Combination therapies

Abstract

Described herein are methods of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I) and a second therapeutic agent comprising a GLP-1 receptor agonist, wherein the compound of Formula (I) has the structure; wherein R1, R2, R3, R4, R5, R6, R7, R8, and L are defined herein.

Description

COMBINATION THERAPIESCROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 657,691, filed on June 7, 2024, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

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

[0003] In one aspect, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof :Formula (I); wherein:L is -C(R9a)(R9b)-, -C(O)-, or -C(=N-OR16)-;R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. 10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orR1and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-memberedcycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3.6cycloalkyl optionally substituted with one, two, or three R14groups; or R6aand an R15are taken together to form a bridge that is -CH2- or -CH2CH2-;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-memberedheterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R9aand R% are each independently selected from hydrogen, halogen, -OH, C1-6alkyl, C1-6haloalky 1, and C1-6alkoxy; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-ealkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-gheteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, and Ci.gheteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.gheteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(0)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=0)(=NH)N(R10)(R11), -CH2C(0)N(R10)(R11), -CH2N(R12)C(O)Ri3, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(O)N(R10)(R11), -N(Ri2)C(0)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=0)(=NH)N(R10)(R11), -CH2C(0)N(R10)(R11), -CH2N(R12)C(O)Ri3, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one,two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or two R15are taken together to form a bridge that is -CH2- or -CH2CH2-;Ri6 is selected from hydrogen and C1-6alkyl; and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

[0004] In some embodiments of the methods described herein,embodiments of the methods described herein, R6ais C1-6alkyl optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R6ais unsubstituted C1-6alkyl. In some embodiments of the methods described herein, R6ais -CH3-

[0005] In some embodiments of the methods described herein, R6isembodiments of the methods described herein, n is 0.

[0006] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable

[0007] In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionallysubstituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, - OR10, and -N(R10)(R11). In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen and C1-6alkyl. In some embodiments of the methods described herein, R7and R8are hydrogen. In some embodiments of the methods described herein, R7is hydrogen and R8is - CH3. In some embodiments of the methods described herein, R7is -CH3and R8is hydrogen. In some embodiments of the methods described herein, R7and R8are -CH3.

[0008] In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6- membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three RI4groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted phenyl ring.

[0009] In some embodiments of the methods described herein, Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(0)OR10, or -C(0)N(R10)(R11). In some embodiments of the methods described herein, Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OH. In some embodiments of the methods described herein, Ri is -OH. In some embodiments of the methods described herein, R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R2is hydrogen. In some embodiments of the methods described herein, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R3is C1-6alkyl or C1-6haloalkyl. In some embodiments of the methods described herein, R4is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R4is hydrogen.

[0010] In some embodiments of the methods described herein, R5is hydrogen, halogen, C1-ealkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R5is hydrogen or C1-6alkyl. In some embodiments of the methods described herein, L is - C(R9a)(R9b)-. In some embodiments of the methods described herein, R9ais selected from hydrogen, halogen, and C1-6alkyl. In some embodiments of the methods described herein, R9ais hydrogen. In some embodiments of the methods described herein, R9bis selected from hydrogen, halogen, and -OH. In some embodiments of the methods described herein, R9bis -OH. In some embodiments of the methods described herein, L is -C(O)-.

[0011] In another aspect, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof :Formula (II); wherein:R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. waryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(0)N(R10)(R11), -N(Ri2)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orRi and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3- 6cycloalkyl optionally substituted with one, two, or three R14groups; or R6aand an R15are taken together to form a bridge that is -CH2- or -CH2CH2-;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(0)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(0)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)Ri3, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2. ealkenyl, C2-6alkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)Ri3, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or two R15are taken together to form a bridge that is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

[0012] In another aspect, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof :Formula (III); wherein:R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. 10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orR1and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three RI4groups; or R4and R5 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-memberedheterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R14groups;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6haloalky, l C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-loaryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalky C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)ORi3, -N(R12)S(O)2Ri3, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(0)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

[0013] In some embodiments of the methods described herein,In some embodiments of the methods described herein, R6ais C1-6alkyl optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R6ais unsubstituted C1-6alkyl. In some embodiments of the methods described herein, R6ais -CH3.

[0014] In some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein, n is 0.

[0015] In some embodiments of the methods described herein, R6is

[0016] In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.gheteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, - OR10, and -N(R10)(R11). In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen and C1-6alkyl. In some embodiments of the methods described herein, R7and R8are hydrogen. In some embodiments of the methods described herein, R7is hydrogen and R8is - CH3. In some embodiments of the methods described herein, R7is -CH3and R8is hydrogen. In some embodiments of the methods described herein, R7and R8are -CH3.

[0017] In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6- membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three Ru groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted phenyl ring.

[0018] In some embodiments of the methods described herein, Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, or -C(O)N(R10)(R11). In some embodiments of the methods described herein, Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OH. In some embodiments of the methods described herein, Ri is -OH. In some embodiments of the methods described herein, R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl,or -OR10. In some embodiments of the methods described herein, R2is hydrogen. In some embodiments of the methods described herein, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R3is C1-6alkyl or C1-6haloalkyl. In some embodiments of the methods described herein, R4is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R4is hydrogen.

[0019] In some embodiments of the methods described herein, R5is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R5is hydrogen or C1-6alkyl.

[0020] In some embodiments of the methods described herein, the first therapeutic agent comprising a compound of Formula (I) is 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol.

[0021] In some embodiments of the methods described herein, the second therapeutic agent is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments of the methods described herein, the second therapeutic agent is semaglutide.

[0022] In some embodiments of the methods described herein, the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout. In some embodiments, the metabolic disease is obesity.

[0023] In some embodiments of the methods described herein, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered simultaneously. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered sequentially . In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions.INCORPORATION BY REFERENCE

[0024] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE FIGURES

[0025] Figure 1A. Depicts body weight over 24 days in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0026] Figure IB. Depicts percentage body weight change over 24 days in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0027] Figure 1C. Depicts total body weight change from Day 1 to Day 24 in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0028] Figure ID. Depicts daily food intake from Day 1 to Day 24 in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0029] Figure IE. Depicts total food intake up to Day 24 in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0030] Figure IF. Depicts cumulative calorie intake up to Day 24 in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0031] Figure 2A. Depicts body weight across time of mice fed a regular or a HFD treated with or without Compound 20 (20 mg / kg, PO, BID).

