substituent.

[0026] "Alkyl" refers to a saturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms having 1 to 12 carbon atoms (C1-C 12 The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical. The alkyl group is optionally substituted with a carbon atom or a substituted alkyl radical.

[0027] "Alkenyl" refers to an unsaturated straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having 2 to 12 carbon atoms (C2-C 12 The carbon numbers mentioned relate to the main chain carbons and the side chain carbons, but do not include the carbon atoms belonging to any substituent. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted.

[0028] The term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon group having 2 to 12 carbon atoms (C2-C 12The term "alkynyl" refers to a group having at least one carbon atom (C-C alkynyl), 2 to 9 carbon atoms (C-C alkynyl), or 2 to 6 carbon atoms (C-C alkynyl), or any value within these ranges, and having at least one carbon-carbon triple bond. Examples of alkynyl groups can be selected from ethynyl, propargyl, but-1-ynyl, but-2-ynyl, and the like. The number of carbons mentioned relates to the main chain carbons and the side chain carbons, but does not include the carbon atoms belonging to any substituent. Unless otherwise specifically stated in this specification, alkynyl groups are optionally substituted.

[0029] "Alkoxy" refers to a radical of the formula -OR, wherein R is an alkyl radical as defined above, which may contain from 1 to 12 carbon atoms (C1-C 12 Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0030] "Carbocyclic" or "carbocycle" refers to a ring system in which every one of the ring atoms is carbon.

[0031] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic group consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C 15 Cycloalkyl), three to ten ring carbon atoms (C3-C 10 The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.The alkyl radicals of the present invention are substituted or unsubstituted alkyl radicals.

[0032] "Alkylcycloalkyl" refers to a group of the formula -R a R b A group in which R a is a cyclic hydrocarbon group and R b is alkyl as defined above. Unless stated otherwise specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0033] "Fused" refers to any ring structure described herein that is fused to another ring structure.

[0034] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[0035] "Hydrogen" refers to various isotopes of hydrogen including protium, deuterium and tritium; in particular, when hydrogen appears alone, it can be any one of "protium", "deuterium" and "tritium"; when hydrogen appears with "deuterium" and / or "tritium", it sometimes refers to "protium".

[0036] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0037] "Halocycloalkyl" refers to a cycloalkyl as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0038] "Haloalkylcycloalkyl" refers to a group of the formula -R a R b The group, where R a is a cyclic hydrocarbon group and R b is a haloalkyl group as defined above. Unless stated otherwise specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0039] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. The hydroxyalkyl group is attached to the backbone through an alkyl carbon atom. Unless otherwise specifically stated in the specification, a hydroxyalkyl group is optionally substituted.

[0040] "Heterocyclyl" refers to a 3-18 membered, e.g., 3-10 or 3-8 membered, non-aromatic ring group having 1 to 10 ring carbon atoms (e.g., 2 to 10) and 1 to 6 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in this specification, a heterocyclyl is a partially or fully saturated, monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic, and / or bridged ring systems. The nitrogen, carbon, and sulfur atoms in the heterocyclyl are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolazine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, heterocyclic groups are optionally substituted.

[0041] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl) in which at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxy, halogen, nitro, oxo, thiol, thio, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxyalkyl substituents, each of which may be optionally substituted with one or more of the above substituents.

[0042] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound as described herein sufficient to achieve the intended application, including but not limited to the treatment of diseases as defined below. A therapeutically effective amount can vary depending on the intended therapeutic application (in vivo), or the individual and disease condition being treated, such as the weight and age of the individual, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that induce a specific response in target cells, such as a decrease in platelet adhesion and / or cell migration. The specific dosage will vary depending on the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system it carries.

[0043] As used herein, "treatment" or "treat" refers to a method for obtaining a beneficial or desired result (including but not limited to a therapeutic effect and / or a preventive effect) with respect to a disease, disorder, or medical condition. A therapeutic benefit means a cure or improvement of the underlying disorder being treated. In addition, a therapeutic benefit is achieved by curing or improving one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the individual, even though the individual may still be suffering from the underlying disorder. A preventive effect includes delaying or eliminating the appearance of the disease or condition, delaying or eliminating the onset of symptoms of the disease or condition, slowing, preventing, or reversing the progression of the disease or condition, or any combination thereof. In certain embodiments, for a preventive benefit, a composition is administered to an individual at risk for a particular disease, or to an individual reporting one or more physiological symptoms of a disease, even though the disease may not yet have been diagnosed.

