NLRP3 modulators

Abstract

To provide a modulator compound of NLRP3 (pyrin domain-containing protein 3).SOLUTION: The present invention provides a compound represented by formula (I'), or a pharmaceutically acceptable salt or solvate thereof. As a specific example, sodium ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4,6,7,8-tetrahydro-5,8-ethanofuro[3,2-c]azepin-2-yl)sulfonyl)amide is presented.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 62 / 990,363, filed Mar. 16, 2020, which is incorporated herein by reference in its entirety.

Background Art

[0002] The NLRP3 inflammasome, a member of the NOD-like receptor (NLR) family of proteins containing a pyrin domain, is a very important component of the innate immune response and inflammatory processes, and its abnormal activation is pathogenic in genetic diseases such as cryopyrin-associated periodic syndromes (CAPS) as well as complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Current treatments for NLRP3-related diseases include biologics targeting IL-1. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics considering their improved safety as well as their potential regarding patient comfort and compliance.

Summary of the Invention

[0003] In one aspect, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof

[0004]

Chemical Formula

[0005]

Chem.

[0006]

Chem.

[0007] In another aspect, this specification also includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof

[0008]

Chemical formula

[0009]

Chemical formula

[0010]

Chemical formula

[0011] In some embodiments, R1 is,

[0012]

Chemical formula

[0013] [Chemistry] is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Y2 is C(R9), and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R9 is hydrogen or C1-C6 alkyl, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R9 is hydrogen, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Y2 is N, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Y1 is O, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Y1 is S, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Y1 is N(R8), and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R8 is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R8 is hydrogen, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R8 is C1-C6 alkyl, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R8 is C3-C6 cycloalkyl, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is,

[0014] [Chemistry] is a compound of formula (I’) or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0015]

Chemical formula

[0016] [Chemistry] is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0017] [Chemistry] is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, s is 1, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, t is 1, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Z2 is C(R 19 ) and is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 19 is hydrogen, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Z2 is N, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0018] [Chemistry] is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Z1 is S, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Z1 is O, and it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Z1 is -C(R 17 )=C(R 17)- is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R 17 is hydrogen, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 11 and R 12 are joined to form a 5- or 6-membered cycloalkyl ring, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 13 is phenyl which may optionally be substituted by 1, 2, 3, or 4 R 16 groups, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 13 is C2-C9 heteroaryl which may optionally be substituted by 1, 2, 3, or 4 R 16 groups, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 13 is pyridyl which may optionally be substituted by 1, 2, 3, or 4 R 16 groups, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R 16 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R 16 is C1-C6 alkoxy, a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is,

[0019]

Chemical formula

[0020] In another aspect, there is described herein a pharmaceutical composition comprising a compound of formula (I’) or (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0021] In some embodiments, there is described herein a method of treating a metabolic disorder in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’) or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there is described herein a method of treating a metabolic disorder in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’) or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disorder is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

[0022] In some embodiments, a method of treating a liver disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a liver disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

[0023] In some embodiments, a method of treating a lung disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a lung disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

[0024] In some embodiments, a method of treating a central nervous system disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a central nervous system disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease.

[0025] In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus erythematosus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0026] In some embodiments, a method of treating a cardiovascular disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a cardiovascular disease in a patient is described herein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke.

[0027] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Best Mode for Carrying Out the Invention

[0028] Detailed Description of the Invention Definitions In connection with this disclosure, many terms are utilized.

[0029] 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 the claimed subject matter belongs. In case of multiple definitions for the terms in this specification, those in this section shall prevail. All patents, patent applications, publications, and publicly available nucleotide and amino acid sequences (e.g., sequences available in GenBank and other databases) referred to herein are incorporated by reference. When a URL or other such identifier or address is referenced, such identifier may change and the individual information on the Internet may move, but it is understood that equivalent information can be found by searching the Internet. Such reference serves as evidence of the availability and dissemination of such information to the public.

[0030] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular form includes the plural unless specifically stated otherwise. It should be noted that when used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Also, the use of the terms “including” and other forms, such as “include,” “includes,” and “included,” is not limiting.

[0031] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0032] Definitions of standard chemical terms are, for example, but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4 thIt can be found in the references including “Ed.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology were used.

[0033] Unless specific definitions are provided, the nomenclature, as well as the test methods and techniques, adopted in analytical chemistry, synthetic organic chemistry, and in relation to pharmaceuticals and pharmaceutical chemistry described herein are those recognized in the art. Standard techniques for chemical synthesis, chemical analysis, pharmaceuticals, formulations, and delivery, and for the treatment of patients can be used. Standard techniques for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection) can be used. Reaction and purification techniques can be carried out, for example, using kits according to the manufacturer's specifications, or as generally achieved in the art, or as described herein. The above-mentioned techniques and procedures of conventional methods can be widely implemented as described in various general and more specific materials cited and discussed throughout this specification.

[0034] It should be understood that the methods and compositions described herein are not limited to the specific methodologies, protocols, cell lines, constructs, and reagents described herein and can therefore vary. It should also be understood that the terminology used herein is for the purpose of describing only specific embodiments and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0035] As used herein, C1~C x includes C1~C2, C1~C3 ··· C1~C x C1~C x means the number of carbon atoms constituting the moiety it refers to (excluding any substituents).

[0036] An "alkyl" group consists solely of carbon and hydrogen atoms and refers to a straight-chain or branched hydrocarbon chain group that contains no unsaturation. In some embodiments, an "alkyl" group can have from 1 to 6 carbon atoms (when it appears in this specification, a numerical range such as "1 to 6" means each integer within the given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms, but this definition also includes the appearance of the term "alkyl" for which no numerical range is specified). The alkyl groups of the compounds described herein can be designated as "C1-C6 alkyl" or a similar designation. By way of example only, "C1-C6 alkyl" indicates that there are 1 to 6 carbon atoms in the alkyl chain; that is, the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and hexyl. The alkyl group can be either substituted or unsubstituted. Depending on the structure, the alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0037] "Alkoxy" refers to an "-O-alkyl" group, where alkyl is as defined herein.

[0038] The term "alkenyl" consists solely of carbon and hydrogen atoms and refers to a straight-chain or branched hydrocarbon chain group that contains at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. In some embodiments, an alkenyl group can have from 2 to 6 carbons. The alkenyl group can be either substituted or unsubstituted. Depending on the structure, the alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0039] The term "alkynyl" consists solely of carbon and hydrogen atoms and refers to a straight-chain or branched hydrocarbon chain group containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. In some embodiments, the alkynyl group can have 2 to 6 carbons. The alkynyl group may be substituted or unsubstituted. Depending on the structure, the alkynyl group may be a monoradical or a diradical (i.e., an alkynylene group).

[0040] "Amino" refers to the -NH2 group.

[0041] The term "alkylamine" or "alkylamino" refers to the -N(alkyl) x H y group, where alkyl is as defined herein, and x and y are selected from the group of x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl group can, together with the attached nitrogen, optionally form a cyclic ring system. "Dialkylamino" refers to the -N(alkyl)2 group, where alkyl is as defined herein.

[0042] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n + 2 π electrons, where n is an integer. The aromatic ring can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatics can optionally be substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0043] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be formed from 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group can optionally be substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0044] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety can be replaced with a "carboxylic acid bioisostere" which means a functional group or moiety that exhibits physical and / or chemical properties similar to a carboxylic acid moiety. The carboxylic acid bioisostere has biological properties similar to a carboxylic acid group. A compound having a carboxylic acid moiety has a carboxylic acid moiety replaced with a carboxylic acid bioisostere and can have similar physical and / or biological properties compared to a compound containing a carboxylic acid. For example, in one embodiment, the carboxylic acid bioisostere ionizes to approximately the same extent as a carboxylic acid group at physiological pH. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0045]

Chemical formula

[0046] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, where each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. The cycloalkyl can be saturated or partially unsaturated. The cycloalkyl can be fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). In some embodiments, the cycloalkyl group includes groups having 3 to 10 ring atoms.

[0047] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. A "heteroaromatic" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0048] A "heterocycloalkyl" group or "heteroalicyclic" group means a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The group may be fused to an aryl or heteroaryl. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise defined, heterocycloalkyl has 2 - 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (i.e., the skeletal atoms of the heterocycloalkyl ring) that make up the heterocycloalkyl (including heteroatoms).

[0049] The term "halo" or, alternatively, "halogen" means fluoro, chloro, bromo, and iodo.

[0050] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens may be the same or different. Non-limiting examples of haloalkyl include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, etc.