[0032] Figure 2B. Depicts total calorie intake across time of mice fed a regular or a HFD treated with or without Compound 20 (20 mg / kg, PO, BID).

[0033] Figure 3A. Depicts relative fat mass expressed as percentage (%) of body weight in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0034] Figure 3B. Depicts fasting blood glucose levels in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0035] Figure 3C. Depicts HOMA-IR index in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0036] Figure 3D. Depicts HbAlc levels in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0037] Figure 3E. Depicts LDL cholesterol levels in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0038] Figure 3F. Depicts HDL cholesterol levels in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0039] Figure 3G. Depicts liver mass in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0040] Figure 3H. Depicts quantification of hepatic lipid accumulation using Oil Red O- positive staining in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0041] Figure 4A. Depicts plasma levels of pro -thrombotic marker PAI-1 in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0042] Figure 4B. Depicts plasma levels of pro-thrombotic marker fibrinogen in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0043] Figure 4C. Depicts circulating levels of suPAR in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0044] Figure 4D. Depicts circulating levels of sVCAM in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0045] Figure 4E. Depicts kidney injury marker of KIM-1 measured in plasma in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.

[0046] Figure 4F. Depicts kidney injury marker of Cys-C measured in plasma in mice fed a regular or a high fat diet (HFD) and treated with vehicle, Compound 20, semaglutide, or a combination of Compound 20 and semaglutide.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0047] In the context of this disclosure, a number of terms shall be utilized.

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the eventthat there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0049] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0050] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0051] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used.

[0052] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0053] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein andas such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0054] As used herein, C1-Cxincludes C1-C2, C1-C3. . . C1-Cx. C1-Cxrefers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

[0055] An “alkyl” group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. In some embodiments, the “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “ 1 to 6” refers to each integer in the given range; e.g. , “ 1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Ci-Cealkyl” or similar designations. By way of example only, “Ci- C6alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or un substituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0056] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.

[0057] The term “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon -carbon double bond. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, - CH=CHCH3, -CH=C(CH3)2and -C(CH3)=CHCH3. In some embodiments, an alkenyl groups may have 2 to 6 carbons. Alkenyl groups canbe substituted or un substituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0058] The term “alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon -carbon triple bond. Non-limiting examples of an alkynyl group include -C=CH, -C=CCH3, -C=CCH2CH3and -C=CCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0059] “ Amino” refers to a -NH2group.

[0060] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHygroup, where alkyl is as defined herein and x and y are selected from the group x=l, y=l andx=2, y=0. When x=2, thealkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2group, where alkyl is as defined herein.

[0061] The term “aromatic” refers to a planar ring having a delocalized 7i-electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0062] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0063] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,

[0064] The term “cycloalkyl” refers to a monocyclic or polycyclic non -aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0065] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0066] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0067] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0068] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non -limiting examples of haloalkyls include -CH2C1, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0069] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH2F, - OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like.

[0070] The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, - CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2- N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3and -CH2-O- Si(CH3)3. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

[0071] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[0072] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0073] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0074] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.

[0075] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di -substituted amino groups (e.g. -NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituents may be LSRS, wherein each Lsis independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, - C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(Ci-C6alkyl)-, or -(C2- C6alkenyl)-; and each Rsis independently selected from among H, (C1-C6alkyl), (C3- C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

[0076] As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0077] The term a “therapeutically effective amount” as used herein refers to the amount of a NLRP3 inhibitor that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent diseases or conditions described herein.

[0078] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0079] The term “modulate” encompasses either a decrease or an increase in activity or expression depending on the target molecule.

[0080] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

[0081] The term “subject”, “patient”, or “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0082] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.

[0083] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0084] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2 -dimethylaminoethanol, 2 -diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0085] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.NLRP3 inhibitor / GLP-1 agonist combinations

[0086] NLRP3 is an intracellular signaling molecule that senses many pathogen -derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). NLRP3 has been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

[0087] Glucogen-like peptide- 1 (GLP-1) is an important, gut-derived, incretin hormone; this glucose homeostasis regulator is released after the oral ingestion of carbohydrates or fats. GLP-1 receptor agonists bind to and activate the GLP-1 receptor, enhancing insulin secretion and slowing gastric emptying. Some GLP-1 receptor agonists are FDA-approved for weight loss and weight management in individuals with obesity, but there is a need for improved therapies.

[0088] The central nervous system (CNS) plays a major role in the regulation of metabolic balance and energy homeostasis. Activation of nonneuronal cells, such as microglia and astrocytes, has been demonstrated to be associated with excessive weight gain in animal models through impairment of the hypothalamic energy homeostasis system. This “reactive gliosis”response involves entry of saturated fatty acids into the cerebrospinal fluid through diet, which leads to inflammatory activation of hypothalamic microglia. This neuroinflammatory response is a potentially important aspect in the pathogenesis of diet-induced obesity. For the energy homeostasis system to function properly, key hypothalamic neurons provide “adiposity negative feedback” from signals such as insulin and leptin. Impaired neuronal responsiveness to these signals likely results in the obesogenic effect of hypothalamic gliosis.

[0089] One of the major pathways by which innate immune cells integrate pathogen- and dam age -as so dated signals with inflammation is via assembly and activation of intracellular protein complexes known as inflammasomes. Inflammasome activation is implicated in a range of inflammatory diseases.

[0090] Saturated fatty acids, present during obesity, are potential activators of the NLRP3 inflammasome. Chronic low-grade inflammation is observed in subjects with obesity, both peripherally in adipose tissues and centrally in the hypothalamus. Nonclinical research has demonstrated this relationship between NLRP3 and obesity, as Nlrp3 -knockout mice have been shown to be protected from diet-induced obesity. In addition, dosing with a selective NLRP3 inhibitors demonstrated reversal of diet-induced obesity (DIO) in mice. The effect of NLRP3 inhibition was associated with enhanced reductions in hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk compared to semaglutide treatment or calorie restriction. In the evaluation of these NLRP3 inhibitors, inflammatory responses played a key role in driving obesity, and NLRP3 activation in the brain was implicated in the pathogenesis of obesity.