[0044] As used herein, the terms "co-administration," "combined administration," and grammatical equivalents thereof encompass the administration of two or more pharmaceutical agents to animals, including humans, such that both agents and / or their metabolites are present in the individual at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0045] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0046] "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness of the free base, are biologically tolerable, or are otherwise biologically suitable for administration to an individual. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptylsulfonic acid, Acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0047] "Pharmaceutically acceptable base addition salts" refers to salts that retain the biological effectiveness of the free base, are biologically tolerable, or are otherwise biologically suitable for administration to an individual. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic reactions. Pharmaceutically acceptable base addition salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-ethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0048] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary ammonium alkyl halide salts (eg, methyl bromide).

[0049] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of a protein (e.g., NLRP3 inflammasome or NEK7) or by inhibiting the association of NLRP3 inflammasome with NEK7. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological action of the target protein. Although preferred antagonists herein particularly interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also particularly included in this definition. The preferred biological activity inhibited by the antagonist is associated with the development, growth, or spread of a tumor.

[0050] As used herein, the term "agonist" refers to a compound that has the ability to induce or enhance the biological function of a target protein, whether or not by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological action of the target polypeptide. Although preferred agonists herein particularly interact with (e.g., bind to) the target, compounds that induce or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also particularly included in this definition.

[0051] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted into and within cells to elicit intracellular responses.

[0052] The term "selective inhibition" or "selectively inhibits" refers to the ability of a biologically active agent, through direct or indirect interaction with the target, such that the agent preferentially reduces target signaling activity compared to off-target signaling activity.

[0053] "Subject" refers to an animal, such as a mammal, such as a human. The methods described herein can be used for human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0054] "Mammal" includes humans and livestock animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals, etc.

[0055] "Prodrug" is intended to mean a compound (e.g., a compound of structure (I)) that can be converted into a bioactive compound as described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some aspects, the prodrug is inert when applied to a subject, but is converted into an active compound in vivo, such as by hydrolysis. Prodrug compounds often provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms. The term "prodrug" also means any covalently bonded carrier that releases the active compound in vivo when such prodrugs are applied to mammalian individuals. Prodrugs of active compounds as described herein are typically prepared by modifying the functional groups present in the active compound in such a way that the modification is cleaved into the parent active compound in conventional operations or in vivo. Prodrugs include compounds wherein a hydroxyl, amino, or thiol group is connected to any group, and when the prodrug of the active compound is applied to a mammalian individual, it is cleaved to form free hydroxyl, free amino, or free thiol groups. Examples of prodrugs include, but are not limited to, acetic acid, formic acid, and benzoic acid derivatives of a hydroxy functional group or acetamide, formamide, and benzamide derivatives of an amine functional group in the active compound, and the like.

[0056] The term "in vivo" refers to events that occur within the body of an individual.

[0057] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of structure (I).

[0058] Certain embodiments are also intended to include in vivo metabolites of the disclosed compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, embodiments include compounds produced by methods comprising administering a compound of the disclosure to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the disclosure to an animal (e.g., rat, mouse, guinea pig, monkey) or to a human, allowing sufficient time for metabolism, and isolating its conversion products from urine, blood, or other biological samples.

[0059] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0060] Typically, crystallization produces solvates of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the disclosure and one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the disclosure may be true solvates, while in other cases, the compounds of the disclosure retain only adventitious water or are a mixture of water plus some adventitious solvent.

[0061] "Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstances occur and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups without substituents.

[0062] "Pharmaceutical composition" refers to a preparation of a compound of the present disclosure and a medium generally accepted in the art for delivering the compound of the present disclosure to a mammal (e.g., a human). Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0063] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

[0064] "Stereoisomers" refer to compounds composed of the same atoms bonded to the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0065] The compounds of the present disclosure (i.e., compounds of structure (I)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and thus may produce stereoisomers, such as enantiomers, diastereomers and other stereoisomeric forms, which are defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of an amino acid. Embodiments therefore include all such possible isomers, as well as racemic and optically pure forms thereof. Optional active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis of suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0066] Embodiments of the present disclosure include all forms and conformationally restricted states of rotational isomers of the compounds of the present invention. Also included are atropisomers, which are stereoisomers arising from hindered rotation about a single bond, where energy differences due to steric strain or other contributing factors create a rotational barrier high enough to allow separation of the individual conformers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers, or may be purified or enriched to allow the presence of a single atropisomer.

