Combination therapies

Abstract

Described herein are methods of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) and a second therapeutic agent comprising a GLP-1 receptor agonist, wherein the compound of Formula (I) has the structure: Formula (I); wherein X1, X2, X3, R1, and R2 are defined herein.

Description

WSGR Docket No.56756-712.601 COMBINATION THERAPIES CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No.63 / 657,685, filed on June 7, 2024, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] Obesity is a chronic health condition that raises the risk for diabetes, heart disease, stroke, arthritis, and some cancers. The economic burden is estimated to be about $100 billion annually in the United States alone. Practicing healthier eating habits and increased physical activity are key to weight loss. In addition to these lifestyle changes, medication may aid in obesity treatment. SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I); 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(R17)=C(R17)-; Z2 is N or C(R19); ,- 1 -WSGR Docket No.56756-712.601 ;3 s y rogen, - 14, - , - 2, or - ( O)2R15; each R4 is independently selected from hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, and -C1- C6alkyl-N(R7)2; each R5 is independently selected from hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, and -C1- C6alkyl-N(R7)2; each R6 is independently selected from C1-C6alkyl, -C1-C6alkyl-CO2R18, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; each R7 is independently selected from hydrogen and C1-C6alkyl; R8 is hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, -C1-C6alkyl-N(R7)2, or C3-C6cycloalkyl; R9 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; R10 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- N(R7)2; R11 and R12 are independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, - C1-C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; or R11and R12are combined to form a 5- or 6- membered cycloalkyl ring; R13 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C5cycloalkyl, C2-C9heterocycloalkyl, phenyl, or C2-C9heteroaryl, wherein C3-C5cycloalkyl, C2- C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R16; R14 is hydrogen or C1-C6alkyl; R15 is C1-C6alkyl; each R16 is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl, wherein C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; each R17is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; R18 is hydrogen or C1-C6alkyl; - 2 -WSGR Docket No.56756-712.601 R19 is hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- 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; and t is 1, 2, or 3; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist.

[0004] In some embodiments of the methods described herein,some embodiments, some embodiments,Y2 is C(R9). In some embodiments, R9 is hydrogen or C1-C6alkyl. In some embodiments, R9 is hydrogen. In some embodiments, Y2 is N. In some embodiments, Y1 is O. In some embodiments, Y1 is S. In some embodiments, Y1 is N(R8). In some embodiments, R8 is hydrogen, C1-C6alkyl, or C3- C6cycloalkyl. In some embodiments, R8 is hydrogen. In some embodiments, R8 is C1-C6alkyl. In some embodiments, R8 is C3-C6cycloalkyl. In some embodiments,some embodiments, some embodiments, R10 is hydrogen. In some embodiments, each R6 is independently selected from C1-C6alkyl. In some embodiments, each R6 is -CH3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 0. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, m is 1. In some embodiments, p is 1. In some embodiments, R1 is ,- 3 -WSGR Docket No.56756-712.601 . In some embodiments, R2 issome embodiments, s is 1. In some embodiments, t is 1. In some embodiments, Z2 is C(R19). In some embodiments, R19 is hydrogen. In some embodiments, R19 is halogen. In some embodiments, Z2 is N. In some embodiments, R2 some embodiments, Z1 is S. In some embodiments, Z1 is O. In someembodiments, Z1 is -C(R17)=C(R17)-. In some embodiments, each R17 is independently selected from hydrogen and halogen. In some embodiments, each R17 is hydrogen. In some embodiments, R11 and R12 are combined to form a 5- or 6-membered cycloalkyl ring. In some embodiments, R11 and R12 are combined to form a 5-membered cycloalkyl ring. In someembodiments, R11 and R12 are independently selected from hydrogen, halogen, and C1-C6alkyl.In some embodiments, R13 is phenyl optionally substituted by 1, 2, 3, or 4 R16. In some embodiments, R13 is C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 R16. In some embodiments, R13 is pyridyl optionally substituted by 1, 2, 3, or 4 R16. In some embodiments, each R16 is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy. In some embodiments, each R16 is C1-C6alkoxy. In some embodiments, R13 is C1-C6alkyl. In some embodiments, R13 is C3-C5cycloalkyl. In some embodiments, ,some embodiments, X2 is -N(R4)-. In some embodiments, each R4 ishydrogen. In some embodiments, X3 is -N(R5)-. In some embodiments, X3 is -C(R5)2-. In some embodiments, each R5 is hydrogen. In some embodiments, X1 is O. - 4 -WSGR Docket No.56756-712.601

[0005] In some embodiments of the methods described herein, the second therapeutic agent is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments of the methods described herein, the second therapeutic agent is semaglutide.