[0051] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups substituted with one or more fluorine atoms, respectively. Non-limiting examples of fluoroalkyl include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, etc. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, etc.

[0052] The term "heteroalkyl" refers to an alkyl group in which one or more of the backbone chain atoms are atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom can be at any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Further, two or fewer heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3 by way of example. Except for the number of heteroatoms, "heteroalkyl" can have 1 to 6 carbon atoms.

[0053] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms joined by the bond are considered to be part of a larger substructure.

[0054] The term "moiety" refers to a particular part or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or attached to a molecule.

[0055] As used herein, the substituent "R" that appears alone without a number designation means a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0056] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and includes both the case where the event or circumstance occurs and the case where it does not occur.

[0057] The term "optionally substituted" or "substituted" means that the recited group can be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6 alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, such as mono- and disubstituted amino groups (e.g., -NH2, -NHR, -N(R)2), and protected derivatives thereof. By way of example, any substituent can be L s R s where each L s is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(C1-C6 alkyl)-, or -(C2-C6 alkenyl)-, and each R s is independently selected from H, (C1-C6 alkyl), (C3-C8 cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6 heteroalkyl. Protecting groups that can form protected derivatives of the above substituents are found in sources such as Greene and Wuts cited above.

[0058] As used herein, the term "about" or "approximately" means within 20%, preferably within 10%, more preferably within 5% of a given value or range.

[0059] The term "therapeutically effective amount" as used herein means the amount of an NLRP3 inhibitor that is effective to at least partially improve or at least partially prevent a condition associated with skin aging when administered to a mammalian subject in need thereof.

[0060] As used herein, the term "expression" includes the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide, or protein.

[0061] The term "modulate" encompasses a decrease or increase in activity or expression in response to a target molecule.

[0062] The term "activator" as used herein means a molecular species that will cause activation of a receptor as indicated herein, whether or not the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered locally. Thus, the activator may be a ligand of the receptor or an activator that is metabolized to a ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

[0063] The term "patient" or "mammal" means a human, non-human primate, dog, cat, cow, sheep, pig, mouse, or other veterinary or research mammal. As will be appreciated by those skilled in the art, a treatment that reduces the severity of a condition in one species of mammal predicts the effect of that treatment on another species of mammal.

[0064] "Pharmaceutically acceptable salts" include both acid and base addition salts. The pharmaceutically acceptable salts of any compound described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0065] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, are not undesirable in a biological or other sense, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed from organic acids such as aliphatic mono- and dicarboxylic acids, alkanoic acids substituted with phenyl, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, typical salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, etc. Also considered are salts of amino acids such as arginate, gluconate, and galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt.

[0066] "Pharmaceutically acceptable base addition salts" mean salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared by addition of an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are formed from metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and salts such as these. See Berge et al., supra.

[0067] As used herein, "treat" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying disease being treated. Also, a therapeutic benefit can be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, even though the patient still suffers from the underlying disease, as improvement is observed in the patient. For prophylactic benefit, the compositions are administered to patients at risk of developing a particular disease or patients who complain of one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0068] NLRP3 modulator NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. When activated, NLRP3 binds to an apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates called ASC specks.

[0069] The polymerized ASC forms a complex called an inflammasome in conjunction with the cysteine protease caspase-1. This results in the activation of active caspase-1, which activates these cytokines by cleaving the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-ιβ and pro-IL-18, respectively). Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC speck aggregates can also recruit and activate caspase-8, process pro-IL-ιβ and pro-IL-18, and cause apoptotic cell death.

[0070] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms and secretes them from the cell. Active caspase-1 also cleaves gasdermin-D to cause pyroptosis. By controlling its pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, resulting in its reduction and enabling the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Some other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathway, may contribute to caspase-1-dependent inflammation.

[0071] NLRP3-dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation. The active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to form the immune response to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 cooperate with IL-23 to induce the production of IL-17 by memory CD4 Th17 cells and by γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also cooperate to induce the production of IFN-γ from memory T cells and NK cells that drive the Th1 response.

[0072] The hereditary CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3 and thus define NLRP3 as a critical component of the inflammatory process. NLRP3 is also involved in the pathogenesis of several complex diseases, including metabolic diseases such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0073] The role of NLRP3 in central nervous system diseases is emerging, and it has been shown that lung diseases are also affected by NLRP3. In addition, NLRP3 has a role in the development of liver diseases, kidney diseases, and aging. Many of these associations have been defined using NLRP3 KO mice, but there is also insight into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-ιβ signaling, resulting in cell death and inflammation.

[0074] Current treatments for diseases related to NLRP3 include biologics that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologics are being used in clinical trials for other IL-1β related diseases. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics considering the potential for improved safety (minimal risk of infection and ease of discontinuation compared to biologics) as well as patient comfort and compliance.

[0075] The compounds of formula (I’), (I), or (Ia) described herein are NLRP3 modulators. The compounds of formula (I’), (I), or (Ia) described herein, and compositions containing these compounds, are useful for the treatment of diseases related to NLRP3 including, but not limited to, type 2 diabetes, atherosclerosis, obesity, and gout.

[0076] In some embodiments, the present specification also includes a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof

[0077]

Chemical Structure

[0078]

Chem.

[0079]

Chem.

[0080] In some embodiments, R1 is,

[0081]

Chemical formula

[0082]

Chemical formula

[0083]

Chemical formula

[0084]

Chemical formula

[0085]

Chemical formula

[0086] In some embodiments, m is 1, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, m is 0, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, m is 2, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof.

[0087] In some embodiments, p is 1, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, p is 0, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, p is 2, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof.

[0088] In some embodiments, m is 1 and p is 1, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof.

[0089] In some embodiments, each R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, and C1-C6 heteroalkyl, and it is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is C1-C6 alkyl, -C1-C6 alkyl-CO2R 18and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, independently selected from C1-C6 haloalkyl. In some embodiments, each R7 is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, independently selected from C1-C6 alkyl. In some embodiments, each R7 is -CH3, a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof.

[0090] In some embodiments, provided herein are a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments, provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments, provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments, provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments, provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 4.

[0091] In some embodiments, R1 is

[0092] [Chemical formula] a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof.

[0093] In some embodiments, Y1 is O, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y1 is S, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y1 is N(R8), and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y1 is N(R8), R8 is hydrogen or C1-C6 alkyl, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0094] In some embodiments, Y2 is N, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), R9 is selected from hydrogen and C1-C6 alkyl, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), R9 is hydrogen, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), R9 is C1-C6 alkyl, and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0095] In some embodiments, R1 is

[0096]

Chemical formula

[0097]

Chem.

[0098]

Chem.

[0099]

Chem.

[0100]

Chem.

[0101]

Chem.

[0102]

Chem.

[0103] [Chemistry] Provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0104] [Chemistry] Provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0105] [Chemistry] Provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments, R2 is

[0107] [Chemistry] Provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0108] [Chemistry] Provided herein is a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1 and t is 1. In some embodiments, R2 is

[0109] [Chemistry] wherein s is 1, t is 1, and Z2 is C(R 19) The compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, R2 is,

[0110]

Chem.

[0111]

Chem.

[0112] In some embodiments, R2 is,

[0113]

Chem.

[0114]

Chem.

[0115]

Chem.

[0116]

Chemical formula

[0117]

Chemical formula

[0118] In some embodiments, R2 is

[0119]

Chemical formula

[0120]

Chemical formula

[0121]

Chemical formula

[0122]

Chemical formula

[0123]

Chemical formula

[0124]

Chemical formula

[0125]

Chemical formula

[0126]

Chemical formula

[0127]

Chemical formula

[0128]

Chemical formula

[0129]

Chemical formula

[0130]

Chemical formula

[0131]

Chemical formula

[0132]

Chemical formula

[0133]

Chemical formula

[0134]

Chemical formula

[0135]

Chemical formula

[0136] In some embodiments, R2 is

[0137]

Chemical formula

[0138]

Chemical formula

[0139]

Chemical formula

[0140]

Chemical formula

[0141]

Chem.

[0142]

Chem.

[0143]

Chem.

[0144]

Chem.

[0145]

Chem.

[0146]

Chem.

[0147] In some embodiments, R2 is

[0148] [Chemical Formula] The compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0149] In some embodiments, R2 is

[0150] [Chemical Formula] The compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0151] In some embodiments, X2 is -N(R5)-, and the compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided by the present invention. In some embodiments, X2 is -N(R5)- and R5 is hydrogen, and the compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided by the present invention. In some embodiments, X2 is -N(R5)- and R5 is C1-C6 alkyl, and the compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided by the present invention. In some embodiments, X2 is -C(R5)2-, and the compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided by the present invention. In some embodiments, X2 is -C(R5)2- and each R5 is hydrogen, and the compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, is provided by the present invention.