[0091] NLRP3 inhibitors have also been shown in DIO models to work in combination with GLP-1 agonists, resulting in superior weight loss and improvement in a broad range of inflammatory and metabolic parameters or biomarkers, significantly greater than that observed with the GLP-1 agonist alone.

[0092] The compounds of Formula (I), (II), or (III) described herein are NLRP3 modulators. In some embodiments, compounds of Formula (I), (II), or (III) described herein, in combination with a GLP-1 receptor agonist described herein, are useful for the treatment of metabolic diseases including, but not limited to, type 2 diabetes, atherosclerosis, obesity, and gout.

[0093] In some embodiments, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof :wherein:L is -C(R9a)(R9b)-, -C(O)-, or -C(=N-OR16)-;R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(0)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(Ri2)C(O)R13, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orR1and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3.6cycloalkyl optionally substituted with one, two, or three R14groups; or R6aand an R15are taken together to form a bridge that is -CH2- or -CH2CH2-;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R9aand R9b are each independently selected from hydrogen, halogen, -OH, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(0)N(R10)(R11), -N R12C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(0)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=0)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(O)N(R10)(R11), -N(Ri2)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or two R15are taken together to form a bridge that is -CH2- or -CH2CH2-;Ri6 is selected from hydrogen and C1-6alkyl; and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist.

[0094] In some embodiments of the methods described herein, L is -C(R9a)(R9b)-. In some embodiments of the methods described herein, L is -C(R9a)(R9b)- and R9ais selected from hydrogen, halogen, and C1-6alkyl. In some embodiments of the methods described herein, L is - C(R9a)(R9b)- and R9b is selected from hydrogen, halogen, and -OH. In some embodiments of the methods described herein, L is -C(R9a)(R9b)- and R9b is selected from hydrogen, halogen, and - OH. In some embodiments of the methods described herein, L is -CH2-. In some embodiments of the methods described herein, L is -CH(OH)-. In some embodiments of the methods described herein, L is -CH(CH3)-. In some embodiments of the methods described herein, L is - C(OH)(CH3)-.

[0095] In some embodiments of the methods described herein, L is -C(O)-.

[0096] In some embodiments of the methods described herein, L is -C(=N-OR16)-. In some embodiments of the methods described herein, L is -C(=N-OH)-. In some embodiments of the methods described herein, L is -C(=N-OR16)- and Rig is C1-6alkyl.

[0097] In some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein,In some embodiments of the methods described herein, R6is. In some embodiments of the methods described herein,R6isIn some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein, R6is

[0098] In some embodiments of the methods described herein, R6ais C1-6alkyl optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R6ais unsubstituted C1-6alkyl. In some embodiments of the methods described herein, R6a is -CH3. In some embodiments of the methods described herein, R6ais -CH2CH3. In some embodiments of the methods described herein, R6ais hydrogen. In some embodiments of the methods described herein, n is 0.

[0099] In some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein, n is 0.

[0100] In some embodiments of the methods described herein, R6is selected fromembodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods describedherein,In some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein,some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein, R6

[0101] In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-ghaloalkyl, -OR10, and -N(R10)(R11). In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen and C1-6alkyl. In some embodiments of the methods described herein, R7and R8are hydrogen. In some embodiments of the methods described herein, R7and R8are Ci.galkyl. In some embodiments of the methods described herein, R7and R8are -CH3. In some embodiments of the methods described herein, R7is hydrogen and R8is -CH3. In some embodiments of the methods described herein, R7is -CH3and R8is hydrogen.

[0102] In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups. In some embodiments of themethods described herein, R7and R8are combined to form a phenyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted phenyl ring. In some embodiments of the methods described herein, R7and R8are combined to form a 5- or 6-membered heteroaryl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring. In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0103] In some embodiments of the methods described herein, Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(0)OR10, or -C(0)N(R10)(R11). In some embodiments of the methods described herein, R1is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OH. In some embodiments of the methods described herein, R1is -OR10. In some embodiments of the methods described herein, R1is -OH. In some embodiments of the methods described herein, R1is hydrogen. In some embodiments of the methods described herein, Ri is halogen. In some embodiments of the methods described herein, Ri is C1-6alkyl. In some embodiments of the methods described herein, R1is -CH3. In some embodiments of the methods described herein, R1is C1-6haloalkyl. In some embodiments of the methods described herein, Ri is -CF3.

[0104] In some embodiments of the methods described herein, R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R2is hydrogen. In some embodiments of the methods described herein, R2is halogen. In some embodiments of the methods described herein, R2is C1-6alkyl. In some embodiments of the methods described herein, R2is -CH3. In some embodiments of the methods described herein, R2is C1-6haloalkyl. In some embodiments of the methods described herein, R2is -CF3. In some embodiments of the methods described herein, R2is -OR10. In some embodiments of the methods described herein, R2is -OH.

[0105] In some embodiments of the methods described herein, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R3is C1-6alkyl or C1-6haloalkyl. In some embodiments of the methods described herein,R3is C1-6alkyl. In some embodiments of the methods described herein, R3is -CH3. In some embodiments of the methods described herein, R3is C1-6haloalkyl. In some embodiments of the methods described herein, R3is -CF3. In some embodiments of the methods described herein, R3is hydrogen. In some embodiments of the methods described herein, R3is halogen. In some embodiments of the methods described herein, R3is -OR10. In some embodiments of the methods described herein, R3is -OH. In some embodiments of the methods described herein, R3is -N(R10)(R11).

[0106] In some embodiments of the methods described herein, R4is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R4is hydrogen. In some embodiments of the methods described herein, R4 is halogen. In some embodiments of the methods described herein, R4is C1-6alkyl. In some embodiments of the methods described herein, R4is -CH3. In some embodiments of the methods described herein, Rj is C1-6haloalkyl. In some embodiments of the methods described herein, R4is -CF3. In some embodiments of the methods described herein, R4is -OR10. In some embodiments of the methods described herein, R4is -OH.