[0006] In some embodiments of the methods described herein, the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout. In some embodiments, the metabolic disease is obesity.

[0007] In some embodiments of the methods described herein, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered simultaneously. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered sequentially. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions. INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein 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. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0009] In the context of this disclosure, a number of terms shall be utilized.

[0010] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information. - 5 -WSGR Docket No.56756-712.601

[0011] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the 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. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0012] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0013] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used.

[0014] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0015] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0016] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. C1-Cxrefers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

[0017] An “alkyl” group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. In some embodiments, the - 6 -WSGR Docket No.56756-712.601 “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “C1-C6alkyl” or similar designations. By way of example only, “C1- C6alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0018] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.

[0019] The term “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, - CH=CHCH3, -CH=C(CH3)2 and –C(CH3)=CHCH3. In some embodiments, an alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0020] The term “alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond. Non-limiting examples of an alkynyl group include –C≡CH, -C≡CCH3, –C≡CCH2CH3and –C≡CCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons.Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0021] “Amino” refers to a -NH2 group.

[0022] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHy group, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2 group, where alkyl is as defined herein.

[0023] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl). - 7 -WSGR Docket No.56756-712.601

[0024] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0025] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to, O O N N N O N S N ,

[0026] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0027] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0028] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in - 8 -WSGR Docket No.56756-712.601 a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0029] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0030] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0031] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH2F, - OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like.

[0032] The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior 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. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O- Si(CH3)3. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

[0033] 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 larger substructure.

[0034] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0035] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0036] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.

[0037] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected - 9 -WSGR Docket No.56756-712.601 from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. –NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituents may be LsRs, wherein each Lsis 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-C6alkyl)-, or -(C2- C6alkenyl)-; and each Rsis independently selected from among H, (C1-C6alkyl), (C3- C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

[0038] As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0039] The term a “therapeutically effective amount” as used herein refers to the amount of a NLRP3 inhibitor that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent diseases or conditions described herein.

[0040] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0041] The term “modulate” encompasses either a decrease or an increase in activity or expression depending on the target molecule.

[0042] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

[0043] The term “subject”, “patient”, or “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0044] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass 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. - 10 -WSGR Docket No.56756-712.601

[0045] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, 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, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (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 forms with a sufficient amount of the desired acid to produce the salt.

[0046] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with 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, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra. - 11 -WSGR Docket No.56756-712.601

[0047] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. NLRP3 inhibitor / GLP-1 agonist combinations

[0048] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). NLRP3 has been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

[0049] Glucogen-like peptide-1 (GLP-1) is an important, gut-derived, incretin hormone; this glucose homeostasis regulator is released after the oral ingestion of carbohydrates or fats. GLP-1 receptor agonists bind to and activate the GLP-1 receptor, enhancing insulin secretion and slowing gastric emptying. Some GLP-1 receptor agonists are FDA-approved for weight loss and weight management in individuals with obesity, but there is a need for improved therapies.

[0050] The central nervous system (CNS) plays a major role in the regulation of metabolic balance and energy homeostasis. Activation of nonneuronal cells, such as microglia and astrocytes, has been demonstrated to be associated with excessive weight gain in animal models through impairment of the hypothalamic energy homeostasis system. This “reactive gliosis” response involves entry of saturated fatty acids into the cerebrospinal fluid through diet, which leads to inflammatory activation of hypothalamic microglia. This neuroinflammatory response is a potentially important aspect in the pathogenesis of diet-induced obesity. For the energy homeostasis system to function properly, key hypothalamic neurons provide “adiposity negative feedback” from signals such as insulin and leptin. Impaired neuronal responsiveness to these signals likely results in the obesogenic effect of hypothalamic gliosis.

[0051] One of the major pathways by which innate immune cells integrate pathogen- and damage-associated signals with inflammation is via assembly and activation of intracellular - 12 -WSGR Docket No.56756-712.601 protein complexes known as inflammasomes. Inflammasome activation is implicated in a range of inflammatory diseases.

[0052] Saturated fatty acids, present during obesity, are potential activators of the NLRP3 inflammasome. Chronic low-grade inflammation is observed in subjects with obesity, both peripherally in adipose tissues and centrally in the hypothalamus. Nonclinical research has demonstrated this relationship between NLRP3 and obesity, as Nlrp3-knockout mice have been shown to be protected from diet-induced obesity. In addition, dosing with a selective NLRP3 inhibitors demonstrated reversal of diet-induced obesity (DIO) in mice. The effect of NLRP3 inhibition was associated with enhanced reductions in hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk compared to semaglutide treatment or calorie restriction. In the evaluation of these NLRP3 inhibitors, inflammatory responses played a key role in driving obesity, and NLRP3 activation in the brain was implicated in the pathogenesis of obesity.