[0067] In some embodiments, the compound of structure (I) is a mixture of enantiomers or diastereomers. In other embodiments, the compound of structure (I) is substantially a single enantiomer or diastereomer.

[0068] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The embodiments therefore include tautomers of the disclosed compounds.

[0069] "NLRP3-mediated disorders" refers to diseases or pathological processes associated with the activation and dysfunction of NLRP3, including autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions, etc.; in particular, including type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis and Mueller-Weiss syndrome, etc. NLRP3-mediated disorders include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease, and cancer.

[0070] Compound

[0071] The present application provides a compound as shown in Formula I

[0072] or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,

[0073] in,

[0074] X1 is selected from -N- or -CR6-;

[0075] X2 is selected from -O-, -S-, or -NR7-;

[0076] R1 is selected from optionally substituted with 1 or 2 R 11 C 2-8 Alkynyl, optionally substituted with 1 or 2 R 11 C 2-8 Alkenyl, optionally substituted with 1 or 2 R 11 C 2-8 Haloalkynyl or optionally substituted with 1 or 2 R 11 C 2-8Halogenated alkenyl; wherein R 11 Each independently selected from hydroxy or NR'R", R' and R" are each independently selected from hydrogen or C 1-6 alkyl;

[0077] R2 is selected from hydrogen, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy or C 1-8 Haloalkoxy; R3 is selected from hydrogen, halogen, or C 1-8 Alkyl; wherein at least one of R2 and R3 is not hydrogen;

[0078] R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy or C 1-8 haloalkoxy;

[0079] R6 is selected from hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy or C 1-8 haloalkoxy;

[0080] R7 is selected from hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl or C 1-8 alkoxy;

[0081] L is selected from -NR8-, -O-, -S- or -CR9R 10 -;

[0082] R8 is selected from hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy or C 1-8 haloalkoxy;

[0083] R9 and R 10 are independently selected from hydrogen, hydroxy, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy or C 1-8 Haloalkoxy; or, R9 and R 10 Together with the C atom to which they are attached, they form a C optionally substituted with R0 3-8 Cycloalkyl, wherein R0 is selected from halogen, hydroxyl, C 1-3 Alkyl or C 1-3 alkoxy;

[0084] W is optionally substituted with 1 or 2 RW 4- to 10-membered heterocyclyl containing up to 3 heteroatoms independently selected from N and O, and the maximum number of O heteroatoms is 1, wherein R W Each independently selected from hydrogen, oxo, hydroxy, hydroxyl C 1-8 Alkyl, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl or NR w1 R w2 ; Among them, R w1 and R w2 are each independently selected from hydrogen and C 1-6 alkyl.

[0085] In one embodiment, R1 is C 2-8 Alkynyl or C 2-8 Alkenyl.

[0086] In one embodiment, R1 is ethynyl, vinyl, or propynyl (including, for example, prop-1-yn-1-yl, prop-1-yn-3-yl).

[0087] In one embodiment, R4 and R5 are hydrogen.

[0088] In one embodiment, one of R2 and R3 is C 1-3 The alkyl group is for example methyl, and the other is hydrogen.

[0089] In one embodiment, X1 is CH.

[0090] In one embodiment, X2 is -O-, -S-, -NH- or -NC 1-3 alkyl-.

[0091] In one embodiment, X2 is -O-.

[0092] In one embodiment, L is -NH-, -O-, -S-, or -CH2-.

[0093] In one embodiment, L is -NH-.

[0094] In one embodiment, W is optionally substituted with 1 or 2 R W 4- to 8-membered heterocyclyl containing up to 3 heteroatoms independently selected from N and O, and the maximum number of O heteroatoms is 1, wherein R W Each independently selected from hydrogen, hydroxy, oxo, hydroxy C 1-6 Alkyl, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl or NR w1 R w2 ; Among them, R w1 and R w2 are each independently selected from hydrogen and C 1-6 The 4- to 8-membered heterocyclic group may be a monocyclic heterocyclic group or a condensed heterocyclic group, for example, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, and the like.

