NLRP3 inhibitors and GLP-1 agonists combination therapies

Abstract

Provided herein are combinations of NLRP3 inflammasome inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists and methods comprising administering to a subject in need thereof such combinations for the treatment of a GLP-1 linked disease and / or a weight disorder.

Description

RELATED APPLICATION

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 621,412 filed January 16, 2024, the content of which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Autoimmune and autoinflammatory diseases are associated with the overproduction of proinflammatory factors. One of them is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system like dendritic cells. IL-1 is involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis (Masters, S. L., et. al., Annu. Rev. Immunol. 2009. 27:621-68).

[0003] In humans, 22 NLR proteins are divided into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NODI and N0D2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members are associated with inflammasome formation.

[0004] Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability activate in response to endogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are effective triggers of NLRP3 activation. Similarly, cholesterol crystals found in atherosclerotic patients can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators led to IL-1 and IL-18 being implicated in a diverse range of pathophysiological indications including metabolic, physiologic, inflammatory, hematologic and immunologic disorders.

[0005] Glucagon-like peptide-1 receptor (GLP-1) agonists provide effective treatment of weight disorders. Combining the beneficial effects of an NLRP3 inflammasome inhibitor with the effects of a GLP-1 receptor agonist may result in additive or synergistic effects that provide a more effective treatment of diseases or disorders related to weight (e.g., obesity, metabolic syndromes, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, NonAlcoholic SteatoHepatitis (NASH) and / or atherosclerosis) and Parkinson’s disease.

[0006] The disclosure arises from a need to provide further treatments of weight disorders. In particular, use of compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing compounds or combinations are desirable. Combination therapies can yield unexpected synergistic and advantageous effects as compared to administration of one agent alone. Developing new combination therapies for the treatment of various weight disorders remains a critical unmet clinical need. SUMMARY

[0007] In some aspects, the present disclosure provides anNLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subject.

[0008] In some aspects, the present disclosure provides anNLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a GLP-1 linked disease or a weight disorder in a subject; wherein the GLP-1 linked disease or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0009] In some aspects, the present disclosure provides anNLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject.

[0010] In some aspects, the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CFhjo-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5-to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or Ri (ii), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein nia and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; and each Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or R1 n 0 A3J. N. X R"2 N o R’ Rb H (in), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, 0, or S, as valency allows; A3 is CR2, N, NR2a, 0, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-Ce alkyl), -O-(C2-Ce alkenyl), -O-(C2-Ce alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3-to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more j^N2a. each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-C12 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-C10 aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0011] In some aspects, the NLRP3 inflammasome inhibitor is Compound Al: (Compound Al), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] In some aspects, the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] In some aspects, the NLRP3 inflammasome inhibitor is Compound C3: 0              (Compound C3), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0014] In some aspects, the GLP-1 receptor agonist is semaglutide.

[0015] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0016] In some aspects, the present disclosure provides a method of treating or preventing a GLP-1 linked disease and / or a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0017] In some aspects, the present disclosure provides a method of treating or preventing a GLP-1 linked disease or a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;

[0018] wherein the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

[0019] In some aspects, the present disclosure provides anNLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject;

[0020] wherein the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain). In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0021] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

[0022] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0023] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder; wherein the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0024] In some aspects, the present disclosure provides a kit comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0025] In some aspects, the present disclosure provides a pharmaceutical package comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0026] In some aspects, the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0027] In some aspects, the weight disorder is selected from a metabolic disorder, obesity, excessive body weight, and enhanced appetite.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0029] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE FIGURES

[0030] FIG. 1 depicts effects of Compound Al, semaglutide or combined treatment with Compound Al and semaglutide in Diet-Induced Obesity (DIO) hCESl mice. FIG. 1A depicts % change in baseline body weights of DIO hCESl mice treated therapeutically with Vehicle (orally (p.o.), three times a day (t.i.d.)), Compound Al (100 mg / kg p.o., t.i.d.), semaglutide (0.005 mg / kg subcutaneous (s.c.), daily (q.d.)) or combined treatment of Compound Al and semaglutide for 28 days. FIG. IB depicts Average daily calorie intake of control chow fed hCESl and DIO hCESl mice, from FIG. 1A over the 28 days. Data are expressed as mean ± SEM and analysed by two-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vl0.0.2. Significance is calculated relative to semaglutide only group *p<0.001; **p<0.05 (A).

[0031] FIG. 2 depicts effects of Compound C3, semaglutide or combined treatment with Compound C3 and semaglutide in DIO hCES 1 mice. FIG. 2A depicts % change in baseline body weights of DIO hCESl mice treated therapeutically with Vehicle (p.o., t.i.d.), Compound C3 (100 mg / kg p.o., t.i.d.), semaglutide (0.005 mg / kg s.c., q.d.) or combined treatment of Compound C3 and semaglutide for 28 days. FIG. 2B depicts Average daily calorie intake of control chow fed hCESl and DIO hCESl mice, from FIG. 2A over the 28 days. Data are expressed as mean ± SEM.

[0032] FIG. 3 depicts effects of Compound Al on weight re-gain following semaglutide cessation in DIO hCESl mice. FIG. 3A depicts % change in baseline body weights of DIO hCESl mice initially treated therapeutically in the main study (0-28 days) with semaglutide (0.005 mg / kg s.c., q.d) or semaglutide (0.005 mg / kg s.c., q.d.) and Compound Al (100 mg / kg p.o., t.i.d.), followed by an extension study (28-56 days) consisting of treatment with Vehicle (p.o., t.i.d.) or Compound Al (100 mg / kg p.o., t.i.d.) only. FIG. 3B depicts Average daily calorie intake of DIO hCESl mice, from FIG. 3 A during the extension study (days 28-56). Data are expressed as mean ± SEM.

[0033] FIG. 4 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on body weight change in DIO mice switched to a Polyunsaturated Fatty Acid (PUFA) diet. DIO mice fed high-fat diet (HFD) were dosed therapeutically with Compound Al (100 mg / kg, p.o., t.i.d.), semaglutide (0.005 mg / kg, s.c., q.d.), or in combination from day 0-28. On day 29, diet was switched to PUFA diet and the respective treatment continued (over days 29-56). An additional group of mice served as calorie restricted controls whose body weights were maintained as close to Compound Al-dosed mice as possible by controlling the degree of calorie restriction throughout the experiment. Overnight fasting into day 55 was performed to facilitate the analysis of further exploratory endpoints. Data are expressed as mean and analysed by two-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vlO.4.1. Significance is calculated using GraphPad Prism vlO.4.1, ****p<0.0001, ***p<o o°i, **p<0 01, *P<0.05.

[0034] FIG. 5 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on absolute body weight in DIO mice switched to a PUFA diet. DIO mice were dosed as in FIG. 4. Data are expressed as mean and analysed by two-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vlO.4.1. Significance is calculated using GraphPad Prism vlO.4.1, ****p<0.0001, ***p<0.001, **p<0.01.

[0035] FIG. 6 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on A) average daily food intake or B) average daily calorie (kcal) intake during HFD exposure (days 0-28). Data are expressed as mean ± SEM and analysed by oneway ANOVA with Tukey's multiple comparisons test using GraphPad Prism vl0.4.1. Significance is calculated using GraphPad Prism vlO.4.1, ****p<0.0001.

[0036] FIG. 7 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on A) fat mass (%), B) lean mass (%) or C) bone mineral content (%) as assessed by body composition DEXA scans at day 28. Data are expressed as mean ± SEM and analysed by one-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vlO.4.1. Significance is calculated using GraphPad Prism vlO.4.1, ***p<0.001, ****p<0.0001.

[0037] FIG. 8 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on A) average daily food intake or B) average daily calorie (kcal) intake during PUFA diet exposure (days 29-56). Data are expressed as mean ± SEM and analysed by one-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vl0.4.1. Significance is calculated using GraphPad Prism vlO.4.1, *p<0.05, ****p<0.0001.

[0038] FIG. 9 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on hypothalamic Glial Fibrillary Acidic Protein (GFAP) expression. GFAP immunoreactivity was assessed within the arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH) and ventral medial hypothalamus (VMH) of DIO mice following continuous dosing with Compound Al (100 mg / kg, p.o., t.i.d.), semaglutide (0.005 mg / kg, s.c., q.d.), the combination of Compound Al and semaglutide, or calorie restriction over 56 days in DIO mice. A) Average total GFAP staining (%), B) average strong GFAP staining (%), or C) total GFAP positive cell numbers per mm2, across the ARC, DMH and VMH was calculated. Data are expressed as mean ± SEM and analysed by one-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vlO.2.2. Significance is calculated using GraphPad Prism vlO.2.2, *p<0.05, **p<0.01.

[0039] FIG. 10 depicts effects of Compound Al, semaglutide or a combination of Compound Al and semaglutide on organ body weights at study end (day 56). A) liver, B) heart, C) brain, D) left kidney, E) right kidney, F) colon weights (mg). Data are expressed as mean ± SEM and analysed by one-way ANOVA with Tukey's multiple comparisons test using GraphPad Prism vlO.2.2. Significance is calculated using GraphPad Prism vlO.2.2, ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05. DETAILED DESCRIPTION Definitions

[0040] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0041] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0042] It is to be understood that a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound the present disclosure is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound. In some embodiments, the amine of a compound of the present disclosure is protonated.

[0043] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0044] As used herein, “alkyl,” “Ci, C2, C3, C4, C5 or Ce alkyl” or “Ci-Ce alkyl” is intended to include Ci, C2, C3, C4, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or Ce branched saturated aliphatic hydrocarbon groups. For example, CrC6 alkyl is intends to include Cb C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (i.e., CH3), ethyl (i.e., CH2CH3), n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0045] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0046] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “Cs-Ce” includes alkenyl groups containing three to six carbon atoms.