[0053] NLRP3 inhibitors have also been shown in DIO models to work in combination with GLP-1 agonists, resulting in superior weight loss and improvement in a broad range of inflammatory and metabolic parameters or biomarkers, significantly greater than that observed with the GLP-1 agonist alone.

[0054] The compounds of Formula (I) or (Ia) described herein are NLRP3 modulators. In some embodiments, compounds of Formula (I) or (Ia) described herein, in combination with a GLP-1 receptor agonist described herein, are useful for the treatment of metabolic diseases including, but not limited to, type 2 diabetes, atherosclerosis, obesity, and gout.

[0055] In some embodiments, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I); 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(R17)=C(R17)-; Z2 is N or C(R19); - 13 -WSGR Docket No.56756-712.601 ,3 s ydrogen, -O 14, -CN, -NO2, or -S( O)2 15; each R4 is independently selected from hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, and -C1- C6alkyl-N(R7)2; each R5 is independently selected from hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, and -C1- C6alkyl-N(R7)2;each R6 is independently selected from C1-C6alkyl, -C1-C6alkyl-CO2R18, C1-C6haloalkyl, -C1-C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; each R7 is independently selected from hydrogen and C1-C6alkyl; R8 is hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, -C1-C6alkyl-N(R7)2, or C3-C6cycloalkyl; R9 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; R10 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- N(R7)2; R11 and R12 are independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, - C1-C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; or R11 and R12 are combined to form a 5- or 6- membered cycloalkyl ring; R13 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C5cycloalkyl, C2-C9heterocycloalkyl, phenyl, or C2-C9heteroaryl, wherein C3-C5cycloalkyl, C2- C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R16; R14 is hydrogen or C1-C6alkyl; R15 is C1-C6alkyl; each R16 is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl, - 14 -WSGR Docket No.56756-712.601 wherein C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; each R17 is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; R18 is hydrogen or C1-C6alkyl; R19 is hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- 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; and t is 1, 2, or 3; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon- like peptide-1 (GLP-1) receptor agonist.

[0056] In some embodiments of the methods described herein,some embodiments of the methods described herein, someembodiments of the methods described herein, someembodiments of the methods described herein,embodiments of the methods described herein, .- 15 -WSGR Docket No.56756-712.601

[0057] In some embodiments of the methods described herein, m is 1. In some embodiments of the methods described herein, m is 0. In some embodiments of the methods described herein, m is 2.

[0058] In some embodiments of the methods described herein, p is 1. In some embodiments of the methods described herein, p is 0. In some embodiments of the methods described herein, p is 2.

[0059] In some embodiments of the methods described herein, m is 1 and p is 1.

[0060] In some embodiments of the methods described herein, each R7 is independently selected from C1-C6alkyl, -C1-C6alkyl-CO2R18, C1-C6haloalkyl, and C1-C6heteroalkyl. In some embodiments of the methods described herein, each R7 is independently selected from C1- C6alkyl, -C1-C6alkyl-CO2R18, and C1-C6haloalkyl. In some embodiments of the methods described herein, each R7 is independently selected from C1-C6alkyl. In some embodiments of the methods described herein, each R7 is -CH3.

[0061] In some embodiments of the methods described herein, q is 0, 1, 2, or 3. In some embodiments of the methods described herein, q is 0. In some embodiments of the methods described herein, q is 1. In some embodiments of the methods described herein, q is 2. In some embodiments of the methods described herein, q is 3. In some embodiments of the methods described herein, q is 4.

[0062] In some embodiments of the methods described herein, R1 is ,. [] n some em o ments o the methods described herein, Y1 is O. In some embodiments of the methods described herein, Y1 is S. In some embodiments of the methods described herein, Y1 is N(R8). In some embodiments of the methods described herein, Y1 is N(R8) and R8 is hydrogen or C1-C6alkyl.

[0064] In some embodiments of the methods described herein, Y2 is N. In some embodiments of the methods described herein, Y2 is C(R9). In some embodiments of the methods described herein, Y2 is C(R9) and R9 is selected from hydrogen and C1-C6alkyl. In some embodiments of the methods described herein, Y2 is C(R9) and R9 is hydrogen. In some embodiments of the methods described herein, Y2 is C(R9) and R9 is C1-C6alkyl. - 16 -WSGR Docket No.56756-712.601

[0065] In some embodiments of the methods described herein, R1 is ,some embodiments of the methods described herein, R1 is . In some embodimentsof the methods described herein, some embodiments of the methodsdescribed herein, R1 is . In some embodiments of the methods described herein,. In some embodiments of the methods described herein, R1 is. In some embodiments of the methods described herein,some embodiments of the methods described herein, .- 17 -WSGR Docket No.56756-712.601

[0066] In some embodiments of the methods described herein, someembodiments of the methods described herein, someembodiments of the methods described herein,some embodiments of the methods described herein,C(H). In some embodiments of the methods described herein, Z2 is N.- 18 -WSGR Docket No.56756-712.601

[0067] In some embodiments of the methods described herein, someembodiments of the methods described herein, someembodiments of the methods described herein,some embodiments of the methods described herein,C(H). In some embodiments of the methods described herein, Z2 is N.