[0107] In some embodiments of the methods described herein, R5is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R5is hydrogen or C1-6alkyl. In some embodiments of the methods described herein, R5is hydrogen. In some embodiments of the methods described herein, R5is C1-6alkyl. In some embodiments of the methods described herein, R5is -CH3. In some embodiments of the methods described herein, R5is halogen. In some embodiments of the methods described herein, R5is C1-6haloalkyl. In some embodiments of the methods described herein, R5is -CF3. In some embodiments of the methods described herein, R5is -OR10. In some embodiments of the methods described herein, R5is -OH. In some embodiments of the methods described herein, R5is -N(R10)(R11).

[0108] In some embodiments, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein:R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. 10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orRi and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3.6cycloalkyl optionally substituted with one, two, or three R14groups; or R6aand an Ri5are taken together to form a bridge that is -CH2- or -CH2CH2-;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyn C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(0)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one,two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15 is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- galkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(Ri2)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(0)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or two R15are taken together to form a bridge that is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist.

[0109] In some embodiments of the methods described herein,some embodiments of the methods described herein,embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods describedIn some embodiments of the methods described herein, R6is

[0110] In some embodiments of the methods described herein, R6ais C1-6alkyl optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, Reais unsubstituted C1-6alkyl. In some embodiments of the methods described herein, R6ais -CH3. In some embodiments of the methods described herein, Rea is -CH2CH3. In some embodiments of the methods described herein, R6ais hydrogen. In some embodiments of the methods described herein, n is 0.

[0111] In some embodiments of the methods described herein,some embodiments of the methods described herein, n is 0.

[0112] In some embodiments of the methods described herein, Re is selected fromembodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methodsdescribed herein,In some embodiments of the methods described herein, In some embodiments of the methods described herein,In some embodiments of the methods described herein, In some embodimentsof the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein, R6isIn some embodiments of the methods described herein,some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein,In some embodiments of the methods described herein, R6In some embodiments of the methods described herein,

[0113] In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2.galkenyl, C2.galkynyl, C3.gcycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl areoptionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments of the methods described herein, R7and R6are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein, R7and Rg are each independently selected from hydrogen and C1-6alkyl. In some embodiments of the methods described herein, R7and Rg are hydrogen. In some embodiments of the methods described herein, R7and Rg are C1-6alkyl. In some embodiments of the methods described herein, R7and Rg are -CH3. In some embodiments of the methods described herein, R7is hydrogen and Rg is -CH3. In some embodiments of the methods described herein, R7is -CH3and Rg is hydrogen.

[0114] In some embodiments of the methods described herein, R7and Rg are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and Rg are combined to form a phenyl ring optionally substituted with one, two, or three RI4groups. In some embodiments of the methods described herein, R7and Rg are combined to form an unsubstituted phenyl ring. In some embodiments of the methods described herein, R7and Rg are combined to form a 5- or 6-membered heteroaryl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and Rg are combined to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments of the methods described herein, R7and Rg are combined to form a 4-, 5-, or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and Rg are combined to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring. In some embodiments of the methods described herein, R7and Rg are combined to form a 4-, 5-, or 6-membered cycloalkyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and Rg are combined to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0115] In some embodiments of the methods described herein, R1is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, or -C(O)N(R10)(R11). In some embodiments of the methods described herein, Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OH. In some embodiments of the methods described herein, R1is -OR10. In some embodiments of the methods described herein, R1is -OH. In some embodiments of the methods described herein, Ri is hydrogen. In some embodiments of the methods described herein, Ri is halogen. In some embodiments of the methods described herein, R1is C1-6alkyl. In someembodiments of the methods described herein, R1is -CH3. In some embodiments of the methods described herein, Ri is C1-6haloalkyl. In some embodiments of the methods described herein, Ri is -CF3.

[0116] In some embodiments of the methods described herein, R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R2is hydrogen. In some embodiments of the methods described herein, R2is halogen. In some embodiments of the methods described herein, R2is C1-6alkyl. In some embodiments of the methods described herein, R2is -CH3. In some embodiments of the methods described herein, R2is C1-6haloalkyl. In some embodiments of the methods described herein, R2is -CF3. In some embodiments of the methods described herein, R2is -ORw In some embodiments of the methods described herein, R2is -OH.

[0117] In some embodiments of the methods described herein, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R3is C1-6alkyl or C1-6haloalkyl. In some embodiments of the methods described herein, R3is C1-6alkyl. In some embodiments of the methods described herein, R3is -CH3. In some embodiments of the methods described herein, R3is C1-6haloalkyl. In some embodiments of the methods described herein, R3is -CF3. In some embodiments of the methods described herein, R3is hydrogen. In some embodiments of the methods described herein, R3is halogen. In some embodiments of the methods described herein, R3is -OR10. In some embodiments of the methods described herein, R3is -OH. In some embodiments of the methods described herein, R3is -N(R10)(R11).

[0118] In some embodiments of the methods described herein, R4is hydrogen, halogen, C1-ealkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R4is hydrogen. In some embodiments of the methods described herein, R4 is halogen. In some embodiments of the methods described herein, R4is C1-6alkyl. In some embodiments of the methods described herein, R4is -CH3. In some embodiments of the methods described herein, R4is C1-6haloalkyl. In some embodiments of the methods described herein, R4is -CF3. In some embodiments of the methods described herein, R4is -OR10In some embodiments of the methods described herein, R4is -OH.

[0119] In some embodiments of the methods described herein, R5is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -ORw, or -N(Rw)(R11). In some embodiments of the methods described herein, R5is hydrogen or C1-6alkyl. In some embodiments of the methods described herein, R5is hydrogen. In some embodiments of the methods described herein, R5is C1-6alkyl. In some embodiments of the methods described herein, R5is -CH3. In some embodiments of the methods described herein, R5is halogen. In some embodiments of the methods described herein, R5is C1-6haloalkyl. In some embodiments of the methods described herein, R5is -CF3. In some embodiments of the methods described herein, R5is -OR10. In some embodiments of the methods described herein, R5is -OH. In some embodiments of the methods described herein, R5is -N(R10)(R11).