[0047] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0048] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “CsCe” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups.

[0049] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0050] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0051] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be nonaromatic.

[0052] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ,1,2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2.l]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, l-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multi cyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic.

[0053] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[0054] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or, e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (ie., N^O and S(O)P, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0055] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0056] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl). As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0057] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0058] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0059] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O'

[0060] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0061] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0062] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0063] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and tri chi or om ethoxy.

[0064] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C,” “selected from A, B, and C,” and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, ie., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0065] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0066] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated those compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0067] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0068] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, MB., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art

[0069] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0070] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0071] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0072] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0073] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0074] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can or may also be used to prevent a relevant disease, condition, or disorder, or used to identify suitable candidates for such purposes.

[0075] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0076] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al, Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan etaL, Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0077] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0078] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0079] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0080] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0081] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g, intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenedi aminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0082] As used herein, the term “therapeutically effective amount,” refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.

[0083] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0084] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0085] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0086] The active compounds can be prepared with pharmaceutically acceptable diluents, adjuvants, excipients, or carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0087] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0088] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0089] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0090] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0091] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4-toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0092] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0093] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0094] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0095] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0096] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0097] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0098] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.

[0099] “Combination therapy” or “combination treatment” refers to the use of two or more drugs or agents in treatment, e.g., the use of a compound of Formula (I), (II), or (III) of the present disclosure together with another agent useful to treat a GLP-1 linked disease or a weight disorders (e.g., a GLP-1 receptor agonist), and symptoms and manifestations of each thereof is a combination therapy. Administration in “combination” refers to the administration of two agents (e.g., a compound of Formula (I), (II), or (III) of the present disclosure, and another agent) in any manner in which the pharmacological effects of both manifest in the subject. Thus, administration in combination does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both agents or that the two agents be administered at precisely the same time. Both agents can also be formulated in a single pharmaceutically acceptable composition. In some embodiments, the each agent may be administered in temporal proximity, sequentially, or in alternation. NLRP3 Inflammasome Inhibitor

[0100] In some embodiments, an NLRP3 inflammasome inhibitor can be used in accordance with the combinations and / or methods described herein.

[0101] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula I: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12-membered heterocycloalkyl, or 5- to 6membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; RHs H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH^o-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5-to 7-membered heterocycloalkyl is optionally substituted by one or more R?s.

[0102] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (I’) or (I”): 0          (I’),                       0          (I"); or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein Ri, R3, and R4 are as described herein for Formula (I).

[0103] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of any one of Formulae (I-a), (F-a), and (I”-a): or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R3 and R4 are as described herein for Formula (I).

[0104] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of any one of Formulae (I-b), (F-b), and (I”-b): 0          (I-b), 0          (I’-b);                        0          (I”-b); or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein Ri, R4, and R7 are as described herein for Formula (I).

[0105] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of any one of Formulae (I-c), (F-c), and (I”-c): 0          (I-c), 0          (I’-c);                             O (I”_C); or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R4 and R7 are as described herein for Formula (I).

[0106] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of any one of Formulae (I-d), (F-d), (I”-d), (I-e), (F-e), and (I”-e): (I-d); 0            (I’-e);                       0            (I”-e); or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein Ri and R3 are as described herein for Formula (I).

[0107] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of any one of Formulae (I-f), (I’-f), (I”-f), (I-g), (I’-g), and (I”-g): 0           (i-O; or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein Ri and R7 are as described herein for Formula (I).

[0108] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of any one of Formulae (I-h), (F-h), (I”-h), (I-i), (I’-e), and (I”-e): or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R? is as described herein for Formula (I).

[0109] In some embodiments, the NLRP3 inflammasome inhibitor is selected from Table 1 A. Table 1A Compound No. Structure A3 3 7° o °z A34 \J H A A3 5 T }=O ' o A c A36 Fx C y= / \ IZ \=o O c A37 ^:~ Q o V / ZI, A3 8 X. JU JU / x /      ''q" Y H       0 A3 9 IZ\_n 1= (J o O      Q o I A40 TZ ^o o oJ O =\ ^o Compound No. Structure A41 £ v Z \=o o o=^ z T A42 N ° X. JU Jk V>U xz / Z    n o >Z V-J H o A43 ZE 2 x° o O=\  A=\  z^, o 4      z । A44 1 Z—a     o ^Zz \= / X=o o A45 IZ   m >° o o= / z O       \\ z A46 x> o r N £Ju JU H       A 0 A47 o z n Jk Y N o £H ° Compound No. Structure A48 IZ  \ >° A49 J XXr o < n Jk Y N O H 0 A50 fY ° F H 0 A51 iz Q >° o o zZ A52 IZ Q o p-J A53 Q— TZ  Q >° o p3 A54 Oz °L >—2 y=o o ....... A55 _ / 1   ° f N VA. Jk N 0 H       0 Compound No. Structure A63 I z o o=^   / =\ O z A A64 ti—p— ti TZ   ti ^>=o o o= /  z—. A65 3 £z v b Z T L^^ci A66 n X) r if 0 f N AAL a \— / H      o A67 TZ   -H )=O o o_^ \z A68 A° q A69 r\      । AxZ 0 VJ H     o A70 T o — O\    o b .......y z T Compound No. Structure A78 N 4 A?15 H J A79 Cl AY O Y N 0 H          " 1                   0 A80 —, if f f AA A. A.oh <TY 0 n VJ H     o A81 F YY ° r n A. JA Y a / \--• H        o A82 zz V' o A83 N z Ay o a-n Aw A°h V—' H       o A84 1 f °\ wo b Q W1 U \ Z T Compound No. Structure A92 f^A^A 0 ZN"N VaA- 1 H          0 A93 if 0 Z N A, JL A A ZZ / / y n o qZ \J H     o A94 <fz) b □ = / .,     ZI A95 x> X^ AVoV^ V-j H      o A96 ° r° Y / o'Y \J H S A97 N ih ° r A, A A A AJ H    o A98 r ii ° rN fA Ao '" Af 0 \J H     H Compound No. Structure A99 / —tYH \ CH A zQ r       ° f N AA A A zOH z       ov Y V-7 h      o A100 I z Q o o= /  Z—, AIOI o—A        p=N A. / A if o Z N A. A. A. zz / Ao H     o A102 IZ >° q o=a^ o x A103 > \     °x O    )— O    fe- 0 b ZI A104 Vo / \Y b o= / ZI A105 TZ >° q °AA Compound No. Structure A106 IZ X n / =° Q o=Qi < r A107 fA 8 Z=^..................O b o=^ ZT A108 r—\     nA / y^N^o'1’y°Y\ vJ h   o M A109 XN n f j / V O A. X. JL J's .oh \--' H        o AllO o o z, z w Alli IZ >° q =^-\z VA Al 12 N n / V O / N Compound No. Structure A113 IZ )=° q, Q— /  Z ° ZJ^S^ Al 14 IZ ^=o o O   s Z A115 a^3~a IZ >° o o=( z-s O       7 _A / z Al 16 / n"n^ y Y ° A N / ks / L JL vk^o-s^^x Z  n o Ar W \—'  H     o Ly Al 17 A^A IZ >° o O z. z a r A118 1            N^As A o JJ JkQ / ly 0 >s / H                   II | A119 Vx A A A °\ —A A120 o^ o z 2 A A2 Compound No. Structure A121 k / £)  £ T LI a A 0 , VJ H      0   । A122 z=^ £° □ o—^ A123 Cl                 0     1 A124 0 o=^ z / ozv? A125 £. J if A-p 0 r n Cl H          0     1

[0110] In some embodiments, the NLRP3 inflammasome inhibitor is Compound Al: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0111] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula II: Ri (II), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; and each Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0112] In some aspects, the NLRP3 inflammasome inhibitor is of Formula (II) or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more -OH; and R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Ci-Ce alkyl.

[0113] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ila-1): o o o AV-H H ' k2 (iia-1) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2 and R3 are as described herein for Formula (II).

[0114] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ila-2): O owo NANXN'R3 H H R k2 (IIa-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ris, R2 and R3 are as described herein for Formula (II).

[0115] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ilb-1): R2S (Hb-1) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri, R2S, and R3 are as described herein for Formula (II).

[0116] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ilb-2): O O O r-nWR3 H H I R2S (lib-2) or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri, R2S, and R3 are as described herein for Formula (II).

[0117] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (IIc-1): or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri, R2, and Rss are as described herein for Formula (II).

[0118] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (IIc-2): (IIc-2), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri and R2 are as described herein for Formula (II).

[0119] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (IIc-3): (IIc-3), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri and R2 are as described herein for Formula (II).

[0120] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ild-1): (IId-1), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri and R2S are as described herein for Formula (II).

[0121] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ild-2): (IId-2), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein Ri and R2S are as described herein for Formula (II).

[0122] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ile-1): or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2S is as described herein for Formula (II).

[0123] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ile-2): R2S (IIe-2), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2S is as described herein for Formula (II).

[0124] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ile-3): or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2S is as described herein for Formula (II).

[0125] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (Ile-4): R2S (IIe-4), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2S is as described herein for Formula (II).