[0068] In some embodiments of the methods described herein,embodiments of the methods described herein, some- 19 -WSGR Docket No.56756-712.601 embodiments of the methods described herein,some embodiments of the methods described herein, , and each R17 is independently selected from hydrogenan a ogen. n some em o men s o the methods described herein, some embodiments of themethods described herein, are combined to form a 5- or 6- membered cycloalkyl ring.In some embodiments of the methods described herein, R2 is are combined to form a 5-membered cycloalkyl ring. In someembodiments of the methods described herein, are independently selected from hydrogen, halogen, and C1-C6alkyl. In some embodiments of the methods described herein, optionally substituted by1, 2, or 3 R16. In some embodiments of the methods described herein, is pyridyl optionally substituted by 1 or 2 R16. In some embodiments of the methods described herein, pyridyl optionally substituted by 1 or 2 R16, and each R16 is- 20 -WSGR Docket No.56756-712.601 independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy. In some embodiments of the methods described herein, pyridyl optionally substituted by 1 R16, and R16 is selected from haogen, 1- 6a y , 1-C6haloalkyl, and C1- C6alkoxy. In some embodiments of the methods described herein, pyridyl optionally substituted by 1 R16, and R16 is C1-C6alkoxy. Insome embod ments o the methods described herein, hydrogen, C1-C6alkyl, C1-C6haloalkyl, C r C -C h3-C5cycloalkyl, o 2 9 eterocycloalkyl. In some embodiments of the methods describeddescribed herein, C5cycloalkyl.

[0069] In some embodiments of the methods described herein, ,- 21 -WSGR Docket No.56756-712.601 some embodiments of the methods described herein, some embodiments ofthe methods described herein, some embodiments of the methodsdescribed herein, some embodiments of the methods described herein, R2some embodiments of the methods described herein,some embodiments of the methods described herein, some embodiments ofthe methods described herein, some embodiments of the methods- 22 -WSGR Docket No.56756-712.601

[0070] In some embodiments of the methods described herein, .

[0071] In some embodiments of the methods described herein, ,, [007 ] n some embod ments o t e met ods descrbed ere n, 2 s -N( 5)-. n some embodiments of the methods described herein, X2 is -N(R5)- and R5 is hydrogen. In some embodiments of the methods described herein, X2 is -N(R5)- and R5 is C1-C6alkyl. In some embodiments of the methods described herein, X2 is -C(R5)2-. In some embodiments of the methods described herein, X2 is -C(R5)2- and each R5 is hydrogen.

[0073] In some embodiments of the methods described herein, X3is -N(R5)-. In some embodiments of the methods described herein, X3 is -N(R5)- and R5 is hydrogen. In some embodiments of the methods described herein, X3 is -N(R5)- and R5 is C1-C6alkyl. In some embodiments of the methods described herein, X3 is -C(R5)2-. In some embodiments of the methods described herein, X3 is -C(R5)2- and each R5 is hydrogen.

[0074] In some embodiments of the methods described herein, X1 is O. In some embodiments of the methods described herein, X1 is S. In some embodiments of the methods described herein, X1 is N(R3).

[0075] In some embodiments, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: - 23 -WSGR Docket No.56756-712.601Formula (Ia); wherein: Y1 is O, S, or N(R8); Y2 is N or C(R9); Z1 is O, S, N(R3), or -C(R17)=C(R17)-; Z2 is N or C(R19); ,each R6 is independently selected from C1-C6alkyl, -C1-C6alkyl-CO2R18, C1-C6haloalkyl, -C1-C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; each R7 is independently selected from hydrogen and C1-C6alkyl; R8 is hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, -C1-C6alkyl-N(R7)2, or C3-C6cycloalkyl; R9 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; R10 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- N(R7)2; R11 and R12 are independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; or R11 and R12 are combined to form a 5- or 6- membered cycloalkyl ring; R13 is phenyl or C2-C9heteroaryl, wherein phenyl and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R16; each R16 is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl, wherein C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl are - 24 -WSGR Docket No.56756-712.601 optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; each R17 is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; R18 is hydrogen or C1-C6alkyl; R19 is hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1- C6alkyl-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; and t is 1, 2, or 3; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon- like peptide-1 (GLP-1) receptor agonist.