[0120] In some embodiments, provided herein is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof :Formula (III); wherein:Ri, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, Ce- 10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2- ealkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orR1and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R14groups;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionallysubstituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci.gheteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(0)N(R10)(R11), - C(0)C(0)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

[0121] In some embodiments of the methods described herein,In some embodiments of the methods described herein, R6ais Ci.galkyl optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R6ais unsubstituted C1-6alkyl. In some embodiments of the methods described herein, R6ais -CH3. In some embodiments of the methods described herein, R6ais -CH2CH3. In some embodiments of the methods described herein, R6ais hydrogen. In some embodiments of the methods described herein, n is 0.

[0122] In some embodiments of the methods described herein,some embodiments of the methods described herein, n is 0.

[0123] In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11). In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein, R7and R8are each independently selected from hydrogen and C1-6alkyl. In some embodiments of the methods described herein, R7and R8are hydrogen. In some embodiments of the methods described herein, R7and R8are C1-6alkyl. In some embodiments of the methods described herein, R7and R8are -CH3. In some embodiments of the methods described herein, R7is hydrogen and Rs is -CH3. In some embodiments of the methods described herein, R7is -CH3and R8is hydrogen.

[0124] In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three RI4groups. In some embodiments of the methods described herein, R7and R8are combined to form a phenyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted phenyl ring. In some embodiments of the methods described herein, R7and R8are combined to form a 5- or 6-membered heteroaryl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methods described herein, R7and R8are combined to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring. In some embodiments of the methods described herein, R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring optionally substituted with one, two, or three R14groups. In some embodiments of the methodsdescribed herein, R7and R8are combined to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0125] In some embodiments of the methods described herein, R1is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(0)OR10, or -C(0)N(R10)(R11). In some embodiments of the methods described herein, R1is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OH. In some embodiments of the methods described herein, R1is -OR10In some embodiments of the methods described herein, R1is -OH. In some embodiments of the methods described herein, R1is hydrogen. In some embodiments of the methods described herein, Ri is halogen. In some embodiments of the methods described herein, Ri is C1-6alkyl. In some embodiments of the methods described herein, R1is -CH3. In some embodiments of the methods described herein, R1is C1-6haloalkyl. In some embodiments of the methods described herein, Ri is -CF3.

[0126] In some embodiments of the methods described herein, R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10. In some embodiments of the methods described herein, R2is hydrogen. In some embodiments of the methods described herein, R2is halogen. In some embodiments of the methods described herein, R2is C1-6alkyl. In some embodiments of the methods described herein, R2is -CH3. In some embodiments of the methods described herein, R2is Ci-6haloalkyl. In some embodiments of the methods described herein, R2is -CF3. In some embodiments of the methods described herein, R2is -OR10. In some embodiments of the methods described herein, R2is -OH.

[0127] In some embodiments of the methods described herein, R3is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R3is C1-6alkyl or C1-6haloalkyl. In some embodiments of the methods described herein, R3is C1-6alkyl. In some embodiments of the methods described herein, R3is -CH3. In some embodiments of the methods described herein, R3is C1-6haloalkyl. In some embodiments of the methods described herein, R3is -CF3. In some embodiments of the methods described herein, R3is hydrogen. In some embodiments of the methods described herein, R3is halogen. In some embodiments of the methods described herein, R3is -OR10. In some embodiments of the methods described herein, R3is -OH. In some embodiments of the methods described herein, R3is -N(R10)(R11).

[0128] In some embodiments of the methods described herein, R4is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10- In some embodiments of the methods described herein, R4is hydrogen. In some embodiments of the methods described herein, R4is halogen. In some embodiments of the methods described herein, R4is C1-6alkyl. In some embodiments of the methods described herein, R4is -CH3. In some embodiments of the methods described herein, R4is C1-6haloalkyl. In some embodiments of the methods described herein, R4is -CF3. In some embodiments of the methods described herein, R4is -OR10. In some embodiments of the methods described herein, R4is -OH.

[0129] In some embodiments of the methods described herein, R5is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, or -N(R10)(R11). In some embodiments of the methods described herein, R5is hydrogen or C1-6alkyl. In some embodiments of the methods described herein, R5is hydrogen. In some embodiments of the methods described herein, R5is C1-6alkyl. In some embodiments of the methods described herein, R5is -CH3. In some embodiments of the methods described herein, R5is halogen. In some embodiments of the methods described herein, R5is C1-6haloalkyl. In some embodiments of the methods described herein, R5is -CF3. In some embodiments of the methods described herein, R5is -OR10. In some embodiments of the methods described herein, R5is -OH. In some embodiments of the methods described herein, R5is -N(R10)(R11).

[0130] In some embodiments of the methods described herein, the compound of Formula (I), (II), or (III) is selected from:or a pharmaceutically acceptable salt or solvate thereof.

[0131] In some embodiments of the methods described herein, the compound of Formula (I),(II), or (III) is:or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments of the methods described herein, the compound of Formula (I),(II), or (III) is selected from:

[0133] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.

[0134] In some embodiments, the therapeutic agent(s) (e.g. compound of Formula (I), (II), or (III)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. Insome embodiments, any compound described above is suitable for any method or composition described herein.Further Forms of Compounds Disclosed HereinIsomers

[0135] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.Labeled compounds

[0136] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically -labeled compounds,which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically -labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i. e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e ,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

[0137] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0138] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0139] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.Solvates

[0140] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further describedherein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0141] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Synthesis of Compounds

[0142] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[0143] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

[0144] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1 -17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1 -5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1 -40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein.Use of Protecting Groups

[0145] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0146] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and maybe used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0147] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidativelyremovable protective groups such as 2,4 -dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0148] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi -acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

[0149] Typically blocking / protecting groups may be selected from:

[0150] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).Methods of Treatment and Prevention

[0151] In some embodiments is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), ora pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating atherosclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating obesity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating gout in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compoundof Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, andalbiglutide. In some embodiments, Glucagon- like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide- 1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP- 1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide.

[0153] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments, Glucagon- like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide- 1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP- 1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide.

[0154] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments, Glucagon- like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide- 1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP- 1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide.