[0126] In some embodiments, the NLRP3 inflammasome inhibitor is selected from Table IB. Table IB Compound No. Structure B2’ N-l / X> Y r\ XX A V Yv < Yr n n- a \__1 H      0 B2 N-l / < Yr   n   n- a \ /   H      0 B2B N-NZ n Yn XX a V Yv < Yr n n- a \__ / H      0 B3 N-NZ X? Yn XX A °S-NYv / Y< N N- A X / H    ° B3A N-NZ X? Yn o a % XQ / Y< N N- A X / H    ° B3B N-NZ X? Yn O a VYY / Y< N N- A X / H    ° B4 N-NZ X> Y rx £i a V"YY° Yr h N-' '0 Compound No. Structure B6B B7 B7A B7B B8 B8A B8B

[0127] In some embodiments, the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0128] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (III): or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, O, or S, as valency allows; A3 is CR2, N, NR2a, O, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0129] In some embodiments, the NLRP3 inflammasome inhibitor is a compound of Formula (III), wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, O, or S, as valency allows; A3 is CR2, N, NR2a, O, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, wherein when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-C3-Ci2 cycloalkyl, or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10membered heteroaryl is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=0)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0130] In some embodiments, the NLRP3 inflammasome inhibitor is selected from a compound of Formula (Ill-a), (Ill-b), (III-c), (Ill-d), (IILe), (Ill-f), or (Ill-g): O Ra. Ra R1                  (IILd), r1                  (IILe), R1                   (IILf), or or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1, R2, Ra, and RN2 are as described herein for Formula (III).

[0131] In some embodiments, the NLRP3 inflammasome inhibitor is selected from Table IC. Table IC Compound No Structure Cl z "z' Z-Z   ' IZ b C2 / -'ll N 0 S H Compound No Structure C3 S H C4 z M °=<)—( Z-Z   ' A IZ b C5 o f\^n auu, <i a h C6 S H C7 / o ZI \ z-z / —C )=° Jz C8 Vn'nY^n ° 0      H C9 \           0 N'^r / F a H CIO cf ZI \ z-z / — o z 1 Cll o °=O~( Z-Z ' $=° IZ b Compound No Structure C12 q ZI q \   Z-Z / —c o C13 C14 C15 \ I n ° qq C16 qw' S H C17 Y z o Z-Z   \ q IZ >=\ C18 £ H C19 Cf Z-Z   x IZ C20 VmN;:T^n 0 a h C21 z^ 0=0-A Z-Z   x q IZ Compound No Structure C22 C23 C24 o _ / ^ii  N °  O Br—e         1     II           । "    H    U C25 A H u C26 C27 Vm-nV^n o n^yf 1              1 II 1 H o      H C28 Vm'N^i N 0 N^ii & H C29 K:$ / p C30 0  N^><F J Ah N C31 KvAX) Compound No Structure C32 ==< zi \ z-z / —C / ^° C33 A-JvO S H C34 C35 °=O— z-z C36 \_7-S| N o n^Vf MJO 1 A J S H C37 •^JXX S H C38 S H C39 4 H C40 d _y°'^h   N   0 Br—\ J   '    II L H A H C41 S H Compound No Structure C42 ° Y    N N A      H C43 Q \ z-z / —C )=° ri A C44 \__ / °^| N 0 C45 o A “T \ z-z / —C / ^° ^z^ C46 M °=<AA z-z X IZ = I C47 X                        OH । h r / '"' £ H C48 Q \ z-z / —c 'z A C49 Q \ z-z / —C / ^° Compound No Structure C50 \ ..'NAn 0 NAN hA n A A / A H C51 Y z M Z-Z   ' )=* o J C52 Jss           PH Br<r^ i#1 s AA^ fl H C53 AjJ C54 l\ / Ai  N  0  N-A \ J    ।    ]i    n > A H C55 C56 A^x> S H C57 l\ / °Ai N o NA >AJI n A A / fl H Compound No Structure C58 Y    ° A H C59 o             ph S H C60 PyLy a JJ S H C61 r\__ / °>| N 0 N^YCI OSJl nA A J S H C62 O             PH >4T' ? rf- S H C63 1                        ° PyAAS ? N^Ao^ AAnJW s H C64 r\ / °^fi N o n-y S H C65 C66 Compound No Structure C67 1                        ° / O-Ti N O nYAY a J S H C68 1 l\ / 0-(i N  0 N^Y^ MJj i a J S H C69 YY' C70 A$jy S H C71 A.^^n N ° NY1 AA / YYJ ° Y     N N S H C72 F\            IT / ^n^yS ? jn s-"\<N^NAr S H C73 —°           jp Yx, / --(1 n ° N^ii HNA J n A A J S H C74 Y / Y S H C75 S H Compound No Structure C76 C77 S H C78 A H C79 S H C80 o n      N v S      H C81 k / Vn 0 n     N v S      H C82 °=C)—( Z-Z ' b IZ zb z C83 ZI b z-z —c C84 S H Compound No Structure C85 A H C86 D D         jP ° Nf      N N S      H C87 J Ah N C88 hn<L^naJ 5 H C89 Q ~T z-z [>— z C90 \   / ^1  N O S △ h C91 u\,        N ° N<X HN \ 1 N J! k U S H C92 rX z=< ZI °5 z-z / —^=o ^Z

[0132] In some embodiments, the NLRP3 inflammasome inhibitor is Compound C3: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0133] In some embodiments, the NLRP3 inflammasome inhibitor is selected from the compounds disclosed in: US 2023 / 250070; WO 2020 / 254697; WO 2021 / 255279; WO 2023 / 118521; EP 4129986; WO 2021 / 193897; WO 2022 / 230912; WO 2023 / 003002; WO 2023 / 275366; US 2023 / 0051130; WO 2022 / 204227; WO 2023 / 147468; WO 2021 / 093820; WO 2022 / 237780; WO 2022 / 237781; WO 2022 / 237782; WO 2023 / 137885; WO 2022 / 006433; WO 2022 / 035204; WO 2022 / 109268; WO 2022 / 232632; WO 2023 / 044043; WO 2023 / 192390; WO 2023 / 288039; WO 2017 / 129897; WO 2021 / 150574; WO 2023 / 004257; CN 116496255; WO 2022 / 171185; WO 2023 / 186020; WO 2022 / 187804; WO 2017 / 184604; WO 2017 / 184623; WO 2017 / 184624; WO 2019 / 023145; WO 2019 / 023147; WO 2019 / 079119; WO 2020 / 010118; WO 2020 / 010140; WO 2020 / 010143; WO 2020 / 102096; WO 2020 / 102098; WO 2020 / 102100; WO 2020 / 102574; WO 2020 / 102576; WO 2020 / 154321; WO 2020 / 154499; WO 2021 / 002887; WO 2016 / 131098; WO 2017 / 140778; WO 2018 / 215818; WO 2019 / 008025; WO 2019 / 008029; WO 2019 / 034686; WO 2019 / 034688; WO 2019 / 034690; WO 2019 / 034692; WO 2019 / 034693; WO 2019 / 034696; WO 2019 / 034697; WO 2019 / 068772; WO 2019 / 092170; WO 2019 / 092171; WO 2019 / 092172; WO 2019 / 166623; WO 2019 / 166624; WO 2019 / 166627; WO 2019 / 166628; WO 2019 / 166629; WO 2019 / 166632; WO 2019 / 166633; WO 2019 / 206871; WO 2019 / 211463; WO 2020 / 035464; WO 2020 / 035465; WO 2020 / 035466; WO 2020 / 079207; WO 2020 / 104657; WO 2021 / 032588; WO 2021 / 032591; WO 2021 / 043966; WO 2021 / 089769; WO 2021 / 089776; WO 2021 / 089781; WO 2021 / 165245; WO 2023 / 025264; WO 2021 / 209539; WO 2021 / 209552; WO 2021 / 219784; WO 2021 / 239885; WO 2022 / 063876; WO 2022 / 063896; WO 2022 / 184842; WO 2022 / 184843; WO 2022 / 229315; WO 2023 / 275230; WO 2021 / 132577; WO 2023 / 032987; WO 2018 / 136890; WO 2020 / 018970; WO 2020 / 018975; WO 2023 / 209109; WO 2022 / 022646; WO 2022 / 166890; WO 2023 / 098612; WO 2023 / 129987; WO 2023 / 220408; US 2020 / 0361898; US 2020 / 0361899; WO 2020 / 021447; WO 2020 / 0234715; WO 2023 / 002399; US 6166064; WO 98 / 32733; WO 2023 / 028534; WO 2023 / 028536; WO 2023 / 159148; WO 2022 / 238347; WO 2022 / 253936; WO 2022 / 268935; WO 2022 / 269010; WO 2023 / 066825; WO 2023 / 088856; WO 2023 / 088987; WO 2023 / 156311; WO 2023 / 232917; WO 2023 / 156643; WO 2020 / 222010; WO 2023 / 194964; WO 2022 / 253326; WO 2022 / 135567; WO 2017 / 017469; WO 2019 / 001416; WO 2022 / 234447; WO 2022 / 098108; WO 2022 / 115417; WO 2023 / 230002; US 11319319; US 11618751; WO 2022 / 216971; WO 2023 / 183943; WO 2023 / 220715; WO 2014 / 190015; WO 2021 / 011592; WO 2023 / 204967; WO 2023 / 056264; WO 2023 / 066377; WO 2018 / 103583; WO 2023 / 178099; WO 2023 / 278438; WO 2021 / 009567; WO 2018 / 225018; WO 2019 / 043610; WO 2020 / 148619; WO 2021 / 048809; WO 2021 / 111351; WO 2021 / 171230; WO 2023 / 026222; WO 2024 / 013395; WO 2024 / 023266; WO 2024 / 090469; WO 2024 / 141534; WO 2024 / 141535; WO 2024 / 064655; WO 2024 / 140824; WO 2024 / 109922; WO 2024 / 169858; WO 2024 / 193699; WO 2024 / 193703; WO 2024 / 140704; WO 2024 / 157953; WO 2024 / 057013; WO 2024 / 041460; WO 2024 / 094150; WO 2024 / 193541; WO 2024 / 240153; WO 2024 / 160690; WO 2024 / 160691; WO 2024 / 160692; WO 2024 / 160693; WO 2024 / 160694; WO 2024 / 048519; WO 2024 / 177126; WO 2024 / 177127; WO 2024 / 010772; WO 2024 / 148029; WO 2024 / 027723; WO 2024 / 064245; WO 2024 / 097598; WO 2024 / 137319; WO 2024 / 249389; WO 2024 / 249539; WO 2024 / 158941; WO 2024 / 006559; WO 2024 / 138045; WO 2024 / 249901; WO 2024 / 249929; WO 2024 / 028782; WO 2024 / 145623; WO 2024 / 017924; WO 2024 / 099992; WO 2024 / 099993; WO 2024 / 099996; WO 2024 / 121086; WO 2024 / 121184; WO 2024 / 213552; WO 2024 / 218100; WO 2024 / 188994; WO 2024 / 169895; WO 2024 / 033845; WO 2024 / 157205; WO 2024 / 214046; WO 2024 / 094185; WO 2023 / 131277; WO 2024 / 217442; WO 2024 / 097629; WO 2024 / 196786; and WO 2024 / 196788.