[0076] In some embodiments of the methods described herein,some embodiments of the methods described herein, someembodiments of the methods described herein,embodiments of the methods described herein,embodiments of the methods described herein, .

[0077] In some embodiments of the methods described herein, m is 1. In some embodiments of the methods described herein, m is 0. In some embodiments of the methods described herein, m is 2. - 25 -WSGR Docket No.56756-712.601

[0078] In some embodiments of the methods described herein, p is 1. In some embodiments of the methods described herein, p is 0. In some embodiments of the methods described herein, p is 2.

[0079] In some embodiments of the methods described herein, m is 1 and p is 1.

[0080] In some embodiments of the methods described herein, each R7 is independently selected from C1-C6alkyl, -C1-C6alkyl-CO2R18, C1-C6haloalkyl, and C1-C6heteroalkyl. In some embodiments of the methods described herein, each R7 is independently selected from C1- C6alkyl, -C1-C6alkyl-CO2R18, and C1-C6haloalkyl. In some embodiments of the methods described herein, each R7 is independently selected from C1-C6alkyl. In some embodiments of the methods described herein, each R7 is -CH3.

[0081] In some embodiments of the methods described herein, q is 0, 1, 2, or 3. In some embodiments of the methods described herein, q is 0. In some embodiments of the methods described herein, q is 1. In some embodiments of the methods described herein, q is 2. In some embodiments of the methods described herein, q is 3. In some embodiments of the methods described herein, q is 4. , [] n some em o ments o t e met o s escr e ere n, 1 s . n some embodiments of the methods described herein, Y1 is S. In some embodiments of the methods described herein, Y1 is N(R8). In some embodiments of the methods described herein, Y1 is N(R8) and R8 is hydrogen or C1-C6alkyl.

[0084] In some embodiments of the methods described herein, Y2 is N. In some embodiments of the methods described herein, Y2 is C(R9). In some embodiments of the methods described herein, Y2 is C(R9) and R9 is selected from hydrogen and C1-C6alkyl. In some embodiments of the methods described herein, Y2 is C(R9) and R9 is hydrogen. In some embodiments of the methods described herein, Y2 is C(R9) and R9 is C1-C6alkyl. ,- 26 -WSGR Docket No.56756-712.601 . Insome embodiments of the methods described herein, R1 is. In some embodiments of the methods described herein, some embodiments of the methodsdescribed herein, R1 is . In some embodiments of the methods described herein,. In some embodiments of the methods described herein, R1 is. In some embodiments of the methods described herein,some embodiments of the methods described herein, .

[0086] In some embodiments of the methods described herein,embodiments of the methods described herein, some- 27 -WSGR Docket No.56756-712.601 embodiments of the methods described herein,some embodiments of the methods described herein,C(H). In some embodiments of the methods described herein, Z2 is N.

[0087] In some embodiments of the methods described herein, someembodiments of the methods described herein, someembodiments of the methods described herein,some embodiments of the methods described herein,some embodiments of the methods described herein, are combined to form a 5- or 6-membered cycloalkyl ring. In some embodiments of the methods - 28 -WSGR Docket No.56756-712.601 described herein, optionally substituted by1, 2, or 3 R16. In some embodiments of the methods described herein, , and R13 is pyridyl optionally substituted by 1 or 2 R16. In some embodmens o e me os described herein, pyridyl optionally substituted by 1 or 2 R16, and each R16is indepenen y seece rom aogen, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy. In some embodiments of the methods described herein, pyridyl optionally substituted by 1 R16, and R16 is selected fromaogen, 1- 6a y, 1- 6aloalkyl, and C1-C6alkoxy. In some embodiments of the methods described herein, 1, R13 is pyridyl optionally substituted by 1 R16, and R16 is C1-C6alkoxy.

[0088] In some embodiments of the methods described herein, ,some embodiments of the methods described herein, some embodiments of- 29 -WSGR Docket No.56756-712.601 the methods described herein, some embodiments of the methodsdescribed herein, some embodiments of the methods described herein, R2some embodiments of the methods described herein,some embodiments of the methods described herein, some embodiments ofthe methods described herein, some embodiments of the methods

[0089] In some embodiments of the methods described herein, the compound of Formula (I) or (Ia) is selected from: - 30 -WSGR Docket No.56756-712.601 accepa e sa o sovae eeo.

