Methods for the treatment of overweight

Abstract

Described herein are methods of treating overweight, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, and / or reducing adipose weight in a subject, the methods comprising administering an incretin mimetic and an inflammasome modulator to the subject. In some embodiments the method of treatment comprises administering an incretin mimetic and administering a compound of formulae (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VII), or (0).

Description

Attorney Docket No. 63243-709.601METHODS FOR THE TREATMENT OF OVERWEIGHTCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 693,129, filed September 10, 2024, and US 63 / 738,156, filed December 23, 2024; both of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] It is estimated that over 40% of adults in the United States have obesity. Obesity often precipitates other health complications, such as cardiovascular disease, type 2 diabetes, sleep apnea, and fatty liver disease. Despite the significance of the obesity epidemic, limited pharmacological treatments exist to manage patient weight. Therefore, novel methods for the treatment of obesity and overweight are needed.

[0003] Additionally, it is estimated that over 10% of adults in the United States have diabetes. Type II diabetes is characterized by insulin resistance leading to hyperglycemia. Diabetes causes a range of symptoms including fatigue, frequent urination, and compromised vision. Hyperglycemia resulting from diabetes may lead to tissue and nerve damage. Diabetes is a chronic condition with growing prevalence; therefore, novel methods for the treatment of diabetes are needed.SUMMARY OF THE INVENTION

[0004] In one aspect, provided herein is a method of treating overweight in a subject with a combination therapy provided herein. In one aspect, provided herein is a method of weight management in a subject with a combination therapy provided herein. In one aspect, provided herein is a method of treating diabetes in a subject with a combination therapy provided herein. In one aspect, provided herein is a method of lowering blood glucose in a subject with a combination therapy provided herein. In one aspect, provided herein is a method of reducing insulin resistance in a subject with a combination therapy provided herein. In one aspect, provided herein is a method of reducing serum triglyceride levels in a subject with a combination therapy provided herein. In one aspect, provided herein is a method of reducing the adipose weight of a subject with a combination therapy provided herein.

[0005] The subject may have diabetes, such as type 2 diabetes. The subject may have obesity. The subject may be overweight. The overweight may be obesity. The overweight may be a symptom of a disease or condition of the subject experiencing overweight. The overweight may be a symptom of and / or associated with diabetes, hypothyroidism, metabolic syndrome, fatty liver disease, polycystic ovary syndrome, Cushing’s disease, or aAttorney Docket No. 63243-709.601 combination thereof. The overweight may be a symptom of lifestyle, e.g., a sedentary lifestyle and / or a lack of physical activity. The overweight may be a symptom of food consumption in excess of a subject’s metabolic requirements and / or consumption of certain foods, such as highly processed foods, foods high in sugar, saturated fat, etc. The overweight may be a symptom of stress, poor sleep and / or a medication.

[0006] In one aspect, provided herein is a method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (V) wherein: A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5; X is N or CH; Y is CHOH or NH; R1is H or Ci-C6alkyl; R2is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; R4is H, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-memberedAttorney Docket No. 63243-709.601 heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; and R5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0007] In some embodiments, the compound of Formula (V), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction, inhibits the priming step of the NLRP3 inflammasome, and / or and inhibits the formation of NLRP3 (protein)-NEK7 (protein) interactions. In some embodiments, the GLP-1 receptor agonist comprises semaglutide, exenatide, lixisenatide, albiglutide, beinaglutide, dulaglutide, efpeglenatide, liraglutide, polyethylene glycol loxenatide, taspoglutide, ecnoglutide, utreglutide, maridebart cafraglutide, tirzepatide, pegapamodutide, mazdutide, survodutide, bamadutide, pemvidutide, cotadutide, retatrutide, lithium chloride, efocipegtrutide, SAR441255, GZR18, BLX-7006, orforglipron, aleniglipron (GSBR-1290), amycretin, ECC5004, HS-10535, CT-966, VK2735, danuglipron, or a compound comprising a peptide at least 80% identical to the amino acid sequence of any one of SEQ ID NOS: 1-32. In some embodiments, the GLP-1 receptor agonist comprises semaglutide or BLX-7006. In some embodiments, the GLP-1 receptor agonist is a single GLP-1 agonist, a GLP-l / glucagon receptor dual agonist, or a GLP-l / GIP / glucagon receptor triagonist.

[0008] In some embodiments, the subject is overweight, and the overweight is a symptom of and / or associated with diabetes, hypothyroidism, metabolic syndrome, fatty liver disease, polycystic ovary syndrome, Cushing’s disease, or a combination thereof. In some embodiments, the subject has a body mass index (BMI) over 25, over 30, over 35, or over 40.

[0009] In some embodiments, the compound of Formula (V), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered orally or subcutaneously. In some embodiments, the GLP-1 receptor agonist, or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered orally or subcutaneously.

[0010] In some embodiments, the method further comprises administering to the subject an anti -hyperglycemic agent. In some embodiments, the subject is presently taking, or has within the past 6 months taken, an anti-hyperglycemic agent. In some embodiments, the anti- hyperglycemic agent is metformin, a sulfonylurea, a dipeptidyl peptidase 4 (DPP -4) inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a thiazolidinedione. or a pharmaceutically acceptable salt or solvate thereof, optionally wherein the anti- hyperglycemic agent is metformin.Attorney Docket No. 63243-709.601

[0011] In some embodiments, the method results in the treatment of diabetes, reduces blood glucose, reduces insulin resistance, reduces serum triglyceride levels, reduces adipose weight, improves lipid profile, reduces VLDL levels, increases HDL levels, reduces adipose tissue inflammation, or results in a combination of two or more thereof. In some embodiments, the method of treating results in the treatment of diabetes. In some embodiments, the diabetes is comorbid with hypertension, dyslipidemia, chronic kidney disease, diabetic peripheral neuropathy, diabetic retinopathy, fatty liver disease, overweight, obesity, hypothyroidism, metabolic syndrome, polycystic ovary syndrome, Cushing’s disease, Prader-Willi syndrome, osteoarthritis, sleep apnea, hypertension, heart disease, stroke, gout, kidney disease, an eating disorder, or two or more thereof.

[0012] In some embodiments, R1is H. In some embodiments, R4is H or Ci-Ce alkyl. In some embodiments, R4is H. In some embodiments, Y is NH. In some embodiments, Y is CHOH. In some embodiments, A is Ce-Cio aryl, optionally substituted with one or more R5.

[0013] In some embodiments, the compound of Formula (V) is a compound of Formula (Va), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: X is N or CH; R2is Ci-Ce alkyl, Cs-Cs cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, Ci-Ce alkyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci- Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; R5is, at eachAttorney Docket No. 63243-709.601 occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl; and n is 0 to 4.

[0014] In some embodiments, each R5is independently selected from halo. In some embodiments, the compound is a compound of Formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (Vbl) wherein: R2is Ci-Ce alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5- thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3- 8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; and each R5is F; and n is 0 or 1.

[0015] In some embodiments, R2is branched C3-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0016] In some embodiments, R2is:Attorney Docket No. 63243-709.601

[0018] In some embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4- oxadiazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4- triazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl,C3-C8 haloalkylcycloalkyl, Ci-Ce cyanoalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, Ci-Ce cyanoalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, and Ci-Ce cyanoalkyl. In some embodiments, R3is 5-isoxazolyl optionally substituted with one more substituents selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, and Ci-Ce cyanoalkyl. In some embodiments, R3is 5-isoxazolyl optionally substituted with one more substituents selected from C3-C5 alkyl; C3-C5 haloalkyl; C3-C5 cycloalkyl optionally substituted with one or more substituents independently selected from C1-C3 alkyl and C1-C3 haloalkyl; and C2-C4 cyanoalkyl. In some embodiments, R3is 5-isoxazolyl optionally substituted with one more substituents independently selected from C3-4 alkyl; C4 haloalkyl; C3 cycloalkyl substituted with one -CF3; C4 cycloalkyl substituted with one -CH3; and C3 alkyl substituted with one - CN.

[0019] In some embodiments, R3is:Attorney Docket No. 63243-709.601

[0021] In some embodiments, n is 0. In some embodiments, n is 1.Attorney Docket No. 63243-709.601

[0022] In some embodiments, the compound or salt of Formula (V) is a compound listed in Table IE, or a pharmaceutically acceptable salt or solvate thereof.

[0023] In some embodiments, the compound of Formula (V) is V-l, V-2, V-5, V-8, V-10, V-l l, V-12, V-13, V-14, V-21, V-22, V-24, V-29, V-30, V-41, V44, V-46, V-52, V-57, V-60, or V-66, or a pharmaceutically acceptable salt or solvate thereof.

[0024] In one aspect, provided herein is a method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon- like peptide 1 (GLP-1) receptor agonist and a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I) wherein: A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H; R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6- membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- Ce alkoxy and 3- to 8-membered heterocyclyl; R3is H; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4- oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5 -thiadi azolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5is H; and each R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0025] In one aspect, provided herein is a method of treating overweight, treating obesity,Attorney Docket No. 63243-709.601 weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon- like peptide 1 (GLP-1) receptor agonist and a compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (II) wherein: X is N or CH; A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene; R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl; R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl; R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; or R3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl; R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0026] In one aspect, provided herein is a method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon- like peptide 1 (GLP-1) receptor agonist and a compound of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (III)Attorney Docket No. 63243-709.601 wherein: A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene; X is N or CR4; Y is N or CH; R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl; R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; or R2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl; R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl; R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0027] In one aspect, provided herein is a method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon- like peptide 1 (GLP-1) receptor agonist and a compound of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (IV) wherein: A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5; X is N or CRlc; Y is N or CRld; Z is C(R6)(R7) or NR6; Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl; R2aand R2bare each independently H, halo, cyano, Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3- Cs cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H; R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy; R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy; R5is, at each occurrence, independentlyAttorney Docket No. 63243-709.601 halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R6is H, Ci-Ce alkyl, C2- Ce alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.

[0028] In one aspect, provided herein is a method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon- like peptide 1 (GLP-1) receptor agonist and a compound of Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (VI) wherein: = represents a double or a single bond such that all valences are satisfied; A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl; X is N or CR3; Y is C or N; W is CH or N; Z is CH orN; R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce- C10 aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; R2is optionally substituted aryl or optionally substituted heteroaryl; and R3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0029] In one aspect, provided herein is a method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon- like peptide 1 (GLP-1) receptor agonist and a compound of Formula (0), or aAttorney Docket No. 63243-709.601 pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (0) wherein: each is independently a double or a single bond such that all valences are satisfied; A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X1is C or N; X2is C or N; wherein when X1is N, then X2is C; wherein when X2is N, then X1is C; X3is C(R2), N(R2), or N; X4is C(R3), N(R3), or N; X7is C or N; X8is C(R8) or N; X9is C(RX) or N; X10is C(R10) or N; wherein no more than five of X1, X2, X3, X4, X7, X8, X9, and X10are N; Y is NH; R1is H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl; R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- Ce haloalkyl, C3-C8 cycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- Cs halocycloalkyl, or combinations thereof; R5is H; each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl, or; L is a direct bond, O, or CRL1RL2; RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-C 10 cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6Attorney Docket No. 63243-709.601 alkoxy, Ci-Ce haloalkoxy, cyano, hydroxy, Ci-6 hydroxyalkyl or Ci-6 haloalkyl; and RL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, Ci-6 alkyl, Ci-6 alkoxy, Ci-Ce haloalkoxy, cyano, Ci-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl; R8is H, C1-6 alkoxy, C1-6 haloalkoxy, or halogen; and R10is H, C1-6 alkoxy, C1-6 haloalkoxy, or halogen.

[0030] In some embodiments, for the methods described herein, (a) prior to the administering, the subject has an HbAlc level between 7.5 and 10.5%, and / or after the administering the subject has a reduced HbAlc level, optionally wherein the reduction is at least a 1.5% reduction; (b) after the administering the subject has at least a 5% reduction in body weight, optionally wherein the at least 5% reduction in body weight is measured about 85 days after the administering commences; (c) after the administering the subject has a decrease in body fat, optionally wherein the decrease in body fat is measured about 85 days after the administering commences, further optionally wherein the body fat is measured using a DEXA scan; (d) after the administering the subject has a decrease in BMI (body mass index), optionally wherein the decrease in BMI is measured about 85 days after the administering commences; (e) after the administering the subject has a decrease in waist circumference, optionally wherein the decrease in waist circumference is measured about 85 days after the administering commences; (f) after the administering the subject has a decrease in waist-to-hip ratio, optionally wherein the decrease in waist-to-hip ratio is measured about 85 days after the administering commences; or (g) any combination of two or more of (a) to (e).

[0031] In some embodiments, prior to the administering the subject: (a) is 18 to 65 years of age; (b) has a BMI of 27 kg / m2to 40 kg / m2; (c) has a body weight less than 150 kg; (d) has a HbAlC of 7.5% to 10.5%, (e) has type II diabetes, (f) does not have type I diabetes; (g) is not currently using insulin, repaglinide, saxagliptin, or a sulfonylurea; (h) does not have diabetic ketoacidosis within 90 days of the administering; (i) does not have pancreatitis; (j) does not have severe gastroparesis; (k) does not have medullary thyroid cancer or multiple endocrine neoplasia type 2; (1) has calcitonin > 20 ng / L; (m) does not have one or more of the following: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels S? 3.0 x the upper limit of normal (ULN), absolute neutrophil count of < 1500 / mm3, absolute lymphocyte count of < 750 / mm3, absolute white blood cell (WBC) count of < 3000 / mm3, Hemoglobin < 9.0 g / dL, Thrombocytopenia, as defined by a platelet count < 100,000 / mm3, or total bilirubin1.5 x the ULN; (n) current or history of clinically significant liver orAttorney Docket No. 63243-709.601 biliary disease or significantly abnormal liver function test (LFT); (o) current acute or chronic HCV and / or HBV infection; (p) current or history of clinically significant renal disease or eGFR<60mL / min / 1.73m2; (q) current or prior history of malignancy within the past 5 years except for cervical carcinoma in situ that has been completely resected with no evidence of recurrence or metastatic disease for at least 12 months or cured basal cell carcinoma with no evidence of recurrence for at least 12 months, (r) history of a major organ transplant (e.g. kidney, heart, liver, lung) or hematopoietic stem cell / bone marrow transplant, (s) history of lymphoproliferative disease or signs / symptoms suggestive of possible lymphoproliferative disease, including splenomegaly of lymphadenopathy, (t) history or current moderate to severe congestive heart failure (New York Heart Association class III or IV), or within the last 6 months, a cerebrovascular accident, myocardial infarction, unstable angina, unstable arrhythmia; (u) undergone any major surgery within 8 weeks prior to the administering; (v) inherited or acquired thrombophilia and / or current or history of thromboembolic events / disease; (w) screening 12-lead ECG that demonstrates relevant abnormalities that are clinically significant (e.g., QTc >450 msec or a QRS interval >120 msec); (x) pregnant or breast-feeding; (y) blood donation within a month of the administering; or (z) any combination of two or more of (a)-(y).BRIEF DESCRIPTION OF THE FIGURES

[0032] Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

[0033] FIG. 1 is a graph depicting the percentage change in body weight over a 28-day period in diet-induced obese mice following treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0034] FIG. 2 is a bar graph depicting the percentage change in body weight in diet-induced obese mice at termination of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0035] FIG. 3 is a bar graph depicting the fasting blood glucose in diet-induced obese mice following 23 days of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0036] FIG. 4A is a graph depicting the glucose tolerance test in diet-induced obese miceAttorney Docket No. 63243-709.601 following 23 days of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0037] FIG. 4B is a bar graph depicting the area under the curve of glucose tolerance test in diet-induced obese mice following 23 days of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0038] FIG. 5A is a graph depicting the insulin tolerance test in diet-induced obese mice following 25 days of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0039] FIG. 5B is a bar graph depicting the area under the curve of insulin tolerance test in diet-induced obese mice following 25 days of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0040] FIG. 6A is a bar graph depicting the serum triglyceride concentration in diet-induced obese mice at termination of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0041] FIG. 6B is a bar graph depicting the serum total cholesterol concentration in diet- induced obese mice at termination of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0042] FIG. 6C is a bar graph depicting the serum HDL cholesterol concentration in diet- induced obese mice at termination of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.

[0043] FIG. 6D is a bar graph depicting the serum LDL cholesterol concentration in diet- induced obese mice at termination of treatment according to some embodiments, compared to controls.

[0044] FIG. 7 are bar graphs depicting the body composition of various tissues in diet- induced obese mice at termination of treatment with a GLP-1 receptor agonist (semaglutide), compound of Formula (I) (Compound 10), or a combination of GLP-1 receptor agonist and compound of Formula (I), compared to vehicle.Attorney Docket No. 63243-709.601DETAILED DESCRIPTION OF THE INVENTION

[0045] In one aspect, provided herein are compounds that are modulators of the NLRP3 inflammasome, a multimeric protein complex which acts as an intracellular sensor for a variety of danger signals and responds by initiating an inflammatory response, which includes release of the proinflammatory cytokines IL-ip and IL- 18, as well as pyroptotic cell death.

[0046] In some embodiments, compounds herein, in combination with a GLP-1 receptor agonist (which is inclusive of a GLP-1 single receptor agonist, GLP-l / glucagon receptor dual agonist, GIP / GLP-1 dual agonist, and GLP-l / GIP / glucagon receptor triagonist) demonstrate enhanced, and synergistic, weight control in rat models of obesity as compared to the GLP-1 receptor agonist alone. In some embodiments, compounds herein, in combination with a GLP-1 receptor agonist provide enhanced, and synergistic reduction in blood glucose as compared to the GLP-1 receptor agonist alone. In some embodiments, compounds herein, in combination with a GLP-1 receptor agonist provide enhanced, and synergistic reduction in insulin resistance as compared to the GLP-1 receptor agonist alone. In some embodiments, compounds herein, in combination with a GLP-1 receptor agonist provide enhanced, and synergistic reduction in serum triglyceride as compared to the GLP-1 receptor agonist alone. In some embodiments, compounds herein, in combination with a GLP-1 receptor agonist provide enhanced, and synergistic reduction in adipose weight as compared to the GLP-1 receptor agonist alone.