[0134] In some embodiments, the NLRP3 inflammasome inhibitor is selected from Table ID. Table ID GLP-1 Receptor Agonist

[0135] In some embodiments, the GLP-1 receptor agonist that can be used in accordance with the combinations and / or methods described herein may be an agonists of more than one target.

[0136] In some embodiments, the GLP-1 receptor agonist is a dual agonist (e.g., targeting GLP-1 and GIP).

[0137] In some embodiments, the GLP-1 receptor agonist is a triple agonist (e.g, targeting GLP-1, GIP, and glucagon).

[0138] In some embodiments, the GLP-1 receptor agonist targets, at least, GLP-1.

[0139] In some embodiments, the GLP-1 receptor agonist is selected from Table 2.

[0140] In some embodiments, the GLP-1 receptor agonist is semaglutide, or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the GLP-1 receptor agonist is semaglutide. Table 2 GLP-1 Receptor Agonist Albiglutide Danuglipron Dulaglutide Exenatide Liraglutide Lixisenatide Semaglutide Taspoglutide Tirzepatide Cotadutide Retatrutide Orforglipron Lotiglopron

[0142] In some embodiments, the GLP-1 receptor agonist is selected from Table 3. Table 3 Compositions

[0143] In some aspects, composition or pharmaceutic compositions are disclosed herein.

[0144] In some embodiments, the present disclosure provides a pharmaceutical compositions comprising an NLRP3 inflammasome inhibitor, or a pharmaceuically acceptable salt thereof (e.g., an NLRP3 inflammasome inhibitor of Formula (I), (II), or (III)), a GLP-1 receptor agonist, and a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. Methods of Use

[0145] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subj ect.

[0146] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subject; wherein the GLP-1 linked disease or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0147] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject.

[0148] In some aspects, the present disclosure provides Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject. In some aspects, the present disclosure provides Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject.

[0149] In some aspects, the present disclosure provides Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject.

[0150] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subj ect.

[0151] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subject; wherein the GLP-1 linked disease or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0152] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide, for use in combination for treating or preventing a weight disorder in a subject.

[0153] In some aspects, the present disclosure provides Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide for use in combination for treating or preventing a weight disorder in a subject.

[0154] In some aspects, the present disclosure provides Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide for use in combination for treating or preventing a weight disorder in a subject.

[0155] In some aspects, the present disclosure provides Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide for use in combination for treating or preventing a weight disorder in a subject.

[0156] In some aspects, the present disclosure provides a method of treating or preventing a GLP-1 linked disease and / or a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0157] In some aspects, the present disclosure provides a method of treating or preventing a GLP-1 linked disease and / or a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0158] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0159] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0160] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0161] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0162] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) semaglutide.

[0163] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) semaglutide.

[0164] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) semaglutide.

[0165] In some aspects, the present disclosure provides a method of treating or preventing a weight disorder, comprising administering to a subject: (a) Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) semaglutide.

[0166] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

[0167] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder; wherein the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g.. type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0168] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0169] In some aspects, the present disclosure provides Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0170] In some aspects, the present disclosure provides Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0171] In some aspects, the present disclosure provides Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0172] In some aspects, the present disclosure provides an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0173] In some aspects, the present disclosure provides Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0174] In some aspects, the present disclosure provides Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0175] In some aspects, the present disclosure provides Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0176] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0177] In some aspects, the present disclosure provides use of Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP- 1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0178] In some aspects, the present disclosure provides use of Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0179] In some aspects, the present disclosure provides use of Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0180] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

[0181] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder; wherein the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction- associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0182] In some aspects, the present disclosure provides use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with semaglutide in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0183] In some aspects, the present disclosure provides use of Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with semaglutide in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0184] In some aspects, the present disclosure provides use of Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with semaglutide in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0185] In some aspects, the present disclosure provides use of Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with semaglutide in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0186] In some aspects, the present disclosure provides a kit comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0187] In some aspects, the present disclosure provides a kit comprising Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0188] In some aspects, the present disclosure provides a kit comprising Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0189] In some aspects, the present disclosure provides a kit comprising Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0190] In some aspects, the present disclosure provides a kit comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0191] In some aspects, the present disclosure provides a kit comprising Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0192] In some aspects, the present disclosure provides a kit comprising Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0193] In some aspects, the present disclosure provides a kit comprising Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0194] In some aspects, the present disclosure provides a pharmaceutical package comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0195] In some aspects, the present disclosure provides a pharmaceutical package comprising Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0196] In some aspects, the present disclosure provides a pharmaceutical package comprising Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0197] In some aspects, the present disclosure provides a pharmaceutical package comprising Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0198] In some aspects, the present disclosure provides a pharmaceutical package comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0199] In some aspects, the present disclosure provides a pharmaceutical package comprising Compound Al, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0200] In some aspects, the present disclosure provides a pharmaceutical package comprising Compound B2, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0201] In some aspects, the present disclosure provides a pharmaceutical package comprising Compound C3, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and semaglutide.

[0202] In some embodiments, the kit or pharmaceutical package further comprises instructions for use.

[0203] In some embodiments, after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 7 days, about 14 days, about 28 days, or about 35 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

[0204] In some embodiments, after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 7 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

[0205] In some embodiments, after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 14 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

[0206] In some embodiments, after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 28 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

[0207] In some embodiments, after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 35 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

[0208] In some embodiments, the NLRP3 inflammasome inhibitor is administered as a monotherapy after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for 7 days.

[0209] In some embodiments, the NLRP3 inflammasome inhibitor is administered as a monotherapy after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for 14 days.

[0210] In some embodiments, the NLRP3 inflammasome inhibitor is administered as a monotherapy after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for 28 days.

[0211] In some embodiments, the NLRP3 inflammasome inhibitor is administered as a monotherapy after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for 35 days.

[0212] In some embodiments, the weight disorder is selected from a metabolic disorder, obesity, excessive body weight, and enhanced appetite.

[0213] In some embodiments, the weight disorder is a metabolic disorder.

[0214] In some embodiments, the weight disorder is obesity.

[0215] In some embodiments, the weight disorder is excessive body weight.

[0216] In some embodiments, the weight disorder is enhanced appetite.

[0217] In some embodiments, the GLP-1 linked disease and / or the weight disorder is selected from cardiovascular disease or disorder (e.g., angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, major adverse cardiac events (MACE)), metabolism disorder (e.g., type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, insulin resistance), bone disease (e.g., osteoporosis, bone metabolism, osteoarthritis), renal disease (e.g., chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, fibrosis), hepatic disease (e.g., alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis), gastrointestinal disease or disorder (e.g., motility disorders, inflammatory bowel disease), central nervous system (CNS) disease or disorder (e.g., neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, traumatic brain injury), skin disease (e.g., psoriasis), muscle disease (e.g., sarcopenia), lung disease (e.g., cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis), and others (e.g., polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, neuropathic pain).

[0218] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a cardiovascular disease or disorder.

[0219] In some embodiments, the cardiovascular disease or disorder is selected from angina pectoris, coronary heart disease, ischemic heart disease, myocardial infarction, reperfusion injury, heart disease, heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), right ventricular diastolic dysfunction, coronary microvascular dysfunction, aortic valve disease, cardiovascular risk reduction, and major adverse cardiac events (MACE).

[0220] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a metabolism disorder.

[0221] In some embodiments, the metabolism disorder is selected from type I diabetes, type II diabetes, glucose intolerance, hyperglucagonemia, hyperglycemia, metabolic syndrome, and insulin resistance.

[0222] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a bone disease.

[0223] In some embodiments, the bone disease is selected from osteoporosis, bone metabolism, and osteoarthritis.

[0224] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a renal disease.

[0225] In some embodiments, the renal disease is selected from chronic kidney disease, chronic renal insufficiency, diabetic nephropathy, and fibrosis.

[0226] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a hepatic disease.

[0227] In some embodiments, the hepatic disease is selected from alcoholic fatty liver disease (AFLD), alcohol related steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis.

[0228] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a gastrointestinal disease or disorder.

[0229] In some embodiments, the gastrointestinal disease or disorder is selected from motility disorders and inflammatory bowel disease.

[0230] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a central nervous system (CNS) disease or disorder.

[0231] In some embodiments, the central nervous system (CNS) disease or disorder is selected from neurodegenerative diseases such as cognition, Parkinson’s disease, or Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, stroke, and traumatic brain injury.

[0232] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a skin disease.

[0233] In some embodiments, the skin disease is psoriasis.

[0234] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a muscle disease.

[0235] In some embodiments, the muscle disease is sarcopenia.

[0236] In some embodiments, the GLP-1 linked disease and / or the weight disorder is a lung disease.