[0090] In some embodiments of the methods described herein, the compound of Formula (I) or (Ia) is selected from:- 31 -WSGR Docket No.56756-712.601pharmaceutically acceptable salt or solvate thereof. [] n some emo ments o te methods described herein, the compound of Formula (I) or (Ia) is selected from: ,- 32 -WSGR Docket No.56756-712.601pharmaceutically acceptable salt or solvate thereof. [] n some em o ments o t e methods described herein, the second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments of the methods described herein, the second therapeutic agent is semaglutide. In some embodiments of the methods described herein, the second therapeutic agent is dulaglutide. In some embodiments of the methods described herein, the second therapeutic agent is liraglutide. In some embodiments of the methods described herein, the second therapeutic agent is exenatide. In some embodiments of the methods described herein, the second therapeutic agent is tirzepatide. In some embodiments of the methods described herein, the second therapeutic agent is lixisenatide. In some embodiments of the methods described herein, the second therapeutic agent is albiglutide.

[0093] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds. Further Forms of Compounds Disclosed Herein Isomers

[0094] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the - 33 -WSGR Docket No.56756-712.601 applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the 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 diastereoisomeric 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 distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. Labeled compounds

[0095] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,l5N,17O,18O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i. e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled - 34 -WSGR Docket No.56756-712.601 compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

[0096] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0097] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0098] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. Solvates

[0099] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0100] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. 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, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein 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 herein. - 35 -WSGR Docket No.56756-712.601 Synthesis of Compounds

[0101] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[0102] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

[0103] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in 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 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. Use of Protecting Groups

[0104] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0105] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, - 36 -WSGR Docket No.56756-712.601 methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0106] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0107] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd0-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

[0108] Typically blocking / protecting groups may be selected from:

[0109] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal 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 incorporated herein by reference for such disclosure). Methods of Treatment and Prevention

[0110] In some embodiments is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In - 37 -WSGR Docket No.56756-712.601 some embodiments is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is 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), or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating obesity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating gout in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0111] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) or - 38 -WSGR Docket No.56756-712.601 (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide.

[0112] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a - 39 -WSGR Docket No.56756-712.601 first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments, Glucagon- like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide- 1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP- 1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide.

[0113] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a - 40 -WSGR Docket No.56756-712.601 first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments, Glucagon- like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide- 1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP- 1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide. Pharmaceutical compositions and methods of administration

[0114] NLRP3 inhibitors (compounds of Formula (I) and (Ia)) described herein and GLP-1 receptor agonists described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent metabolic diseases, disorders or conditions.

[0115] In certain embodiments, the NLRP3 inhibitors and GLP-1 receptor agonists described herein are administered as a pure chemical. In other embodiments, the NLRP3 inhibitors and GLP-1 receptor agonists described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0116] In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are formulated in a single pharmaceutical composition. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are formulated in separate pharmaceutical compositions. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are administered simultaneously. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are administered simultaneously in a - 41 -WSGR Docket No.56756-712.601 single pharmaceutical composition. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are administered simultaneously in separate pharmaceutical compositions. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered sequentially.

[0117] Accordingly, in some embodiments provided herein is a pharmaceutical composition comprising a NLRP3 inhibitor described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. In some embodiments provided herein is a pharmaceutical composition comprising a GLP-1 receptor agonist described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. In some embodiments provided herein is a pharmaceutical composition comprising a NLRP3 inhibitor and a GLP-1 receptor agonist described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers. As described herein, the carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[0118] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.

[0119] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient(s) is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0120] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly - 42 -WSGR Docket No.56756-712.601 throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0121] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0122] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0123] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0124] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic - 43 -WSGR Docket No.56756-712.601 aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, 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.

[0125] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper 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

[0126] The dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[0127] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0128] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

[0129] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0130] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the NLRP3 inhibitor and the particular therapeutic effect to be achieved and (b) the limitations - 44 -WSGR Docket No.56756-712.601 inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration. EXAMPLES

[0131] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. Example 1: Synthesis of compounds

[0132] Compounds 1-22 were prepared as described in US 2021 / 0292336, which is herein incorporated by reference in its entirety. Compound Structure Name- 45 -WSGR Docket No.56756-712.601- 46 -WSGR Docket No.56756-712.601- 47 -WSGR Docket No.56756-712.601Example 2: Mouse BMDM IL-1b Assay

[0133] Mouse bone marrow cells from C57BL6 tibia and femur were culture in complete Isocov’s Media supplemented with 20 ng / mL MCSF (BMDM media) at a density of 50 million cells / 15 cm Petri dish. Fresh media was changed every 3 days, and bone marrow derived macrophages were collected, washed, and counted on day 7. Cells were seeded into 96 well plates at a density of 5x104cells per well in 100 uL of BMDM media and cultured overnight. The cells were stimulated at 37oC with 200 ng / mL Ultrapure LPS-B5 for 3 hours before pre- diluted compounds were added. 30 minutes after compound addition, 5mM ATP was added for the secondary stimulation for 45 minutes. After stimulation, the plates were briefly spun down, and 50 uL of supernatant was harvested from each well. ELISA for mouse IL-1b was performed with 1:10 and 1:100 diluted supernatant using pre-coated kits. IL-1b concentrations were - 48 -WSGR Docket No.56756-712.601 calculated based on pre-titrated standards, and compound inhibition IC50 is generated using the Levenberg Marquardt damped lease-square method.