[0047] Accordingly, provided herein are methods of treating overweight with a compound disclosed herein in combination with a GLP-1 receptor agonist, e.g., GLP-1 single receptor agonist, GLP-l / glucagon receptor dual agonist, GIP / GLP-1 dual agonist, or GLP- l / GIP / glucagon receptor triagonist. Also provided are methods of weight management with a compound disclosed herein in combination with a GLP-1 receptor agonist, e.g., GLP-1 single receptor agonist, GLP-l / glucagon receptor dual agonist, GIP / GLP-1 dual agonist, or GLP- l / GIP / glucagon receptor triagonist. Also provided are methods of reducing glucose in a subject with a compound disclosed herein in combination with a GLP-1 receptor agonist, e.g., GLP-1 single receptor agonist, GLP-l / glucagon receptor dual agonist, GIP / GLP-1 dual agonist, or GLP-l / GIP / glucagon receptor triagonist. Also provided are methods of treating diabetes with a compound disclosed herein in combination with a GLP-1 receptor agonist, e.g., GLP-1 single receptor agonist, GLP-l / glucagon receptor dual agonist, GIP / GLP-1 dual agonist, or GLP-l / GIP / glucagon receptor triagonist. The compound disclosed herein is, for example, a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV),Attorney Docket No. 63243-709.601Formula (V), Formula (VI), or Formula (VII).

[0048] In some embodiments, compounds herein (e.g., inflammasome modulators such as compounds of Formula (0-VII), in combination with an anti-hyperglycemic agent demonstrate enhanced, and synergistic, management of diabetes. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic reduction in blood glucose as compared to the anti-hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic reduction in insulin resistance as compared to the anti- hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic reduction in serum triglyceride as compared to the anti-hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic reduction in adipose weight as compared to the anti-hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic improvement of lipid profiles as compared to the anti- hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti -hyperglycemic agent provide enhanced, and synergistic reduction of VLDL levels as compared to the anti-hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic increase in HDL levels as compared to the anti-hyperglycemic agent alone. In some embodiments, compounds herein, in combination with an anti-hyperglycemic agent provide enhanced, and synergistic reduction of adipose tissue inflammation as compared to the anti-hyperglycemic agent alone.

[0049] In some embodiments, the synergistic effect of the anti-hyperglycemic agent and inflammasome modulator allows for lower doses of the anti-hyperglycemic agent. In some embodiments, a therapeutic dose of combination of the anti-hyperglycemic agent and inflammasome modulator produces a more tolerable side effect profile than a therapeutic dose of either compound separately.

[0050] Accordingly, provided herein are methods of treating diabetes with a compound disclosed herein (e.g., inflammasome modulators such as compounds of Formula (0-VII), in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of treating polycystic ovary syndrome (PCOS) with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of reducing blood glucose with a compound disclosed herein in combination with an antiAttorney Docket No. 63243-709.601 hyperglycemic agent. Accordingly, provided herein are methods of reducing insulin resistance with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of reducing serum triglyceride levels with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of reducing adipose weight with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of improving lipid profile with a compound disclosed herein in combination with an anti- hyperglycemic agent. Accordingly, provided herein are methods of reducing VLDL levels with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of increasing HDL levels with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of reducing adipose tissue inflammation with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of treating diabetes with a compound disclosed herein in combination with an anti- hyperglycemic agent. Accordingly, provided herein are methods of treating type 2 diabetes with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of treating type 1 diabetes with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of treating polycystic ovary syndrome (PCOS) with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of treating polycystic ovary syndrome (PCOS) with concomitant insulin resistance with a compound disclosed herein in combination with an anti-hyperglycemic agent. Accordingly, provided herein are methods of treating insulin resistance resulting from polycystic ovary syndrome (PCOS) with a compound disclosed herein in combination with an anti-hyperglycemic agent.

[0051] The compound disclosed herein is, for example, a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII).Terms

[0052] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are described herein for clarity and / or for ready reference, and the inclusion of such should not necessarily beAttorney Docket No. 63243-709.601 construed to represent a substantial difference over what is generally understood in the art.

[0053] As used in the specification, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0054] A “pharmaceutical composition” refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, c.g, humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefore.

[0055] “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0056] “Amino” refers to the -NH2 radical.

[0057] “Carboxy” or "carboxyl" refers to the -CO2H radical.

[0058] “Cyano” refers to the -CN radical.

[0059] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0060] “Nitro” refers to the -NO2 radical.

[0061] Oxo” refers to the =0 substituent.

[0062] Thiol” refers to the -SH substituent.

[0063] Thioxo” refers to the =S substituent.

[0064] “Alkyl” refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-Ce alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, c.g, methyl, ethyl, / / -propyl,1 -methylethyl (Ao-propyl), / / -butyl, / / -pentyl, 1,1 -dimethylethyl ( / -butyl), 3 -methylhexyl,2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[0065] “Alkenyl” refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), or any value within theseAtorney Docket No. 63243-709.601 ranges, and which is atached to the rest of the molecule by a single bond, e.g., ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.

[0066] “Alkynyl” refers to unsaturated straight or branched hydrocarbon radical, having 2 to 12 carbon atoms (C2-C12 alkynyl), two to nine carbon atoms (C2-C9 alkynyl), or two to six carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-l-ynyl, but-2-ynyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.

[0067] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0068] “Aminyl” refers to a radical of the formula -NRaRb, where Raand Rb are each independently H or Ci-Ce alkyl as defined above. When both of Ra and Rb are H, an "aminyl" group is the same as an "amino" group as defined above. The Ci-Ce alkyl portion of an aminyl group is optionally substituted unless stated otherwise.

[0069] “Aminylalkylcycloalkyl” refers to a radical of the formula -RaRbNRcRd where Ra is cycloalkyl as defined herein, Rb is Ci-Ce alkyl, Re is H or Ci-Ce alkyl and Rd is Ci-Ce alkyl as defined above. The cycloalkyl and each Ci-Ce alkyl portion of an aminylalkylcycloalkyl group are optionally substituted unless stated otherwise.

[0070] “Aromatic ring” refers to a cyclic planar molecule or portion of a molecule (z.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a set of covalently bound co-planar atoms and comprises a number of 7t-electrons (for example, alternating double and single bonds) that is even but not a multiple of 4 (z.e., 4n + 27t- electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl,Attorney Docket No. 63243-709.601 pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.

[0071] “Aryl” refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (Ce-Cio aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, a.s-indacene, -indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0072] “Cyanoalkyl” refers to an alkyl group comprising at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.

[0073] "Carbocyclic" or "carbocycle" refers to a ring system, wherein each of the ring atoms are carbon.

[0074] “Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.

[0075] “Alkylcycloalkyl” refers to a radical group of the formula -RaRb where Rais a cycloalkyl group and Rb is an alkyl group as defined above. Unless otherwise stated specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0076] “Fused” refers to any ring structure described herein which is fused to another ring structure.

[0077] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0078] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by oneAttorney Docket No. 63243-709.601 or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0079] “Halocycloalkyl” refers to a cycloalkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0080] “Haloalkylcycloalkyl” refers to a radical group of the formula -RaRb where Rais a cycloalkyl group and Rb is a haloalkyl group as defined above. Unless otherwise stated specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0081] “Hydroxylalkyl” refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical. The hydroxyalkyl radical is joined at the main chain through the alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.

[0082] “Heterocyclyl” refers to a 3- to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic and / or bridged ring systems. Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quatemized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- IH-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[0083] “Haloheterocyclylalkyl” refers to a radical group of the formula -RaRb where Ra is an alkyl group and Rb is a haloheterocyclyl group as defined herein. Unless otherwise statedAttomey Docket No. 63243-709.601 specifically in the specification, a haloheterocyclylalkyl group is optionally substituted.

[0084] “Heterocyclylalkyl” refers to a radical group of the formula -RaRb where Rais an alkyl group and Rb is a heterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0085] “Heteroaryl” refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1 -phenyl- U7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (z.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0086] Oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5 -oxadi azolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3- thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5 -thiadiazolyl and 1, 3, 4-thiadiazolyl refer to the following structures, respectively:

[0088] wherein the oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-Attorney Docket No. 63243-709.601 oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2,3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl are attached to the remainder of the molecule by a covalent bond to one of the carbon atoms in the ring of the oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4- oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl.

[0089] In some embodiments, a heteroaryl group has one of the following structures:

[0090] The term "substituted" as used herein means any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroaryl alkyl and / or hydroxylalkyl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of nonhydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0091] In some specific embodiments, the optional substitutions are independently selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, Ce-Cio aryl,5- or 6-membered heteroaryl, Ci-Ce alkoxy and 3-8 membered heterocyclyl.

[0092] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound(s) described herein that is sufficient to affect the intended application including but not limited to overweight treatment, as defined below.

[0093] Treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition, including but not limited to, overweight.

[0094] The term "co-admini strati on," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separateAttorney Docket No. 63243-709.601 compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0095] “Pharmaceutically acceptable salt” includes both acid and base addition salts.

[0096] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5-disulfonic acid, naphthal ene-2- sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4- aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p- toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0097] “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable base addition saltsAttorney Docket No. 63243-709.601 are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0098] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as NLRP3 inflammasome or NEK7 or the association of NLRP3 inflammasome - NEK7. Accordingly, the terms "antagonist" and "inhibitors" may be defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0099] The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0100] "Signal transduction" is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.

[0101] The term "selective inhibition" or "selectively inhibit" refers to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity asAttorney Docket No. 63243-709.601 compared to off target signaling activity, via direct or indirect interaction with the target.

[0102] “Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0103] “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0104] The term "in vivo" refers to an event that takes place in a subject’s body.

[0105] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples.

[0106] " 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.

[0107] Often crystallizations produce a solvate of the compounds disclosed herein. As used herein, the term “solvate” refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some aspects, the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent.

[0108] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.Attorney Docket No. 63243-709.601The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0109] The compounds of the disclosure (compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5 -, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0110] Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the invention. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0111] In some embodiments, the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are substantially one enantiomer or diastereomer.

[0112] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0113] The chemical naming protocol and structure diagrams used herein are a modifiedAttorney Docket No. 63243-709.601 form of the I.U.P.A.C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0114] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0115] The disclosure provides that wherever embodiments are provided herein with the term “comprising,” the analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided, if such analogous embodiments are not explicitly provided. The disclosure further provides that wherever embodiments are described herein with the phrase “consisting essentially of,” the analogous embodiments described in terms of “consisting of’ are also provided. The disclosure also provides that wherever embodiments are described herein with the phrase “consisting of,” the analogous embodiments described in terms of “consisting essentially of’ are also provided.

[0116] The term “and / or” as used in a phrase with a list of members is intended to include all members individually and all combination of full or partial list of members. For example, a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0117] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Non-Limiting Compounds Applied in the Methods of Treatment

[0118] Described herein are methods of treating overweight in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a glucagon-like peptide 1 (GLP-1) receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II),Attorney Docket No. 63243-709.601Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of weight management in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of treating diabetes in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing blood glucose in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing insulin resistance in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing serum triglyceride in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula(IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing adipose weight in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, theAttorney Docket No. 63243-709.601 compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula(V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. The subject may be currently taking an anti-hyperglycemic agent. The methods may further comprise administering an anti-hyperglycemic agent.

[0119] Described herein are methods of treating diabetes in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti -hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing blood glucose in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula(II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing insulin resistance in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula(VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing serum triglyceride in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of reducing adipose weight in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceuticallyAttorney Docket No. 63243-709.601 acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome.

[0120] Also described herein are methods of improving lipid profiles in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. Also described herein are methods of reducing VLDL levels in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti- hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. Also described herein are methods of increasing HDL levels in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. Also described herein are methods of reducing adipose tissue inflammation in a subject, comprising administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. InAttorney Docket No. 63243-709.601 some embodiments, the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome.

[0121] Embodiments described herein provide a compound having Formula (0-Z):Formula (0-Z) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N;X1is C or N;X2is C or N;X3is CH or N;X4is C or N;Y is NH;R1is H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl;R5is H; each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl,Attorney Docket No. 63243-709.601L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl.

[0122] Embodiments described herein provide a compound having Formula (0):Formula (0) wherein: each is independently a double or a single bond such that all valences are satisfied;A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X1is C or N;X2is C or N; wherein when X1is N, then X2is C; wherein when X2is N, then X1is C;X3is C(R2), N(R2), or N;X4is C(R3), N(R3), or N;X7is C or N;X8is C(R8) or N;X9is C(R') or N;X10is C(R10) or N; wherein no more than five of X1, X2, X3, X4, X7, X8, X9, and X10are N;Y is NH;Attorney Docket No. 63243-709.601R1is H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci- Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof;R5is H; each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl, or;L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, Ci-Ce haloalkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, Ci-Ce haloalkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3- 6 cycloalkyl;R8is H, C1-6 alkoxy, C1-6 haloalkoxy, or halogen; and R10is H, C1-6 alkoxy, C1-6 haloalkoxy, or halogen.Attorney Docket No. 63243-709.601In some embodiments, the compound or salt of Formula (0) is a compound of Formulae (0-A):Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601, or a salt of any thereof. In some embodiments, Formula(0), (0-A), (0-B), (0-C), (0-D), (0-E), (0-F), (0-G), (0-H), (0-1), (0-J), (0-K), (0-L), (OM), (0-N), (0-0), (0-P), (0-Q), (0-R), or (0-S), is optionally substituted. In some embodiments, no more than four of X1, X2, X3, X4, X7, X8, X9, and X10are N. In some embodiments, no more than six of X1, X2, X3, X4, X7, X8, X9, and X10are N. In some embodiments, no more than three of X1, X2, X3, X4, X7, X8, X9, and X10are N. In some embodiments, no more than two of X1, X2, X3, X4, X7, X8, X9, and X10are N. In some embodiments, at least two of X1, X2, X3, X4, X7, X8, X9, and X10are N. In some embodiments, at least three of X1, X2, X3, X4, X7, X8, X9, and X10are N. In some embodiments, R4of Formula (0) is selected from R4of Formula (I), R4of Formula (V), R4of Formula (V-A), or R4of Formula (V-B). In some embodiments, R3of Formula (0) is selected from R3of Formula (I), R3of Formula (V), R3of Formula (V-A), or R3of Formula (V-B). In some embodiments, R2of Formula (0) is selected from R2of Formula (I), R2of Formula (V), R2of Formula (V-A), or R2of Formula (V-B). In some embodiments, the ring comprising X1, X2, X3, X4, and X7is aromatic. In some embodiments, the bicyclic fused ring system comprising X1, X2, X3, X4, X7, X8, X9, and X10is aromatic. In some embodiments, the bicyclic fused ring system comprising X1, X2, X3, X4, X7, X8, X9, X10, and the carbon bearing the -NH2 moiety is aromatic. In some embodiments, each = is independently a double or a single bond such that all valences are satisfied and such that the bicyclic fused ringAttorney Docket No. 63243-709.601 system comprising X1, X2, X3, X4, X7, X8, X9, X10, and the carbon bearing the -NH2 moiety is aromatic.

[0123] In some embodiments, the compound of Formula (0) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (0) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (0) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (0) is administered to treat overweight. In some embodiments, the compound of Formula (0) is administered to manage weight. In some embodiments, the compound of Formula (0) is administered to treat diabetes. In some embodiments, the compound of Formula (0) is administered to reduce blood glucose. In some embodiments, the compound of Formula (0) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (0) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (0) is administered to reduce adipose weight. In some embodiments, the compound of Formula (0) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (0) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (0) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (0) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti-hyperglycemic agent.

[0124] Embodiments described herein provide a compound having Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one moreAttorney Docket No. 63243-709.601 substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2- Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- Cs halocycloalkyl, or combinations thereof;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, cyano, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0125] In some embodiments of the compound of Formula (I):A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl and Ci-Ce alkoxy;Attorney Docket No. 63243-709.601R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2- Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0126] In some embodiments of the compound of Formula (I):A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2- Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- Cs halocycloalkyl;Attorney Docket No. 63243-709.601R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0127] In some embodiments, A is any suitable functional group as described herein. In some embodiments, A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is Ce-Cio aryl optionally substituted with one or more R6. In some embodiments, A is 5-6 membered monocyclic heteroaryl optionally substituted with one or more R6. In some embodiments, A is C3-C10 cycloalkyl. In some embodiments, A is 3-10 membered heterocyclyl optionally substituted with one or more R6.

[0128] In some embodiments, A is a divalent optionally substituted Ce-io aryl. In some embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, A is a divalent optionally substituted 3- 10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0129] In some embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl,Attorney Docket No. 63243-709.6011.3.4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1.3.4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0130] In some embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted. In other embodiments, A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0131] In some embodiments, A is pyrimidinyl, which is optionally substituted.

[0132] In some embodiments, X is any suitable atom as described herein. In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0133] In some embodiments, Y is any suitable linker as described herein. In some embodiments, Y is NH.

[0134] In some embodiments, R1is any suitable functional group described herein. In some embodiments, R1is H. In some embodiments, R1is Ci-Ce alkyl. In some embodiments, R1is methyl, ethyl, n-propyl, or isopropyl.

[0135] In some embodiments, R2is any suitable functional group described herein. In some embodiments, R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl. In some embodiments R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. InAttorney Docket No. 63243-709.601 some embodiments, R2is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8- membered heterocyclyl. In some embodiments, R2is cyclopropyl or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is oxetanyl. In some embodiments, R2is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R2is N-methyl substituted pyrrolidinyl. In some embodiments, R2is unsubstituted cyclobutyl.

[0136] In some embodiments, R2is:

[0137] In some embodiments, R2is:

[0138] In some embodiments, R3is any suitable functional group described herein. In some embodiments, R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R3is H or Ci- Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R3is H. In some embodiments, R3is Ci-Ce alkyl. In some embodiments, R3is methyl, ethyl, n-propyl, or isopropyl.

[0139] In some embodiments, R4is any suitable functional group described herein. In some embodiments, R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-memberedAttorney Docket No. 63243-709.601 heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- Cs halocycloalkyl, and combinations thereof.

[0140] In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4- oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl.

[0141] In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0142] In some embodiments, R4is thiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0143] In some embodiments, R4is isothiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl,Attorney Docket No. 63243-709.601C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0144] In some embodiments, R4is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8- membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0145] In some embodiments, R4is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8- membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0146] In some embodiments, R4is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0147] In some embodiments, R4is 1, 3, 4-oxadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, 3- to 8-membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0148] In some embodiments, R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0149] In some embodiments, R4is:Atorney Docket No. 63243-709.601Attomey Docket No. 63243-709.601

[0152] In some embodiments, R5is any suitable functional group described herein. In some embodiments, R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R5is H or Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R5is H. In some embodiments, R5is Ci-Ce alkyl. In some embodiments, R5is methyl, ethyl, n-propyl, or isopropyl.

[0153] In some embodiments, each R6is any suitable functional group described herein. In some embodiments, each R6is independently halo, Ci-Ce alkyl, cyano, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl. In some embodiments, each R6is chloro or fluoro. In some embodiments, each R6is fluoro. In some embodiments, each R6is Ci-CeAttorney Docket No. 63243-709.601 hydroxylalkyl. In some embodiments, each R6is Ci-Ce hydroxylalkyl. In some embodiments, each R6is -CH2CH2OH. In other embodiments, each R6is cyano. In some embodiments, each R6is Ci-Ce alkoxy. In some embodiments, each R6is methoxy.