[0237] In some embodiments, the lung disease is selected from cystic fibrosis, interstitial lung disease, and idiopathic pulmonary fibrosis.

[0238] In some embodiments, the GLP-1 linked disease and / or the weight disorder is selected from polycystic ovary syndrome (PCOS), fibrosis, addiction (e.g., drug addiction or alcohol addiction), smoking cessation, binge eating disorder, post bariatric surgery treatment, multiple sclerosis, obstructive sleep apnea (OSA), rheumatoid arthritis, and neuropathic pain.

[0239] In some embodiments, the subject is a human.

[0240] In some embodiments, the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered in temporal proximity, sequentially, or in alternation.

[0241] In some embodiments, the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered in temporal proximity.

[0242] In some embodiments, the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered sequentially.

[0243] In some embodiments, the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered in alternation.

[0244] In some embodiments, the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered as different formulations. EXEMPLARY EMBODIMENTS

[0245] Embodiment 1. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subject.

[0246] Embodiment 2. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject.

[0247] Embodiment 3. The NLRP3 inflammasome inhibitor of Embodiment 1 or Embodiment 2, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH2)o-3-C5-C6 aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or o 0 0 r’'n--V'n'r’ (II), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Ris; and each R3S independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each ' is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, O, or S, as valency allows; A3 is CR2, N, NR2a, 0, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci- Ce alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0248] Embodiment 4. The NLRP3 inflammasome inhibitor of any one of Embodiments 1-3, wherein the NLRP3 inflammasome inhibitor is selected from Table 1 A, Table IB, or Table IC.

[0249] Embodiment 5. The NLRP3 inflammasome inhibitor of any one of Embodiments 1-4, wherein the NLRP3 inflammasome inhibitor is Compound Al: (Compound Al); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0250] Embodiment 6. The NLRP3 inflammasome inhibitor of any one of Embodiments 1-4, wherein the NLRP3 inflammasome inhibitor is Compound B2: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0251] Embodiment 7. The NLRP3 inflammasome inhibitor of any one of Embodiments 1-4, wherein the NLRP3 inflammasome inhibitor is Compound C3: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0252] Embodiment 8. The GLP-1 receptor agonist of any one of the preceding Embodiments, wherein the GLP-1 receptor agonist is selected from Table 2.

[0253] Embodiment 9. The GLP-1 receptor agonist of any one of the preceding Embodiments, wherein the GLP-1 receptor agonist is semaglutide.

[0254] Embodiment 10. A method of treating or preventing a GLP-1 linked disease and / or a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0255] Embodiment 11. A method of treating or preventing a weight disorder, comprising administering to a subject: (a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and (b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0256] Embodiment 12. The method of Embodiment 10 or Embodiment 11, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH^o-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or o 0 0 r’'n--V'n'r’ H H I K2 (II), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: n1b Ri is "1a , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; and each Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, O, or S, as valency allows; A3 is CR2, N, NR2a, 0, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0257] Embodiment 13. The method of any one of Embodiments 10-12, wherein the NLRP3 inflammasome inhibitor is selected from Table 1 A, Table IB, or Table IC.

[0258] Embodiment 14. The method of any one of Embodiments 10-13, wherein the NLRP3 inflammasome inhibitor is Compound Al: N .0 (Compound Al); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0259] Embodiment 15. The method of any one of Embodiments 10-13, wherein the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0260] Embodiment 16. The method of any one of Embodiments 10-13, wherein the NLRP3 inflammasome inhibitor is Compound C3: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0261] Embodiment 17. The method of any one of Embodiments 10-16, wherein the GLP-1 receptor agonist is selected from Table 2.

[0262] Embodiment 18. The method of any one of Embodiments 10-17, wherein the GLP-1 receptor agonist is semaglutide.

[0263] Embodiment 19. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

[0264] Embodiment 20. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

[0265] Embodiment 21. TheNLRP3 inflammasome inhibitor of Embodiment 19 or Embodiment 20, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; RJs H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CEEjo-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or O O O ,-,v H H r2 (II), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein nia and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; and each Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or R1 n 0 N o R’ R" H (in), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, 0, or S, as valency allows; A3 is CR2, N, NR2a, 0, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci- Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12- membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0266] Embodiment 22. The NLRP3 inflammasome inhibitor of any one of Embodiments 19-21, wherein the NLRP3 inflammasome inhibitor is selected from Table 1 A, Table IB, or Table IC.

[0267] Embodiment 23. The NLRP3 inflammasome inhibitor of any one of Embodiments 19-22, wherein the NLRP3 inflammasome inhibitor is Compound Al: N .0 (Compound Al); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0268] Embodiment 24. The NLRP3 inflammasome inhibitor of any one of Embodiments 19-22, wherein the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0269] Embodiment 25. The NLRP3 inflammasome inhibitor of any one of Embodiments 19-22, wherein the NLRP3 inflammasome inhibitor is Compound C3: (Compound C3); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0270] Embodiment 26. The GLP-1 receptor agonist of any one of Embodiments 19-25, wherein the GLP-1 receptor agonist is selected from Table 2.

[0271] Embodiment 27. The GLP-1 receptor agonist of any one of Embodiments 19-26, wherein the GLP-1 receptor agonist is semaglutide.

[0272] Embodiment 28. Use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

[0273] Embodiment 29. Use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

[0274] Embodiment 30. The use of an NLRP3 inflammasome inhibitor of Embodiment 28 or Embodiment 29, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: °           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; RHs H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CEEjo-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, - (CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or o 0 0 R-N--V'N'R’ H H I K2 (II), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: nib Ri is "1a , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2s is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2ss independently is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; and each R3S independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or R1 r"2 OR’ Rb H (in), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, 0, or S, as valency allows; A3 is CR2, N, NR2a, 0, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, - C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=0)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0275] Embodiment 31. The use of an NLRP3 inflammasome inhibitor of any one of Embodiments 28-30, wherein the NLRP3 inflammasome inhibitor is selected from Table 1A, Table IB, or Table IC.

[0276] Embodiment 32. The use of an NLRP3 inflammasome inhibitor of any one of Embodiments 28-31, wherein the NLRP3 inflammasome inhibitor is Compound Al: N .0 (Compound Al); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0277] Embodiment 33. The use of an NLRP3 inflammasome inhibitor of any one of Embodiments 28-31, wherein the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0278] Embodiment 34. The use of an NLRP3 inflammasome inhibitor of any one of Embodiments 28-31, wherein the NLRP3 inflammasome inhibitor is Compound C3: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0279] Embodiment 35. The use of a GLP-1 receptor agonist of any one of Embodiments 28-34, wherein the GLP-1 receptor agonist is selected from Table 2.

[0280] Embodiment 36. The use of a GLP-1 receptor agonist of any one of Embodiments 28-35, wherein the GLP-1 receptor agonist is semaglutide.

[0281] Embodiment 37. A kit comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0282] Embodiment 38. The kit of Embodiment 37, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH^o-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2s is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2ss independently is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Ris; and each R3S independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, 0, or S, as valency allows; A3 is CR2, N, NR2a, 0, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, O, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=0)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0283] Embodiment 39. The kit of Embodiment 37 or Embodiment 38, wherein the NLRP3 inflammasome inhibitor is selected from Table 1 A, Table IB, or Table IC.

[0284] Embodiment 40. The kit of any one of Embodiments 37-39, wherein the NLRP3 inflammasome inhibitor is Compound Al: (Compound Al); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0285] Embodiment 41. The kit of any one of Embodiments 37-39, wherein the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0286] Embodiment 42. The kit of any one of Embodiments 37-39, wherein the NLRP3 inflammasome inhibitor is Compound C3: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0287] Embodiment 43. The kit of any one of Embodiments 37-42, wherein the GLP-1 receptor agonist is selected from Table 2.

[0288] Embodiment 44. The kit of any one of Embodiments 37-43, wherein the GLP-1 receptor agonist is semaglutide.

[0289] Embodiment 45. A pharmaceutical package comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0290] Embodiment 46. The pharmaceutical package of Embodiment 45, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III: 0           (I), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re; R3 is H or C1-C4 alkyl optionally substituted with one or more R7; FLds H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH^o-s-Cs-Ce aryl; Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; and Rs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; or o 0 0 r’'n--V'n'r’ (II), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: Ri is nia , wherein ma and nib each independently are 0 or 1; R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2; R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss; each R2ss independently is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, or oxo; R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Ris; and each R3S independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; or or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein: each ' is independently a single bond or double bond as valency permits; A2 is CR2, N, NR2a, O, or S, as valency allows; A3 is CR2, N, NR2a, O, or S, as valency allows; A4 is CR2, N, NR2a, 0, or S, as valency allows, wherein at least one of A2, A3, or A4 is N, NR2a, O, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S; R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S; each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl; each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S, or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S; each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl; each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl); each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl; RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a; each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=0)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; and each RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

[0291] Embodiment 47. The pharmaceutical package of Embodiment 45 or Embodiment 46, wherein the NLRP3 inflammasome inhibitor is selected from Table 1A, Table IB, Table IC, or Table ID.

[0292] Embodiment 48. The pharmaceutical package of any one of Embodiments 45-47, wherein the NLRP3 inflammasome inhibitor is Compound Al: N .0 (Compound Al); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0293] Embodiment 49. The pharmaceutical package of any one of Embodiments 45-47, wherein the NLRP3 inflammasome inhibitor is Compound B2: (Compound B2); or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0294] Embodiment 50. The pharmaceutical package of any one of Embodiments 45-47, wherein the NLRP3 inflammasome inhibitor is Compound C3: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0295] Embodiment 51. The pharmaceutical package of any one of Embodiments 45-50, wherein the GLP-1 receptor agonist is selected from Table 2 or Table 3.