[0152] In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X3 is -N(R5)-. In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X3 is -N(R5)- and R5 is hydrogen. In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X3 is -N(R5)- and R5 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X3 is -C(R5)2-. In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X3 is -C(R5)2- and each R5 is hydrogen.

[0153] In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X1 is O. In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X1 is S. In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X1 is N(R3). In some embodiments, provided herein are compounds of formula (I’), or pharmaceutically acceptable salts or solvates thereof, wherein X1 is C(NO2)(R4).

[0154] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof

[0155] [Chemical Formula] (wherein X1 is O, S, or N(R3), X2 is -N(R4)- or -C(R4)2-; X3 is -N(R5)- or -C(R5)2-; Y1 is O, S, or N(R8); Y2 is N or C(R9); Z1 is O, S, N(R3), or -C(R 17 )=C(R 17 )-; Z2 is N or C(R 19 ) R1 is,

[0156]

Chemical formula

[0157]

Chemical formula

[0158] In some embodiments, R1 is,

[0159]

Chemical formula

[0160]

Chemical formula

[0161]

Chemical formula

[0162]

Chemical formula

[0163]

Chemical formula

[0164] In some embodiments, m is 1, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, m is 0, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, m is 2, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0165] In some embodiments, p is 1, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, p is 0, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, p is 2, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0166] In some embodiments, m is 1 and p is 1, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0167] In some embodiments, each R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, and C1-C6 heteroalkyl, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is C1-C6 alkyl, -C1-C6 alkyl-CO2R 18A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, which is independently selected from C1-C6 haloalkyl. In some embodiments, each R7 is a compound of formula (I) independently selected from C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is -CH3, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0168] In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein q is 0, 1, 2, or 3. In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein q is 0. In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein q is 1. In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein q is 2. In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein q is 3. In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein q is 4.

[0169] In some embodiments, R1 is

[0170]

Chemical formula

[0171] In some embodiments, Y1 is O, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y1 is S, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y1 is N(R8), and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y1 is N(R8), and R8 is hydrogen or C1-C6 alkyl, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0172] In some embodiments, Y2 is N, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), and R9 is selected from hydrogen and C1-C6 alkyl, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), and R9 is hydrogen, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, Y2 is C(R9), and R9 is C1-C6 alkyl, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0173] In some embodiments, R1 is

[0174]

Chemical formula

[0175]

Chemical formula

[0176]

Chemical formula

[0177]

Chemical formula

[0178]

Chemical formula

[0179]

Chemical formula

[0180]

Chemical formula

[0181]

Chemical formula

[0182]

Chemical formula

[0183]

Chemical formula

[0184] In some embodiments, R2 is,

[0185]

Chemical formula

[0186]

Chemical formula

[0187]

Chemical formula

[0188] [Chemical formula] There is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1, t is 1, and Z2 is C(H). In some embodiments, R2 is

[0189] [Chemical formula] There is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1, t is 1, and Z2 is N.

[0190] In some embodiments, R2 is

[0191] [Chemical formula] There is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0192] [Chemical formula] There is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is S. In some embodiments, R2 is

[0193] [Chemical formula] There is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is -C(R 17 )=C(R 17 )-. In some embodiments, R2 is

[0194] [Chemical formula] The compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1 is -C(H)=C(H)-, is provided herein. In some embodiments, R2 is

[0195] [Chemical formula] and R 11 and R 12 are joined to form a 5- or 6-membered cycloalkyl ring. The compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, R2 is

[0196] [Chemical formula] wherein q is 1 and R 13 is C2-C9 heteroaryl optionally substituted by one, two, or three R 16 groups. The compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, R2 is

[0197] [Chemical formula] wherein q is 1 and R 13 is pyridyl optionally substituted by one or two R 16 groups. The compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, R2 is

[0198] [Chemical formula] wherein q is 1 and R 13 is pyridyl optionally substituted by one or two R 16 groups, and each R 16The present specification provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, which is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some embodiments, R2 is,

[0199]

Chemical formula

[0200]

Chemical formula

[0201] In some embodiments, R2 is,

[0202]

Chemical formula

[0203]

Chemical formula

[0204]

Chemical formula

[0205]

Chemical formula

[0206]

Chemical formula

[0207]

Chemical formula

[0208]

Chemical formula

[0209]

Chemical formula

[0210]

Chemical formula

[0211]

Chemical formula

[0212] In some embodiments, X2 is -N(R5)-, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X2 is -N(R5)- and R5 is hydrogen, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X2 is -N(R5)- and R5 is C1-C6 alkyl, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X2 is -C(R5)2-, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X2 is -C(R5)2- and each R5 is hydrogen, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0213] In some embodiments, X3 is -N(R5)-, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X3 is -N(R5)- and R5 is hydrogen, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X3 is -N(R5)- and R5 is C1-C6 alkyl, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X3 is -C(R5)2-, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X3 is -C(R5)2- and each R5 is hydrogen, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0214] In some embodiments, X1 is O, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X1 is S, and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X1 is N(R3), and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein. In some embodiments, X1 is C(NO2)(R4), and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided herein.

[0215] In some embodiments, provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof

[0216] [Chemical Formula] (wherein, Y1 is O, S, or N(R8), Y2 is N or C(R9), Z1 is O, S, N(R3), or -C(R17 )=C(R 17 )- and Z2 is N or C(R 19 ) R1 is

[0217] [Chemical formula] and R2 is

[0218] [Chemical formula] and each R6 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, -C1-C6 alkyl-OR7, and -C1-C6 alkyl-N(R7)2 each R7 is independently selected from hydrogen and C1-C6 alkyl R8 is hydrogen, C1-C6 alkyl, -C1-C6 alkyl-OR7, -C1-C6 alkyl-N(R7)2, or C3-C6 cycloalkyl R9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7, or -C1-C6 alkyl-N(R7)2 R 11 and R 12 are independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7, and -C1-C6 alkyl-N(R7)2, or R 11 and R 12 are joined to form a 5- or 6-membered cycloalkyl ring R 13 is phenyl or C2-C9 heteroaryl, where phenyl and C2-C9 heteroaryl are optionally substituted with 1, 2, 3, or 4 R 16may be replaced by, each R 16 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 aryl, C2-C9 heteroaryl, where C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C6-C 10 aryl, C2-C9 heteroaryl may optionally be substituted with 1, 2, or 3 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, each R 17 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7, and -C1-C6 alkyl-N(R7)2, R 18 is hydrogen or C1-C6 alkyl, R 19 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-OR7, or -C1-C6 alkyl-N(R7)2, m is 0, 1, or 2, n is 1, 2, or 3, p is 0, 1, or 2, q is 0, 1, 2, 3, or 4, s is 1, 2, or 3, t is 1, 2, or 3) is provided.

[0219] In some embodiments, R1 is

[0220]

Chemical formula

[0221] [Chemical formula] is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0222] [Chemical formula] is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0223] [Chemical formula] is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0224] [Chemical formula] is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0225] In some embodiments, m is 1, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, m is 0, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, m is 2, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0226] In some embodiments, p is 1, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, p is 0, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, p is 2, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0227] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and p is 1.

[0228] In some embodiments, each R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , C1-C6 haloalkyl, and C1-C6 heteroalkyl, of the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is independently selected from C1-C6 alkyl, -C1-C6 alkyl-CO2R 18 , and C1-C6 haloalkyl, of the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is independently selected from C1-C6 alkyl, of the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is -CH3, of the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0229] In some embodiments, a compound of formula (Ia) wherein q is 0, 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein q is 0, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein q is 1, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein q is 2, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein q is 3, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein q is 4, or a pharmaceutically acceptable salt or solvate thereof is provided herein.

[0230] In some embodiments, R1 is

[0231]

Chemical formula

[0232] In some embodiments, a compound of formula (Ia) wherein Y1 is O, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein Y1 is S, or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein Y1 is N(R8), or a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, a compound of formula (Ia) wherein Y1 is N(R8) and R8 is hydrogen or C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof is provided herein.