[0154] In some embodiments, A is:

[0156] In some embodiments, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

[0157] In some embodiments, R2ais a branched Ci-Ce alkyl substituted with hydroxyl. InAttorney Docket No. 63243-709.601 some embodiments, R2ais C3-C8 cycloalkyl. In some embodiments, R2ais:

[0158] In some embodiments, R4ais isoxazolyl substituted with C3-C8 haloalkylcycloalkyl. In some embodiments, R4ais C3-C8 fluoroalkylcycloalkyl. In some embodiments, R4ais fluoroalkyl cyclopropyl or fluoroalkylcyclobutyl. In some embodiments, R4ais:

[0159] In some embodiments, the compound is a compound of Formula (lb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl and Ci-Ce alkoxy;Attorney Docket No. 63243-709.601R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0160] In some embodiments, the compound of Formula (I) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (I) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) is administered to treat overweight. In some embodiments, the compound of Formula (I) is administered to manage weight. In some embodiments, the compound of Formula (I) is administered to treat diabetes. In some embodiments, the compound of Formula (I) is administered to reduce blood glucose. In some embodiments, the compound of Formula (I) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (I) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (I) is administered to reduce adipose weight. In some embodiments, the compound of Formula (I) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (I) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (I) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (I) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti-hyperglycemic agent.

[0161] In various embodiments, the compound has one of the structures set forth in Table 1 A below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.Attorney Docket No. 63243-709.601

[0162] Compounds in Table 1 A were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or H NMR.Table 1A: Representative Compounds of Formula (I)Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0163] Embodiments described herein provide a compound having Formula (II):Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3- 10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N- heterocyclyloxy, or 5-6 membered heteroaryl; orR3 joins with an occurrence of R4 attached to a carbon adjacent to a carbon to which R3 is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.In some embodiments, A is Ce-Cio arylene. In certain embodiments, A is phenylene. In some specific embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some more specific embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene.In certain embodiments, A is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, A is substituted with one or more halo substituents. In some specific embodiments, A is unsubstituted.In some embodiments, R1is H. In certain embodiments, R1is Ci-Ce alkyl. In some specific embodiments, R1is methyl. In certain embodiments, R1is C3-C10 cycloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R1is halo (e.g., fluoro, chloro, bromo, etc.).In certain embodiments, R2is H. In some more specific embodiments, R2is halo. In more specific embodiments, R2is chloro or fluoro. In some other embodiments, R2is C3-C10Attorney Docket No. 63243-709.601 cycloalkyl (e.g., cyclopropyl). In some embodiments, R2is Ci-Ce alkyl, Ci-Ce haloalkyl, or 3- 10 membered heterocyclyl. In some embodiments, R2is Ci-Ce alkyl (e.g., methyl).In some embodiments, X is CH or CR3. In some specific embodiments, the compound has the following structure (Ila):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.In some embodiments, the compound has the following structure (lib) :or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.In certain embodiments, X is N. In certain more specific embodiments, the compound has the following structure (lie):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.In some embodiments, the compound has the following structure (lid):Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, whereinR3ais, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, aminylalkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N- heterocyclyloxy, or 5-6 membered heteroaryl; and m is 0, 1, 2, 3, or 4.In some embodiments, R3ais, at each occurrence, independently halo or 3-10 membered heterocyclyl. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In certain embodiments, m is 1. In some embodiments, m is 1. In some embodiments, m is 2. In certain embodiments, m is 3.In some embodiments, the compound has the following structure (Ildl):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.In some embodiments, R3is substituted. In some embodiments, R3is unsubstituted. In some embodiments, R3is substituted with alkyl (e.g., Ci-Ce alkyl), heterocyclyl, halo, haloalkyl (e.g., Ci-Ce haloalkyl), alkylcarbonyl (e.g., -C(=O)CH3), hydroxyalkyl, alkoxyalkyl, cycloalkyl (e.g., C3-C8 cycloalkyl), alkylamino, or combinations thereof.In some of the above embodiments, R3is aminylalkyl. In certain embodiments, R3has the following structure:Attorney Docket No. 63243-709.601In some embodiments, R3is a 3-10 membered heterocyclyl. In some embodiments, R3is morpholino. In certain embodiments, R3is piperazinyl. In some specific embodiments, R3has one of the following structures:In certain embodiments, R3is a 3-10 membered heterocyclylalkyl. In certain more specific embodiments, R3has one of the following structures:Attorney Docket No. 63243-709.601In some embodiments, R3is 3-10 membered heterocyclylcarbonyl. In a more specific embodiment, R3has the following structure:In some embodiments, R3is a 5-6 membered heteroaryl. For example, in some embodiments, R3has the following structure:In some embodiments, R3is a 3-10 membered heterocyclylalkenyl. In more specific embodiments, R3has the following structure:In some embodiments, R3is a 3-10 membered N-heterocyclyloxy. In more specific embodiments, R3has one of the following structures:In some embodiments, R3has one of the following structures:Attorney Docket No. 63243-709.601In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some other embodiments, n is 1. In some specific embodiments, R4is, at each occurrence, independently chloro, fluoro, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Cs-Cs halocycloalkyl, or Cs-Cs cycloalkyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, methoxy, trifluoromethoxy, 2,2- difluorocyclopropyl, or cyclopropyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl.In some embodiments, X is N and n is 3. In some embodiments, X is N and n is 2. In more specific embodiments, X is N and n is 1. In some other embodiments, X is N and n is 0.In some embodiments, X is CH and n is 4. In some other embodiments, X is CH and n is 3. In some embodiments, X is CH and n is 2. In more specific embodiments, X is CH and n is 1. In some other embodiments, X is CH and n is 0.

[0164] In some embodiments, the compound of Formula (II) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (II) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) is administered to treat overweight. In some embodiments, the compound of Formula (II) is administered to manage weight. In some embodiments, the compound of Formula (II) is administered to treat diabetes. In some embodiments, the compound of Formula (II) is administered to reduce blood glucose. In some embodiments, the compound of Formula (II) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (II) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (II) is administered to reduce adipose weight. In some embodiments, the compound of Formula (II) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (II) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (II) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent.Attorney Docket No. 63243-709.601In some embodiments, the compound of Formula (II) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti -hyperglycemic agent.

[0165] In various different embodiments, the compound has one of the structures set forth in Table IB below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0166] Compounds in Table IB were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / orJH NMR.Table IB: Representative Compounds of Formula (II)Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0167] Embodiments described herein provide a compound having Formula (III):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclyl ene, or 5-6 membered heteroarylene;X is N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orAttorney Docket No. 63243-709.601R2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0168] In some embodiments, A is Ce-Cio arylene. In some specific embodiments, A is phenylene. In certain embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene. In more specific embodiments, A is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In certain more specific embodiments, A is substituted with one or more halo substituents. In other embodiments, A is unsubstituted.

[0169] In certain embodiments, X is CR4. In more specific embodiments, R4is H or Ci- Ce alkyl. In some embodiments, R4is H. In certain specific embodiments, X is N.

[0170] In some embodiments, R1is Ci-Ce alkyl. In some more specific embodiments, R1is methyl or iso-propyl. In certain embodiments, R1is Ci-Ce hydroxylalkyl. In certain more specific embodiments, R1has one of the following structures:

[0171] In some embodiments, R1has one of the following structures:

[0172] In certain embodiments, R1is Ci-Ce carboxyalkyl. In more specific embodiments,R1has one of the following structures:

[0173] In some embodiments, R1is Ci-Ce alkoxyalkyl. In some embodiments, R1has the following structure:Attorney Docket No. 63243-709.601

[0174] In some embodiments, R1is C3-C10 cycloalkyl. In more specific embodiments, R1is cyclopropyl or cyclobutyl. In certain embodiments, R1is 3-10 membered heterocyclyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, or piperidinyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, azetidinyl, or piperidinyl.

[0175] In some embodiments, R1is Ci-Ce alkynyl. In certain embodiments, R1has one of the following structures:

[0176] In some embodiments, R1is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, R1is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -S(O)2CH3, -S(O)2cyclopropyl, or C3-C8 cycloalkyl. In more specific embodiments, R1is substituted with one or more Ci-Ce alkyl substituents. In other embodiments, R1is unsubstituted.

[0177] In certain specific embodiments, R1has one of the following structures:

[0178] In some embodiments, R1has one of the following structures:Attorney Docket No. 63243-709.601

[0179] In some specific embodiments, the compound has the following Structure (Illa):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0180] In some embodiments, Y is N. In other embodiments, Y is CH.

[0181] In certain specific embodiments, the compound has the following Structure (Illb) :or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0182] In some embodiments, R2is a 3-10 membered heterocyclyl. In some specific embodiments, R2is morpholino. In other specific embodiments, R2is piperazinyl. In some more specific embodiments, R2has one of the following structures:

[0183] In some embodiments, R2is a 3-10 membered heterocyclylalkyl. In certain more specific embodiments, R2has one of the following structures:Atorney Docket No. 63243-709.601

[0184] In some more specific embodiments, R2has one of the following structures:Attorney Docket No. 63243-709.601

[0185] In some embodiments, R2is 3-10 membered heterocyclylcarbonyl. In certain more specific embodiments, R2has the following structure:

[0186] In some embodiments, R2is a 5-6 membered heteroaryl. In some more specific embodiments, R2has the following structure:

[0187] In some embodiments, R2is 3-10 membered heterocyclyloxy. In certain more specific embodiments, R2has the following structure:

[0188] In some embodiments, R2has one of the following structures:

[0189] In some more specific embodiments, R2has the following structure:Attorney Docket No. 63243-709.601

[0190] In some embodiments, n is 0. In some embodiments, n is 1 or 2. In certain embodiments, n is 1. In some embodiments, R3is halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or Cs-Cs cycloalkyl. In certain specific embodiments, R3is methyl, chloro, fluoro, cyano, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl. In some specific embodiments, n is 1 or 2 and R3is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or Cs-Cs cycloalkyl. In some embodiments, n is 1 and R3is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or Cs-Cs cycloalkyl. In some embodiments, n is 1 and R3is methyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl.

[0191] In some embodiments, the compound has the following Structure (IIIc):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:R3ais halo or 3-10 membered heterocyclyl; and nl is 1, 2, or 3.

[0192] In some embodiments, R3ais fluoro or piperazinyl. In more specific embodiments, the compound has the following Structure (IIIc 1 ):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.Attorney Docket No. 63243-709.601

[0193] In some embodiments, the compound of Formula (III) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (III) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is administered to treat overweight. In some embodiments, the compound of Formula (III) is administered to manage weight. In some embodiments, the compound of Formula (III) is administered to treat diabetes. In some embodiments, the compound of Formula (III) is administered to reduce blood glucose. In some embodiments, the compound of Formula (III) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (III) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (III) is administered to reduce adipose weight. In some embodiments, the compound of Formula (III) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (III) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (III) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (III) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti -hyperglycemic agent.

[0194] In various different embodiments, the compound has one of the structures set forth in Table 1C below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0195] Compounds in Table 1C were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / orJH NMR.Table 1C: Representative compounds of Structure (III)Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No.63243-709.601- Ill -Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0196] Embodiments described herein provide a compound having Formula (IV):Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; andR7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.In some embodiments, A is Ce-Cio aryl. In certain embodiments, A is C3-C10 cycloalkyl. In some specific embodiments, A is 3-10 membered heterocyclyl. In certain specific embodiments, A is 5-6 membered monocyclic heteroaryl. In some more specific embodiments, A is substituted with one or more occurrences of R5. In certain more specific embodiments, A is substituted with one or two occurrences of R5. In some embodiments, A isAttorney Docket No. 63243-709.601 substituted with substituents selected from the group consisting of halo, Ci-Ce haloalkyl, and combinations thereof. In certain embodiments, A is substituted with substituents selected from the group consisting of fluoro, trifluoromethyl, and combinations thereof. In more specific embodiments, A is unsubstituted.In some embodiments, X is N. In certain embodiments, X is CRlc. In some specific embodiments, Rlcis H. In certain more specific embodiments, Rlcis halo (e.g., Rlcis chloro). In some other embodiments, Rlcis Ci-Ce alkyl (e.g., Rlcis methyl). In certain embodiments, Rlcis C3-C8 cycloalkyl (e.g., Rlcis cyclopropyl).In some embodiments, Y is N. In other embodiments, Y is CRld. In some embodiments, Rldis H. In certain specific embodiments, Rldis halo, Ci-Ce alkyl, or C3-C8 cycloalkyl.In some embodiments, Z is C(R6)(R7). In more specific embodiments, R6is H. In some embodiments, R7is -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl. In certain specific embodiments, R6and R7are both H.In some other embodiments, Z is NR6. In certain embodiments, R6is H. In certain other embodiments, R6is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.In certain embodiments, Rlais H. In some embodiments, Rlais Ci-Ce alkyl (e.g., Rlais methyl). In some embodiments, Rlais halo or C3-C8 cycloalkyl.In some embodiments, Rlbis H. In certain embodiments, Rlbis halo, Ci-Ce alkyl, or C3-C8 cycloalkyl.In certain embodiments, R2ais Ci-Ce alkyl (e.g., R2ais tert-butyl or methyl). In some embodiments, R2ais C3-C8 cycloalkyl. In more specific embodiments, R2ais cyclopropyl. In some embodiments, the cyclopropyl is unsubstituted. In some embodiments, the cyclopropyl is substituted with at least one haloalkyl (e.g., trifluoromethyl). In certain more specific embodiments, R2ahas the following structure:In some embodiments, R2bis H. In certain embodiments, R2bis halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl.In certain specific embodiments, R3is Ci-Ce alkyl (e.g., R3is methyl).In some embodiments, R3is aryl. For example, in some embodiments, R3is phenyl. In certain embodiments, the phenyl is substituted with one or more substituents selected fromAttorney Docket No. 63243-709.601 halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy. In certain other embodiments, the phenyl is unsubstituted.In some other embodiments, R3is 3-10 membered heterocyclyl. In more specific embodiments, R3is piperidinyl. In certain specific embodiments, the piperidinyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2- Ce alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy. In certain embodiments, R3has the following structure:In some embodiments, R4is H. In more specific embodiments, R4is Ci-Ce alkyl, C2- Ce alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl.

[0197] In some embodiments, the compound of Formula (IV) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (IV) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is administered to treat overweight. In some embodiments, the compound of Formula (IV) is administered to manage weight. In some embodiments, the compound of Formula (IV) is administered to treat diabetes. In some embodiments, the compound of Formula (IV) is administered to reduce blood glucose. In some embodiments, the compound of Formula (IV) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (IV) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (IV) is administered to reduce adipose weight. In some embodiments, the compound of Formula (IV) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (IV) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (IV) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (IV) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti-hyperglycemic agent.

[0198] In various different embodiments, the compound has one of the structures set forth in Table ID below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0199] Compounds in Table ID were prepared as described in the Examples or methodsAttorney Docket No. 63243-709.601 known in the art and analyzed by mass spectrometry and / or1H NMR.Table ID: Representative compounds of Structure (IV)Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0200] Embodiments described herein provide a compound having Formula (V):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Y is CHOH or NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with oneAttorney Docket No. 63243-709.601 more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0201] In some embodiments of structure (V), A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Y is CHOH or NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl;Attorney Docket No. 63243-709.601R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkyl or Ci-Ce haloalkyl.

[0202] One embodiment provides a compound of structure (V) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Y is CHOH or NH;R1is H or Ci-Ce alkyl;R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0203] In certain embodiment, R1is H. In other embodiments, R1is Ci-Ce alkyl, such asAttorney Docket No. 63243-709.601 methyl.

[0204] In one embodiment, compounds of Structure (V) are provided, where R2is branched C3-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C8 heterocyclyl or 5- or 6- membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- Ce alkoxy and 3- to 8-membered heterocyclyl.

[0205] In one embodiment, compounds of Structure (V) are provided, where R2is branched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0206] In another embodiment, compounds of Structure (V) are provided, where R2is branched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0207] In specific embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0208] In different embodiments, R2is methyl, isopropyl, 2-methylpropyl or allyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8- membered heterocyclyl.

[0209] In different embodiments, R2is methyl, ethyl, isopropyl, 2-methylpropyl or allyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0210] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0211] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6Attorney Docket No. 63243-709.601 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, and 3- to 8-membered heterocyclyl.

[0212] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl pyrrolidinyl, or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, and 3- to 8-membered heterocyclyl.

[0213] In still more embodiments, R2is pyridinyl optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0214] In any of the foregoing embodiments, R2is unsubstituted. In other of the foregoing embodiments, R2is substituted with one or more of hydroxyl and fluoro.

[0215] In any of the foregoing embodiments, R2is unsubstituted. In other of the foregoing embodiments, R2is substituted with one or more of hydroxyl, methyl, methoxy, and fluoro.

[0216] In more specific embodiments, R2has one of the following structures:

[0217] In further specific embodiments, R2has one of the following structures:

[0218] In further specific embodiments, R2has one of the following structures:Attorney Docket No. 63243-709.601

[0219] In some embodiments, optionally R2is substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, and 3-8 membered heterocyclyl.

[0220] In some embodiments, R2does not have the following structures:

[0221] In any of the foregoing embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3- oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. For example, in certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. In further specific embodiments, R3is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 halocycloalkyl.

[0222] In further embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4- oxadiazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4- triazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0223] In certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0224] In certain embodiments, R3is thiazolyl optionally substituted with one moreAttorney Docket No. 63243-709.601 substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0225] In certain embodiments, R3is isothiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0226] In certain embodiments, R3is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0227] In certain embodiments, R3is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0228] In certain embodiments, R3is 1,3,4-oxadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0229] In certain embodiments, R3is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0230] In further embodiments, R3is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl or C3-C8 halocycloalkyl, or combinations thereof.

[0231] In various embodiments, R3has one of the following structures:Attorney Docket No. 63243-709.601

[0232] In further embodiments, R3has one of the following structures:

[0233] In further embodiments, R3has one of the following structures:Attorney Docket No. 63243-709.601

[0234] In other embodiments, R4is H. In other embodiments, R4Ci-Ce alkyl, such as methyl.

[0235] In certain embodiments, Y is CHOH. In other embodiments, Y is NH.

[0236] In other embodiments, X is N. In more embodiments, X is CH.

[0237] In various embodiments, A is Ce-Cio aryl, C3-C10 cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5. It is understood that A is a divalent radical.

[0238] In certain embodiments, A is a divalent optionally substituted Ce-io aryl. In certain embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, A is a divalent optionally substituted 3- 10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Attorney Docket No. 63243-709.601

[0239] In certain embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted.

[0240] In other embodiments, A is phenyl. In different embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0241] In further embodiments, A is pyrimidinyl, which is optionally substituted.