[0095] In one embodiment, W is optionally substituted with 1 or 2 R W A 6-membered heterocyclic group containing a single nitrogen heteroatom, such as a piperidinyl group, wherein R W Each independently selected from C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0096] In one embodiment, W is one of the following structural formulas

[0097] Among them, R W Each independently selected from C 1-3 Alkyl, hydroxyl C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0098] In particular, W is one of the following structural formulas

[0099] In one embodiment, the compound is selected from the group consisting of:

[0100] Pharmaceutical composition

[0101] The present disclosure also relates to pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In more embodiments, the pharmaceutical compositions comprise a compound disclosed herein and another therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0102] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0103] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a depot formulation or a sustained release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in the form of a quick-release formulation, an extended-release formulation, or an intermediate-release formulation. In other embodiments, the compounds described herein are administered topically.

[0104] In a method of treatment according to an embodiment of the present invention, an effective amount of at least one compound of structure (I) is administered to an individual suffering from or diagnosed as suffering from such a disease, disorder or medical condition. The effective amount or dosage can be determined by methods such as modeling, dose escalation studies or clinical trials, for example, the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder or condition, the individual's previous or ongoing therapy, the individual's health status and response to drugs, and the judgment of the treating physician.

[0105] The compounds of the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages of 10 to 5000 mg / day, 100 to 5000 mg / day, 1000 to 4000 mg / day, and 1000 to 3000 mg / day are examples of dosages used in some embodiments. The exact dosage depends on the route of administration, the compound form administered, the subject to be treated, the weight of the subject to be treated, the preference and experience of the attending physician.

[0106] In some embodiments, the compounds of the present disclosure are administered in a single dose. Typically, such administration will be by injection, such as intravenous injection, to allow for rapid introduction of the agent. However, other routes may be used as appropriate. A single dose of a compound of the present disclosure may also be used to treat acute conditions.

[0107] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the disclosed compounds into pharmaceutically acceptable formulations. Appropriate formulations depend on the chosen route of administration.

[0108] Provided herein are pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0109] Provided herein is a pharmaceutical composition comprising one or more compounds selected from the compound of structure (I) and a pharmaceutically acceptable diluent, excipient, and carrier. In certain embodiments, the compound is administered as a pharmaceutical composition, wherein one or more compounds selected from the compound of structure (I) are mixed with other active ingredients, such as in a combination therapy. All combinations of the active substances described in the combination therapy section below and all combinations of the active substances described in the disclosure are contemplated herein. In a specific embodiment, the pharmaceutical composition includes one or more compounds of structure (I).

[0110] As used herein, pharmaceutical composition refers to a mixture of one or more compounds selected from the compound of structure (I) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. In certain embodiments, pharmaceutical composition promotes the administration of compound to organisms. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compound of structure (I) provided herein is applied to a mammal suffering from a disease to be treated, a disease or a medical condition in a pharmaceutical composition. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies according to the severity of the disease, the age and relative health status of the individual, the efficacy of the compound used and other factors. Compounds as described herein are used as components of a mixture alone or in combination with one or more therapeutic agents.

[0111] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0112] In certain embodiments, pharmaceutical preparations 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 processing the granular mixture after adding suitable adjuvants (if desired) to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other substances, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. By way of example only, disintegrants include cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0113] application

[0114] The present disclosure also relates to methods of treating NLRP3-mediated disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition of the present disclosure.

[0115] As demonstrated in the disclosure, the compounds disclosed herein have NEK7 enzymatic inhibitory activity and can therefore be used to treat or prevent NLRP3-mediated disorders, as well as to prepare drugs for treating or preventing NLRP3-mediated disorders.

[0116] The host or patient can be of any mammalian species, such as primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are interesting for experimental research and provide models for treating human diseases.

[0117] The NLRP3-mediated disorder can be selected from the group consisting of autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory diseases, and ischemic conditions.

[0118] The NLRP3-mediated disorder can be selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver disease, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis and Mueller-Weiss syndrome.

[0119] The NLRP3-mediated disorder can be selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndromes, cryptopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease, and cancer.

[0120] The examples and formulations provided below further illustrate and exemplify the compounds of the present disclosure and methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and formulations. In the following examples, and throughout the specification and claims, unless otherwise indicated, molecules with a single stereocenter exist as a racemic mixture. Unless otherwise indicated, those molecules with two or more stereocenters exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0121] Some of the compounds of the general formula I of the present invention can be prepared by those skilled in the art of organic synthesis using the following process using standard methods in the art:

[0122] The compound of formula 1 and the compound of formula 2 undergo coupling reaction in the presence of pinacol diboronate under palladium catalysis to generate the compound of formula 3, and the compound of formula 3 is then deprotected to generate the compound of formula I of the present application.