[0296] Embodiment 52. The pharmaceutical package of any one of Embodiments 45-51, wherein the GLP-1 receptor agonist is semaglutide.

[0297] Embodiment 53. The kit or pharmaceutical package of any one of Embodiments 37-52 further comprising instructions for use.

[0298] Embodiment 54. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 7 days, about 14 days, about 28 days, or about 35 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

[0299] Embodiment 55. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein the NLRP3 inflammasome inhibitor is administered as a monotherapy after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for 28 days.

[0300] Embodiment 56. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein the weight disorder is selected from a metabolic disorder, obesity, excessive body weight, and enhanced appetite.

[0301] Embodiment 57. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein the weight disorder is obesity.

[0302] Embodiment 58. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein the subject is a human.

[0303] Embodiment 59. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered in temporal proximity, sequentially, or in alternation.

[0304] Embodiment 60. The combination, use, method, pharmaceutical package, or kit of any one of the preceding Embodiments, wherein the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered as different formulations. EXAMPLES Example 1. Combination Therapy of NLRP3 Inflammasome Inhibitor and GLP-1 Receptor Agonist in Mice

[0305] Studies with ester pro-drug, Compound Al, and Compound C3 were performed in hCESl mice, a novel mouse line, engineered to possess more human-like traits with respect to carboxylesterase biology (Smolak P, Nguyen M, Diamond C, Wescott H, Doedens J, Schooley K, Snouwaert J, Bock M, Harrison D, Watt A, Koller B, and Gabel C (2024) Target cell activation of a structurally novel NLRP3 inflammasome inhibitor NT-0796 enhances potency. J Pharmacol Exp Ther. 388(3), 798-812) specifically, a lack of murine plasma Ceslc and targeted expression of human CES1 to myeloid cells. This strain originated on, and was maintained on a B6,129 background as a homozygous colony. hCESl mice were provided by NodThera and maintained at HD Biosciences (China) Co., Ltd. Experimental procedures were performed in accordance with Guide for Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (IACUC) at HDB. Animals were acclimatized for at least 1 week prior to experiments. All euthanasia was performed using carbon dioxide inhalation and all efforts were made to minimize animal suffering. Animals were group-housed (5 animals per cage) with bedding under controlled temperature (20-25°C), noise, humidity (40-70%), and lighting (12-hour light and 12-hour dark) conditions. All animals had free access to purified water and standard certified rodent chow (Beijing Keao Xieli Feed Co., Ltd., Beijing, China, #2112 / 2151) ad libitum. The general condition (appearance and activity) of all animals was carefully monitored daily by a veterinarian throughout the study. DIO model and compound dosing

[0306] hCESl mice were fed with standard chow diet (SCD) until week 5, then switched to high-fat diet (HFD; Research Diets, New Brunswick, USA, #D12492, Rodent Diet with 60 kcal% Fat, Research diet) for an additional 15 weeks. Prior to compound treatment animals were randomized based on their body weight and total plasma HDL, LDL, TC and TG values. Compound Al and Compound C3 were prepared in vehicle (0.5% methylcellulose + 0.2% Tween80) at 10 mg / ml with a maximum dosing volume of 10 ml / kg (p.o., t.i.d.). Compound Al and Compound C3 were each dosed at 100 mg / kg, p.o. t.i.d. at 8 a.m., 3 p.m. and 10 p.m. Semaglutide was prepared in vehicle containing 0.05% Tween80 in PBS at a final concentration of 0.0005 mg / ml with a dosing volume of 10 ml / kg (s.c; q.d). Calorie intake and body weight

[0307] Food intake was measured by group (per cage) daily throughout study periods. At 8:00 am every day (the beginning of the light cycle), food pellet was weighed and provided to animals ad libitum. At 8:00 am on the following day (the beginning of the light cycle), the remaining food pellet was weighed again, and the difference was recorded as the total food consumption by the group of animals over 24 hours. The results were expressed as average food consumption per mouse (g; total food consumption / number of animals in the cage). Body weight of each animal was measured daily after food intake measurement. Overnight fasting into day 25 was performed during DIO studies to facilitate the analysis of further exploratory endpoints. Average calorie intake was calculated for each group (by calculating the average daily food (g) consumption per cage, then multiplying by the kcal content per food type (3.44 kcal / g for normal chow, or 5.24kcal / g for high fat diet). Results

[0308] The pharmacology of Compound Al, a pro-drug of active metabolite NDT-19795, is enhanced in hCESl mice, which more closely mimics human expression of carboxylesterase-1 (CES-1) in myeloid cells (Smolak et al., supra). We fed mice that transgenically overexpress myeloid hCESl a high fat diet (HFD) for 15 weeks prior to compound treatment.

[0309] Body weight was recorded every day and expressed as % change from day 0. Compared to the vehicle-treated DIO hCESl mice group, treatment with Compound Al (100 mg / kg, p.o. t.i.d.) or semaglutide (0.005 mg / kg, s.c. q.d) reduced body weight by -17, or -15 %, respectively over 28 days. (FIG. 1A). However, combined treatment with Compound Al and semaglutide drove enhanced weight loss (-24 % relative to baseline), which was significantly higher than semaglutide alone (FIG. 1A). Average calorie consumption between the vehicle-treated DIO hCESl mice and a control chow group (non-obese) were similar over the 28-day dosing period. Semaglutide at 0.005 mg / kg, was largely ineffective at lowering average calorie intake (relative to control groups). However, mice dosed with Compound Al, or Compound Al combined with semaglutide, consumed reduced calories over 28 days relative to the vehicle-treated DIO mice FIG. IB).

[0310] Compared to vehicle-treated DIO hCESl mice group, treatment with Compound C3 (100 mg / kg, p.o. t.i.d.) or semaglutide (0.005 mg / kg, s.c. q.d) reduced body weight by -17, or -15 %, respectively over 28 days. (FIG. 2A). However, as with Compound Al, combined treatment with Compound C3 and semaglutide drove enhanced weight loss (-21 % relative to baseline). (FIG. 2A). Mice dosed with Compound C3, or Compound C3 combined with semaglutide, consumed reduced calories over 28 days relative to the vehicle-treated DIO mice (FIG. 2B).

[0311] An extension study was undertaken following the main study with Compound Al, to understand how continual NLRP3 inhibition in DIO hCESl mice may modulate weight re-gain following the cessation of semaglutide (+ / - NLRP3 inhibition) in DIO mice. The extension study period included an additional 28-day period after the main study, running for 56 days in total (FIG. 3A). DIO hCESl mice dosed initially (in the main study) with semaglutide (0.005 mpk) and on extension study having this treatment removed (being treated with vehicle only from day 28), went on to increase their body weight considerably by day 56 (FIG. 3 A). However, this trend for weight re-gain, driven by the semaglutide withdrawal, was prevented by maintaining the hCESl DIO mice on Compound Al (FIG. 3A). In addition, hCESl DIO mice initially dosed with combined semaglutide and Compound Al, before switching to Compound Al only, maintained a lower body weight throughout the extension study (compared to DIO mice receiving an equivalent dose of Compound Al, but having been dosed with semaglutide only during the main study, FIG. 3A).

[0312] The DIO hCESl mice dosed initially with semaglutide only, and on extension study having this treatment removed (vehicle only group) had much elevated calorie intake throughout the extension study period (days 28-56; FIG. 3B). The raised calorie intake, on switching from semaglutide to vehicle, was inhibited by maintaining a dose of Compound Al throughout the extension study (FIG. 3B). Maintenance of Compound Al dosing in hCESl DIO mice that had initially been dosed with semaglutide and Compound Al (during the main study) also sustained the lowest calorie intake during the course of the extension study (FIG. 3B).

[0313] These data indicate that dosing of a centrally-penetrant NLRP3 inflammasome inhibitor drives weight loss in obese mice, and that the effect of an NLRP3 inflammasome inhibitor is additive to GLP1 receptor agonist, semaglutide. In addition, the data demonstrate that dosing a centrally penetrant NLRP3 inflammasome inhibitor prevents weight re-gain apparent on cessation of semaglutide dosing. Further, if semaglutide treatment is initially combined with an NLPR3 inhibitor, the degree of weight re-gain on semaglutide cessation will be further reduced (compared to animals not having initial NLRP3 inhibition). Example 2: NLRP3 Inflammasome Inhibitor in Combination with Semaglutide Normalizes Obesity in Mice During Exposure to a Polyunsaturated Fatty Acid Diet Methods Animals

[0314] Studies with Compound Al were performed in hCESl mice, a mouse line, engineered to possess more human-like traits with respect to carboxylesterase biology (Smolak et al., supra} specifically, a lack of murine plasma Ceslc and targeted expression of human CES1 to myeloid cells. This strain originated on, and was maintained on a B6,129 background as a homozygous colony. hCESl mice were provided by NodThera and maintained at HD Biosciences (China) Co., Ltd. Experimental procedures were performed in accordance with Guide for Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (IACUC) at HDB. Animals were acclimatized for at least 1 week prior to experiments. All euthanasia was performed using carbon dioxide inhalation and all efforts were made to minimize animal suffering. Animals were group-housed (five animals per cage) with bedding under controlled temperature (20-25°C), noise, humidity (40-70%), and lighting (12-hour light and 12-hour dark) conditions. All animals had free access to purified water and standard certified rodent chow (Beijing Keao Xieli Feed Co., Ltd., Beijing, China, #2112 / 2151) ad libitum. The general condition (appearance and activity) of all animals was carefully monitored daily by a veterinarian throughout the study. Diet-induced obesity model and compound dosing