[0242] In certain embodiments, A is a Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene or 5-6 membered monocyclic heteroarylene, each of which is optionally substituted with one or more R5. In certain embodiments, A is a phenylene optionally substituted with one or more R5. In certain embodiments, A is a 1,4-phenylene optionally substituted with one or more R5. In certain embodiments, A is a 1,4-phenylene optionally substituted with one or more -F. In certain embodiments, A is a 1,4-phenylene.

[0243] In any of the foregoing embodiments, A is unsubstituted. In different of the foregoing embodiments, A is substituted with one or more R5. For example, in some embodiments R5is halo. In other embodiments, halo is fluoro or chloro. In other embodiments, R5is fluoro. In other different embodiments, R5is chloro.

[0244] In some embodiments, R5is cyano. In some embodiments, R5is Ci-Ce alkyl. In certain embodiments, R5is methyl. In some embodiments, R5is Ci-Ce haloalkyl. In certain embodiments R5is difluorom ethyl. In further embodiments, R5is Ci-Ce hydroxylalkyl. In certain embodiments R5is -CH2OH.

[0245] In certain embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,Attorney Docket No. 63243-709.601 pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0246] In specific embodiments, A has one of the following structures:

[0247] In other specific embodiments, A has one of the following structures:

[0248] In some embodiments, the compound of Formula (V) is a compound of Formula (Va), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (Va) wherein the variables are as described herein, and can be any combination as described herein.

[0249] In some embodiments, the compound of Formula (V) is a compound of Formula (Va), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-709.601Formula (Va) wherein:X is N or CH;R2is Ci-Ce alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, Ci-Ce alkyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl; and n is 0 to 4.

[0250] In some embodiments, the compound of Formula (V) is a compound of Formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (Vb) wherein the variables are as described herein, and can be any combination as describedAttorney Docket No. 63243-709.601 herein.

[0251] In some embodiments, the compound of Formula (V) is a compound of Formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (Vb) whereinR2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; andR5is F; and n is 0 or 1.

[0252] In some embodiments, the compound of Formula (V) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (V) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is administered to treat overweight. In some embodiments, the compound of Formula (V) is administered to manage weight. In some embodiments, the compound of Formula (V) is administered to treat diabetes. In someAttorney Docket No. 63243-709.601 embodiments, the compound of Formula (V) is administered to reduce blood glucose. In some embodiments, the compound of Formula (V) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (V) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (V) is administered to reduce adipose weight. In some embodiments, the compound of Formula (V) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (V) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (V) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (V) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti -hyperglycemic agent.

[0253] In some embodiments, the compound of Formula (Va) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (Va) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (Va) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (Va) is administered to treat overweight. In some embodiments, the compound of Formula (Va) is administered to manage weight. In some embodiments, the compound of Formula (Va) is administered to treat diabetes. In some embodiments, the compound of Formula (Va) is administered to reduce blood glucose. In some embodiments, the compound of Formula (Va) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (Va) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (Va) is administered to reduce adipose weight. In some embodiments, the compound of Formula (Va) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (Va) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (Va) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (Va) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti-hyperglycemic agent.

[0254] In some embodiments, the compound of Formula (Vb) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (Vb) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (Vb) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (Vb) is administered to treat overweight. In some embodiments, the compound of Formula (Vb) is administered to manage weight. In some embodiments, the compound of Formula (Vb) is administered to treat diabetes. In someAttorney Docket No. 63243-709.601 embodiments, the compound of Formula (Vb) is administered to reduce blood glucose. In some embodiments, the compound of Formula (Vb) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (Vb) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (Vb) is administered to reduce adipose weight. In some embodiments, the compound of Formula (Vb) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (Vb) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (Vb) is administered with a GLP-1 receptor agonist and an anti- hyperglycemic agent. In some embodiments, the compound of Formula (Vb) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti-hyperglycemic agent.

[0255] In various different embodiments, the compound has one of the structures set forth in Table IE below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0256] Compounds in Table IE were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / orJH NMR.Table IE. Representative Compounds of Structure (V)Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0257] Embodiments described herein provide a compound having Formula (VI):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: represents a double or a single bond such that all valences are satisfied;A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6- membered aryl, or an optionally substituted 5-6-membered heteroaryl;X is N or CR3;Y is C or N;W is CH orN;Z is CH orN;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted Ce-Cio aryl,Attorney Docket No. 63243-709.601 optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.In some embodiments, represents a double bond. In some other embodiments, = represents a single bond.In some embodiments, A is a 5-membered heterocyclyl. In certain embodiments, A is a 6-membered heterocyclyl. In some embodiments, A is a 6-membered heteroaryl. In certain embodiments, A is a 5-membered heteroaryl. In some embodiments, A is a 6-membered aryl.In some embodiments, Y is N. In some embodiments, A is unsubstituted. In certain embodiments, A is substituted. In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, and optionally substituted Ci-Ce haloalkoxy.In some embodiments, A is substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, halo, and Ci-Ce haloalkyl. In some embodiments, A is substituted with one or more substituents selected from the group consisting of methyl, fluoro, and trifluorom ethyl.In some embodiments,has the following structure:Attorney Docket No. 63243-709.601In some embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, X is N. In some embodiments, X is CR3. In some embodiments, R3is hydrogen or optionally substituted Ci-Ce alkyl. In certain embodiments, X is CH.In some embodiments, R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is optionally substituted Ci- Ce alkyl. In some embodiments, R1is methyl, ethyl, or / .w-propyl. In certain embodiments, R1is optionally substituted Ci-Ce alkenyl or optionally substituted Ci-Ce alkynyl. In some more specific embodiments, R1has the following structure:In some embodiments, R1is optionally substituted Ci-Ce hydroxyalkyl. In certain embodiments, R1has one of the following structures:In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some more specific embodiments, R1has one of the following structures:Attorney Docket No. 63243-709.601In some embodiments, R1is optionally substituted 3-10 membered heterocyclyl. In certain embodiments, R1has the following structure:In some embodiments, R1is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is unsubstituted pyridinyl. In some embodiments, R1has one of the following structures:In some embodiments, R1is optionally substituted Ci-Ce carboxyalkyl. In certain embodiments, R1has the following structure:In some embodiments, R1is optionally substituted Ci-Ce alkoxyalkyl. In certain embodiments, R1has the following structure:In certain embodiments, R2is optionally substituted phenyl or optionally substituted 5- membered heteroaryl. In some embodiments, R2is optionally substituted phenyl. In certainAttorney Docket No. 63243-709.601 embodiments, R2is optionally substituted 5-membered heteroaryl. In certain embodiments, R2is optionally substituted isoxazolyl or optionally substituted pyrazolyl. In some embodiments, R2is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 5-10-membered heterocyclylalkyl, optionally substituted 5-10-membered heterocyclyloxy, and optionally substituted Ce-Cio aryl.In some embodiments, R2is optionally substituted with one or more substituents selected from the following structures:In some embodiments, R2has one of the following structures:Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0258] In various different embodiments, the compound has one of the structures set forth in Table IF below, or a stereoisomer, tautomer, or salt thereof. Compounds in Table IF were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or 'H NMR. In some embodiments, the compound of Formula (VI) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (VI) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is administered to treat overweight. In some embodiments, the compound of Formula (VI) is administered toAttorney Docket No. 63243-709.601 manage weight. In some embodiments, the compound of Formula (VI) is administered to treat diabetes. In some embodiments, the compound of Formula (VI) is administered to reduce blood glucose. In some embodiments, the compound of Formula (VI) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (VI) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (VI) is administered to reduce adipose weight. In some embodiments, the compound of Formula (VI) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (VI) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (VI) is administered with a GLP-1 receptor agonist and an anti-hyperglycemic agent. In some embodiments, the compound of Formula (VI) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti- hyperglycemic agent.

[0259] In various different embodiments, the compound has one of the structures set forth in Table IF below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0260] Compounds in Table IF were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / orJH NMR.Table IF: Representative compounds of Structure (VI)Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0261] Embodiments described herein provide a compound having Formula (VII):Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:Ring A is a Ce-Cio aryl substituted with 0-4 RA, C3-10 cycloalkyl substituted with 0-4 RA, 3-10 membered heterocyclyl substituted with 0-4 RA, or 5-6 membered monocyclic heteroaryl substituted with 0-4 RA;R is one of the following structural formulas:wherein:L is a direct bond, O, or CR21R22;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc;X1is CR31or N;X2is C or N;X3is CR32or N;X4is C or N; wherein when X2is N, then X4is C; wherein when X4is N, then X2is C;Z1is CH or N;Z2is O or S;Z3is C or N;Z4is C or N;Attorney Docket No. 63243-709.601R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3- 10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12;R2is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;RAare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, cyano, hydroxy, C1-6 hydroxyalkyl, or C1-6 haloalkyl;RBare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 RB1, C3- 10 cycloalkyl substituted with 0-4 RB1, 3-10 membered heterocyclyl substituted with 0-4 RB1, or 5-6 membered heteroaryl substituted with 0-4 RB1;RB1are each independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;Rcare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R31is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R32is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R51and R52are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; R7is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 R70, C3-10 cycloalkyl substituted with 0-4 R70, 3- 10 membered heterocyclyl substituted with 0-4 R70, or 5-6 membered heteroaryl substituted with 0-4 R70;R70is hydrogen, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclic group or NRnR12;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, Ci-ealkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclyl or NRnR12;R11and R12are each independently selected from hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl or C1-6 haloalkyl;Attorney Docket No. 63243-709.601R21and R22are each independently selected from hydrogen, halogen, deuterium, tritium, Ci-6 alkyl, Ci-6 alkoxy, cyano, Ci-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl; and n is 1 or 2.

[0262] In some embodiments, Ring A is a Ce-Cio aryl substituted with 0-4 RA. In some embodiments, Ring A is a C3-10 cycloalkyl substituted with 0-4 RA. In some embodiments, Ring A is a 3-10 membered heterocyclyl substituted with 0-4 RA. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl substituted with 0-4 RA. In some embodiments, Ring A is phenyl with 0 to 1 RA. In some embodiments, Ring A is pyridinyl with 0 to 1 RA. In some embodiments, Ring A is pyrimidinyl with 0 to 1 RA.

[0263] In some embodiments, RAis selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C1-6 haloalkyl. In some embodiments, RAis selected from halogen.

[0264] In some embodiments, Ring A is one of the following structure:

[0265] In some embodiments, R2is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy. In some embodiments, R2is hydrogen or C1-6 alkyl. In some embodiments, R2is hydrogen. In some embodiments, R2is C1-6 alkyl. In some embodiments, R2is C1-6 haloalkyl. In some embodiments, R2is C1-6 alkoxy.

[0266] In some embodiments, R1is Ce-Cio aryl substituted with 0-4 R°, C-3-CioAttorney Docket No. 63243-709.601 cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or 5- 6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12. In some embodiments, R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, C1-6 alkyl substituted with 0-4 R°, or C1-6 alkoxy substituted with 0-4 R°. In some embodiments, R1is a C3-10 cycloalkyl substituted with 0-4 R°, a 3-10 membered heterocyclic group substituted with 0-4 R°, or a C1-6 alkyl substituted with 0-4 R°;R° is each independently hydrogen, halogen, hydroxy, cyano, C1-6 alkyl or C1-6 haloalkyl. In some embodiments, Ri is a C3-10 cycloalkyl group such as a cyclopropyl group. In some embodiments, R1is a 3-10 membered heterocyclic group substituted with 0-1 R°, a C2-6 alkenyl group substituted with 0-1 R°, or a C1-6 alkyl group substituted with 0-1 R°; R° is independently selected from halogen, hydroxy, cyano or C1-3 alkoxy.

[0267] In some embodiments, R1is one of the following structures:

[0268] In some embodiments, R is one of the structural formulas:Attorney Docket No. 63243-709.601In some embodiments,some embodiments,In some embodiments,

[0269] In some embodiments, R is isoxazolyl substituted with one R7, oxazolyl substituted with one R7, oxadi azolyl substituted with one R7, triazolyl substituted with one R7, thiazolyl substituted with one R7, isothiazolyl substituted with one R7or thiadiazolyl substituted with one R7wherein R7is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, cyano, hydroxy, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, Ce-io aryl substituted with 0-1 R70, C3-10 cycloalkyl substituted with 0-1 R70, 3-10 membered heterocyclyl substituted with 0-1 R70, or 5-6 membered heteroaryl substituted with 0-1 R70; R70is each independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C 1-6 haloalkyl. In some embodiments,hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl substituted with 0-1 R70; R70is selected from hydrogen, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl or 3-8 membered heterocyclyl; Z2is O or S; Z3is C or N; Z4is C or N.

[0270] In some embodiments, Z2is O, Z3is CH, and Z4is N; or Z2is N, Z3is CH, and Z4is O; or Z2is S, Z3is CH, and Z4is N; or Z2is S, Z3is N, and Z4is N. In some embodiments, R is one of the following:wherein RBais a C1-6 alkyl group, a C1-6 haloalkyl group, or a C3-6 cyclic hydrocarbon group substituted with one RBla, wherein RBlais C1-6 alkyl or C1-6 haloalkyl.

[0271] In some embodiments, R isAttorney Docket No. 63243-709.601wherein RBis hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, cyano, hydroxy, Ci-6 hydroxyalkyl or Ci-6 haloalkyl;aryl group substituted with 0-1 Rc, a C3-10 cycloalkyl group substituted with 0-1 Rc, a 3-10 membered heterocyclyl group substituted with 0-1 Rc, or a 5-6 membered heteroaryl group substituted with 0-1 Rc; and Rcis halogen or C1-6 alkyl.

[0272] In some embodiments, RLisRBbis Ci -6 alkyl.

[0273] In some embodiments, R is:L is O or CH2, RBbis C1-3 alkyl, and RBcis hydrogen or C1-3 haloalkyl, such as trifluoromethyl.

[0274] In some embodiments, R isAttorney Docket No. 63243-709.601RBbis Ci-6 alkyl, R51and R52are each independently hydrogen, halogen, deuterium, tritium or Ci-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; and n is 1 or 2.

[0275] In some embodiments,R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl group; R61and R62are each independently selected from hydrogen, halogen, deuterium or tritium, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl group; and RBbis C1-6 alkyl; and n is 1 or 2.

[0276] In some embodiments, wherein X1and X2are both N, X3is CH, and X4is C. In some embodiments, wherein X1, X2, and X3are N, and X4is C. In some embodiments, X1and X3are CH, X2is C, and X4is N. In some embodiments, X1and X3are CH, X2is N, and X4is C. In some embodiments, X1and X4are N, X2is C, and X3is CH. In some embodiments, X1is CH, X2and X3are N, and X4is C. In some embodiments, X1is CH, X2is C, and X3and X4are N. In some embodiments, X1, X3, and X4are N, and X2is C.

[0277] In some embodiments, the compound has the structure of the following formula VII-A:Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:R is one of the following structural formulas:wherein:L is a direct bond, O, or CR21R22;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc;X1is CR31or N;X2is C or N;X3is CR32or N;X4is C or N;X5is CR33or N;Z1is CH or N;Z2is O or S;Z3is C or N;R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3- 10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12;Attorney Docket No. 63243-709.601RBare each independently selected from hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, cyano, hydroxy, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, Ce-io aryl substituted with 0-4 RB1, C3- 10 cycloalkyl substituted with 0-4 RB1, 3-10 membered heterocyclyl substituted with 0-4 RB1, or 5-6 membered heteroaryl substituted with 0-4 RB1;RB1are each independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;Rcare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R31is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R32is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R33is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R51and R52are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; R7is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 R70, C3-10 cycloalkyl substituted with 0-4 R70, 3- 10 membered heterocyclyl substituted with 0-4 R70, or 5-6 membered heteroaryl substituted with 0-4 R70;R70is hydrogen, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclic group or NRnR12;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclyl or NRnR12;R11and R12are each independently selected from hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl or C1-6 haloalkyl;R21and R22are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl; and n is 1 or 2.

[0278] In some embodiments, X5is CR33, wherein R33is fluorine, hydrogen, methoxy, or trifluoromethoxy. In some embodiments, X5is N. In some embodiments, R1is a C3-10Attorney Docket No. 63243-709.601 cycloalkyl substituted with 0-1 R°, a 3-10 membered heterocyclic group substituted with 0-1 R°, or a Ci-6 alkyl substituted with 0-1 R°; R° is each independently selected from hydrogen, halogen, hydroxy, cyano, Ci-6 alkyl or Ci-6 haloalkyl. In some embodiments, R1is a C3-10 cycloalkyl such as a cyclopropyl. . In some embodiments, R1is a 3-10 membered heterocyclic group substituted with 0-1 R°, a C2-6 alkenyl group substituted with 0-1 R°, or a C1-6 alkyl group substituted with 0-1 R°; R° is independently selected from halogen, hydroxy, cyano or C1-3 alkoxy.

[0279] In some embodiments, R1is one of the following structures:

[0280] In some embodiments X1and X2are both N, X3is CH, and X4is C; or X1, X2, and X3are N, and X4is C; or X1and X3are CH, X2is C, and X4is N; or X1and X3are CH, X2is N, and X4is C; or X1and X4are N, X2is C, and X3is CH; or , X1is CH, X2and X3are N, and X4is C; or X1is CH, X2is C, and X3and X4are N; or X1, X3, and X4are N, and X2is C.

[0281] In some embodiments,hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl substituted with 0-1 R70; R70is selected from hydrogen, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl or 3-8 membered heterocyclyl; Z2is O or S; Z3is C or N; Z4is C or N.

[0282] In some embodiments, Z2is N, Z3is CH, Z4is O; or Z2is S, Z3is CH, Z4is N; or Z2is S, Z3is CH, Z4is N. In some embodiments, Z2is O, Z3is CH, Z4is N; or Z2is S, Z3is CH, Z4is N; or Z2is S, Z3is CH, Z4is N.

[0283] In some embodiments, R is one of the following:Attorney Docket No. 63243-709.601wherein RBais a Ci-6 alkyl group, a Ci-6 haloalkyl group, or a C3-6 cyclic hydrocarbon group substituted with one RBla, wherein RBlais C1-6 alkyl or C1-6 haloalkyl.

[0284] In some embodiments, R iswherein RBis hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;membered heterocyclyl group substituted with 1 Rc; and Rcis C1-3 alkyl.

[0285] In some embodiments, RLisRBbis Ci -6 alkyl.

[0286] In some embodiments, R is:L is O or CH2, RBbis C1-3 alkyl, and RBcis hydrogen or C1-3 haloalkyl, such as trifluoromethyl. In some embodiments, RBbis methyl; and RBcis hydrogen or trifluoromethyl.