[0233] In some embodiments, provided herein are compounds of formula (Ia) wherein Y2 is N, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds of formula (Ia) wherein Y2 is C(R9), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds of formula (Ia) wherein Y2 is C(R9) and R9 is selected from hydrogen and C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds of formula (Ia) wherein Y2 is C(R9) and R9 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds of formula (Ia) wherein Y2 is C(R9) and R9 is C1-C6 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0234] In some embodiments, R1 is

[0235]

Chemical formula

[0236]

Chemical formula

[0237]

Chemical formula

[0238] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0239] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0240] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0241] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0242] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0243] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R1 is

[0244] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0245] In some embodiments, R2 is

[0246] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0247] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1 and t is 1. In some embodiments, R2 is

[0248] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1, t is 1, and Z2 is C(R 19 ). In some embodiments, R2 is

[0249] [Chemical formula] Provided herein is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1, t is 1, and Z2 is C(H). In some embodiments, R2 is

[0250] [Chemical formula] The compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1, t is 1, and Z2 is N, is provided herein.

[0251] In some embodiments, R2 is

[0252]

Chemical formula

[0253]

Chemical formula

[0254]

Chemical formula

[0255]

Chemical formula

[0256]

Chemical formula

[0257]

Chem.

[0258]

Chem.

[0259]

Chem.

[0260]

Chem.

[0261]

Chemical formula

[0262] In some embodiments, R2 is

[0263]

Chemical formula

[0264]

Chemical formula

[0265]

Chemical formula

[0266] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0267] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0268] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0269] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0270] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0271] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R2 is

[0272] [Chemistry] There is provided herein a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0273] In some embodiments, herein

[0274] [Chemical formula] There is provided a compound selected from, or a pharmaceutically acceptable salt or solvate thereof.

[0275] In some embodiments, herein

[0276] [Chemical formula]

[0277] [Chemical formula] There is provided a compound selected from, or a pharmaceutically acceptable salt or solvate thereof.

[0278] In some embodiments, herein

[0279] [Chemical formula] There is provided a compound selected from, or a pharmaceutically acceptable salt or solvate thereof.

[0280] All combinations described above for the various variable codes are contemplated by the present invention. Throughout this specification, the groups and their substituents can be selected by one skilled in the art to provide stable moieties and compounds.

[0281] In some embodiments, the therapeutic agent (e.g., a compound of formula (I’), (I), or (Ia)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any of the compounds described above are suitable for any of the methods or compositions described herein.

[0282] Further forms of the compounds disclosed herein Isomers In addition, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. All cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as corresponding mixtures thereof are included in the compounds shown herein. In some cases, the compounds exist as tautomers. The compounds described herein include all tautomers possible within the formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as corresponding mixtures thereof. In additional embodiments of the compounds and methods provided by the present invention, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the uses described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatography resolution of a racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered from the resolving agent by practical means that do not cause racemization.

[0283] Labeled compound In some embodiments, the compounds described herein exist in a form labeled with their isotopes. In some embodiments, the methods disclosed herein include methods of treating a disease by administering a compound labeled with such an isotope. In some embodiments, the methods disclosed herein include methods of treating a disease by administering a compound labeled with such an isotope as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include compounds labeled with isotopes that are the same as those listed herein but in which one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes incorporated into the compounds described herein are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof are within the scope of this invention. Compounds labeled with certain isotopes, such as radioactive isotopes, such as 3 H and 14 C incorporated therein are useful for drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred because of the ease of their preparation and detectability. Further, heavy isotopes, such as deuterium, i.e., 2Replacement by H results in certain therapeutic advantages as a consequence of greater metabolic stability, such as an increased in vivo half-life or a reduced required dosage. In some embodiments, the isotopically labeled compound, a pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

[0284] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0285] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as 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 as a pharmaceutical composition.

[0286] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with many inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt so formed.

[0287] Solvates In some embodiments, the compounds described herein exist as solvates. In some embodiments, methods of treating a disease by administering such solvates are provided. Further provided herein are methods of treating a disease by administering such solvates as a pharmaceutical composition.

[0288] Solvates contain a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, are formed during a crystallization process using a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture containing, but not limited to, an organic solvent such as dioxane, tetrahydrofuran, or MeOH. Further, the compounds provided by the present invention exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided by the present invention.

[0289] Synthesis of Compounds In some embodiments, the synthesis of the compounds described herein is achieved using means described in the chemical literature, using the methods described herein, or a combination thereof. Further, the solvents, temperatures and other reaction conditions shown herein may vary.

[0290] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0291] In further embodiments, the compounds described herein, and related compounds having other different substituents, are synthesized using techniques and materials described herein and, for example, Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3 rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods of preparing the compounds disclosed herein can be derived from the reactions, which can be varied by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulas listed herein. The following synthetic methods can be utilized for reference.

[0292] Use of protecting groups In the reactions described, if reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups are desired in the final product, it may be necessary to protect them to avoid their unwanted participation in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. Each protecting group is preferably removable by different means. Protecting groups that cleave under completely different reaction conditions meet the requirements for differential removal.

[0293] Protecting groups can be removed by acids, bases, reducing conditions (such as hydrogenolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetals and t-butyldimethylsilyl are acid-labile and can be used to protect carboxy and hydroxy reactive moieties in the presence of an amino group protected with a Cbz group removable by hydrogenolysis, and the Fmoc group is base-labile. Carboxylic acid and hydroxy reactive moieties can be blocked by base-labile groups such as, but not limited to, methyl, ethyl, and acetyl, acid-labile groups such as t-butyl carbamate or in the presence of an amine blocked with a carbamate that is stable to both acids and bases but removable hydrolytically.

[0294] Carboxylic acid and hydroxy reactive moieties can also be blocked with hydrolytically removable protecting groups such as a benzyl group, while an amine group that can hydrogen bond to an acid can be blocked with a base-labile group such as Fmoc. The carboxylic acid reactive moiety can be protected by conversion to a simple ester compound exemplified herein including conversion to an alkyl ester, or blocked with an oxidatively removable protecting group such as 2,4-dimethoxybenzyl, while an amino group present simultaneously can be blocked with a silyl carbamate that is fluoride-labile.

[0295] An allyl protecting group is useful in the presence of acid and base protecting groups. This is because the former is stable and can then be removed by a metal or a π - acid catalyst. For example, a carboxylic acid blocked with allyl can be deprotected by a reaction catalyzed by Pd in the presence of a t - butyl carbamate that is acid - labile or an acetate amine protecting group that is base - labile. 0 Another form of protecting group is a resin to which a compound or an intermediate can be attached. As long as the residue is attached to the resin, its functional group is blocked and cannot react. When released from the resin, its functional group is available for reaction.

[0296] Typically, the blocking / protecting groups can be

[0297]

Chemical formula

[0298] Details of other protecting groups, as well as techniques applicable to the creation and removal of protecting groups, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are hereby incorporated by reference for such disclosure.

[0299] Therapeutic and prophylactic methods In some embodiments, a method of treating a metabolic disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a metabolic disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disorder is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments, a method of treating type 2 diabetes in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating atherosclerosis in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating obesity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating gout in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0300] In some embodiments, a method for treating liver disease in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method for treating liver disease in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, or cirrhosis.

[0301] In some embodiments, a method for treating lung disease in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the lung disease is selected from asthma, COPD, and idiopathic pulmonary fibrosis.

[0302] In some embodiments, a method for treating a central nervous system disease in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease.

[0303] In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is rheumatoid arthritis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is multiple sclerosis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is psoriasis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is lupus erythematosus. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is an intestinal disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is Crohn's disease.In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, wherein the disease is ulcerative colitis, comprising administering to the patient a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0304] In some embodiments, a method of treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a cardiovascular disease in a patient in need thereof, wherein the cardiovascular disease is atherosclerosis or stroke, comprising administering to the patient a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating atherosclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I’), (I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0305] Pharmaceutical Compositions and Methods of Administration The NLRP3 inhibitors described herein are administered to a subject in a biologically compatible form suitable for administration to treat or prevent a disease, disorder or condition. Administration of the NLRP3 inhibitors described herein is effected in any pharmacological form including a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0306] In certain embodiments, the compounds described herein are administered as pure chemical entities. In other embodiments, the compounds described herein are combined with a chosen route of administration and a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on standard pharmaceutical practices such as those described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0307] Accordingly, provided herein are pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers. The carrier (or excipient) is compatible with the other ingredients of the composition and is acceptable or suitable, provided that it is not harmful to the recipient (i.e., subject) of the composition.

[0308] Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I’), (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, in some embodiments. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I’), or a pharmaceutically acceptable salt or solvate thereof, in some embodiments. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in some embodiments. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, in some embodiments.