[0315] All hCESl mice were fed standard chow diet until week 7, then switched to high-fat diet (HFD; 60 kcal% fat) for an additional 15 weeks to drive diet-induced obesity (DIO). Control animals received standard chow diet throughout the experiments. DIO animals remained on ad libitum HFD or ad libitum polyunsaturated fatty acid (PUFA) diet (with 40 kcal% fat) where stated. Compound Al was prepared at 10 mg / mL in a vehicle of 0.5% methylcellulose and 0.2% Tween 80 with a dosing volume of 10 mL / kg for a dose of 100 mg / kg (p.o., t.i.d.). Semaglutide was prepared at a final concentration of 0.0005 mg / mL in a vehicle of 0.05% Tween 80 in PBS with a dosing volume of 10 mL / kg for a dose of 0.005 mg / kg (s.c., q.d.). Combination dosed animals received both Compound Al (p.o., t.i.d.) and semaglutide (s.c., q.d.). Respective vehicles were dosed to all animals such that each animal received an oral and subcutaneous administration. A calorie restricted group was included that matched the weights of animals dosed with Compound Al alone. The amount of food supplied to animals under calorie restriction was based on the average food intake of animals dosed with Compound Al monotherapy. Food intake and body weight measurement

[0316] Food intake was measured daily for each cage by recording the weight difference of the food pellet provided at 8:00 a.m. and the remaining food the following morning at 8:00 a.m. and noted as the total food consumption by the group in 24 hours. Final results were expressed as average food consumption per mouse by dividing the total food consumption by the number of animals in each cage. Average daily calorie intake was calculated using the average food intake by each group times the calorie content of each diet per gram. Body weight of each animal was measured daily after food intake measurement. First day of each treatment regime was defined as the baseline value for calculating raw weight and percentage weight change for each animal. Body composition and organ weights

[0317] Body composition (bone mineral content, fat tissue, lean tissue) was measured using an InAlyzer dual-energy X-ray absorptiometry (DEXA) scan at study end. At study end, animals were sacrificed using CO2 inhalation and all efforts were made to minimize suffering. Organs (liver, heart, brain, kidneys and colon) were collected and weighed. GFAP immunohistochemistry

[0318] Brain tissues were collected for the assessment of hypothalamic GFAP expression by immunohistochemistry. Following assignment of the arcuate nucleus (ARC), dorsomedial hypothalamic nucleus (DMH) and ventromedial hypothalamic nucleus (VMH) areas, GFAP immunoreactivity was assessed in Multiplex IHC v3.2.3 module of the HALO® Image Analysis Platform. The average total GFAP staining (%), average strong GFAP staining (%), or the total number of GFAP positive cells (per pm2) across the ARC, DMH and VMH was calculated. Statistical analysis

[0319] Statistical analysis was performed in GraphPad Prism 10.4.1 using one- or two-way ANOVA followed by Dunnett’s or Tukey’s post-hoc statistical analysis. A p-value of <0.05 was considered to be statistically significant. Results

[0320] The pharmacology of Compound Al is enhanced in hCESl mice, with humanized expression of carboxylesterase-1 (CES-1) in myeloid cells (Smolak et al., supra). The combinatorial weight loss efficacy of NLRP3 inflammasome inhibitor, Compound Al with GLP-1 receptor agonist, semaglutide, was assessed in hCESl DIO mice during initial exposure (days 028) to high fat diet (HFD) and following a switch to translationally-relevant polyunsaturated fatty acid (PUFA) diet (days 29-56).

[0321] Dosing of DIO mice (during HFD exposure), with Compound Al (100 mg / kg, p.o., t.i.d.) monotherapy or semaglutide (0.005 mg / kg, s.c., q.d.) monotherapy drove significant weight loss, reaching -7.4%, and -12.7%, respectively, by 28 days (FIG. 4). However, the combination of Compound Al and semaglutide drove -20.0% weight loss, significantly greater than either monotherapy alone at the mid-study point (FIG. 4). On switching to PUFA diet ad libitum at day 29, DIO control mice, maintained consistent body weight over days 29-56 (FIG. 4 and FIG. 5). Compound Al-dosed DIO mice, continued to lose additional body weight (-13.8%, by day 56), whereas semaglutide-induced weight loss at day 56 was largely equal to the mid-study point (-12.7 v -11.1%; FIG. 4). The calorie-restricted DIO mice matched the weight loss of the Compound Al dosed group, reaching -11.8% reduction at day 56 (FIG. 4). Switching DIO mice to a PUFA diet, whilst maintaining combined dosing of Compound Al and semaglutide, continued to drive further weight loss in these animals, such that by day 43, the obesogenic state had been completely reversed and mice weighed the same as chow fed control mice (FIG. 5). This corresponded to a -30.3% weight loss by day 56 (FIG. 4), in response to Compound Al and semaglutide combination treatment, which was significantly greater than reductions achieved by either monotherapy alone (FIG. 4 and FIG. 5).

[0322] Body weight changes during the first 28 days of the study correlated with food intake (FIG. 6A) and calorie intake (FIG. 6B). Compound Al or semaglutide monotherapy drove significant reductions in calorie intake, and the combination of Compound Al and semaglutide drove additional calorie intake suppression, greater than either monotherapy alone (FIG. 6B).

[0323] Dual-energy x-ray absorptiometry (DEXA) scans confirmed that combination therapy of Compound Al and semaglutide was most effective at reducing % body fat relative to DIO control mice at day 28; Compound Al (-5.1%), semaglutide (-11.9%), Compound Al and semaglutide combination (-15.7%, FIG. 7A). In addition, combination therapy was most effective at preserving % lean mass relative to DIO control mice at day 28; Compound Al (+4.7%), semaglutide (+11.4%), Compound Al and semaglutide combination (+15.2%, FIG. 7B). DEXA scans also revealed that combination therapy provided the greatest preservation of % bone mineral content relative to DIO control mice; Compound Al (+0.4%), semaglutide (+0.5%), Compound Al and semaglutide combination (+0.6%, FIG. 7C).

[0324] DIO mice dosed with Compound Al also consumed less calories on PUFA diet relative to DIO control mice (FIGs. 8A-B). Semaglutide dosing during PUFA diet exposure also lowered calorie intake of DIO mice (FIG. 8B). However, combined dosing of Compound Al with semaglutide, suppressed calorie intake during the PUFA diet period to a greater extent than monotherapy interventions (FIG. 8B). The calorie restricted group maintained equivalent calorie intake to the Compound Al monotherapy group (FIG. 8B).

[0325] At study end, the astrogliosis marker, glial fibrillary acidic protein (GFAP) was quantified by immunohistochemistry. Average immunoreactivity across the arcuate nucleus (ARC), dorsomedial (DMH) and ventral hypothalamus (VMH) of mice was assessed. Relative to normal chow fed animals, the average total percent GFAP staining (FIG. 9A), percentage of strongly-stained GFAP (FIG. 9B), and total GFAP positive cell numbers (FIG. 9C) were elevated in DIO control mice. Relative to the DIO control mice, dosing with Compound Al monotherapy, or Compound Al in combination with semaglutide, drove significant reductions in average total percent GFAP staining (FIG. 9A), percentage of strongly-stained GFAP (FIG. 9B), and total GFAP positive cell numbers GFAP (FIG. 9C) across these hypothalamic brain regions. Calorie restriction or semaglutide monotherapy trended to reduce GFAP staining across these regions, but this did not reach significance (FIGs. 9A-C).

[0326] Compared to the DIO control mice, all treatment interventions decreased liver weights (FIG. 10A). Semaglutide monotherapy or semaglutide in combination with Compound Al provided greatest treatment-driven reductions in liver weight (FIG. 10A). Calorie restriction also significantly reduced liver weights (FIG. 10A). Heart weights were also increased in DIO control mice, relative to chow fed controls (FIG. 10B). Compound Al or semaglutide monotherapy significantly reduced heart weights relative to DIO controls (FIG. 10B). Combination dosing of semaglutide and Compound Al provided the largest reductions in heart weights of DIO control mice (FIG. 10B).

[0327] Brain weights remained unchanged across study groups (FIG. 10C). Left and right kidney weights trended to increase in response to DIO challenge (relative to chow fed controls) (FIGs. 10D-E). Compound Al combined with semaglutide reduced left and right kidney weights, relative to DIO control mice (FIGs. 10D-E). Compound Al monotherapy also reduced both kidney weights (FIGs. 10D-E). Semaglutide monotherapy trended (left) or significantly reduced (right) kidney weight (FIGs. 10D-E). Calorie restriction was less effective a reducing kidney weights compared to drug interventions (FIGs. 10D-E). Colon weights were reduced in response to DIO challenge but not significantly altered by drug interventions (FIG. 10F).

[0328] These data indicate that dosing of a centrally-penetrant NLRP3 inflammasome inhibitor drives weight loss and that this mechanism combines with that of a GLP-1 receptor agonist, such as semaglutide, to achieve superior efficacy compared to either monotherapy alone. Importantly, the data demonstrate that simultaneous targeting of the NLRP3 inflammasome and the GLP-1 receptor pathway normalizes the obesogenic phenotype in mice, with full correction of body weight within eight weeks of dosing. In addition to the effects on body weight, the combined dosing of an NLRP3 inflammasome inhibitor with semaglutide, a GLP-1 receptor agonist, provides further improvements in obese mice, including greater reductions in neuroinflammation and enhanced preservation of lean mass and bone mineral content. EQUIVALENTS

[0329] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0330] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

1. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a GLP-1 linked disease and / or a weight disorder in a subject.

2. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing a weight disorder in a subject.