[0123] The present invention is further illustrated by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. One skilled in the art will readily recognize that various noncritical parameters can be varied or modified to achieve substantially the same results. The following example compounds were found to be NLRP3 inhibitors according to one or more of the assays described herein.

[0124] Example 1: (R)-5-ethynyl-3-methyl-2-(2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-5-yl)phenol

[0125] Synthesis route:

[0126] Step A: 4-Bromo-2-methoxy-6-methylphenol

[0127] To a 250 mL round-bottom flask, add 10.0 g (72.5 mmol, 1.0 eq) of 2-methoxy-6-methylphenol, 12.9 g (72.5 mmol, 1.0 eq) of NBS, and 50 mL of acetic acid. The mixture was allowed to react at room temperature for 4 hours. LCMS confirmed complete conversion of the starting material. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to afford 4-bromo-2-methoxy-6-methylphenol (12.0 g, yield = 77%) as a yellow oil.

[0128] LC-MS: (MH) - ; m / z = 216.9.

[0129] Step B: 2-Methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenol

[0130] To a 50 mL three-necked flask, 6.00 g (27.6 mmol, 1.0 eq) of 4-bromo-2-methoxy-6-methylphenol, 27.2 g (276 mmol, 10.0 eq) of trimethylethynylsilane, 2.02 g (2.76 mmol, 0.1 eq) of Pd(dppf)Cl2, 1.05 g (5.52 mmol, 0.2 eq) of CuI, 19.2 mL (138 mmol, 5.0 eq) of triethylamine, and 40 mL of tetrahydrofuran were added. The reaction mixture was stirred at 80°C under nitrogen for 12 hours. After completion of the reaction, LCMS was performed. The reaction mixture was filtered through celite while still hot and the celite layer was washed with ethyl acetate (50 mL). The filtrate was extracted with water (25 mL), and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (25 mL). The organic phases were separated, combined, and concentrated under reduced pressure to obtain the crude product as a brown oil. The crude product was purified by reverse flash (5% to 80% ACN in H2O) to give 2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenol (1.20 g, yield = 19%) as a yellow solid.

[0131] LC-MS: (MH) - ; m / z = 233.2.

[0132] Step C: 2-Methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl trifluoromethanesulfonate

[0133] A 50 mL round-bottom flask was charged with 1.20 g (5.12 mmol, 1.0 eq) of 2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenol, 0.98 g (7.68 mmol, 1.5 eq) of pyridine, and 15 mL of dichloromethane. Then, 1.73 g (6.14 mmol, 1.2 eq) of trifluoromethanesulfonic anhydride was slowly added dropwise at 0°C. After the addition was complete, the reaction mixture was returned to room temperature and allowed to incubate for 2 hours, monitored by LCMS. After completion, 2 mL of water was added to quench the reaction. The organic phase was separated, washed with 2 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl trifluoromethanesulfonate (1.30 g, yield = 69%) as a yellow solid.

[0134] LC-MS: (MH) - ; m / z = 365.1.

[0135] Step D: (R)-5-(2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl)-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0136] In a 25 mL three-necked flask, 476 mg (1.53 mmol, 1.4 eq) (R)-5-bromo-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine, 79.9 mg (0.109 mmol, 0.1 eq) Pd(dppf)Cl2, 1109 mg (4.37 mmol, 4.0 eq) diboronic acid pinacol ester, 536 mg (5.46 mmol, 5.0 eq) potassium acetate and 10 mL of toluene were added. The reaction was carried out at 110 ° C for 1 hour under nitrogen. LCMS detection showed that an intermediate product was generated. To the reaction system were added 400 mg (1.09 mmol, 1.0 eq) of 2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl trifluoromethanesulfonate, 754 mg (5.46 mmol, 5.0 eq) of KCO, and 1 mL of water. The reaction was continued under nitrogen for 2 hours. LCMS confirmed that the starting material conversion was complete. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (50 mL). The combined organic phases were concentrated under reduced pressure. Reverse flash purification (5%-80% ACN in H2O) afforded 5-(2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl)-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine (125 mg, 0.279 mmol, 26%, 92% purity) as a crude yellow solid. 15 mg of the crude product was purified by preparative chromatography (mobile phase A: 10 M ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 15%-50% B, 20 min; flow rate: 19 mL / min) and lyophilized to give a white solid (7.00 mg, yield = 13%).