[0309] Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable carrier and a compound of formula (I’), (I), or (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition comprising essentially a pharmaceutically acceptable carrier and a compound of formula (I’) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition comprising essentially a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition comprising essentially a pharmaceutically acceptable carrier and a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof.

[0310] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as contaminating intermediates or by-products, produced in one or more steps of the synthetic method, for example.

[0311] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.

[0312] Representative pharmaceutical compositions are in the form of pharmaceuticals and are used, for example, in solid, semi-solid, or liquid form and contain, as the active ingredient, one or more of the disclosed compounds as a mixture with an organic or inorganic carrier or excipient suitable for topical, enteric, or parenteral application. In some embodiments, the active ingredient is a compound included with a normal non-toxic pharmaceutically acceptable carrier for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect against the disease process or condition.

[0313] In some embodiments, the NLRP3 inhibitors described herein are administered to a subject in a biologically compatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. "Biologically compatible form suitable for topical administration" means a form of the inhibitor being administered in which the therapeutic effect of the inhibitor exceeds any toxic effects. Administration of the NLRP3 inhibitors described herein may be in any pharmacological form that includes a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0314] Topical administration of the NLRP3 inhibitor can be in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. The term "semi-solid composition" means an ointment, a cream, a salve, a jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of Lea and Febiger (1970), The Theory and Practice of Industrial Pharmacy, by Lachman, Lieberman and Kanig, and in Chapter 67 of Mack Publishing Company (1975), Remington's Pharmaceutical Sciences, 15th Edition.

[0315] The skin patch is yet another method for the transdermal delivery of the therapeutic agents or pharmaceutical compositions described herein. The patch can provide an absorption enhancer such as DMSO to increase the absorption of the compound. The patch can include something to control the rate of drug delivery to the skin. The patch can provide various dosage systems, each including a reservoir system or a monolithic system. The reservoir design can have, for example, four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of drug molecules, a reservoir of drug molecules, and a waterproof backing. Such a design delivers a uniform amount of drug over a specified time, and the rate of delivery must be below the saturation limit of various types of skin. The monolithic design typically has only three layers: an adhesive layer, a polymeric matrix containing the compound, and a waterproof backing. This design brings a saturated amount of drug to the skin. Thereby, the delivery is controlled by the skin. As the amount of drug in the patch drops below the saturation level, the delivery rate decreases.

[0316] In one embodiment, the topical composition can be in the form of a hydrogel based on, for example, polyacrylic acid or polyacrylamide, as an ointment based on polyethylene glycol (PEG) such as standard ointment DAB 8 (50% PEG 300, 50% PEG 1500), or as an oil-in-water or water-in-oil emulsion, particularly a microemulsion, optionally with liposomes added. Suitable penetration enhancers (carriers) include sulfoxide derivatives such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO) and transcutol (diethylene glycol monoethyl ether) or cyclodextrin, as well as pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and its fatty acid esters, urea derivatives such as dodecyl urea, 1,3-didodecyl urea, and 1,3-diphenyl urea, and terpenes such as D-limonene, menthone, a-terpineol, carbol, limonene oxide, or 1,8-cineole.

[0317] Ointments, pastes, creams and gels can also contain excipients such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used to make aerosol drugs. Generally, such methods involve pressurizing the container of the solution with a normally inert carrier gas or providing means for pressurizing and passing the pressurized gas through a small orifice. Sprays can further contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0318] The carrier can also contain other pharmaceutically acceptable excipients for modifying or maintaining the pH, osmolality, viscosity, transparency, color, sterility, stability, dissolution rate, or odor of the formulation. The anti-aging composition can also further include antioxidants, sunscreen agents, natural retinoids (such as retinol), and other additives commonly found in skin treatment compositions.

[0319] In some embodiments for preparing solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier such as a conventional tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum, and other pharmaceutical diluents such as water to form a solid preliminary formulation composition containing a homogeneous mixture of the disclosed compound or its non-toxic pharmaceutically acceptable salts. When these preliminary formulation compositions are said to be homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition and the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0320] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition is one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid, (2) binders such as, for example, carboxymethyl cellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia, (3) humectants such as glycerol, (4) disintegrants such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) dissolution retardants such as paraffin, (6) absorption promoters such as quaternary ammonium compounds, (7) wetting agents such as, for example, sodium docusate, cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the composition contains a buffering agent. In some embodiments, similar types of solid compositions are also used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycol and the like.

[0321] In some embodiments, the tablets are made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared with a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium), and a surfactant or dispersing agent. In some embodiments, triturated tablets are made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, are prepared with scored or with coatings and shells, such as enteric coatings and other coatings.

[0322] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, the liquid dosage forms contain, in addition to the subject composition, inert diluents, such as water or other solvents, solubilizers, and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0323] In some embodiments, suspensions contain, in addition to the subject composition, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0324] In some embodiments, the powder and spray contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, the spray further contains conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0325] Alternatively, the compositions and compounds disclosed herein are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal formulation, or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellant) suspensions are used. In some embodiments, ultrasonic nebulizers are used because they minimize the time of exposure of the agent to shear that causes degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the individual subject composition, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, saccharides, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0326] Pharmaceutical compositions suitable for parenteral administration comprise the subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted immediately prior to use into sterile injectable solutions or dispersions, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0327] Examples of suitable aqueous and non-aqueous carriers for pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Suitable fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0328] The dosage of the composition containing at least one compound described herein will vary depending on the condition of the patient (e.g., human), i.e., the stage of the disease, general health, age, and other factors.

[0329] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage as well as the appropriate period and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the individual form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment plan provide the composition in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and / or overall survival, or alleviation of the severity of symptoms). The optimal dosage is generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dosage depends on the patient's body mass, weight, or blood volume.

[0330] Oral dosages are typically in the range of about 1.0 mg to about 1000 mg, taken 1 to 4 or more times per day.

[0331] Drug administration can be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0332] It is particularly advantageous to formulate the composition into dosage unit forms for ease of administration and uniformity of administration. As used herein, dosage unit forms refer to physically discrete units suitable as a single dosage for the mammalian subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for dosage unit forms are directly dependent on and indicated by (a) the unique properties of the NLRP3 inhibitor and the individual therapeutic effect to be achieved, as well as (b) the limitations inherent in the art of compounding such active compounds for the treatment of individual sensitivities. Specific dosages can be readily calculated by one skilled in the art, for example, according to the approximate body weight or body surface area or volume of the body space occupied by the patient. Dosages are also calculated depending on the individual route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely performed by one skilled in the art. Such calculations can be performed by one skilled in the art without undue experimentation in light of the activity of the NLRP3 inhibitors disclosed herein in the assay preparation of target cells. The exact dosage is determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by the attending physician in view of relevant circumstances including one or more conditions to be treated, the selection of the composition to be administered, age, body weight, and individual patient response, the severity of the patient's symptoms, and the chosen route of administration.

[0333] The toxicity and therapeutic effect of such NLRP3 inhibitors can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, LD 50 (the dose lethal to 50% of the population) and ED 50 (the therapeutically effective dose in 50% of the population). The dosage ratio between toxicity and therapeutic effect is the therapeutic index, the ratio LD 50 / ED 50It can be represented as such. NLRP3 inhibitors showing a large therapeutic index are preferred. NLRP3 inhibitors showing toxic side effects may be used, but care must be taken to design a delivery system that targets the site of the tissue invaded by the disease in order to reduce the side effects by minimizing potential damage to non-infected cells.

[0334] Data obtained from cell culture assays and animal studies can be used to formulate the range of dosages to be used in humans. The dosage of such NLRP3 inhibitors is preferably within the range of blood concentrations containing no or little toxicity of ED 50 The dosage may vary within this range depending on the dosage form used and the route of administration utilized. For any NLRP3 inhibitor used in the methods described herein, a therapeutically effective dosage can first be evaluated from cell culture assays. The dosage can be determined in cell culture to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the NLRP3 inhibitor that achieves maximum half-inhibition of the symptoms). Such information can be used to more accurately determine useful dosages in humans. Plasma levels can be measured, for example, by high performance liquid chromatography.

Examples

[0335] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. In these examples, and throughout this specification, all cited references are incorporated herein for all legal purposes by reference. The starting materials and reagents used in the synthesis of the compounds described herein can be synthesized or, without limitation, obtained from commercial sources such as Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0336] Standard abbreviations and acronyms defined in J. Org. Chem. 2007 72(1): 23A-24A are used herein. Other abbreviations and acronyms used herein are as follows.