3. The NLRP3 inflammasome inhibitor of claim 1 or claim 2, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III:°           (I),or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re;R3 is H or C1-C4 alkyl optionally substituted with one or more R7;Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH2)o-3-C5-C6 aryl;Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3;R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; andRs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; oro O 0r’'n--V'n'r’(II),or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ri is nia , wherein ma and nib each independently are 0 or 1;R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2;R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss;each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, or oxo;R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; andeach Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; oror a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:each ' is independently a single bond or double bond as valency permits;A2 is CR2, N, NR2a, 0, or S, as valency allows;A3 is CR2, N, NR2a, 0, or S, as valency allows;A4 is CR2, N, NR2a, 0, or S, as valency allows,wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 isCR2, NR2a, 0, or S;R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S;each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl;each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S,or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S;each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl;each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl);each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl;RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a;each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=0)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; andeach RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

4. The NLRP3 inflammasome inhibitor of any one of claims 1-3, wherein the NLRP3 inflammasome inhibitor is selected from Table 1 A, Table IB, or Table IC.

5. The NLRP3 inflammasome inhibitor of any one of claims 1-4, wherein the NLRP3 inflammasome inhibitor is Compound Al:(Compound Al);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

6. The NLRP3 inflammasome inhibitor of any one of claims 1-4, wherein the NLRP3 inflammasome inhibitor is Compound B2:(Compound B2);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

7. The NLRP3 inflammasome inhibitor of any one of claims 1-4, wherein the NLRP3inflammasome inhibitor is Compound C3:(Compound C3);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

8. The GLP-1 receptor agonist of any one of the preceding claims, wherein the GLP-1 receptor agonist is selected from Table 2.

9. The GLP-1 receptor agonist of any one of the preceding claims, wherein the GLP-1 receptor agonist is semaglutide.

10. A method of treating or preventing a GLP-1 linked disease and / or a weight disorder, comprising administering to a subject:(a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

11. A method of treating or preventing a weight disorder, comprising administering to a subject:(a) an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

12. The method of claim 10 or claim 11, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III:0           (I),or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re;R3 is H or C1-C4 alkyl optionally substituted with one or more R7;Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH^o-s-Cs-Ce aryl;Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3;R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; andRs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; oro 0 0r’'n--V'n'r’H H I K2 (II),or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:n1bRi is "1a, wherein ma and nib each independently are 0 or 1;R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2;R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss;each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo;R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; andeach Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; oror a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:each is independently a single bond or double bond as valency permits;A2 is CR2, N, NR2a, O, or S, as valency allows;A3 is CR2, N, NR2a, 0, or S, as valency allows;A4 is CR2, N, NR2a, 0, or S, as valency allows,wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 isCR2, NR2a, 0, or S;R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S;each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl;each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S,or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S;each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl;each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl);each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl;RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a;each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; andeach RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

13. The method of any one of claims 10-12, wherein the NLRP3 inflammasome inhibitor is selected from Table 1A, Table IB, or Table IC.

14. The method of any one of claims 10-13, wherein the NLRP3 inflammasome inhibitor is Compound Al:N .0(Compound Al);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

15. The method of any one of claims 10-13, wherein the NLRP3 inflammasome inhibitor is Compound B2:'—'                     (Compound B2);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

16. The method of any one of claims 10-13, wherein the NLRP3 inflammasome inhibitor is Compound C3:NON(Compound C3);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

17. The method of any one of claims 10-16, wherein the GLP-1 receptor agonist is selected from Table 2.

18. The method of any one of claims 10-17, wherein the GLP-1 receptor agonist is semaglutide.

19. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

20. An NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of a weight disorder in a subject.

21. Use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 linked disease and / or a weight disorder in a subject.

22. Use of an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a weight disorder in a subject.

23. A kit comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

24. A pharmaceutical package comprising an NLRP3 inflammasome inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

25. The NLRP3 inflammasome inhibitor of claim 19 or claim 20, the use of an NLRP3 inflammasome inhibitor of claim 21 or claim 22, the kit of claim 23, or the pharmaceutical package of claim 24, wherein the NLRP3 inflammasome inhibitor is a compound of Formula I, Formula II, or Formula III:0           (I),or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ri is C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, C5-C10 aryl, 8- to 12membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the C3-C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more Re;R3 is H or C1-C4 alkyl optionally substituted with one or more R7;Rus H, Ci-Ce alkyl, -(CH2)o-3-(C3-Ce cycloalkyl), or -(CH^o-s-Cs-Ce aryl;Re is Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, C3-C8 cycloalkyl, halo, oxo, -OH, -CN, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3;R7 is -ORs, C5-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C5-C10 aryl or 5-to 10-membered heteroaryl is optionally substituted by one or more R?s, wherein each R?s is independently Ci-Ce alkyl, Ci-Ce alkoxy, 5- to 10-membered heteroaryl, halo, -OH, -CN, -(CH2)o-3-NH2, -(CH2)o-3-NH(Ci-C6 alkyl), -(CH2)o-3-N(Ci-C6 alkyl)2, -CH2F, -CHF2, or -CF3; andRs is Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 5- to 7-membered heterocycloalkyl is optionally substituted by one or more R?s; orRi(II),or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Ri is nia , wherein nia and nib each independently are 0 or 1;R2 is -(CH2)n2-R2s, wherein n2 is 1 or 2;R2S is 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with one or more R2ss;each R2SS independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, halo, -CN, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or oxo;R3 is 5- or 6-membered heteroaryl optionally substituted with one or more Rss; andeach Rss independently is halo, Ci-Ce alkyl, or Ci-Ce haloalkyl; orR1n 0N o R’ R" H (in), or a prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:each is independently a single bond or double bond as valency permits;A2 is CR2, N, NR2a, 0, or S, as valency allows;A3 is CR2, N, NR2a, 0, or S, as valency allows;A4 is CR2, N, NR2a, 0, or S, as valency allows,wherein at least one of A2, A3, or A4 is N, NR2a, 0, or S, provided that when A2 is S, A4 is CR2, NR2a, 0, or S;R1 is H, -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl, wherein the -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, or C3-C12 cycloalkyl is optionally substituted with one or more R1S;each R1S independently is halogen, cyano, -OH, or Ci-Ce alkyl;each R2 independently is H, halogen, cyano, -OH, -NH2, -NO2, -C(=0)NH2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is optionally substituted with one or more R2S,or two R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C3-C12 cycloalkyl or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R2S;each R2S independently is halogen, -OH, -O(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, or C3-C12 cycloalkyl;each R2a independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -(CH2)o-3-(C3-Ci2 cycloalkyl), or -(CH2)o-3-(3- to 12-membered heterocycloalkyl);each Ra independently is H or Ci-Ce alkyl; or two Ra, together with the atom they attach to, form C3-C12 cycloalkyl;RN2 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C12 cycloalkyl, 3-to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(Ci-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(Ci-Ce alkyl), -NH-(C2-Ce alkenyl), -NH-(C2-Ce alkynyl), C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2a;each RN2a independently is oxo, halogen, cyano, -OH, -NH2, -C(=0)H, -C(=0)0H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(Ce-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl); wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(Ci-Ce alkyl), -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=0)0(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), -S(=O)2N(Ci-Ce alkyl)2, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(Ci-Ce alkyl)-(C3-Ci2 cycloalkyl), -(Ci-Ce alkyl)-(3- to 12-membered heterocycloalkyl), -(Ci-Ce alkyl)-(C6-Cio aryl), or -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RN2ab; andeach RN2ab independently is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(=O)(Ci-C6 alkyl), -C(=O)O(Ci-C6 alkyl), -NHC(=O)O(Ci-C6 alkyl), -S(=O)2(Ci-C6 alkyl), or -S(=O)2N(Ci-C6 alkyl)2.

26. The NLRP3 inflammasome inhibitor, the use of an NLRP3 inflammasome inhibitor, the kit, or the pharmaceutical package of any one of claims 19-25, wherein the NLRP3 inflammasome inhibitor is selected from Table 1 A, Table IB, Table IC, or Table ID.

27. The NLRP3 inflammasome inhibitor, the use of an NLRP3 inflammasome inhibitor, the kit, or the pharmaceutical package of any one of claims 19-26, wherein the NLRP3 inflammasome inhibitor is Compound Al:or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

28. The NLRP3 inflammasome inhibitor, the use of an NLRP3 inflammasome inhibitor, thekit, or the pharmaceutical package of any one of claims 19-26, wherein the NLRP3inflammasome inhibitor is Compound B2:N-NZ(Compound B2);or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

29. The NLRP3 inflammasome inhibitor, the use of an NLRP3 inflammasome inhibitor, the kit, or the pharmaceutical package of any one of claims 19-26, wherein the NLRP3 inflammasome inhibitor is Compound C3:or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

30. The NLRP3 inflammasome inhibitor, the use of an NLRP3 inflammasome inhibitor, the kit, or the pharmaceutical package of any one of claims 19-29, wherein the GLP-1 receptor agonist is selected from Table 2 or Table 3.

31. The NLRP3 inflammasome inhibitor, the use of an NLRP3 inflammasome inhibitor, the kit, or the pharmaceutical package of any one of claims 19-30, wherein the GLP-1 receptor agonist is semaglutide.

32. The kit or the pharmaceutical package of any one of claims 23-31 further comprising instructions for use.

33. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for about 7 days, about 14 days, about 28 days, or about 35 days, the NLRP3 inflammasome inhibitor is administered as a monotherapy.

34. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the NLRP3 inflammasome inhibitor is administered as a monotherapy after treatment of the combination of NLRP3 inflammasome inhibitor and GLP-1 receptor agonist for 28 days.

35. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the weight disorder is selected from a metabolic disorder, obesity, excessive body weight, and enhanced appetite.

36. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the weight disorder is obesity.

37. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the subject is a human.

38. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered in temporal proximity, sequentially, or in alternation.

39. The combination, use, method, pharmaceutical package, or kit of any one of the preceding claims, wherein the NLRP3 inflammasome inhibitor and GLP-1 receptor agonist are administered as different formulations.

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