[0137] LC-MS: (M+H) + ; m / z = 449.4;

[0138] 1 H-NMR(400MHz,DMSO-d6)δ8.43(d,J=7.9Hz,1H),7.70(d,J=8.0Hz,1H),7.02(s,1H) ,6.96(d,J=1.4Hz,1H),6.82(d,J=8.0Hz,1H),3.76(s,1H),3.65(s,3H),2.91(d,J= 10.3Hz,1H),2.60(d,J=10.8Hz,1H),2.19(s,3H),1.96(s,3H),1.91(d,J=11.3Hz,2 H),1.77-1.65(m,1H),1.53(q,J=12.4,12.0Hz,1H),1.39-1.21(m,2H),0.25(s,9H).

[0139] Step E: (R)-5-ethynyl-3-methyl-2-(2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-5-yl)phenol

[0140] 55.1 mg (123 μmol, 1.0 eq) of (R)-5-(2-methoxy-6-methyl-4-((trimethylsilyl)ethynyl)phenyl)-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine was dissolved in 3 mL of anhydrous dichloromethane. After cooling to -70°C, 308 mg (1.23 mmol, 10.0 eq) of boron tribromide was added to the reaction system. After the addition was complete, the temperature was naturally raised to room temperature and the reaction was continued with stirring for 3 hours. LC-MS results confirmed the complete reaction of the starting material. After cooling to 0°C, 1 mL of 25% ammonia was added to quench the reaction and the mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative chromatography (mobile phase A: 10 M ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 15%-50% B, 20 min; flow rate: 19 mL / min) and lyophilized to give a white solid (5.40 mg, yield = 12%).

[0141] LC-MS: (M+H) + ; m / z = 363.2;

[0142] 1 H-NMR(400MHz,CDCl3)δ10.64(br s,1H),7.56(d,J=8.2Hz,1H),7.13(d,J=8.3Hz,1H),7.02(s,1H),6.97(s,1H),4.22(s,1H),3.05(s,1H) ,2.84-2.63(m,2H),2.56-2.47(m,1H),2.43(s,3H),2.33(s,3H),2.25-2.16(m,1H),2.12-1.68(m,5H).

[0143] Intermediate (INT-A): (R)-5-bromo-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0144] Synthesis route:

[0145] Step A: 5-Bromooxazolo[4,5-b]pyridine-2-thiol

[0146] 5.00 g (26.4 mmol, 1.0 eq) of 2-amino-6-bromopyridin-3-ol, 4.66 g (29.0 mmol, 1.1 eq) of potassium ethylxanthate, and 50 mL of pyridine were purged with nitrogen three times and stirred at 100°C overnight. LCMS indicated complete reaction. Add 50 mL of water to the reaction solution, adjust the pH to 4-5 with 10% aqueous hydrochloric acid, and extract three times with ethyl acetate (50 mL). The organic phases were combined and washed three times with saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude yellow solid (4.5 g, yield = 73%).

[0147] LC-MS: (MH) + ; m / z = 230.8.

[0148] Step B: 5-Bromo-2-(methylthio)oxazolo[4,5-b]pyridine

[0149] 4.50g (19.4mmol, 1.0eq) 5-bromooxazolo[4,5-b]pyridine-2-thiol, 5.92g (42.8mmol, 2.2eq) potassium carbonate, 50mL tetrahydrofuran, added to a 100mL reaction bottle, cooled to 0°C, 4.15g (29.2mmol, 1.5eq) iodomethane was slowly added dropwise to the reaction solution, naturally warmed to room temperature, and stirred at room temperature for 2 hours. LCMS showed that the raw materials were completely reacted. The reaction solution was added with 50mL of water and extracted three times with ethyl acetate (50mL). The organic phases were combined and washed three times with saturated brine (20mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid product (4.50g, yield = 94%).

[0150] LC-MS: (M+H) + ; m / z = 244.8.