[0155] In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments is a method of treating type 2 diabetes in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating atherosclerosis in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating obesity in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments is a method of treating gout in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide. In some embodiments, Glucagon- like peptide-1 (GLP-1) receptor agonist is semaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is dulaglutide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is liraglutide. In some embodiments, Glucagon-like peptide- 1 (GLP-1) receptor agonist is exenatide. In some embodiments, Glucagon-like peptide-1 (GLP- 1) receptor agonist is tirzepatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is lixisenatide. In some embodiments, Glucagon-like peptide-1 (GLP-1) receptor agonist is albiglutide.Pharmaceutical compositions and methods of administration

[0156] NLRP3 inhibitors (compounds of Formula (I), (II), or (III)) described herein and GLP- 1 receptor agonists described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent metabolic diseases, disorders or conditions.

[0157] In certain embodiments, the NLRP3 inhibitors and GLP-1 receptor agonists described herein are administered as a pure chemical. In other embodiments, the NLRP3 inhibitors and GLP-1 receptor agonists described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0158] In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are formulated in a single pharmaceutical composition. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are formulated in separate pharmaceutical compositions. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are administered simultaneously. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are administered simultaneously in a single pharmaceutical composition. In some embodiments, the NLRP3 inhibitor and GLP-1 receptor agonist described herein are administered simultaneously in separate pharmaceutical compositions. In some embodiments, the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered sequentially.

[0159] Accordingly, in some embodiments provided herein is a pharmaceutical composition comprising a NLRP3 inhibitor described herein, ora pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. In some embodiments provided herein is a pharmaceutical composition comprising a GLP-1 receptor agonist described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. In some embodiments provided herein is a pharmaceutical composition comprising a NLRP3 inhibitor and a GLP-1 receptor agonist described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers. As described herein, the carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[0160] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.

[0161] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient(s) is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0162] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0163] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solidcompositions of a similar type are also employed as fillers in soft and hard -filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0164] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0165] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0166] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically -acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutionsor dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacterio stats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0167] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants .

[0168] The dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[0169] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type andseverity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0170] Oral doses typically range from about 1 .0 mg to about 1000 mg, one to four times, or more, per day.

[0171] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0172] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the NLRP3 inhibitor and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximatebody weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration .EXAMPLES

[0173] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compoundsdescribed herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.Example 1: Compound Synthesis

[0174] Compounds 1-53 were prepared as described in US 2023 / 0295113, which is herein incorporated by reference in its entirety.Example 2: Human Monocyte IL-lb Assay

[0175] Serially diluted testing compounds were incubated with 200 mL of fresh human whole blood for0.5 hours. Cells were primed with 100 ng / mL lipopolysaccharide (LPS) for 3.5 hours at 37°C followed by stimulation with 5 mM ATP for an additional 45 minutes. The concentration of IL-lb concentration in the supernatant was determined with commercially available ELISA kits. Negative controls are wells without stimulation, while positive controls are wells with stimulation but only DMSO without compounds added. After background subtraction, compound treatment wells were then normalized to the positive controls for IC50calculations.

[0176] IC50 values are shown in the table below.A: IC50 < 500 nM; B: 500 nM < IC50 < 3 pM; C: 3 pM < IC50 < 10 pMExample 3: Effect of an NLRP3 Inhibitor and Semaglutide Combination Treatment on Body Weight, Glucose and Lipid metabolism, and Liver Steatosis in Diet-Induced Obesity (DIO) Mice

[0177] Male C57BL / 6J mice were purchased from GemPharmatech Co., Ltd or from Cyagen Laboratory. All euthanasia was performed using carbon dioxide inhalation and all efforts were made to minimize animal suffering. Animals were group -housed (4 animals per cage) with bedding under controlled temperature (20-25°C), noise, humidity (40%-70%), and lighting (12- hour light and 12-hour dark) conditions. All animals had free access to purified water and standard certified rodent chow. C57BL / 6J mice were fed with standard chow diet (SCD) till week 5, then the diet was switched to HFD for an additional 15 weeks (D12492, Rodent Diet with 60 kcal% Fat, Research diet) before the experimental start of the study. The animals were regrouped based on body weight and plasma high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG) levels before initiation of test compound treatment. Mice on regular diet were not treated. DIO mice were treated for 28 days via oral gavage with vehicle, or 20 mg / kg of Compound 20 twice per day (12-hour interval), or via subcutaneous injection with 10 pg / kg semaglutide once per day, or via a combination of 20 mg / kg of Compound 20 twice per day (12-hour interval) and subcutaneous injection with 10.g / kg semaglutide once per day. The general condition (appearance and activity) of all animals was carefully monitored daily by the veterinarian. Food intake was measured daily until day 24. All animals were group housed, and food intake was measured by group (cage). At 8:00 am every day (the beginning of light cycle; lights on), food pellets were weighed and provided to the animals in the cage ad libitum. At 8:00 am on the following day (the beginning of light cycle; lights on), the remaining food pellets were weighed again, and the total food consumption by the group of animals in 24 hours was calculated. The final results were expressed as average food consumption per mouse (e.g., total food consumption / number of animals in the cage). Body weight was measured daily after food intake measurement. Animals were fasted overnight between day 24 and day 25 for fasting blood glucose (Accu-Chek glucometer, Roche Diagnostics) and insulin levels (MSD Mouse / Rat Insulin Kit, MesoScaleDiscovery, Cat# K152BZC). HOMA-IR was defined as fasting blood glucose (mmol / L) x fasting insulin (pU / mL) / 22.5. HbAlc was measured with the blood from tail vein by Siemens DCA Vantage analyzer. At the end of the study on day 28, blood was collected into tubes pre -coated with EDTA-K2 for plasma preparation by centrifugation (4000 rpm, 10 minutes, 4°C) before the animals were euthanized using CO2. Tissues were then collected after perfusion with saline and their weight recorded.