[0287] In some embodiments, R isAttorney Docket No. 63243-709.601RBbis Ci-6 alkyl, R51and R52are each independently hydrogen, halogen, deuterium, tritium or Ci-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; and n is 1 or 2.

[0288] In some embodiments,R51and R52are each independently selected from hydrogen, halogen, deuterium or tritium, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl group; R61and R62are each independently selected from hydrogen, halogen, deuterium or tritium, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl group; and RBbis C1-6 alkyl; and n is 1 or 2. In some embodiments, RBbis methyl.

[0289] In some embodiments, the compound has the structure of the following formula VII-B:Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:X1is CR31or N;X2is C or N;X3is CR32or N;X4is C or N;X5is CR33or N;R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3- 10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12;R31is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R32is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl orC1-6 haloalkyl;R33is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclyl or NRnR12;R11and R12are each independently selected from hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl or C1-6 haloalkyl;Ring B is a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O or S, and the ring B is substituted with m number of R8;R8are each independently protium, deuterium, tritium, halogen, hydroxyl, cyano, C1-6 alkyl optionally substituted with R80, C1-6 alkoxy optionally substituted with R80, C3-6Attorney Docket No. 63243-709.601 cycloalkyl optionally substituted with R80, Ce-io aryl optionally substituted with R80, 3-10 membered heterocyclyl optionally substituted with R80, -CONR81R82or -COR83;R80are each independently deuterium, halogen, hydroxyl, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl or Ci-6 haloalkoxy;R81and R82are each independently hydrogen or Ci-6 alkyl;R83is Ci-6 alkyl; and m is 1, 2, or 3.

[0290] In some embodiments, Ring B is one of the following:and wherein the B ring is substituted with two R8. some embodiments, ring B is:and ring B is substituted with 2 to 3 R8.

[0292] In some embodiments, two R8are Ci-6 alkyl optionally substituted with protium, deuterium, tritium, halogen, or R80, and the other R8is aryl optionally substituted with R80. In some embodiments, X5is CR33, and R33is fluoro, hydrogen, methoxy, or trifluoromethyl.

[0293] In some embodiments X1and X2are both N, X3is CH, and X4is C; or X1, X2, and X3are N, and X4is C; or X1and X3are CH, X2is C, and X4is N; or X1and X3are CH, X2is N, and X4is C; or X1and X4are N, X2is C, and X3is CH; or , X1is CH, X2and X3are N, and X4is C; or X1is CH, X2is C, and X3and X4are N; or X1, X3, and X4are N, and X2is C. In some embodiments, X1and X2is N, X3is Ch, and X4is C.

[0294] In some embodiments, the compound has a structure of the following formulaVII-B1 :Attorney Docket No. 63243-709.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:R1is C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, Ci-ealkyl, or C1-6 haloalkyl;R33is halogen or C1-6 alkyl;R91is C1-6 alkyl optionally substituted with R90, C3-6 cycloalkyl optionally substituted with R90, C3-6 cycloalkyl optionally substituted with R90, 3-10 membered heterocyclyl optionally substituted with R90;R92is phenyl optionally substituted with R90or 3-10 membered heterocyclic group optionally substituted with R90;R93is protium, deuterium, tritium, halogen or C1-6 alkyl; andR90is each independently selected from protium, deuterium, tritium, halogen, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl;

[0295] In some embodiments, R1is C3-6 cycloalkyl, for example a cyclopropyl. In some embodiments, R91is a C1-6 alkyl group such as tert-butyl, R92is phenyl optionally substituted with R90, each R90are independently halogen such as fluorine, C1-6 alkyl such as methyl, ethyl or isopropyl, or C1-6 alkoxy such as methoxy; and R93is protium. In some embodiments, R91is a C3-6 cycloalkyl group optionally substituted with R90, each R90are independently aC1-6 haloalkyl, for example, R91is; R92is phenyl optionally substituted with R90; each R90being independently selected from halogen such as fluorine, C1-6 alkyl such as methyl, ethyl or isopropyl, or C1-6 alkoxy such as methoxy; and R93is protium. In some embodiments, R92is one of the follow structures:Attorney Docket No. 63243-709.601

[0296] In various different embodiments, the compound has one of the structures set forth in Table 1G below, or a stereoisomer, tautomer, or salt thereof. Compounds in Table 1G were prepared as described in by methods known in the art and analyzed by mass spectrometry and / orJH NMR. In some embodiments, the compound of Formula (VII) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VII) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (VII) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VII) is administered to treat overweight. In some embodiments, the compound of Formula (VII) is administered to manage weight. In some embodiments, the compound of Formula (VII) is administered to treat diabetes. In some embodiments, the compound of Formula (VII) is administered to reduce blood glucose. In some embodiments, the compound of Formula (VII) is administered to reduce insulin resistance. In some embodiments, the compound of Formula (VII) is administered to reduce serum triglyceride. In some embodiments, the compound of Formula (VII) is administered to reduce adipose weight. In some embodiments, the compound of Formula (VII) is administered with a GLP-1 receptor agonist. In some embodiments, the compound of Formula (VII) is administered with an anti-hyperglycemic agent. In some embodiments, the compound of Formula (VII) is administered with a GLP-1 receptor agonist and an anti- hyperglycemic agent. In some embodiments, the compound of Formula (VII) is administered with a GLP-1 receptor agonist, where the subject is already taking an anti-hyperglycemic agent.

[0297] In various different embodiments, the compound has one of the structures set forth in Table 1G below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0298] Compounds in Table 1G were prepared as described by methods known in the art and analyzed by mass spectrometry and / or 'H NMR.Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601Pharmaceutical Compositions

[0299] In one aspect, compounds provided herein are formulated into pharmaceutical compositions that are useful in a variety of applications including, but not limited to, therapeutic methods, such as treating overweight, treating diabetes, weight management, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride, or reducing adipose weight, or a combination of two or more thereof. The methods of use may be in vitro, ex vivo, or in vivo methods. In various embodiments, the pharmaceutical compositions are formulated for delivery via oral administration. In various embodiments, the pharmaceutical compositions are formulated for delivery via subcutaneous administration. In some cases, a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered orally and a GLP-1 receptor agonist is administered orally. In some cases, a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered orally and a GLP-1 receptor agonist is administered subcutaneously. In some cases, a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered subcutaneously and a GLP-1 receptor agonist is administered orally. In some cases, a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered subcutaneously and a GLP-1 receptor agonist is administered subcutaneously.

[0300] The pharmaceutical compositions may contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of theAttorney Docket No. 63243-709.601 formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that does not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0301] In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) inhibit NEK7 when administered to a patient or a biological sample. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) treat overweight when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) treat diabetes when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) provide weight management when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) reduce blood glucose when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) reduce insulin resistance when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) reduce serum triglyceride when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) reduce adiposeAttorney Docket No. 63243-709.601 weight when administered to a patient in combination with a pharmaceutical composition of a GLP-1 receptor agonist. The compounds may be administered with an anti-hyperglycemic agent. The compounds may be administered to a subject taking an anti -hyperglycemic agent.Methods of Treatment

[0302] Provided herein are methods of treating overweight in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. The compositions may be administered with an anti-hyperglycemic agent. The compositions may be administered to a subject taking an anti-hyperglycemic agent.

[0303] Treatment of overweight includes, without limitation, prevention and / or treatment of eating disorders, such as overweight or obesity. In some embodiments, treatment of overweight includes decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and / or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; and / or delaying gastric emptying.

[0304] In some embodiments, methods disclosed herein prevent weight gain. In some embodiments, a method of preventing weight gain in a subject comprises administering a GLP-1 receptor agonist and an inflammasome modulator. In some embodiments, the combination of administrating a GLP-1 receptor agonist and an inflammasome modulator results in a synergistic effect of the GLP-1 receptor agonist and the inflammasome modulator effectively preventing weight gain. In some embodiments, the combination of the GLP-1 receptor agonist and the inflammasome modulator results in superior prevention of weight gain compared to the sum of their individual effects. In some cases, weight management includes prevention of weight gain.

[0305] The overweight may be a symptom and / or associated with a disease or condition of the subject experiencing overweight. For example, the overweight may be a symptomAttorney Docket No. 63243-709.601 and / or associated with diabetes, hypothyroidism, metabolic syndrome, fatty liver disease, polycystic ovary syndrome, Cushing’s disease, Prader-Willi syndrome, osteoarthritis, sleep apnea, hypertension, heart disease, stroke, gout, kidney disease, an eating disorder, or two or more thereof. The overweight may be a symptom of and / or associated with type 2 diabetes. The overweight may be a symptom of lifestyle, e.g., a sedentary lifestyle and / or a lack of physical activity. The overweight may be a symptom of food consumption in excess of a subject’s metabolic requirements and / or consumption of certain foods, such as highly processed foods, foods high in sugar, saturated fat, etc. The overweight may be a symptom of stress, poor sleep and / or a medication.

[0306] Provided herein are methods of treating diabetes in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a GLP-1 receptor agonist and an inflammasome modulator results in a synergistic effect of the GLP-1 receptor agonist and the inflammasome modulator effectively treating diabetes. In some embodiments, the combination of the GLP-1 receptor agonist and the inflammasome modulator results in superior efficacy in treating diabetes compared to the sum of their individual effects. In some cases, treating diabetes includes reducing blood glucose. In some cases, treating diabetes includes alleviating a symptom or condition associated with diabetes, such as overweight. The compositions may be administered with an anti-hyperglycemic agent. The compositions may be administered to a subject taking an anti-hyperglycemic agent.

[0307] Provided herein are methods of reducing blood glucose in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In example methods, reducing blood glucose means reducing fasting blood glucose. The blood glucose may be lower than prior to administering the GLP-1 receptorAttorney Docket No. 63243-709.601 agonist and inflammasome modulator. Prior to administering the GLP-1 receptor agonist and inflammasome modulator, the subject may have been administered a GLP-1 receptor agonist alone. Prior to administering the GLP-1 receptor agonist and inflammasome modulator, the subject may have not been treated with a GLP-1 receptor agonist. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a GLP-1 receptor agonist and an inflammasome modulator results in a synergistic effect of the GLP-1 receptor agonist and the inflammasome modulator effectively reducing blood glucose. In some embodiments, the combination of the GLP-1 receptor agonist and the inflammasome modulator results in superior efficacy in reducing blood glucose compared to the sum of their individual effects. In some cases, reducing blood glucose includes treating diabetes. In some cases, reducing blood glucose includes alleviating a symptom or condition associated with high blood glucose, such as overweight. The compositions may be administered with an anti- hyperglycemic agent. The compositions may be administered to a subject taking an anti- hyperglycemic agent.

[0308] Provided herein are methods of reducing insulin resistance in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a GLP-1 receptor agonist and an inflammasome modulator results in a synergistic effect of the GLP-1 receptor agonist and the inflammasome modulator effectively reducing insulin resistance. In some embodiments, the combination of the GLP-1 receptor agonist and the inflammasome modulator results in superior efficacy in reducing insulin resistance compared to the sum of their individualAttorney Docket No. 63243-709.601 effects. In some cases, reducing insulin resistance includes treating diabetes. In some cases, reducing insulin resistance includes alleviating a symptom or condition associated with high insulin resistance, such as overweight. The compositions may be administered with an anti- hyperglycemic agent. The compositions may be administered to a subject taking an anti- hyperglycemic agent.

[0309] Provided herein are methods of reducing serum triglyceride in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a GLP-1 receptor agonist and an inflammasome modulator results in a synergistic effect of the GLP-1 receptor agonist and the inflammasome modulator effectively reducing serum triglyceride. In some embodiments, the combination of the GLP-1 receptor agonist and the inflammasome modulator results in superior efficacy in reducing serum triglyceride compared to the sum of their individual effects. In some cases, reducing serum triglyceride includes treating diabetes. In some cases, reducing serum triglyceride includes alleviating a symptom or condition associated with high serum triglyceride, such as overweight. The compositions may be administered with an anti- hyperglycemic agent. The compositions may be administered to a subject taking an anti- hyperglycemic agent.

[0310] Provided herein are methods of reducing adipose weight in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of a GLP-1 receptor agonist and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments,Attorney Docket No. 63243-709.601 the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a GLP-1 receptor agonist and an inflammasome modulator results in a synergistic effect of the GLP-1 receptor agonist and the inflammasome modulator effectively reducing adipose weight. In some embodiments, the combination of the GLP-1 receptor agonist and the inflammasome modulator results in superior efficacy in reducing adipose weight compared to the sum of their individual effects. In some cases, reducing adipose weight treats diabetes. In some cases, reducing adipose weight includes alleviating a symptom or condition associated with high adipose weight, such as overweight. The compositions may be administered with an anti-hyperglycemic agent. The compositions may be administered to a subject taking an anti -hyperglycemic agent.

[0311] The subject described in the method above and herein may further be administered an anti-hyperglycemic agent or is already taking or previously taken an anti-hyperglycemic agent. In some embodiments, the method further comprises administering to the subject an anti-hyperglycemic agent. In some embodiments, the subject is presently taking or has within the past 6 months taken an anti -hyperglycemic agent. In some embodiments, the subject is presently taking or has within the past 5 months taken an anti -hyperglycemic agent. In some embodiments, the subject is presently taking or has within the past 4 months taken an anti- hyperglycemic agent. In some embodiments, the subject is presently taking or has within the past 3 months taken an anti-hyperglycemic agent. In some embodiments, the subject is presently taking or has within the past 2 months taken an anti -hyperglycemic agent. In some embodiments, the subject is presently taking or has within the past month taken an anti- hyperglycemic agent.

[0312] The anti-hyperglycemic agent can by any anti-hyperglycemic agent described herein. In some embodiments, the anti-hyperglycemic agent is metformin, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the anti- hyperglycemic agent is metformin hydrochloride. In some embodiments, the anti- hyperglycemic agent is a sulfonylurea. Non-limiting example sulfonylureas include glimepiride, glipizide, and glyburide. In some embodiments, the anti-hyperglycemic agent is a dipeptidyl peptidase 4 (DPP -4) inhibitor. Non-limiting example DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, and alogliptin. In some embodiments, the anti- hyperglycemic agent is a sodium-glucose transport protein 2 (SGLT2) inhibitor. Non-limiting SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. In some embodiments, the anti-hyperglycemic agent is a thiazolidinedione. Non-limiting thiazolidinediones include pioglitazone and rosiglitazone.Attorney Docket No. 63243-709.601

[0313] Provided herein are methods of treating weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, or a combination of two or more thereof, in a subject, comprising administering to the subject a therapeutically effective amount of an (i) inflammasome modulator; and (ii) an anti-hyperglycemic agent or a GLP-1 receptor agonist, or a combination thereof. In some embodiments, the subject is administered an inflammasome modulator, an anti-hyperglycemic agent, and a GLP-1 receptor agonist. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). The inflammasome modulator, anti-hyperglycemic agent, and GLP-1 receptor agonist can be administered simultaneously, or separately. In some embodiments, the combination of administrating an anti-hyperglycemic agent, a GLP-1 receptor agonist, and an inflammasome modulator results in a synergistic effect. In some embodiments, the combination of the anti- hyperglycemic agent, the GLP-1 receptor agonist, and the inflammasome modulator results in superior efficacy compared to the sum of their individual effects.GLP-1 Receptor Agonists

[0314] In some embodiments, the glucagon-like peptide 1 (GLP-1) receptor agonist is exenatide, lixisenatide, albiglutide, beinaglutide, dulaglutide, efpeglenatide, liraglutide, polyethylene glycol loxenatide, semaglutide, taspoglutide, ecnoglutide, utreglutide, maridebart cafraglutide, tirzepatide, pegapamodutide, mazdutide, survodutide, bamadutide, pemvidutide, cotadutide, retatrutide, lithium chloride, efocipegtrutide, SAR441255, or GZR18. In some embodiments, the GLP-1 receptor agonist is BLX-7006, orforglipron, aleniglipron (GSBR-1290), amycretin, ECC5004, HS-10535, CT-966, VK2735, or danuglipron. GLP-1 receptor agonists may be selected from compounds of W02025026270, such as (3 -(( 1 S,2R)- 1 -(2-((S)-3 -(3 -( 1 -cyclopropyl-4-fluoro-lH-indazol-5-yl)-2-carbonyl-2,3- dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-lH-indol- l-yl)-2-ethynylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one); (3-((lS,2S)-l- (5-((S)-2,2- dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(2- (methyl-d3)-2,7,8,9-tetrahydrooxaheptano[4,3,2-cd]indazol-5-yl)-2-carbonyl-2,3-dihydro- lH-imidazol-l-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH-indol-l- yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one). GLP-1 receptor agonists may be selected from compounds of WO2024160271, CN119431369A, W02025026270, CN202410155253, CN117986264, W02023011539, WO2022228490, CN114903991,Attorney Docket No. 63243-709.601CN111825758, WO2021093883, or W02020030107. GLP-1 receptor agonists may be selected from compounds of WO2025128564, WO2025128561, WO2019183577, WO2025178928, WO2025165934, US20250228804, WO2025128985, WO2025128564, WO2025128561, WO2025122610, W02025097070, WO2024243243A, WO2024226540, WO202223571, or WO 2022235717. GLP-1 receptor agonists may be selected from compounds of US11744873, US20240239843, WO2024107862, WO2025160082, W02023044290, WO2022159395, WO2023158616, WO2024192219, W02020117987, W02024020388, W02024020372, WO2023141044, or WO2024107862.

[0315] In some embodiments, the GLP-1 receptor agonist is exenatide, lixisenatide, albiglutide, beinaglutide, dulaglutide, efpeglenatide, liraglutide, polyethylene glycol loxenatide, semaglutide, taspoglutide, ecnoglutide, utreglutide, maridebart cafraglutide, tirzepatide, pegapamodutide, mazdutide, survodutide, bamadutide, pemvidutide, cotadutide, retatrutide, efocipegtrutide, SAR441255, or GZR18.

[0316] In some embodiments the GLP-1 receptor agonist is exenatide, lixisenatide, albiglutide, efpeglenatide, liraglutide, polyethylene glycol loxenatide, taspoglutide, ecnoglutide, utreglutide, maridebart cafraglutide, pegapamodutide, lithium chloride, or GZR18.

[0317] In some embodiments the GLP-1 receptor agonist is exenatide, lixisenatide, albiglutide, efpeglenatide, liraglutide, polyethylene glycol loxenatide, taspoglutide, ecnoglutide, utreglutide, maridebart cafraglutide, pegapamodutide, or GZR18.

[0318] In some embodiments the GLP-1 receptor agonist is exenatide or liraglutide.

[0319] In some embodiments the GLP-1 receptor agonist is exenatide.

[0320] In some embodiments the GLP-1 receptor agonist is liraglutide.

[0321] In some embodiments, the GLP-1 receptor agonist is BLX-7006.

[0322] In some embodiments, the GLP-1 receptor agonist is a GLP-l / glucagon receptor dual agonist.