[0151] Step C: (R)-5-Bromo-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine

[0152] 800 mg (3.26 mmol, 1.0 eq) of 5-bromo-2-(methylthio)oxazolo[4,5-b]pyridine, 559 mg (4.86 mmol, 1.5 eq) of (R)-1-methylpiperidin-3-amine, 990 mg (9.79 mmol, 3.0 eq) of triethylamine, and 10 mL of isopropanol were added to a 50 mL sealed tube and stirred at 100°C overnight. LCMS showed complete reaction of the starting materials. The reaction solution was concentrated to dryness, slurried with ethyl acetate, filtered, and dried to afford the pure product as a yellow solid (800 mg, yield = 78%).

[0153] LC-MS: (M+H) + ; m / z = 311.1.

[0154] The following examples were prepared with reference to the experimental route and method in Example 1:

[0155] Biological activity experiment: IL-1β secretion test of THP-1 cells

[0156] Experimental Procedure: THP-1 cells were cultured in 1640 medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO2. At the start of the experiment, the cell suspension was gently shaken and transferred to a centrifuge tube for counting. The required volume was removed and added to fresh culture medium. 40 μL of polylysine diluted in sterile water was added to a 96-well plate and incubated at 37°C and 5% CO2 for 30 minutes. The plate was then washed twice with 100 μL of the solution. 50,000 cells were seeded per well of the THP-1 cell suspension (100 μL) at 50 ng / mL PMA (phorbol 12-myristate 13-acetate) in the 96-well plate prepared in step 1 and incubated at 37°C and 5% CO2 for 24 hours. The medium in the 96-well plate was removed and the cells were washed once with 37°C preheated PBS. Add 85 μL of serum-free medium containing 25 nG / mL LPS and incubate the cells at 37°C and 5% CO2 for 3 hours. Add 5 μL of compounds of different concentrations (DMSO concentration is uniformly 1‰) and continue incubating the cells at 37°C and 5% CO2 for 30 minutes. Add 5 μL of diluted Nigericin to a working concentration of 5 μG / mL and continue incubating the cells at 37°C and 5% CO2 for 1 hour. Collect the cell supernatant, store it at -80, and use an ELISA kit to detect the secretion of IL-1β. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound action curve, and calculate the IC50.

[0157] The specific test results are shown in Table 1 below:

[0158] Table 1: Compounds tested for IL-1β secretion in THP-1 cells

[0159] MCC950 is a publicly available, potent, and selective NLRP3 inhibitor with the following structure:

[0160] As can be seen from the data in the table, the compounds in the examples of the present invention have significantly better inhibitory activity against induced IL-1β release in THP-1 cells than the known NLRP3 inhibitor MCC950. This patent invention discloses a novel heterocyclic compound that is an NLRP3 inhibitor and can be used to regulate the treatment of NLRP3-mediated diseases.

[0161] Pharmacokinetic studies

[0162] Male Balb / c mice were divided into groups of 3 and Example 1 was dissolved in a solvent (5% DMSO / 10% Solutol / 85% (20% Captisol in water). The compound of Example 1 was injected intravenously (2 mg / kg) and administered orally (10 mg / kg) by single oral gavage. The animals were fasted overnight before the experiment and fasted from 10 hours before dosing to 4 hours after dosing. Blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. After the animals were anesthetized with isoflurane, 0.3 mL of whole blood was collected and placed in a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. The plasma was transferred to a centrifuge tube and stored at -80°C until sample analysis. Plasma samples were extracted using protein precipitation, and the extracts were analyzed by LC / MS / MS. The pharmacokinetic results are shown in Tables 2 and 3 below:

[0163] Table 2: Pharmacokinetic parameters of the compounds in mouse plasma after intravenous administration

[0164] Table 3: Pharmacokinetic parameters of the compounds in mouse plasma after oral administration

[0165] The data in the table show that the compound of Example 1 of the present invention has good absorption and bioavailability after oral administration, with a bioavailability of 84.5%.

[0166] Blood-brain distribution experiment

[0167] Male Balb / c mice were divided into groups of 3 mice each and were given a single intravenous injection of the example compound (2 mg / kg). The animals were fasted overnight before the experiment and fasted from 10 hours before administration to 4 hours after administration. Each mouse was killed 0.5 hours after administration and blood and brain tissue were collected. The samples were centrifuged at 4°C and 4000rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until sample analysis. The sample in the plasma was extracted using a protein precipitation method, and the extract was analyzed by LC / MS / MS. The results of the blood-brain distribution experiment are shown in Table 4. The data show that the compound of Example 1 of the present invention can pass through the blood-brain barrier, while the compound of Example 11 is less likely to pass through the blood-brain barrier.