[0337]

Table 1-1

[0338]

Table 1-2

[0339] Example 1: Synthesis of Sodium ((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((4,6,7,8-Tetrahydro-5,8-ethanofuro[3,2-c]azepin-2-yl)sulfonyl)amide (13)

[0340]

Chem.

[0341] To a solution of 2 (9.0 g, 42 mmol, 1.0 equiv) in EtOH (190 mL) was added NaOH (5.4 g, 136 mmol, 3 equiv, in 190 mL of water). The reaction mixture was stirred at room temperature for 2 h. The pH was adjusted to 2 with 1 N HCl. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give compound 3 (6 g).

[0342] To a 500 mL RBF, a solution of 3 (5.0 g, 27 mmol, 1.0 eq) in MsOH (150 mL) was added. The reaction mixture was stirred at 130 °C overnight. The mixture was poured onto ice / water, and then the pH was adjusted to 10 with Na2CO3. The mixture was extracted with DCM, and the combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 4 (2.5 g).

[0343] To a solution of 4’ (12.2 g, 54 mmol, 1.5 eq) in THF (60 mL) was added NaH (1.26 g, 54 mmol, 1.5 eq). After stirring for 30 min, 4 (6 g, 36 mmol, 1 eq) was added. The mixture was stirred at room temperature overnight. Water (20 mL) was added dropwise at 0 °C. The mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 5 (11.9 g).

[0344] To a solution of 5 (2.0 g, 8.5 mmol, 1 eq) in MeOH / THF (100 / 10 mL) was added Mg (1.2 g, 34 mmol, 4 eq). The reaction mixture was stirred at room temperature overnight. The mixture was poured into ice-cold 2N HCl (50 mL). The acidic solution was treated with Na2CO3 to bring the pH to 8.5 - 9. The mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 6 (1.7 g).

[0345] To a solution of 6 (1.7 g, 7.2 mmol, 1 eq) in THF (100 mL) was added LAH (5.4 g, 143 mmol, 20 eq). The reaction mixture was stirred at 70 °C overnight. The mixture was quenched with water and NaOHaq. The mixture was filtered, and the solid was washed with MeOH. The solution was concentrated in vacuo, and the residue was purified by silica gel chromatography to give compound 7 (700 mg).

[0346] To a solution of PPh3 (2.2 g, 8.3 mmol, 3 equiv) and DIAD (1.7 g, 8.3 mmol, 3 equiv) in THF (100 mL) was added 7 (500 mg, 2.7 mmol, 1 equiv) at 0 °C. The reaction mixture was stirred at room temperature overnight. The solution was concentrated in vacuo and the residue was purified by silica gel chromatography to afford compound 8 (330 mg).

[0347] To a solution of 8 (326 mg, 2.0 mmol, 1 equiv) in DCM (10 mL) was added SO3DMF (918 mg, 6.0 mmol, 3 equiv) in a microwave tube. The mixture was heated to 70 °C for 1 h with microwave. When the reaction was complete, a dark solid was taken out. The solvent was decanted and the solid was dissolved in water (20 mL) and lyophilized to give a crude mixture of compound 9 (400 mg), which was used directly without further purification.

[0348] To a solution of 9 (670 mg, 2.76 mmol, 1 equiv) in ACN (5 mL) was added Na2CO3 (584 mg, 5.51 mmol, 2 equiv). The mixture was stirred at room temperature for 30 min and then evaporated to dryness under reduced pressure. Then SOCl2 (10 mL) was added. The mixture was heated to 80 °C for 40 min and then evaporated to dryness to afford 10, which was used directly in the next step.

[0349] To a solution of 10 in THF (5 mL) was slowly added NH4OH (5 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to afford 11 (270 mg).

[0350] To a solution of 11 (120 mg, 0.50 mmol, 1.0 equiv) in dry THF (15 mL) was added a solution of t-BuONa (240 mg, 2.5 mmol, 5.0 equiv) at 0 °C under N2. The mixture was stirred at room temperature for 15 min. Then a solution of 11’ (250 mg, 0.75 mmol, 1.5 equiv) was added to the reaction mixture at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to afford 12 (200 mg). LCMS: [M+1] + = 442.

[0351] To an aqueous NaOH solution (22.7 mL, 0.02 N NaOH) was added 12 (200 mg, 0.454 mmol, 1.0 equiv) at 0 °C. The reaction was stirred at room temperature for 30 min. The mixture was then lyophilized to give compound 13 as a pale yellow solid. LCMS: [M-Na+1] + = 442.15. 1 1H NMR (400 MHz, CD3OD) δ 6.85 (s, 1H), 6.67 (s, 1H), 3.87 (s, 2H), 3.22 - 3.10 (m, 2H), 3.04 - 2.95 (m, 3H), 2.81 (t, J = 7.2 Hz, 4H), 2.06 - 1.91 (m, 8H).

[0352] To a solution of a (3.8 g, 21.97 mmol, 1.0 equiv) in dry DCM (50 mL) were slowly added pyridine (10.97 mL, 136.24 mmol, 6.0 equiv) and b (3.99 g, 19.77 mmol, 0.9 equiv) at 0 °C under N2. The reaction mixture was then stirred at room temperature for 2 h. The mixture was diluted with DCM (300 mL) and washed with 0.6 M HCl (300 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 11’ (6.5 g), which was used without further purification.

[0353] Example 2: Synthesis of Sodium ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)((4,6,7,8 - tetrahydro - 5,8 - ethanothieno[3,2 - c]azepin - 2 - yl)sulfonyl)amide (26)

[0354]

Chemical Structure

[0355] To a solution of 15 (3.06 g, 13.46 mmol, 1.0 equiv) in EtOH (30 mL) and H2O (10 mL) was slowly added NaOH (1.62 g, 40.39 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The pH was adjusted to 2 with 3 M HCl. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (80 mL × 3), brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give Compound 16 (2.4 g), which was used in the next step without further purification.

[0356] To a solution of 16 (1.94 g, 9.7 mmol, 1.0 equiv) in MsOH (40 mL) was added a solution of P2O5 (6.9 g, 48.7 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred at 130 °C overnight. The reaction mixture was poured into ice water (200 mL) and extracted with DCM. The combined organic layers were concentrated in vacuo and purified by silica gel chromatography to give Compound 17 (1.24 g).

[0357] To a solution of 4’ (1.56 g, 6.95 mmol, 1.2 eq) was added NaH (1.26 g, 54 mmol, 1.5 eq) at 0 °C. After stirring at 0 °C for 30 min, 17 (1.05 g, 5.8 mmol, 1.0 eq) was added. The mixture was stirred at room temperature overnight. Water (40 mL) was added dropwise at 0 °C. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (40 mL × 3), brine (40 mL), dried over Na2SO4, and concentrated in vacuo to give compound 18 (1.2 g), which was used in the next step without further purification.

[0358] To a solution of 5 (1.2 g, 4.78 mmol, 1.0 eq) in MeOH (40 mL) and THF (4 mL) was added Mg (470 mg, 19.10 mmol, 4.0 eq). The reaction mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 1 with 3 M HCl and extracted with DCM (30 mL × 3). The combined organic layers were washed with NaHCO3 (45 mL), brine (45 mL), dried over Na2SO4, and concentrated in vacuo to give 19 (1.2 g).

[0359] To a solution of 19 (1.2 g, 50.14 mmol, 1.0 eq) in THF (40 mL) was added LAH (3.8 g, 100.29 mmol, 20.0 eq). The reaction mixture was stirred at 80 °C overnight. The mixture was cooled and quenched with ice-water (10 mL), NaOH (3 N, 5 mL), and water (30 mL). The mixture was filtered and the filtrate was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 20 (270 mg).

[0360] To a mixture of 7 (270 mg, 1.37 mmol, 1.0 eq) and PPh3 (1.26 g, 4.79 mmol, 3.5 eq) in dry THF (50 mL) was added DIAD (830 mg, 4.11 mmol, 3.0 eq) slowly at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give 21 (180 mg).

[0361] A mixture of 21 (156 mg, 0.87 mmol, 1.0 equiv) and SO3·DMF (400 mg, 2.61 mmol, 3.0 equiv) in DCM (5 mL) was stirred under microwave at 70 °C for 1 h. The mixture was concentrated in vacuo to give 22 (200 mg), which was used directly without further purification.

[0362] A solution of 22 (90 mg, 0.35 mmol, 1.0 equiv) in SOCl2 (4 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated in vacuo to give 23, which was used in the next step without further purification.

[0363] NH4OH (3 mL) was slowly added to a solution of 23 in THF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give 24 (45 mg).