[0323] In some embodiments, the GLP-l / glucagon receptor dual agonist is beinaglutide, mazdutide, survodutide, bamadutide, pemvidutide, or cotadutide.

[0324] In some embodiments, the GLP-l / glucagon receptor dual agonist is beinaglutide, mazdutide, survodutide, pemvidutide, or cotadutide.

[0325] In some embodiments, the GLP-1 receptor agonist is a GIP / GLP-1 dual receptor agonist.

[0326] In some embodiments, the GIP / GLP-1 dual receptor agonist is dulaglutide, semaglutide, or tirzepatide.Attorney Docket No. 63243-709.601

[0327] In some embodiments, the GIP / GLP-1 dual receptor agonist is semaglutide, tirzepatide, or dulaglutide.

[0328] In some embodiments, the GIP / GLP-1 dual receptor agonist is semaglutide or tirzepatide.

[0329] In some embodiments, the GIP / GLP-1 dual receptor agonist is semaglutide.

[0330] In some embodiments, the GIP / GLP-1 dual receptor agonist is tirzepatide.

[0331] In some embodiments, the GIP / GLP-1 dual receptor agonist is dulaglutide.

[0332] In some embodiments, the GLP-1 agonist is a GLP-l / GIP / glucagon receptor triagonist.

[0333] In some embodiments, the GLP-l / GIP / glucagon receptor triagonist is retatrutide, efocipegtrutide, or SAR441255.

[0334] In some embodiments, the GLP-l / GIP / glucagon receptor triagonist is retatrutide.

[0335] In some embodiments, the GLP-l / GIP / glucagon receptor triagonist is efocipegtrutide.

[0336] In some embodiments, the GLP-l / GIP / glucagon receptor triagonist is SAR441255.

[0337] In some embodiments, the GLP-1 receptor agonist comprises a sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to an amino acid sequence shown in Table 2. In some embodiments, the GLP-1 receptor agonist comprises a sequence with 0, 1 or 2 modifications as compared to an amino acid sequence shown in Table 2. The modification may be an amino acid deletion. The modification may be an amino acid substitution. The modification may be an amino acid insertion.Table 2: Non-Limiting Representative GLP-1 Receptor AgonistsAtorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601Semaglutide

[0338] Semaglutide has the following structure:Attorney Docket No. 63243-709.601

[0339] In some embodiments semaglutide may be present in the composition in its fully or partly ionised form; for example one or more carboxylic acid groups ( — COOH) may be deprotonated into the carboxylate group ( — COO — ) and / or one or more amino groups ( — NH2) may be protonated into the — NH3+group. In some embodiments semaglutide is added to the composition in the form of a salt. In some embodiments semaglutide may be recombinantly produced. In some embodiments semaglutide may be synthetically produced. In some embodiments, semaglutide is present in a subcutaneous dosage form. As a nonlimiting example, semaglutide is Ozempic®. As another non-limiting example, semaglutide is Wegovy®. For example subcutaneous formulations of semaglutide see U.S. patents 7762994, 8114833, 8129343, 8536122, 8684969, 8920383, 9108002, 9132239, 9457154, 9616180, 9687611, 9775953, 9861757, 10220155, 10335462, 10357616, 10376652, 11097063, 11311679, 11446443, RE46363, 8129343, 8536122, 9764003, 10888605, 11318191, and 11752198. In some embodiments, semaglutide is present in an oral dosage form. As a non-limiting example, the semaglutide is Rybelsus®. For example oral formulations of semaglutide see U.S. patents 8129343, 8536122, 9278123, 10086047, 10278923, 10933120, 10960052, 11382957, 11759501, 11759502, and 11759503.Diabetes and other diseases

[0340] Provided herein are methods of treating diabetes in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti -hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII).Attorney Docket No. 63243-709.601In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0341] Treatment of diabetes includes, without limitation, treatment of hyperglycemia, reducing insulin resistance, reducing serum triglyceride levels, weight management, and / or reducing adipose weight.

[0342] Treatment of diabetes includes, without limitation, treatment of hyperglycemia, reducing insulin resistance, reducing serum triglyceride levels, weight management, reducing adipose weight, improving lipid profiles, reducing VLDL levels, increasing HDL levels, and / or reducing adipose tissue inflammation.

[0343] Provided herein are methods of treating polycystic ovary syndrome (PCOS) in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0344] Treatment of polycystic ovary syndrome (PCOS) includes, without limitation, treatment of hyperglycemia, reducing insulin resistance, reducing serum triglyceride levels, weight management, and / or reducing adipose weight.

[0345] Treatment of polycystic ovary syndrome (PCOS) includes, without limitation, treatment of hyperglycemia, reducing insulin resistance, reducing serum triglyceride levels, weight management, reducing adipose weight, improving lipid profiles, reducing VLDL levels, increasing HDL levels, and / or reducing adipose tissue inflammation.

[0346] The diabetes may be comorbid with hypertension, dyslipidemia, chronic kidney disease, diabetic peripheral neuropathy, diabetic retinopathy, fatty liver disease, obesity,Attorney Docket No. 63243-709.601 hypothyroidism, metabolic syndrome, polycystic ovary syndrome, Cushing’s disease, Prader- Willi syndrome, osteoarthritis, sleep apnea, hypertension, heart disease, stroke, gout, kidney disease, an eating disorder, or two or more thereof.

[0347] Provided herein are methods of treating diabetes in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti -hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively treating diabetes. In some embodiments, the combination of the anti- hyperglycemic agent and the inflammasome modulator results in superior efficacy in treating diabetes compared to the sum of their individual effects. In some cases, treating diabetes includes reducing blood glucose. In some cases, treating diabetes includes alleviating a symptom or condition associated with diabetes, such as overweight. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0348] Provided herein are methods of reducing blood glucose in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In example methods, reducing blood glucose means reducing fasting blood glucose. The blood glucose may be lower than prior to administering the anti-hyperglycemic agent and inflammasome modulator. Prior to administering the anti-hyperglycemic agent and inflammasome modulator, the subject may have been administered a anti -hyperglycemic agent alone. Prior to administering the anti-hyperglycemic agent and inflammasome modulator, the subject may have not been treated with a an anti-hyperglycemic agent. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII).Attorney Docket No. 63243-709.601In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively reducing blood glucose. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in reducing blood glucose compared to the sum of their individual effects. In some cases, reducing blood glucose includes alleviating a symptom or condition associated with high blood glucose, such as overweight. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0349] Provided herein are methods of reducing insulin resistance in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively reducing insulin resistance. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in reducing insulin resistance compared to the sum of their individual effects. In some cases, reducing insulin resistance includes treating diabetes. In some cases, reducing insulin resistance includes alleviating a symptom or condition associated with high insulin resistance, such as overweight. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0350] Provided herein are methods of reducing serum triglyceride in a subject in needAttorney Docket No. 63243-709.601 thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating a anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively reducing serum triglyceride. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in reducing serum triglyceride compared to the sum of their individual effects. In some cases, reducing serum triglyceride includes treating diabetes. In some cases, reducing serum triglyceride includes alleviating a symptom or condition associated with high serum triglyceride, such as overweight. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0351] Provided herein are methods of reducing adipose weight in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively reducing adipose weight. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in reducing adipose weight compared to the sum of their individual effects.Attorney Docket No. 63243-709.601In some cases, reducing adipose weight treats diabetes. In some cases, reducing adipose weight includes alleviating a symptom or condition associated with high adipose weight, such as overweight. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0352] Provided herein are methods of improving the lipid profile in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively improve the lipid profile in a subject. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in improving the lipid profile in a subject compared to the sum of their individual effects. In some cases, improving the lipid profile in a subject treats diabetes. In some embodiments, the method reduces levels of VLDL in a subject. In some embodiments, the method increases levels of HDL in a subject. In some embodiments, the method reduces levels of VLDL and increases levels of HDL in a subject. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0353] Provided herein are methods of reducing VLDL levels in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments,Attorney Docket No. 63243-709.601 the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively reducing VLDL levels in a subject. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in reducing VLDL levels in a subject compared to the sum of their individual effects. In some cases, reducing VLDL levels in a subject treats diabetes. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0354] Provided herein are methods of increasing HDL levels in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively increasing HDL levels in a subject. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in increasing HDL levels in a subject compared to the sum of their individual effects. In some cases, increasing HDL levels in a subject treats diabetes. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0355] Provided herein are methods of reducing adipose tissue inflammation in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition isAttorney Docket No. 63243-709.601 administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively reducing adipose tissue inflammation. In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in reducing adipose tissue inflammation compared to the sum of their individual effects. In some cases, reducing adipose tissue inflammation treats diabetes. In some cases, reducing adipose tissue inflammation includes alleviating a symptom or condition associated with high adipose tissue inflammation, such as overweight. The compositions may be administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0356] Provided herein are methods of treating polycystic ovary syndrome (PCOS) in a subject in need thereof by administering to the subject a first composition comprising a therapeutically effective amount of an anti-hyperglycemic agent and administering to the subject a second composition comprising a second therapeutically effective amount of an inflammasome modulator. In some embodiments, the inflammasome modulator is a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the first composition is administered first, and the second composition is administered second. In some embodiments, the first composition is administered second, and the second composition is administered first. In some embodiments, the first composition and the second composition are administered simultaneously. In some embodiments, the combination of administrating an anti-hyperglycemic agent and an inflammasome modulator results in a synergistic effect of the anti-hyperglycemic agent and the inflammasome modulator effectively treating polycystic ovary syndrome (PCOS). In some embodiments, the combination of the anti-hyperglycemic agent and the inflammasome modulator results in superior efficacy in treating polycystic ovary syndrome (PCOS) compared to the sum of their individual effects. In some cases, treating polycystic ovary syndrome (PCOS) includes reducing blood glucose. In some cases, treating polycystic ovary syndrome (PCOS) includes reducing insulin resistance. In some cases, treating polycystic ovary syndrome (PCOS) includes alleviating a symptom or condition associated with diabetes, such as overweight. The compositions may beAttorney Docket No. 63243-709.601 administered with a GLP-1 receptor agonist. The compositions may be administered to a subject taking a GLP-1 receptor agonist.

[0357] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and an inflammasome modulator. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0358] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti -hyperglycemic agent and an inflammasome modulator. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0359] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and an inflammasome modulator. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0360] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti -hyperglycemic agent and an inflammasome modulator. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0361] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance,Attorney Docket No. 63243-709.601 reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and a modulator of the NLRP3 inflammasome. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0362] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti-hyperglycemic agent and a modulator of the NLRP3 inflammasome. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0363] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and an inhibitor of NEK7 kinase. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0364] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti -hyperglycemic agent and an inhibitor of NEK7 kinase. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0365] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction.Attorney Docket No. 63243-709.601The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0366] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti-hyperglycemic agent and an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0367] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and an inflammasome modulator, wherein the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome and inhibits the formation of NLRP3 (protein)-NEK7 (protein) interactions. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0368] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti -hyperglycemic agent and an inflammasome modulator, wherein the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome and inhibits the formation of NLRP3 (protein)-NEK7 (protein) interactions. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0369] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti- hyperglycemic agent and a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or a pharmaceuticallyAttorney Docket No. 63243-709.601 acceptable salt, stereoisomer, or solvate thereof. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0370] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti-hyperglycemic agent and the compound:, or a pharmaceutically acceptable salt or solvate thereof. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0371] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject an anti-hyperglycemic agent and the compound:pharmaceutically acceptable salt or solvate thereof. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0372] In some embodiments, described herein is a method of treating diabetes in a subject, comprising administering to the subject an anti-hyperglycemic agent and the compound:Attorney Docket No. 63243-709.601pharmaceutically acceptable salt or solvate thereof.

[0373] In some embodiments, described herein is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducingVLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject metformin or a pharmaceutically acceptable salt or solvate thereof and the compound:pharmaceutically acceptable salt or solvate thereof. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0374] In some embodiments, described herein is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof, in a subject, comprising administering to the subject metformin or a pharmaceutically acceptable salt or solvate thereofAttorney Docket No. 63243-709.601 and the compound:pharmaceutically acceptable salt or solvate thereof. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0375] In some embodiments, described herein is a method of treating diabetes in a subject, comprising administering to the subject metformin or a pharmaceutically acceptable salt or solvate thereof and the compound:pharmaceutically acceptable salt or solvate thereof. The subject may be further administered a GLP-1 receptor agonist. The subject may be currently taking a GLP-1 receptor agonist.

[0376] In some embodiments, the anti-hyperglycemic agent is metformin or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the anti- hyperglycemic agent is metformin hydrochloride. In some embodiments, the anti- hyperglycemic agent is a sulfonylurea. Non-limiting example sulfonylureas include glimepiride, glipizide, and glyburide. In some embodiments, the anti-hyperglycemic agent is a dipeptidyl peptidase 4 (DPP -4) inhibitor. Non-limiting example DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, and alogliptin. In some embodiments, the anti- hyperglycemic agent is a sodium-glucose transport protein 2 (SGLT2) inhibitor. Non-limiting SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. In some embodiments, the anti-hyperglycemic agent is a thiazolidinedione. Non-limiting thiazolidinediones include pioglitazone and rosiglitazone.

[0377] In some embodiments, the method is a method of treating diabetes, treating polycystic ovary syndrome, reducing blood glucose, reducing insulin resistance, reducingAttorney Docket No. 63243-709.601 serum triglyceride levels, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof. In some embodiments, the method is a method of treating diabetes, treating polycystic ovary syndrome (PCOS), or both. In some embodiments, the method is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing adipose weight, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof.

[0378] In some embodiments, method is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, improving lipid profile, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof. In some embodiments, the method is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, reducing VLDL levels, increasing HDL levels, reducing adipose tissue inflammation, or a combination of two or more thereof.

[0379] In some embodiments, the method is a method of treating diabetes, reducing blood glucose, reducing insulin resistance, or a combination of two or more thereof. In some embodiments, the method is a method of treating diabetes. In some embodiments, the method is a method of treating polycystic ovary syndrome (PCOS). In some embodiments, the method is a method of reducing blood glucose. In some embodiments, the method is a method of reducing insulin resistance. In some embodiments, the method is a method of reducing serum triglyceride levels. In some embodiments, the method is a method of reducing adipose weight. In some embodiments, the method is a method of improving lipid profiles. In some embodiments, the method is a method of reducing VLDL levels. In some embodiments, the method is a method of increasing HDL levels. In some embodiments, the method is a method of reducing adipose tissue inflammation. In some embodiments, the diabetes is type 2 diabetes mellitus. In some embodiments, the diabetes is type 1 diabetes.

[0380] In some embodiments, the diabetes is comorbid with hypertension, dyslipidemia, chronic kidney disease, diabetic peripheral neuropathy, diabetic retinopathy, fatty liver disease, overweight, obesity, hypothyroidism, metabolic syndrome, polycystic ovary syndrome, Cushing’s disease, Prader-Willi syndrome, osteoarthritis, sleep apnea, hypertension, heart disease, stroke, gout, kidney disease, an eating disorder, or two or more thereof.

[0381] In some embodiments, the polycystic ovary syndrome (PCOS) is comorbid with hypertension, dyslipidemia, chronic kidney disease, diabetic peripheral neuropathy, diabetic retinopathy, fatty liver disease, overweight, obesity, hypothyroidism, metabolic syndrome,Attomey Docket No. 63243-709.601 diabetes, Cushing’s disease, Prader-Willi syndrome, osteoarthritis, sleep apnea, hypertension, heart disease, stroke, gout, kidney disease, an eating disorder, or two or more thereof.Anti-Hyperglycemic Agents

[0382] In some embodiments, the anti-hyperglycemic agent is metformin. In some embodiments, the anti-hyperglycemic agent is a sulfonylurea. Non -limiting example sulfonylureas include glimepiride, glipizide, and glyburide. In some embodiments, the anti- hyperglycemic agent is a dipeptidyl peptidase 4 (DPP-4) inhibitor. Non-limiting example DPP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, and alogliptin. In some embodiments, the anti-hyperglycemic agent is a sodium-glucose transport protein 2 (SGLT2) inhibitor. Non-limiting SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. In some embodiments, the anti-hyperglycemic agent is a thiazolidinedione. Non-limiting thiazolidinediones include pioglitazone and rosiglitazone.Metformin

[0383] Metformin (CAS 657-24-9) has the following structure:NH2NHH3C'N^N^NH2CH3In some embodiments metformin may be present in its free base form. In some embodiments metformin may be present as a pharmaceutically acceptable salt and / or solvate. In some embodiments, metformin may be present as a pharmaceutically acceptable salt. In some embodiments, metformin may be present as a pharmaceutically acceptable solvate. In some embodiments, metformin may be present as a hydrochloride salt. In some embodiments, metformin may be present as a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5-disulfonic acid, naphthal ene-2- sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-Attorney Docket No. 63243-709.601 aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p- toluenesulfonic acid, trifluoroacetic acid, or undecylenic acid. Metformin may be present as a tautomeric form.EXAMPLES

[0384] The following examples are illustrative of the embodiments described herein and are not to be interpreted as limiting the scope of this disclosure. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to be limiting. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of this disclosure.

[0385] Examples and procedures for compounds 1 to 66 are herein incorporated by reference from US Patent No. 11,713,321.

[0386] Examples and procedures for compounds II- 1 to 11-67 are herein incorporated by reference from PCT publication WO2022226182A1.

[0387] Examples and procedures for compounds III- 1 to III- 118 are herein incorporated by reference from PCT publication WO2022216680A1.

[0388] Examples and procedures for compounds IV- 1 to IV-22 are herein incorporated by reference from PCT publication WO2022159835A1.

[0389] Examples and procedures for compounds V-l to V-80 are herein incorporated by reference from US Patent Application Publication US 2023 / 0203045 Al and PCT publication WO2021226547A2.