[0168] Table 4 Blood-brain ratio of drug concentrations in mice 0.5 h after IV administration

[0169] The present application has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only as an illustrative example. On this basis, various replacements and improvements can be made to the present application, all of which fall within the scope of protection of the present application.

Claims

1. A compound represented by Formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotopically labeled compound, isomer or prodrug thereof, Among them, X1 is selected from -N- or -CR6-; X2 is selected from -O-, -S-, or -NR7-; R1 is selected from C-alkynyl optionally substituted with 1 or 2 Rs 11 - 2-8 -alkenyl optionally substituted with 1 or 2 Rs 11 - 2-8 -haloalkynyl or C-alkenyl optionally substituted with 1 or 2 Rs 11 - 2-8 -haloalkenyl; wherein each R 11 - 2-8 is independently selected from hydroxy or NR’R”, and R’ and R” are each independently selected from hydrogen or C 11 -alkyl; 1-6 ​ R2 is selected from hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy; R3 is selected from hydrogen, halogen, or C 1-8 alkyl; wherein at least one of R2 and R3 is not hydrogen; R4 and R5 are each independently selected from hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy; R6 is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy; R7 is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy; L is selected from -NR8-, -O-, -S- or -CR9R 10 -; R8 is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy; R9 and R 10 are each independently selected from hydrogen, hydroxy, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy; or, R9 and R 10 together with the C atom to which they are attached form a C 3-8 cycloalkyl optionally substituted with R0, where R0 is selected from halogen, hydroxy, C 1-3 alkyl or C 1-3 alkoxy; W is a 4- to 10-membered heterocyclic group optionally substituted with 1 or 2 Rs W and containing up to 3 heteroatoms independently selected from N and O, with a maximum of 1 O heteroatom, where each R W is independently selected from hydrogen, oxo, hydroxy, hydroxyC 1-8 alkyl, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or NR w1 R w2 ; where R w1 and R w2 are each independently selected from hydrogen and C 1-6 alkyl.

2. The compound according to claim 1, wherein R1 is C 2-8 alkynyl or C 2-8 alkenyl.

3. The compound according to claim 1, wherein R1 is ethynyl, vinyl or propynyl.

4. The compound according to claim 1, wherein R4 and R5 are hydrogen.

5. The compound according to claim 1, wherein One of R2 and R3 is C 1-3 alkyl, and the other is hydrogen.

6. The compound according to claim 1, wherein, X1 is CH.

7. The compound according to claim 1, wherein, X2 is -O-, -S-, -NH- or -NC 1-3 alkyl-.

8. The compound according to claim 1, wherein, X2 is -O-.

9. The compound according to claim 1, wherein, L is -NH-, -O-, -S- or -CH2-.

10. The compound according to claim 1, wherein L is -NH-.

11. The compound according to claim 1, wherein, W is a 4- to 8-membered heterocyclic group optionally substituted with 1 or 2 Rs W wherein the 4- to 8-membered heterocyclic group contains up to 3 heteroatoms independently selected from N and O, and the maximum number of O heteroatoms is 1, and wherein R W are each independently selected from hydrogen, hydroxy, oxo, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl or NR w1 R w2 ; wherein, R w1 and R w2 are each independently selected from hydrogen and C 1-6 alkyl.

12. The compound according to claim 1, wherein W is a 6-membered heteroaryl group containing a single N heteroatom optionally substituted with 1 or 2 Rs W wherein each R W is independently selected from C 1-6 alkyl, hydroxy C 1-6 alkyl or C 3-6 cycloalkyl.

13. The compound according to claim 1, wherein, W is one of the following structural formulas Among them, R W are each independently selected from C 1-3 alkyl, hydroxy C 1-3 alkyl or C 3-6 cycloalkyl.

14. The compound according to claim 13, wherein, W is one of the following structural formulas 15. The compound according to claim 1, wherein, The compound is selected from the following compounds 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, diluent or excipient.

17. A method of treating or preventing an NLRP3-mediated disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16.

18. The method according to claim 17, wherein the disorder is selected from autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions.

19. The method according to claim 17 or 18, wherein the disorder is selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis and Muckle-Wells syndrome.

20. The method according to claim 17 or 18 or 19, wherein the NLRP3-mediated disorder is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease and cancer.

21. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for treating or preventing an NLRP3-mediated disorder.

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