[0364] A solution of t-BuONa (47 mg, 0.48 mmol, 5.0 equiv) was added to a solution of 11 (25 mg, 0.1 mmol, 1.0 equiv) in dry THF (3 mL) at 0 °C under N2. The mixture was stirred at room temperature for 15 min. Then a solution of 11’ (50 mg, 0.15 mmol, 1.5 equiv) was added to the reaction mixture at 0 °C and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give 25 (36 mg). LCMS: [M+1] + = 458.

[0365] 25 (36 mg, 0.078 mmol, 1.0 equiv) was added to an aqueous NaOH solution (7.8 mL, 0.01 N NaOH) at 0 °C. The reaction was stirred at room temperature for 30 min. Then the mixture was lyophilized to give compound 26 (36 mg) as a pale yellow solid. LCMS: 2.75 min, [M - Na + 1] + = 458.1. 1HNMR (400 MHz, D2O) δ 7.32 (s, 1H), 7.09 (s, 1H), 4.08 (s, 2H), 3.16~3.09 (m, 3H), 3.20~2.95 (m, 2H), 2.88 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 2.07~2.01 (m, 8H).

[0366] Compound 27 - 44 was prepared by the same procedure as described in the preceding examples.

[0367]

Table 2 - 1

[0368]

Table 2 - 2

[0369]

Table 2 - 3

[0370] Compound 45 - 54 was prepared by the same procedure as described in the preceding examples.

[0371]

Table 3 - 1

[0372]

Table 3 - 2

[0373] Example 3: Mouse BMDM IL - 1β Assay Mouse bone marrow cells derived from C57BL6 tibia and femur were cultured at a density of 50 million cells per 15-cm Petri dish in complete Isocov’s Media (BMDM medium) supplemented with 20 ng / mL of MCSF. The medium was changed every 3 days, and bone marrow-derived macrophages were collected, washed, and counted on day 7. The cells were seeded at a density of 5×10 4 cells per well in 100 μL of BMDM medium in a 96-well plate and cultured overnight. The cells were stimulated with 200 ng / mL of Ultrapure LPS-B5 at 37 °C 3 hours before adding the pre-diluted compound. 45 minutes after adding the compound, 5 mM of ATP was added for 45 minutes for secondary stimulation. After stimulation, the plates were briefly centrifuged, and 50 μL of supernatant was collected from each well. ELISA for mouse IL-1b was performed with 1:10 and 1:100 diluted supernatants using a pre-coated kit. The IL-1b concentration was calculated based on a pre-titrated standard, and the compound inhibition IC50 was obtained using the Levenberg Marquardt damped least squares method.

[0374] IC 50 values are shown in the following table.

[0375]

Table 4

[0376] Example 4: Human Whole Blood (HWB) IL-1b Assay An assay experiment as described in Tran et al., “Whole blood assay as a model for in vitro evaluation of inflammasome activation and subsequent caspase-mediated interleukin-1 beta release”, PLoS ONE 14(4): e0214999, https: / / doi.org / 10.1371 / journal.pone.0214999. That is, freshly drawn human whole blood containing an anticoagulant was incubated with a test compound at various titration points for 0.5 hours at 37°C in 5% CO2. Subsequently, the cells were primed with 100 ng / mL of LPS for 3.5 hours at 37°C and then further stimulated with 5 mM of ATP for 45 minutes. The supernatant was collected and the human IL-1β concentration was analyzed using a commercially available ELISA kit.

[0377] IC 50 values are shown in the following table.

[0378]

Table 5

[0379] Example 5: Monocyte IL-1β assay Human PBMCs were collected from fresh donor blood using a Ficoll gradient. 50 million PBMC cells in 10 mL of RPMI were seeded into a 15 cm non-tissue culture treated Petri dish and incubated at 37°C for 1 hour. At the end of the incubation, the medium was gently agitated to remove non-adherent cells. The adherent cells were gently scraped and collected and counted. The enriched adherent cells were seeded into a 96-well plate at 2×10 cells per well 4Plated at a density of [quantity] cells per well, stimulated with 200 ng / mL of Ultrapure LPS-B5 for 3 hours, and then added the pre-diluted compound. 30 minutes after the addition of the compound, 5 mM of ATP was added for 45 minutes for secondary stimulation. After stimulation, the plates were gently centrifuged and 50 μL of supernatant was collected from each well. ELISA for human IL-1β was performed using a pre-coated kit with supernatants diluted 1:10 and 1:100. The IL-1β concentration was calculated based on a pre-titrated standard, and the compound inhibition IC50 was obtained using the Levenberg Marquardt attenuated least squares method.

[0380] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or changes are included within the scope of the disclosure and the scope of the appended claims.

Claims

1. A compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein 【Chemical 1】 wherein X １ is O, S, or N(R ３ ) and X ２ is -N(R ４ )- or -C(R ４ ) ２ - and is X ３ is -N(R ５ )- or -C(R ５ ) ２ - and Y １ is O, S, or N(R ８ ) and Y ２ is N or C(R ９ ) and Z １ is O, S, N(R ３ ), or -C(R １７ )=C(R １７ ), and Z ２ is N or C(R １９ ) and R １ is 【Chemical 2】 and R ２ is [Chemical Formula 3] and R ３ is hydrogen, -OR １４ , -CN, -NO ２ , or -S(=O) ２ R １５ and Each R ４ is hydrogen, C １ ~C ６ alkyl, -C １ ~C ６ alkyl-OR ７ and -C １ ~C ６ alkyl-N(R ７ ) ２ is independently selected from, Each R ５ is hydrogen, C １ to C ６ alkyl, -C １ to C ６ alkyl - OR ７ and -C １ to C ６ alkyl - N(R ７ ) ２ is independently selected from, Each R ６ is C １ to C ６ alkyl, -C １ to C ６ alkyl-CO ２ R １８ , C １ to C ６ haloalkyl, -C １ to C ６ alkyl-OR ７ , and -C １ to C ６ alkyl-N(R ７ ) ２ is independently selected from, Each R ７ is independently selected from hydrogen and C １ to C ６ alkyl, R ８ is hydrogen, C １ to C ６ alkyl, -C １ to C ６ alkyl - OR ７ , -C １ to C ６ alkyl - N(R ７ ) ２ , or C ３ to C ６ cycloalkyl, R ９ is hydrogen, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, or C ３ to C ６ cycloalkyl, and R １０ is hydrogen, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, -C １ to C ６ alkyl - OR ７ or -C １ to C ６ alkyl - N(R ７ ) ２ and R １１ and R １２ are each independently selected from hydrogen, halogen, C １ -C ６ -C １ -C ６ haloalkyl, -C １ -C ６ alkyl-OR ７ and -C １ -C ６ alkyl-N(R ７ ) ２ or R １１ and R １２ are joined to form a 5- or 6-membered cycloalkyl ring, R １３ is hydrogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ５ cycloalkyl, C ２ -C ９ heterocycloalkyl, phenyl, or C ２ -C ９ heteroaryl, where C ３ -C ５ cycloalkyl, C ２ -C ９ heterocycloalkyl, phenyl, and C ２ -C ９ heteroaryl may optionally be substituted by 1, 2, 3, or 4 R １６ and may be R １４ is hydrogen or C １ to C ６ alkyl, and R １５ is C １ to C ６ alkyl, Each R １６ is halogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkoxy, C １ -C ６ -haloalkoxy, C ３ -C ６ -cycloalkyl, C ２ -C ９ -heterocycloalkyl, C ６ -C １０ -aryl, C ２ -C ９ -heteroaryl, independently selected from, where C ３ -C ６ -cycloalkyl, C ２ -C ９ -heterocycloalkyl, C ６ -C １０ -aryl, C ２ -C ９ -heteroaryl may optionally be substituted with one, two, or three groups selected from halogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkoxy, and C １ -C ６ -haloalkoxy, and may be substituted, Each R １７ is hydrogen, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, -C １ to C ６ alkyl-OR ７ and -C １ to C ６ alkyl-N(R ７ ) ２ is independently selected from, R １８ is hydrogen or C １ ~C ６ alkyl, and R １９ is hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, -C １ ~C ６ alkyl-OR ７ , or -C １ ~C ６ alkyl-N(R ７ ) ２ and m is 0, 1, or 2; n is 1, 2, or 3; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; s is 1, 2, or 3; t is 1, 2, or 3, the compound, or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein 【Chemical Formula 4】 wherein X １ is O, S, or N(R ３ ) and X ２ is -N(R ４ )- or -C(R ４ ) ２ - and X ３ is -N(R ５ )- or -C(R ５ ) ２ - and Y １ is O, S, or N(R ８ ) and Y ２ is N or C(R ９ ) and Z １ is O, S, N(R ３ ), or -C(R １７ )=C(R １７ )-, and Z ２ is N or C(R １９ ) and R １ is 【Chemical Formula 5】 and R ２ is 【Chemical Formula 6】 and R ３ is hydrogen, -OR １４ , -CN, -NO ２ , or -S(=O) ２ R １５ and Each R ４ is hydrogen, C １ -C ６ -C １ -C ６ alkyl - OR ７ and - C １ -C ６ alkyl - N(R ７ ) ２ is independently selected from, Each R ５ is hydrogen, C １ ~C ６ alkyl, -C １ ~C ６ alkyl - OR ７ and -C １ ~C ６ alkyl - N(R ７ ) ２ is independently selected from, Each R ６ is C １ to C ６ alkyl, -C １ to C ６ alkyl-CO ２ R １８ , C １ to C ６ haloalkyl, -C １ to C ６ alkyl-OR ７ , and -C １ to C ６ alkyl-N(R ７ ) ２ is independently selected from, Each R ７ is independently selected from hydrogen and C １ ~C ６ alkyl, R ８ is hydrogen, C １ ~C ６ alkyl, -C １ ~C ６ alkyl-OR ７ , -C １ ~C ６ alkyl-N(R ７ ) ２ , or C ３ ~C ６ cycloalkyl, and R ９ is hydrogen, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, or C ３ to C ６ cycloalkyl, and R １０ is hydrogen, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, -C １ to C ６ alkyl-OR ７ or -C １ to C ６ alkyl-N(R ７ ) ２ wherein, R １１ and R １２ are halogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -C １ -C ６ alkyl-OR ７ and -C １ -C ６ alkyl-N(R ７ ) ２ are independently selected from, or R １１ and R １２ are joined to form a 5- or 6-membered cycloalkyl ring, R １３ is phenyl or C ２ ~C ９ -heteroaryl, wherein phenyl and C ２ ~C ９ -heteroaryl may optionally be substituted by 1, 2, 3, or 4 R １６ and may be R １４ is hydrogen or C １ ~C ６ alkyl, and R １５ is C １ to C ６ alkyl, and Each R １６ is halogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkoxy, C １ -C ６ -haloalkoxy, C ３ -C ６ -cycloalkyl, C ２ -C ９ -heterocycloalkyl, C ６ -C １０ -aryl, C ２ -C ９ -heteroaryl, independently selected from, where C ３ -C ６ -cycloalkyl, C ２ -C ９ -heterocycloalkyl, C ６ -C １０ -aryl, C ２ -C ９ -heteroaryl may optionally be substituted with 1, 2, or 3 groups selected from halogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkoxy, and C １ -C ６ -haloalkoxy, and may be substituted, Each R １７ is hydrogen, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, -C １ to C ６ alkyl - OR ７ and -C １ to C ６ alkyl - N(R ７ ) ２ is independently selected from, R １８ is hydrogen or C １ to C ６ alkyl, and R １９ is hydrogen, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, -C １ ~C ６ alkyl - OR ７ , or -C １ ~C ６ alkyl - N(R ７ ) ２ and m is 0, 1, or 2; n is 1, 2, or 3; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; s is 1, 2, or 3; t is 1, 2, or 3, the compound, or a pharmaceutically acceptable salt or solvate thereof.