[0390] Examples and procedures for compounds VI- 1 to VI- 137 are herein incorporated by reference from PCT publication W02024059200A1.Example 1: Synthesis Scheme

[0391] The following General Reaction Schemes illustrate examples of compounds of Structure (I):Attorney Docket No. 63243-709.601 or pharmaceutically acceptable salts, stereoisomers or prodrug thereof, wherein each of A, X, Y, R1, R2, R3, R4and R5are as defined herein.General Reaction Scheme 1The following General Reaction Scheme, wherein X1and X2are independently halogens, and X, R1, R2, R3and A have the meanings described herein, illustrates examples of methods of making the amine Intermediate D:1. Cu(II)acetate or Reagent I. NH4OH2. Electrophilic R2or 2. Microwave R2boronateIntermediate B1. Carbocyclic or heterocyclic boronic acid or dioxoborolane derivative / Pd; or2a. Carbocyclic or heterocyclicboronic acid derivative / PdIntermediate C 2b. Fe / NH4C1 Intermediate DAs shown in General Reaction Scheme 1, alkylation of the pyrimidine / pyridine pyrrole (z.e., Intermediate A) with a cycloalkyl boronate or an appropriate electrophile in presence of base affords the Intermediate B. This precursor is treated with ammonium hydroxide to form the pyrolopyrimidine / pyridine-4-amine derivative Intermediate C. The resulting Intermediate C can then be subject to palladium catalyzed arylation to form Intermediate D.General Reaction Scheme 2The following General Reaction Scheme illustrates examples of methods of making the carbamate Intermediate E:HIntermediate EAs shown in General Reaction Scheme 2, Intermediate E can be prepared the in presence of base by reaction of phenyl chloroformates and the indicated heteroaryl amine (an amine-substituted analogue of R4). General Reaction Scheme 2 depicts preparation of compounds wherein R5is H; however, compounds wherein R5is other than H can be prepareAttorney Docket No. 63243-709.601 by similar methods by instilling R5after preparation of Intermediate E, or by using an appropriately substituted heteroaryl amine.General Reaction Scheme 3The following General Reaction Scheme illustrates examples of methods of making the compounds of Structure (I):Intermediate D Intermediate EIntermediate D and Intermediate E are treated with a base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).General Reaction Scheme 4The following General Reaction Scheme illustrates examples of methods of making the compounds of Structure (I):Intermediate D Intermediate E base THFCompounds of Structure (I)Intermediate D is reacted with the phenyl carb onochlori date shown under appropriate conditions to yield Intermediate E. Intermediate E is then coupled with the amine using a suitable base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).

[0392] Any of the above reaction scheme can be modified at any step to add and / or modify a substituent may be added or modified as appropriate during any stage of the overall synthesis of desired compounds.Attorney Docket No. 63243-709.601

[0393] An intermediate Al (4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidinewas prepared as follows: N-iodosuccinimide (1.465 g, 6.51 mmol) was added to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL) at 0 °C and the resulting mixture was stirred at 25 °C for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice cold water (100 mL) and stirred at 25 °C for 15 min. The resulting solid was filtered, washed with water (2 x 25 mL), and dried to afford the title compound as an off-white solid (1.7 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) 5 = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H); LCMS: 279.9 [M+H],

[0394] An intermediate Bl (4-chloro-7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidinewas prepared as follows: Copper (II) acetate (0.650 g, 3.58 mmol), 2,2'- bipyridine (0.559 g, 3.58 mmol), and sodium bicarbonate (0.601 g, 7.16 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Al, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) in di chloroethane (10 mL) and the resulting mixture was stirred at 70 °C under oxygen atmosphere for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of celite which was then rinsed with DCM (2 x 20 mL). The combined filtrates were washed with water (20 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 15% EtOAc in petroleum ether), affording the title compound as an off-white solid (0.7 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) 5 = 8.67 (s, 1H), 7.96 (s, 1H), 3.63-3.69 (m, 1H), 1.06-1.10 (m, 4H). LCMS: 319.9 [M+H],

[0395] An intermediate Cl (7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared as follows: A mixture of 4-chloro-7-cyclopropyl-5-iodo-7H-Attorney Docket No. 63243-709.601 pyrrolo[2,3-d]pyrimidine (Bl, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% in water, 5 mL) was subjected to microwave irradiation at 150 °C for 1 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to afford the title compound as an off-white solid (0.75 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) 5 = 8.12 (s, 1H), 7.39 (s, 1H), 6.57 (bs, 2H), 3.48-3.54 (m, 1H), 0.97-1.01 (m, 4H). LCMS: 301.0 [M+H],

[0396] An intermediate DI (5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7h-pyrrolo[2,3- d]pyrimidin-4-aminewas prepared as follows: A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (Cl, 0.160 g, 0.533 mmol), 2-fhroro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added and the reaction mixture was stirred at 100 °C for 12 h. Following completion of the reaction (as indicated by TLC), the mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230- 400 mesh, eluting with 3% MeOH in DCM), affording the title compound as a yellow solid (0.110 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) 5 = 8.14 (s, 1H), 7.13 (s, 1H), 7.05- 7.09 (m, 1H), 6.95-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52-3.58 (m, 1H), 1.00-1.04 (m, 4H). LCMS: 284.1 [M+H],

[0397] CompoundAttorney Docket No. 63243-709.601 was prepared following the general procedure for urea formation starting from 5-(4-amino-3- fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (DI, 0.10 g, 0.35 mmol) and phenyl (5-(l-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (0.11 g, 0.35 mmol

[0398] Specifically, triethylamine (2.0 eq.) was added to a mixture of DI (1.0 eq.) and El (1.0 eq.) in THF (10 Vol.) and the resulting mixture was stirred at 60 °C for 12 h in a sealed tube. Following completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give crude material which was purified by reverse phase preparative HPLC to afford the desired product. Compound 10 was obtained as an off- white solid (0.010 g, 6% yield). 1H NMR (400 MHz, DMSO-d6) 5 = 9.99 (bs, 1H), 8.86 (bs, 1H), 8.14-8.18 (m, 2H), 7.24-7.36 (m, 3H), 6.90 (s, 1H), 6.15 (bs, 2H), 3.56-3.61 (m, 1H), 1.48-1.57 (m, 4H), 1.02-1.07 (m, 4H). LCMS: 502.2 [M+H],Example 2: Efficacy of Compound 10 and Semaglutide in Diet-Induced Obesity (DIO)Mice

[0399] Male C57BL / 6 mice were used to establish a model of diet-induced obesity (DIO) by feeding them a high-fat diet for 12 weeks prior to initiation of treatment. The study evaluated the efficacy of Compound 10, a Nek7 allosteric compound targeting NLRP3 inflammasome, and semaglutide, a GLP-1 receptor agonist.

[0400] The study employed various dosages to assess the individual and combined effects of Compound 10 and semaglutide. Compound 10 was administered orally at 3.5 mg / kg / day or 5 mg / kg / day. Semaglutide was administered subcutaneously at 1 nmol / kg / day or 2 nmol / kg / day.

[0401] The DIO mice were divided into nine treatment groups: (1) a vehicle group, serving as a control (“Gl”); (2) a group receiving semaglutide alone at 1 nmol / kg / day (“G2”);(3) a group receiving semaglutide alone at 2 nmol / kg / day (“G3”); (4) a group receiving Compound 10 alone at 3.5 mg / kg / day (“G4”); (4) a group receiving Compound 10 alone at 5 mg / kg / day (“G5”); (6) a group receiving a combination of semaglutide at 1 nmol / kg / day and Compound 10 at 3.5 mg / kg / day (“G6”); (7) a group receiving a combination of semaglutide at 2 nmol / kg / day and Compound 10 at 3.5 mg / kg / day (“G7”); (8) a group receiving a combination of semaglutide at 1 nmol / kg / day and Compound 10 at 5 mg / kg / day (“G8”); andAttorney Docket No. 63243-709.601(9) a group receiving a combination of semaglutide at 2 nmol / kg / day and Compound 10 at 5 mg / kg / day (“G9”). Treatments were administered over 28 days. Body weight, food consumption, glucose tolerance, insulin tolerance, serum chemistry, and body composition were monitored to assess the impact of the treatments.

[0402] FIG. 1 illustrates the percentage change in body weight over the 28-day treatment in the nine groups of DIO mice. Treatment with Compound 10 at 3.5 mg / kg / day (G4) or 5 mg / kg / day (G5) resulted in a 4.8 ± 0.9% or 6.4 ± 1.7 % weight change, respectively, after 28 days, while the vehicle control group (Gl) resulted in a 2.6 ± 1.2% weight change.

[0403] Treatment with 1 nmol / kg / day semaglutide (G2) resulted in a 2.1 ± 1.2% weight change after 28 days. However, the addition of Compound 10 at 3.5 mg / kg / day (G6) resulted in a -5.1 ± 1.2% (p<0.05 compared to vehicle control, p<0.01 compared to 1 nmol / kg / day semaglutide alone). Further, the combination of 1 nmol / kg / day semaglutide and Compound 10 at 5 mg / kg / day (G8) resulted in a -5.8 ± 2.5% (p<0.01 compared to vehicle control and 1 nmol / kg / day semaglutide alone) weight change after 28 days.

[0404] Treatment with 2 nmol / kg / day semaglutide (G3) resulted in a -7.3 ± 2.1% (p<0.001 compared to vehicle control) weight change after 28 days. The addition of Compound 10 at 3.5 mg / kg / day (G7) resulted in a -10.7 ± 1.6% (p<0.0001 compared to vehicle control). The combination of 2 nmol / kg / day semaglutide and Compound 10 at 5 mg / kg / day (G9) resulted in -13.0 ± 2.7% (p<0.0001 compared to vehicle control, p<0.05 compared to 2 nmol / kg / day semaglutide alone) weight change after 28 days.

[0405] Accordingly, while treatment with Compound 10 alone resulted in weight gain, the combination of Compound 10 and semaglutide resulted in substantial additional weight loss compared to treatment with semaglutide alone, indicating a synergistic effect between Compound 10 and semaglutide. Treatment with 1 nmol / kg / day semaglutide in combination with 3.5 mg / kg / day or 5 mg / kg / day Compound 10 yielded weight changes not significantly lower than treatment with 2 nmol / kg / day semaglutide alone. FIG. 2 illustrates the percentage change in body weight in the nine groups of DIO mice at termination of the treatment.

[0406] The combination of Compound 10 and semaglutide treatment also reduced fasting glucose and glucose homeostasis (as measured by an oral glucose tolerance test). FIG. 3 illustrates the fasting blood glucose in the nine groups of DIO mice following treatment. As seen in FIG. 3, the vehicle control group (Gl) had the highest fasting glucose level. Groups treated with Compound 10 alone (G4 and G5) showed slightly reduced glucose levels compared to Gl. Groups treated with semaglutide alone (G2 and G3) showed a more significant reduction in glucose level. However, the combination treatments of Compound 10Attorney Docket No. 63243-709.601 and semaglutide (G6, G7, G8, and G9) showed the most substantial reduction in glucose levels, particularly G9, which had the lowest level of glucose. A reduction in glucose level was significantly improved with the combination therapy (57.6% reduction in fasting glucose compared to vehicle control) as compared to treatment with semaglutide alone (24.6% reduction in fasting glucose compared to vehicle control) for subjects administered a high dose of semaglutide and Compound 10 (p<0.0001).

[0407] FIG. 4A illustrates the glucose tolerance test in diet-induced obese mice following the nine treatments. The control group (Gl) had the highest glucose levels over the entire 120 minutes post-injection. Groups treated with Compound 10 alone (G4 and G5) showed slightly lower glucose levels within 30 minutes, stabilizing at lower levels than Gl. Groups treated with semaglutide alone (G2 and G3) showed a significant drop in glucose levels within 30 minutes. However, the combination treatments of Compound 10 and semaglutide (G6, G7, G8, and G9) showed the most significant reductions in glucose levels, with G9 showing the lowest levels across the timeline. FIG. 4B illustrates the area under the curve (AUC) of the glucose tolerance test (GTT) in diet-induced obese mice following the nine treatments. The control group (Gl) had the highest AUC, indicating the highest overall glucose levels during the test. Groups treated with Compound 10 alone (G4 and G5) showed reduced AUC compared to Gl. Groups treated with semaglutide alone (G2 and G3) showed significantly lower AUC, reflecting better glucose tolerance. However, the combination treatments of Compound 10 and semaglutide (G6, G7, G8, and G9) showed the lowest AUC values, with G9 showing the most considerable reduction, indicating the best glucose tolerance among the groups. Glucose tolerance was significantly improved with the combination therapy (52.8% reduction in GTT AUC compared to vehicle control) as compared to treatment with semaglutide alone (37.0% reduction in GTT AUC compared to vehicle control) for subjects administered a high dose of semaglutide and Compound 10 (p<0.01).

[0408] The combination of Compound 10 and semaglutide treatment also reduced insulin resistance, as evaluated by an insulin tolerance test. FIG. 5A illustrates the insulin tolerance test in diet-induced obese mice following the nine treatments. The control group (Gl) maintained relatively high glucose levels throughout the test. Groups treated with Compound 10 alone (G4 and G5) showed some reduction in glucose levels, compared to Gl. Groups treated with semaglutide alone (G2 and G3) showed a significant reduction in glucose levels shortly after insulin injection, stabilizing at lower levels. However, the combination treatments of Compound 10 and semaglutide (G6, G7, G8, and G9) showed the mostAttorney Docket No. 63243-709.601 substantial reductions in glucose levels, particularly G9, which showed the lowest glucose levels throughout the test. FIG. 5B illustrates the area under the curve (AUC) of the glucose tolerance test (GTT) in diet-induced obese mice following the nine treatments. The control group (Gl) had the highest AUC, indicating the poorest insulin sensitivity. Groups treated with Compound 10 alone (G4 and G5) showed reduced AUC compared to Gl. Groups treated with semaglutide alone (G2 and G3) showed significantly lower AUC, reflecting improved insulin sensitivity. However, the combination treatments of Compound 10 and semaglutide (G6, G7, G8, and G9) showed the lowest AUC values, with G9 showing the most significant reduction, indicating the highest insulin sensitivity among the groups. Insulin sensitivity was significantly improved (p<0.01) with the low dose semaglutide combination therapies (42.9% and 44.8% reductions in ITT AUC compared to vehicle control for the combinations with low and high doses of Compound 10, respectively) as compared to treatment with a low dose of semaglutide alone (24.6% reduction in ITT AUC compared to vehicle control), and was significantly improved (p<0.001) with the high dose semaglutide combination therapy (54.9% reduction in ITT AUC compared to vehicle control for the combination with a high dose of Compound 10) as compared to treatment with a high dose of semaglutide alone (30.6% reduction in ITT AUC compared to vehicle control).

[0409] FIG. 6A illustrates the serum triglyceride concentration in diet-induced obese mice at termination of the nine treatments. Groups treated with Compound 10 alone (G4 and G5) and groups treated with 1 nmol / kg / day semaglutide (G2, G6, and G8) showed higher triglyceride concentrations compared to Gl. However, groups treatments with 2 nmol / kg / day semaglutide alone (G3), and in combination with Compound 10 (G7 and G9) showed lower triglyceride concentrations compared to Gl .

[0410] FIG. 6B illustrates the serum total cholesterol concentration in diet-induced obese mice at termination of the nine treatments. Treatments with 2 nmol / kg / day semaglutide (G3) and its combination with Compound 10 (G7 and G9) lead to significant reductions in cholesterol levels compared to Gl. Statistical analysis highlighted the significance of these range reductions with p-values ranging from less than 0.05 to less than 0.0001. In addition, the Sidak test was employed to compare specific treatment groups. The Sidak test highlights comparisons between G6 and G8 versus G2 or G7, in addition to G9 versus G3.Accordingly, the combination treatments, particularly G9, was the most effective in reducing both serum triglyceride and total cholesterol, suggesting that the combination is a superior therapeutic strategy compared to using them individually.

[0411] FIG. 6C illustrates the serum HDL cholesterol concentration in diet-inducedAttorney Docket No. 63243-709.601 obese mice at termination of the nine treatments. G1 showed the highest HDL levels, while treatments with Compound 10 alone (G4 and G5) maintained similarly high HDL levels. Groups treated with 2 nmol / kg / day semaglutide (G3) showed significant reduction in HDL cholesterol compared to Gl. When combined with Compound 10, semaglutide further reduced HDL levels, with groups G6, G7, G8, and G9 displaying the lowest HDL concentrations.

[0412] FIG. 6D illustrates the serum LDL cholesterol concentration in diet-induced obese mice at termination of the nine treatments. Gl showed the highest LDL cholesterol levels, while treatments with Compound 10 alone (G4 and G5) lead to reductions. Groups treated with 2 nmol / kg / day semaglutide (G3) reduced LDL cholesterol compared to GL When combined with Compound 10, semaglutide further reduced LDL levels, with groups G6, G7, G8, and G9 significantly lowering LDL concentrations.

[0413] FIG. 7 illustrates the body composition of various tissues in diet-induced obese mice at termination of the nine treatments, comparing lean tissue, total adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue across different treatment groups. For lean tissue, all groups, including the control and treatment groups, showed similar levels of tissue weight, indicating that the treatments had minimal impact on lean tissue mass. For total adipose tissue, Gl, G4, and G5 had the highest adipose tissue weights. However, semaglutide-treated groups — especially those with 2 nmol / kg / day semaglutide (G3) and in combination with Compound 10 (G7 and G9) showed marked reductions in total adipose tissue. For visceral adipose tissue, a similar trend was observed. Gl, G4, and G5 maintained higher visceral fat levels, while semaglutide-treated groups (G2 and G3) and specifically their combination with Compound 10 (G6, G7, G8 and G9) showed a significant reduction in visceral fat, with G9 having the lowest level. For subcutaneous adipose tissue, Gl, G4, and G5 showed the highest fat content. However, groups treated with semaglutide, and especially when combined with Compound 10 (G7 and G9), showed a significant reduction in subcutaneous fat, with G9 having the greatest reduction. Thus, while lean tissue was unaffected by the treatments, the combination of semaglutide and Compound 10 showed the most significant reduction in total, visceral, and subcutaneous adipose tissue.

[0414] This study is repeated, but the GLP-1 receptor agonist is BLX-7006 rather than semaglutide, and Compound 10 is substituted with a compound of Formula (V), specifically V-l, V-2, V-5, V-8, V-10, V-l l, V-12, V-13, V-14, V-21, V22, V-24, V-29, V-30, V-41, V- 44, V-46, V-52, V-57, V-60, or V-66.Attorney Docket No. 63243-709.601Example 3: Safety Data

[0415] Compound 10 was administered to 36 patients in a Phase I study. No Serious Adverse Event (SAE) occurred. No Treatment Emergent Adverse Event (TEAE) occurred with a grade 3 or higher.

[0416] Compound 10 was administered to 41 patients in a Phase II study. No SAEs occurred. No TEAEs occurred with a grade 3 or higher.Example 4: Phase 2 Clinical Study Evaluating the Safety, Efficacy and Tolerability of Compound 10 and Semaglutide in Obese or Overweight Participants with Type 2 Diabetes Mellitus (T2DM)

[0417] Patients with T2DM will be eligible for inclusion if HbAlc levels are between 7.5 and 10.5% at screening, as this indicates poor glycemic control (high blood glucose levels) over the proceeding two to three months. Concomitant metformin therapy is permitted, as it is often used as baseline for patients with T2DM.