[0178] When compared to the vehicle control group, Compound 20, semaglutide, and the combination of Compound 20 and semaglutide at their respective maximally efficacious doses reduced the body weights of DIO mice (Figures 1A and IB). Moreover, the decrease in body weight was significantly higher when semaglutide was combined with Compound 20 compared to semaglutide alone, suggesting that Compound 20 impacts body weight through a different mechanism(s) than semaglutide. After 20 days of treatment, the Compound 20-treated group showed gradual weight regain that paralleled, but did not converge, with that of the vehicle-treated DIO control mice. Convergence is typically observed following cessation of appetite-suppressing therapies due to increased food intake and weight regain, and the lack of convergence with Compound 20 suggests that it continued to mitigate compensatory hyperphagia. During periods of weight loss or weight stability, both the semaglutide- and Compound 20-treated groups showed significantly reduced food intake compared to the vehicle-treated group. Overtime, food intake began to approach levels observed in the vehicle - treated group (Figure ID). However, at the end of the study, all DIO mice treated with Compound 20, semaglutide, or a combination of Compound 20 and semaglutide, demonstrated significantly less total food intake (Figure IE) and total calorie intake (Figure IF). Moreover, total food intake and total calorie intake were significantly lower when semaglutide was combined with Compound 20 compared to either Compound 20 or semaglutide monotherapy(Figures IE and IF). Importantly, treatment of lean mice with Compound 20 had no significant impact on body weight nor food intake, indicating thatNLRP3 inhibition exerts its effects specifically in the context of obesity (Figures 2A and 2B).

[0179] The reduction in body weight observed in DIO mice treated with either Compound 20, semaglutide or the combination coincides with reduced relative fat mass (Figure 3A). Obesity is often linked with several comorbidities like T2D, MASLD, CVD, and nephropathy. These comorbidities are also observed in mice that are fed an HFD. Indeed, the DIO mice in this study were more resistant to insulin compared to lean mice, as evidenced by the high blood glucose levels after fasting (Figure 3B), the increased homeostatic model assessment for insulin resistance (HOMA-IR) (Figure 3C) and the hemoglobin Ale (HbAlc) levels (Figure 3D). Moreover, lipid metabolism was impaired with increased cholesterol levels in plasma (Figures 3E and 3F), increased relative liver weight (Figure 3G) and liver lipid deposition (oil red O staining) indicating steatosis in the DIO mice (Figure 3H). The cardiovascular disease (CVD) markers plasminogen activator inhibitor- 1 (PAI-1), fibrinogen, soluble urokinase plasminogen activator receptor (suP AR) and soluble vascular cell adhesion molecule-1 (sVCAM-1), and the kidney dysfunction markers kidney injury marker-1 (KIM-1) and cystatin-C (Cys-C), were also increased in DIO mice. Importantly, Compound 20 treatment reduced all observed obesity- associated comorbidities in the DIO mice and further enhanced many of these effects when combined with semaglutide (Figures 4A-4F).

[0180] In summary, these results showcase the therapeutic potential of an NLRP3 inhibitor when combined with the approved anti-obesity drug, semaglutide. By attenuating NLRP3 -driven inflammation, Compound 20 not only mitigates obesity -associated comorbidities but also appears to restore sensitivity to satiety signals, leading to reduced food intake and body weight, and potentially disrupting the obesity -associated feedforward loop.Example 4: Phase II Study to Evaluate Weight Loss in Participants Receiving NLRP3 Inhibitor and GLP-1 Receptor Agonist Combination

[0181] A first-in-human (FIH) study is designed to show if a combination of an NLRP3 inhibitor (compound of Formula (I), (II), or (III)) and a GLP-1 receptor agonist has the greatest weight decreasing effect in comparison to each compound alone and to group with no treatment. Study Design

[0182] The study is designed as follows:Participants

[0183] Approximately 200 adults 35-55 years old will be enrolled and treated in the Dose Escalation phase and Dose Expansion phase, including approximately 38 R / R AML participants planned to be enrolled and treated in the Dose Expansion phase.Dosing

[0184] Drug will be dosed daily for 6 months.Criteria

[0185] Inclusion Criteria:• Stable weight in the previous 6 months• A sedentary lifestyle• No history of diabetes mellitus• Taking medication that affects appetite, or weight within the past 6 months

[0186] Exclusion Criteria:• Severe anemia• Hypothyroidism and hyperthyroidism• Diabetes mellitus• Moderate to severe liver or kidney disease• Body mass index less than 30Primary Outcome

[0187] Weight of each participant will be measured every week for the 6-month duration of the study. Results from each cohort will be compared.

[0188] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

CLAIMSWHAT IS CLAIMED IS:1 . A method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein:L is -C(R9a)(R9b)-, -C(O)-, or -C(=N-OR16)-;R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orR1and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;Rea is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3. 6cycloalkyl optionally substituted with one, two, or three R14groups; or R6aand an R15are taken together to form a bridge that is -CH2- or -CH2CH2-;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R9aand R9b are each independently selected from hydrogen, halogen, -OH, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-ealkyl, C2-6alkenyl, C2-6alkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6. 10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2. ealkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(OOC(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(0)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or two R15are taken together to form a bridge that is -CH2- or -CH2CH2-;R16is selected from hydrogen and C1-6alkyl; and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

2. The method of claim 1, wherein3. The method of claim 1 or claim 2, wherein Reais C1-6alkyl optionally substituted with one, two, or three R14groups.

4. The method of any one of claims 1 -3, wherein R6ais unsubstituted C1-6alkyl.

5. The method of any one of claims 1 -4, wherein R6ais -CH3.

6. The method of claim 1 , wherein7. The method of any one of claims 1 -6, wherein n is 0.

8. The method of claim 1, wherein R6is selected from:

9. The method of any one of claims 1-8, wherein R7and Rs are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2.6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9hetero aryl are optionally substituted with one, two, orthree groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11).

10. The method of any one of claims 1-9, wherein R7and Rs are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl.

11. The method of any one of claims 1-10, wherein R7and R8are each independently selected from hydrogen and C1-6alkyl.

12. The method of any one of claims 1 -11, wherein R7and R8are hydrogen.

13. The method of any one of claims 1 -11, wherein R7is hydrogen and R8is -CH3.

14. The method of any one of claims 1 -11, wherein R7is -CH3and R8is hydrogen.

15. The method of any one of claims 1 -11, wherein R7and R8are -CH3.

16. The method of any one of claims 1-8, wherein R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6- membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups.

17. The method of claim 16, wherein R7and R8are combined to form an unsubstituted phenyl ring.

18. The method of any one of claims 1-17, wherein Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, or -C(O)N(R10)(R11).