[0134] IC50 values are shown in the table below. Compound IL-1b Compound IL-1bExample 3: Human Whole Blood (HWB) IL-1b Assay

[0135] Assay run as 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” PLoSONE 14(4): e0214999.https: / / doi.org / 10.1371 / journal.pone.0214999. Namely, freshly drawn human whole blood with anti-coagulant was incubated with test compounds at various titration points for 0.5 hrs at 37oC in 5% CO2. The cells were subsequently primed with 100 ng / mL LPS for 3.5 hours at 37oC followed by stimulation with 5 mM ATP for an additional 45 minutes. The supernatant was harvested and analyzed for human IL-1b concentration using commercially available ELISA kits.

[0136] IC50 values are shown in the table below. Compound HWB Compound HWB Compound HWB Compound HWBExample 4: Phase II Study to Evaluate Weight Loss in Participants Receiving NLRP3 Inhibitor and GLP1 Receptor Agonist Combination

[0137] A first-in-human (FIH) study is designed to show if a combination of an NLRP3 inhibitor (compound of Formula (I) or (Ia)) and a GLP-1 receptor agonist has the greatest weight decreasing effect in comparison to each compound alone and to group with no treatment. Study Design

[0138] The study is designed as follows: - 49 -WSGR Docket No.56756-712.601Participants

[0139] Approximately 200 adults 35-55 years old will be enrolled and treated in the Dose Escalation phase and Dose Expansion phase, including approximately 38 R / R AML participants planned to be enrolled and treated in the Dose Expansion phase. Dosing

[0140] Drug will be dosed daily for 6 months. Criteria

[0141] Inclusion Criteria: • Stable weight in the previous 6 months • A sedentary lifestyle • No history of diabetes mellitus • Taking medication that affects appetite, or weight within the past 6 months

[0142] Exclusion Criteria: • Severe anemia • Hypothyroidism and hyperthyroidism • Diabetes mellitus • Moderate to severe liver or kidney disease • Body mass index less than 30 Primary Outcome - 50 -WSGR Docket No.56756-712.601

[0143] Weight of each participant will be measured every week for the 6-month duration of the study. Results from each cohort will be compared.

[0144] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims. - 51 -

Claims

WSGR Docket No.56756-712.601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); 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(R17)=C(R17)-; Z2 is N or C(R19); ,3 s y rogen, - 14, - , - 2, or - ( )2 15; each R4 is independently selected from hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, and -C1- C6alkyl-N(R7)2; each R5 is independently selected from hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, and -C1- C6alkyl-N(R7)2; each R6 is independently selected from C1-C6alkyl, -C1-C6alkyl-CO2R18, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; - 52 -WSGR Docket No.56756-712.601 each R7 is independently selected from hydrogen and C1-C6alkyl; R8is hydrogen, C1-C6alkyl, -C1-C6alkyl-OR7, -C1-C6alkyl-N(R7)2, or C3-C6cycloalkyl; R9 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl; R10 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- N(R7)2; R11 and R12 are independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, - C1-C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; or R11 and R12 are combined to form a 5- or 6- membered cycloalkyl ring; R13 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C5cycloalkyl, C2-C9heterocycloalkyl, phenyl, or C2-C9heteroaryl, wherein C3-C5cycloalkyl, C2- C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R16; R14 is hydrogen or C1-C6alkyl; R15 is C1-C6alkyl; each R16 is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl, wherein C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; each R17 is independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, -C1- C6alkyl-OR7, and -C1-C6alkyl-N(R7)2; R18 is hydrogen or C1-C6alkyl; R19 is hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -C1-C6alkyl-OR7, or -C1-C6alkyl- 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; and t is 1, 2, or 3; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon- like peptide-1 (GLP-1) receptor agonist.