3. R １ is [Chemical Formula 7] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein

4. R １ is [Chemical Formula 8] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein

5. Y ２ is C(R ９ ), a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof.

6. R ９ is hydrogen or C １ -C ６ -C alkyl, the compound according to claim 5, or a pharmaceutically acceptable salt or solvate thereof.

7. R ９ The compound according to claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

8. Y ２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

9. Y １ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O.

10. Y １ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S.

11. Y １ is N(R ８ ), a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof.

12. R ８ is hydrogen, C １ ~C ６ alkyl, or C ３ ~C ６ cycloalkyl, the compound according to claim 11, or a pharmaceutically acceptable salt or solvate thereof.

13. R ８ The compound according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

14. R ８ is C １ to C ６ The compound according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C to C alkyl.

15. R ８ is C ３ to C ６ The compound according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C to C cycloalkyl.

16. R １ is 【Chemical Formula 9】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein

17. R １ is 【Chemical Formula 10】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein

18. R １０ The compound according to claim 16 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

19. Each R ６ is C １ -C ６ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, which is independently selected from alkyls.

20. each R ６ is -CH ３ The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

22. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

23. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3.

24. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

26. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

29. R １ is 【Chemical 11】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, which is [specific condition].

30. R １ is 【Chemical 12】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, which is [specific condition].

31. R ２ is 【Chemical 13】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, which is [specific condition].

32. R ２ is 【Chemical 14】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, which is [specific condition].

33. The compound according to claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1.

34. The compound according to any one of claims 31 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein t is 1.

35. Z ２ is C(R １９ ), the compound according to any one of claims 31 to 34, or a pharmaceutically acceptable salt or solvate thereof.

36. R １９ The compound according to claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

37. R １９ The compound according to claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R is halogen.

38. Z ２ The compound according to any one of claims 31 to 34, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

39. R ２ is 【Chemical Formula 15】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, which is [specific condition].

40. Z １ The compound according to claim 39, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is S.

41. Z １ The compound according to claim 39, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is O.

42. Z １ is -C(R １７ )=C(R １７ ), the compound according to claim 39, or a pharmaceutically acceptable salt or solvate thereof.

43. Each R １７ The compound according to claim 42, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently selected from hydrogen and halogen.

44. each R １７ The compound according to claim 42, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is hydrogen.

45. R １１ and R １２ The compound according to any one of claims 39 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein R and R are combined to form a 5- or 6-membered cycloalkyl ring.

46. R １１ and R １２ The compound according to any one of claims 39 to 45, or a pharmaceutically acceptable salt or solvate thereof, wherein R and R are combined to form a 5-membered cycloalkyl ring.

47. R １１ and R １２ are each independently selected from hydrogen, halogen, and C １ -C ６ alkyl, a compound according to any one of claims 39 to 44, or a pharmaceutically acceptable salt or solvate thereof.

48. R １３ wherein R may be optionally substituted by one, two, three or four R １６ and is phenyl, a compound according to any one of claims 39 to 47, or a pharmaceutically acceptable salt or solvate thereof.

49. R １３ which may optionally be substituted by one, two, three or four R １６ C ２ ~C ９ The compound according to any one of claims 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, which is heteroaryl.

50. R １３ wherein R is optionally substituted by one, two, three or four R １６ which is pyridyl, or a pharmaceutically acceptable salt or solvate thereof, according to claim 49.

51. Each R １６ is independently selected from halogen, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, and C １ ~C ６ alkoxy, a compound according to any one of claims 48 to 50, or a pharmaceutically acceptable salt or solvate thereof.

52. Each R １６ is C １ to C ６ alkoxy, the compound according to claim 51, or a pharmaceutically acceptable salt or solvate thereof.

53. R １３ is C １ -C ６ alkyl, a compound according to any one of claims 39 to 47, or a pharmaceutically acceptable salt or solvate thereof.

54. R １３ is C ３ -C ５ The compound according to any one of claims 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl.

55. R ２ is 【Chemical 16】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or solvate thereof, which is [specific condition].

56. X ２ is -N(R ４ ), the compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt or solvate thereof.

57. each R ４ The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is hydrogen.

58. X ３ is -N(R ５ )-, a compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof.

59. X ３ is -C(R ５ ) ２ -, a compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof.

60. Each R ５ is hydrogen, a compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt or solvate thereof.

61. X １ The compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.

62. 【Fig. 17】 A compound selected from [list], or a pharmaceutically acceptable salt or solvate thereof.

63. 【Fig. 18】 【Chemical 19】 A compound selected from [list], or a pharmaceutically acceptable salt or solvate thereof.

64. 【Fig. 20】 【Chemical 21】 A compound selected from [list], or a pharmaceutically acceptable salt or solvate thereof.

65. A pharmaceutical composition comprising the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

66. A method for treating a metabolic disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof.

67. The method according to claim 66, wherein the metabolic disorder is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

68. A method for treating a liver disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof.

69. The method according to claim 68, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

70. A method for treating a lung disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof.

71. The method according to claim 70, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

72. A method for treating a central nervous system disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof.

73. The method according to claim 72, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease.

74. A method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof.

75. The method according to claim 74, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus erythematosus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

76. A method for treating a cardiovascular disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof.

77. The method according to claim 76, wherein the cardiovascular disease is atherosclerosis or stroke.

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