[0418] SynopsisAtorney Docket No. 63243-709.601Atorney Docket No. 63243-709.601Attorney Docket No. 63243-709.601

[0419] Following the signing of the informed consent form (ICF), potential study participants will be screened for eligibility. Screening is to occur over a period of up to 28 days, during which time a participant’s full medical history will be taken, comprehensive of medication use and prior weight loss strategies. Potential participants who are currently onAttorney Docket No. 63243-709.601 weight loss medication that is not semaglutide (Ozempic® 1 mg) or have had previous weight loss surgery will not be eligible to participate in the study. Participants on concomitant with metformin are not excluded. To confirm their eligibility, participants will undergo a complete physical examination, 12-lead ECG and clinical laboratory testing. Women of childbearing potential (WOCBP) will be requested to undergo a serum pregnancy test. Participants who are found not eligible on the basis of screening evaluations will be discontinued from the study.

[0420] All eligible participants will be randomized into one of the two treatment arms using a centralized block randomization schedule, generated using a computer-based program. The two treatment arms are as follows: Arm 1 : Compound 10 (2 mg) + semaglutide (Ozempic®, 1 mg); Arm 2: placebo + semaglutide (Ozempic®, 1 mg).

[0421] Both the drug and the placebo will be matched in appearance to ensure blinding. Neither the participants nor the Investigators will know the treatment allocation throughout the study (double-blind design).

[0422] Participants will be scheduled for their day 1 (visit 2) clinic visit to coincide with the day of their next semaglutide SC injection. All participants - irrespective of the treatment arm to which they are assigned - will continue to receive semaglutide 1 mg once a week for the duration of the treatment and follow-up phases of the study. Whilst in the study (from the signing of the informed consent form to the final follow up visit) the cost of each participant’s semaglutide will be reimbursed by the sponsor. During the day 1 clinic visit, participants will attend the clinic having fasted for approximately 8 hours. Blood collection will take place for clinical laboratory testing, and participants will receive their semaglutide injection, prior to the first dose of Compound 10 (2 mg) or placebo. They will be requested to remain in the clinic for at least 4 hours for the Investigator to document adequate tolerability. Whilst in the clinic, each participant will have sufficient medication dispensed (Compound 10 or placebo) to last until their next scheduled clinic visit and will receive comprehensive dosing instructions and training on how to use their study diary. Participants will be instructed to continue to use their regular semaglutide for the duration of the study. Daily Compound 10 or placebo and weekly semaglutide dosing will continue on an outpatient basis. For the days when semaglutide and Compound 10 or placebo are taken, participants will be instructed to take their semaglutide first. Participants will be requested to complete their study diary and record information, including, but not limited to, the timing of drug administration, use of concomitant medications, and any adverse events.

[0423] Participants will be assessed in the clinic every four weeks [day 29 (visit 3), dayAttorney Docket No. 63243-709.60157 (visit 4), and day 85 (visit 5) - all visits ± 3 days] for drug safety and tolerability. Fasted blood samples will be taken for clinical and safety laboratory assessments (as per the SoA) at each clinic visit. Unscheduled clinic visits may occur as needed for assessment per Investigator’s discretion. In addition, early study termination (ET) would warrant a clinic visit. Participants are also to be followed as needed for the resolution or stabilization of a clinically significant AE or laboratory abnormality, including after the last dose, consistent with the Investigator’s medical judgement. Upon completion of the study (ET or EOS), participants will continue to take semaglutide as per their usual healthcare plan.

[0424] The study population of the inclusion and exclusion criteria are provided below. Inclusion CriteriaParticipants are eligible to be included in the study only if all the following criteria apply:1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent.2. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.3. BMI between 27 kg / m2and 40 kg / m2.4. Stable body weight (± 5 kg) within 90 days of screening, and body weight <150 kg.5. HbAlc is 7.5-10.5% at screening.6. Established diagnosis of T2DM.7. Receiving a stable Img SC qlwk dose of semaglutide (Ozempic®) for > 90 days prior to signing informed consent.8. Females must meet one of the following:1. Postmenopausal (>45 years of age with amenorrhea for at least 12 months, without using exogenous hormonal contraception and with FSH > 40 IU / L).2. Surgically sterile (hysterectomy, bilateral salpingectomy; oophorectomy) for at least 6 months.3. Using a double contraception including a barrier method (condom, diaphragm, or occlusive cap) and a highly effective method of birth control, which includes the following: i. Established use (i.e. at least 90 days prior to signing of ICF) of combined (estrogen and progestogen) oral, intravaginal, or transdermal hormonal contraceptive associated with inhibition of ovulation ii. Established use (i.e. at least 90 days prior to signing of ICF) of progestogen-only oral, injectable, or implantable hormonalAttorney Docket No. 63243-709.601 contraceptive associated with inhibition of ovulation iii. Established use (i.e. at least 90 days prior to signing of ICF) of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) iv. Bilateral tubal occlusion completed at least 90 days prior to signing of ICF4. Vasectomized partner with the appropriate post-vasectomy documentation of the absence of spermatozoa in the ejaculate. Participant must provide documentation before the first dose of Compound 10 (study day 1).5. Sexual abstinence, when this is in line with the preferred and usual lifestyle of the participant9. Male participants who are sexually active with a woman of childbearing potential must agree to use a double contraception including a barrier method (male condom) and a highly effective method of contraception (highly effective methods of contraception are listed above) during the study and for 30 days after the last dose of Compound 10 / placebo.10. In the case of WOCBP, participants must have a negative serum pregnancy test (P- human chorionic gonadotropin [P-hCG]) at screening and negative urine pregnancy tests on first day of dosing and at each study visit.11. Able to comply with the study procedures in the view of the Investigator.Exclusion CriteriaParticipants are excluded from the study if any of the following criteria apply:1. Any prescription or over-the-counter medications intended for weight loss within 6 months of screening, excluding semaglutide.2. History of, or known hypersensitivity to, monoclonal antibody drugs or a contraindication to semaglutide (e.g., Ozempic® or Wegovy®)3. Use of other investigational drugs at the time of screening or within 30 days or 5 halflives prior to signing of the ICF, whichever is longer, or longer if required by local regulations4. Previous or current diagnosis of Type 1 diabetes mellitus (T 1DM) or current gestational diabetes.5. Diagnosis of T2DM requiring current use of insulin, repaglinide, saxagliptin, and sulfonylureas.Note. Use of Metformin for the purposes of glycemic control is not exclusionary.Attorney Docket No. 63243-709.6016. History of diabetic ketoacidosis (within 90 days of screening), or proliferative or severe retinopathy (i.e., retinopathy requiring acute treatment).7. Previous bariatric surgery, liposuction, or planned weight loss surgery.8. Current or past diagnosis of pancreatitis9. Current or past diagnosis of severe gastroparesis10. Personal or within first-degree relative family history of medullary thyroid cancer or multiple endocrine neoplasia type 211. Calcitonin >20 ng / L measured by central laboratory at screening (individuals with elevated calcitonin at initial screening may be re-screened)12. Presence of any of the following laboratory abnormalities at screening: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 3...

Claims

Attorney Docket No. 63243-709.601CLAIMSWHAT IS CLAIMED IS:

1. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (V) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Y is CHOH or NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;Attorney Docket No. 63243-709.601R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

2. The method of claim 1, wherein the compound of Formula (V), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction, inhibits the priming step of the NLRP3 inflammasome, and / or and inhibits the formation of NLRP3 (protein)-NEK7 (protein) interactions.

3. The method of claims 1 or 2, wherein the GLP-1 receptor agonist comprises semaglutide, exenatide, lixisenatide, albiglutide, beinaglutide, dulaglutide, efpeglenatide, liraglutide, polyethylene glycol loxenatide, taspoglutide, ecnoglutide, utreglutide, maridebart cafraglutide, tirzepatide, pegapamodutide, mazdutide, survodutide, bamadutide, pemvidutide, cotadutide, retatrutide, lithium chloride, efocipegtrutide, SAR441255, GZR18, BLX-7006, orforglipron, aleniglipron (GSBR-1290), amycretin, ECC5004, HS-10535, CT-966, VK2735, danuglipron, or a compound comprising a peptide at least 80% identical to the amino acid sequence of any one of SEQ ID NOS: 1-32.

4. The method of claim 3, wherein the GLP-1 receptor agonist comprises semaglutide or BLX-7006.

5. The method of any one of claims 1-4, wherein the GLP-1 receptor agonist is a single GLP-1 agonist, a GLP-l / glucagon receptor dual agonist, or a GLP-l / GIP / glucagon receptor triagonist.

6. The method of any one of claims 1-5, wherein the subject is overweight, and the overweight is a symptom of and / or associated with diabetes, hypothyroidism, metabolic syndrome, fatty liver disease, polycystic ovary syndrome, Cushing’s disease, or a combination thereof.

7. The method of any one of claims 1-6, wherein the subject has a body mass index (BMI) over 25, over 30, over 35, or over 40.

8. The method of any one of claims 1-7, wherein the compound of Formula (V), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered orally or subcutaneously.Attorney Docket No. 63243-709.6019. The method of any one of claims 1-8, wherein the GLP-1 receptor agonist, or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered orally or subcutaneously.

10. The method of any one of claims 1-9, wherein the method further comprises administering to the subject an anti-hyperglycemic agent.

11. The method of any one of claims 1-10, wherein the subject is presently taking, or has within the past 6 months taken, an anti-hyperglycemic agent.

12. The method of claim 10 or 11, wherein the anti-hyperglycemic agent is metformin, a sulfonylurea, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a thiazolidinedione. or a pharmaceutically acceptable salt or solvate thereof, optionally wherein the anti-hyperglycemic agent is metformin.

13. The method of any one of claims 1-12, wherein the method results in the treatment of diabetes, reduces blood glucose, reduces insulin resistance, reduces serum triglyceride levels, reduces adipose weight, improves lipid profile, reduces VLDL levels, increases HDL levels, reduces adipose tissue inflammation, or results in a combination of two or more thereof.

14. The method of any one of claims 1-13, wherein the method of treating results in the treatment of diabetes.

15. The method of claim 14, wherein the diabetes is comorbid with hypertension, dyslipidemia, chronic kidney disease, diabetic peripheral neuropathy, diabetic retinopathy, fatty liver disease, overweight, obesity, hypothyroidism, metabolic syndrome, polycystic ovary syndrome, Cushing’s disease, Prader-Willi syndrome, osteoarthritis, sleep apnea, hypertension, heart disease, stroke, gout, kidney disease, an eating disorder, or two or more thereof.

16. The method of any one of claims 1 to 15, wherein R1is H.

17. The method of claim any one of claims 1 to 16, wherein R4is H or Ci-Ce alkyl.

18. The method of claim any one of claims 1 to 17, wherein R4is H.

19. The method of any one of claims 1 to 18, wherein Y is NH.

20. The method of any one of claims 1 to 18, wherein Y is CHOH.

21. The method of any one of claims 1 to 20, wherein A is Ce-Cio aryl, optionally substituted with one or more R5.

22. The method of any one of claims 1 to 15, wherein the compound of Formula (V) is a compound of Formula (Va), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-709.601Formula (Va) wherein:X is N or CH;R2is Ci-Ce alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, Ci-Ce alkyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl; and n is 0 to 4.

23. The method of any one of claims 1 to 15 or 22, wherein each R5is independently selected from halo.

24. The method of claim 23, wherein each R5is fluoro.

25. The method of any one of claims 1 to 15, wherein the compound is a compound of Formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-709.601Formula (Vbl) wherein:R2is Ci-Ce alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3- Cs haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyl alkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; and each R5is F; and n is 0 or 1.

26. The method of any one of claims 1 to 25, wherein R2is branched C3-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

27. The method of any one of claims 1 to 26, wherein R2is:Attorney Docket No. 63243-709.60129. The method of any one of claims 1 to 28, wherein R3is oxazolyl, isoxazolyl, 1, 2, 3- oxadiazolyl, 1, 3, 4-oxadiazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4- thiadiazolyl or 1, 2, 4-triazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, Ci-Ce cyanoalkyl, cyano, Ci- Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

30. The method of any one of claims 1 to 29, wherein R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, Ci-Ce cyanoalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

31. The method of any one of claims 1 to 30, wherein R3is isoxazolyl optionally substituted with one more substituents selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, and Ci-Ce cyanoalkyl.

32. The method of any one of claims 1 to 30, wherein R3is 5-isoxazolyl optionally substituted with one more substituents selected from Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, and Ci-Ce cyanoalkyl.Attorney Docket No. 63243-709.60133. The method of any one of claims 1 to 30, wherein R3is 5-isoxazolyl optionally substituted with one more substituents selected from C3-C5 alkyl; C3-C5 haloalkyl; C3-C5 cycloalkyl optionally substituted with one or more substituents independently selected fromC1-C3 alkyl and C1-C3 haloalkyl; and C2-C4 cyanoalkyl.

34. The method of any one of claims 1 to 30, wherein R3is 5-isoxazolyl optionally substituted with one more substituents independently selected from C3-4 alkyl; C4 haloalkyl;C3 cycloalkyl substituted with one -CF3; C4 cycloalkyl substituted with one -CH3; and C3 alkyl substituted with one -CN.

35. The method of any one of claims 1 to 29, wherein R3is:Attorney Docket No. 63243-709.60137. The method of any one of claims 1 to 36, wherein n is 0.

38. The method of any one of claims 1 to 36, wherein n is 1.

39. The method of claim 11, wherein the compound or salt of Formula (V) is a compound listed in Table IE, or a pharmaceutically acceptable salt or solvate thereof.

40. The method of claim 1, wherein the compound of Formula (V) is V-l, V-2, V-5, V-8, V-10, V-l l, V-12, V-13, V-14, V-21, V-22, V-24, V-29, V-30, V-41, V44, V-46, V-52, V- 57, V-60, or V-66, or a pharmaceutically acceptable salt or solvate thereof.

41. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I) wherein:Attorney Docket No. 63243-709.601A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; and each R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

42. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-709.601Formula (II) wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

43. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-709.601Formula (III) wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;X is N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

44. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (IV)Attorney Docket No. 63243-709.601 wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; andR7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.

45. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Attorney Docket No. 63243-709.601Formula (VI) wherein:= represents a double or a single bond such that all valences are satisfied;A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;X is N or CR3;Y is C or N;W is CH orN;Z is CH orN;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

46. A method of treating overweight, treating obesity, weight management, treating diabetes, reducing blood glucose, reducing insulin resistance, reducing serum triglyceride levels, or reducing adipose weight, or a combination of two or more thereof, in a subject, the method comprising administering to the subject a glucagon-like peptide 1 (GLP-1) receptor agonist and a compound of Formula (0), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereofAttorney Docket No. 63243-709.601Formula (0) wherein: each = is independently a double or a single bond such that all valences are satisfied;A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X1is C or N;X2is C or N; wherein when X1is N, then X2is C; wherein when X2is N, then X1is C;X3is C(R2), N(R2), or N;X4is C(R3), N(R3), or N;X7is C or N;X8is C(R8) or N;wherein no more than five of X1, X2, X3, X4, X7, X8, X9, and X10are N;Y is NH;R1is H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: each of which is optionally substituted with one moreAttorney Docket No. 63243-709.601 substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci- Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof;R5is H; each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl, or;L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, Ci-Ce haloalkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, Ci-Ce haloalkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3- 6 cycloalkyl;R8is H, C1-6 alkoxy, C1-6 haloalkoxy, or halogen; andR10is H, C1-6 alkoxy, C1-6 haloalkoxy, or halogen.

47. The method of any one of claims 1-46, wherein: (a) prior to the administering, the subject has an HbAlc level between 7.5 and 10.5%, and / or after the administering the subject has a reduced HbAlc level, optionally wherein the reduction is at least a 1.5% reduction; (b) after the administering the subject has at least a 5% reduction in body weight, optionally wherein the at least 5% reduction in body weight is measured about 85 days after the administering commences; (c) after the administering the subject has a decrease in body fat, optionally wherein the decrease in body fat is measured about 85 days after the administering commences, further optionally wherein the body fat is measured using a DEXA scan; (d) after the administering the subject has a decrease in BMI (body mass index), optionally wherein the decrease in BMI is measured about 85 days after the administering commences; (e) after the administering the subject has a decrease in waist circumference, optionally wherein the decrease in waist circumferenceAttorney Docket No. 63243-709.601 is measured about 85 days after the administering commences; (f) after the administering the subject has a decrease in waist-to-hip ratio, optionally wherein the decrease in waist- to-hip ratio is measured about 85 days after the administering commences; or (g) any combination of two or more of (a) to (e).

48. The method of any one of claims 1-46, wherein: prior to the administering the subject: (a) is 18 to 65 years of age; (b) has a BMI of 27 kg / m2to 40 kg / m2; (c) has a body weight less than 150 kg; (d) has a HbAlC of 7.5% to 10.5%, (e) has type II diabetes, (f) does not have type I diabetes; (g) is not currently using insulin, repaglinide, saxagliptin, or a sulfonylurea; (h) does not have diabetic ketoacidosis within 90 days of the administering; (i) does not have pancreatitis; (j) does not have severe gastroparesis; (k) does not have medullary thyroid cancer or multiple endocrine neoplasia type 2; (1) has calcitonin > 20 ng / L; (m) does not have one or more of the following: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels3.0 x the upper limit of normal (ULN), absolute neutrophil count of < 1500 / mm3, absolute lymphocyte count of < 750 / mm3, absolute white blood cell (WBC) count of < 3000 / mm3, Hemoglobin < 9.0 g / dL, Thrombocytopenia, as defined by a platelet count < 100,000 / mm3, or total bilirubin ^ 1.5 x the ULN; (n) current or history of clinically significant liver or biliary disease or significantly abnormal liver function test (LFT); (o) current acute or chronic HCV and / or HBV infection; (p) current or history of clinically significant renal disease or eGFR<60mL / min / 1.73m2; (q) current or prior history of malignancy within the past 5 years except for cervical carcinoma in situ that has been completely resected with no evidence of recurrence or metastatic disease for at least 12 months or cured basal cell carcinoma with no evidence of recurrence for at least 12 months, (r) history of a major organ transplant (e.g. kidney, heart, liver, lung) or hematopoietic stem cell / bone marrow transplant, (s) history of lymphoproliferative disease or signs / symptoms suggestive of possible lymphoproliferative disease, including splenomegaly of lymphadenopathy, (t) history or current moderate to severe congestive heart failure (New York Heart Association class III or IV), or within the last 6 months, a cerebrovascular accident, myocardial infarction, unstable angina, unstable arrhythmia; (u) undergone any major surgery within 8 weeks prior to the administering; (v) inherited or acquired thrombophilia and / or current or history of thromboembolic events / disease; (w) screening 12-lead ECG that demonstrates relevant abnormalities that are clinically significant (e.g., QTc >450Attorney Docket No. 63243-709.601 msec or a QRS interval >120 msec); (x) pregnant or breast-feeding; (y) blood donation within a month of the administering; or (z) any combination of two or more of (a)-(y).

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