19. The method of any one of claims 1-18, wherein Ri is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OH.

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

21. The method of any one of claims 1-20, wherein R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10.

22. The method of any one of claims 1-21, wherein R2is hydrogen.

23. The method of any one of claims 1-22, wherein R3 is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, -OR10, or -N(R10)(R11).

24. The method of any one of claims 1-23, wherein R3is C1-6alkyl or C1-6haloalkyl.

25. The method of any one of claims 1-24, wherein R4is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10.

26. The method of any one of claims 1-25, wherein R4is hydrogen.

27. The method of any one of claims 1-26, wherein R5is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, -OR10, or -N(R10)(R11).

28. The method of any one of claims 1-27, wherein R5is hydrogen or C1-6alkyl.

29. The method of any one of claims 1-28, wherein L is -C(R9a)(R9b)-.

30. The method of claim 29, wherein R9ais selected from hydrogen, halogen, and C1-6alkyl.

31. The method of claim 30, wherein Rgais hydrogen.

32. The method of any one of claims 29-31, wherein R9b is selected from hydrogen, halogen, and -OH.

33. The method of claim 32, wherein Rgbis -OH.

34. The method of any one of claims 1-28, wherein L is -C(O)-.

35. A method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein:R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. 10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2- -alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orR1and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl optionally substituted with one, two, or three R14groups; or R6aand an R15are taken together to form a bridge that is -CH2- or -CH2CH2-;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-ehaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6. 10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10,-N(R10)(R11), -C(O)OR10, -OC(0)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(Ri2)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(0)C(0)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(0)2N(R10)(R11)-, S(=0)(=NH)N(R10)(R11), -CH2C(0)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2. 6alkenyl, C2-6alkynyl, C3-ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci.gheteroaryl, - OR10, -SR10, -N(R10)(R11), -C(0)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); or two R15are taken together to form a bridge that is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

36. A method of treating a metabolic disease in a subject in need thereof, comprising administering to the subject a first therapeutic agent comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III); wherein:R1, R2, R3, R4, and R5are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-ecycloalkyl, C2-9heterocycloalkyl, Ce- aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(0)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, S(=0O(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); orRi and R2are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R2and R3are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-,5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; orR3and R4are combined to form a 4-, 5- , or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; or R4and R5are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups;R6ais selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R14groups;R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); or R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Cl.gheteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R14is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(0)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); each R15 is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci.gheteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N)R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl,C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and - N(R10)(R11); and n is 0, 1, 2, 3, or 4; and a therapeutically effective amount of a second therapeutic agent comprising a Glucagon -like peptide- 1 (GLP-1) receptor agonist.

37. The method of claim 35 or claim 36, wherein38. The method of any one of claims 35-37, wherein Rea is C1-6alkyl optionally substituted with one, two, or three R14groups.

39. The method of any one of claims 35-38, wherein Rea is unsubstituted C1-6alkyl.

40. The method of any one of claims 35-39, wherein Rea is -CH3.

41. The method of claim 35 or claim 36, wherein42. The method of any one of claims 35-41, wherein n is 0.

43. The method of claim 35, wherein Rea is selected from:

44. The method of any one of claims 35-43, wherein R7and R8are each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2. ealkenyl, C2-6alkynyl, C3.ecycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9hetero aryl are optionally substituted with one, two, orthree groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11).

45. The method of any one of claims 35-44, wherein R7and R8are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl.

46. The method of any one of claims 35-45, wherein R7and R8are each independently selected from hydrogen and C1-6alkyl.

47. The method of any one of claims 35-46, wherein R7and R8are hydrogen.

48. The method of any one of claims 35-46, wherein R7is hydrogen and R8is -CH3.

49. The method of any one of claims 35-46, wherein R7is -CH3and R8is hydrogen.

50. The method of any one of claims 35-46, wherein R7and R8are -CH3.

51. The method of any one of claims 35-43, wherein R7and R8are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6- membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14groups.

52. The method of claim 51, wherein R7and R8are combined to form an unsubstituted phenyl ring.

53. The method of any one of claims 35-52, wherein Ri is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, or -C(O)N(R10)(R11).

54. The method of any one of claims 35-53, wherein Ri is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, or -OH.

55. The method of any one of claims 35-54, wherein Ri is -OH.

56. The method of any one of claims 35-55, wherein R2is hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, or -OR10.

57. The method of any one of claims 35-56, wherein R2is hydrogen.

58. The method of any one of claims 35-57, wherein R3is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, -OR10, or -N(R10)(R11).

59. The method of any one of claims 35-58, wherein R3is C1-6alkyl or C1-6haloalkyl.

60. The method of any one of claims 35-59, wherein R4is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, or -OR10.

61. The method of any one of claims 35-60, wherein R4is hydrogen.

62. The method of any one of claims 35-61, wherein R5is hydrogen, halogen, C1-6alkyl, C1-ehaloalkyl, -OR10, or -N(R10)(R11).

63. The method of any one of claims 35-62, wherein R5is hydrogen or C1-6alkyl.

64. The method of claim 1, wherein the first therapeutic agent comprising a compound of Formula (I) is selected from:pharmaceutically acceptable salt or solvate thereof.

65. The method of claim 1, wherein the first therapeutic agent comprising a compound of Formula (I) is 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin- 3 -y l)-5 -(trifluoromethy l)phenol .

66. The method of any one of claims 1 -65, wherein the second therapeutic agent is selected from semaglutide, dulaglutide, liraglutide, exenatide, tirzepatide, lixisenatide, and albiglutide.

67. The method of any one of claims 1 -66, wherein the second therapeutic agent is semaglutide.

68. The method of any one of claims 1-67, wherein the metabolic diseaseis selected from type 2 diabetes, atherosclerosis, obesity and gout.

69. The method of any one of claims 1 -68, wherein the metabolic disease is obesity.

70. The method of any one of claims 1 -69, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered simultaneously.

71. The method of any one of claims 1 -70, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated together in a single composition.

72. The method of any one of claims 1 -69, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are administered sequentially.

73. The method of claim 70 or claim 72, wherein the therapeutically effective amount of the first therapeutic agent and the therapeutically effective amount of the second therapeutic agent are formulated in separate compositions.

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