2. The method of claim 1, wherein .- 53 -WSGR Docket No.56756-712.601 3. The method of claim 1, wherein .

4. The method of any one of claims1-3, wherein Y2 is C(R9).

5. The method of claim 4, wherein R9 is hydrogen or C1-C6alkyl.

6. The method of claim 5, wherein R9 is hydrogen.

7. The method of any one of claims 1-3, wherein Y2 is N.

8. The method of any one of claims 1-7, wherein Y1 is O.

9. The method of any one of claims 1-7, wherein Y1 is S.

10. The method of any one of claims 1-7, wherein Y1is N(R8).

11. The method of claim 10, wherein R8 is hydrogen, C1-C6alkyl, or C3-C6cycloalkyl.

12. The method of claim 11, wherein R8 is hydrogen.

13. The method of claim 11, wherein R8 is C1-C6alkyl.

14. The method of claim 11, wherein R8 is C3-C6cycloalkyl.

15. The method of claim 1, wherein .

16. The method of claim 1, wherein .

17. The method of claim 15 or claim16, wherein R10 is hydrogen.

18. The method of any one of claims 1-17, wherein each R6 is independently selected from C1- C6alkyl.

19. The method of any one of claims 1-18, wherein each R6 is -CH3.

20. The method of any one of claims 1-19, wherein q is 1.

21. The method of any one of claims 1-19, wherein q is 2.

22. The method of any one of claims 1-19, wherein q is 3.

23. The method of any one of claims 1-17, wherein q is 0.

24. The method of any one of claims 1-23, wherein n is 2.

25. The method of any one of claims 1-23, wherein n is 1.

26. The method of any one of claims 1-25, wherein m is 1.

27. The method of any one of claims 1-26, wherein p is 1. - 54 -WSGR Docket No.56756-712.601 28. The method of claim 1, wherein R1 is ,.

29. The method of claim 1, wherein R1 is .

30. The method of any one of claims 1-29, wherein .

31. The method of any one of claims 1-29, wherein .

32. The method of claim 30 or claim 31, wherein s is 1.

33. The method of any one of claims 30-32, wherein t is 1.

34. The method of any one of claims 30-33, wherein Z2 is C(R19).

35. The method of claim 34, wherein R19 is hydrogen.

36. The method of claim 34, wherein R19 is halogen.

37. The method of any one of claims 30-33, wherein Z2 is N.

38. The method of any one of claims 1-29, wherein .

39. The method of claim 38, wherein Z1 is S.

40. The method of claim 38, wherein Z1 is O.

41. The method of claim 38, wherein Z1 is -C(R17)=C(R17)-.

42. The method of claim 41, wherein each R17 is independently selected from hydrogen and halogen.

43. The method of claim 41, wherein each R17 is hydrogen. - 55 -WSGR Docket No.56756-712.601 44. The method of any one of claims 38-43, wherein R11 and R12 are combined to form a 5- or 6-membered cycloalkyl ring.

45. The method of any one of claims 38-44, wherein R11 and R12 are combined to form a 5- membered cycloalkyl ring.

46. The method of any one of claims 38-43, wherein R11 and R12 are independently selected from hydrogen, halogen, and C1-C6alkyl.

47. The method of any one of claims 38-46, wherein R13 is phenyl optionally substituted by 1, 2, 3, or 4 R16.

48. The method of any one of claims 38-46, wherein R13 is C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 R16.

49. The method of claim 48, wherein R13 is pyridyl optionally substituted by 1, 2, 3, or 4 R16.

50. The method of any one of claims 47-49, wherein each R16 is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy.

51. The method of claim 50, wherein each R16 is C1-C6alkoxy.

52. The method of any one of claims 38-46, wherein R13 is C1-C6alkyl.

53. The method of any one of claims 38-46, wherein R13 is C3-C5cycloalkyl.

54. The method of any one of claims 1-29, wherein.

55. The method of any one of claims 1-54, wherein X2 is -N(R4)-.

56. The method of any one of claims 1-55, wherein each R4 is hydrogen.

57. The method of any one of claims 1-56, wherein X3 is -N(R5)-.

58. The method of any one of claims 1-56, wherein X3 is -C(R5)2-.

59. The method of any one of claims 1-58, wherein each R5 is hydrogen.

60. The method of any one of claims 1-59, wherein X1 is O.

61. The method of claim 1, wherein the compound of Formula (I) is selected from: ,- 56 -WSGR Docket No.56756-712.601 ,- 57 -WSGR Docket No.56756-712.601 ,pharmaceutically acceptable salt or solvate thereof.6 . e met od o any one o c a ms 1-61, wherein the second therapeutic agent is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide.

63. The method of any one of claims 1-62, wherein the second therapeutic agent is semaglutide.

64. The method of any one of claims 1-63, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout.

65. The method of any one of claims 1-64, wherein the metabolic disease is obesity.

66. The method of any one of claims 1-65, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered simultaneously. - 58 -WSGR Docket No.56756-712.601 67. The method of any one of claims 1-66, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition.

68. The method of any one of claims 1-65, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered sequentially.

69. The method of claim 66 or 68, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions. - 59 -

Images