Use of NLRP3 inhibitor in drug

Abstract

Provided is a use of an NLRP3 inhibitor in the preparation of a drug for preventing or treating hepatitis, fatty liver, hyperlipidemia, obesity, obesity complications, and metabolic disorders or for enhancing physical performance.

Description

Uses of NLRP3 inhibitors in medicine Technical Field

[0001] This invention relates to the use of NLRP3 inhibitors in the preparation of drugs for the prevention or treatment of hepatitis, fatty liver, hyperlipidemia, obesity, obesity complications, metabolic disorders, or for the preparation of drugs to enhance athletic performance. Background Technology

[0002] NOD-like receptors (NLRs), which are nucleotide-binding oligomerization domains (NOD), are a class of cytoplasmic pattern recognition receptors (PRRs) in mammalian cells, playing a crucial role in innate immune responses. NLRs are a group of cytoplasmic proteins with signal transduction functions, widely involved in the body's inflammatory responses. The NLR family includes NOD, NALP (NLRP), CIITA (NLRA), and IPAF (NLRC), with the NLRP and NLRC subfamilies being the two main types of NOD-like receptors (NLRs). NLRP can be further divided into inflammasome members such as NLRP1, NLRP3, NLRP6, NLRP7, and NLRP12. The NLRP3 inflammasome is a multi-protein complex composed of the NLRP3 protein itself, caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC). It can recognize various pathogenic microorganisms and stress-related endogenous signaling molecules. Classical NLRP3 inflammasome activation is triggered by two signals: the first activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting nuclear transcription factor κB translocation into the nucleus and inducing the production of precursors such as IL-1β and IL-18. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex. When activated, the NLRP3 complex polymerizes with apoptosis-associated specklike protein (ASC) containing a caspase activation and recruitment domain. ASC then interacts with cysteine ​​protease caspase-1 to form a complex called the inflammasome. The pro-caspase-1 self-cleaves into its activated form (Wen, H., Miao, EA & Ting, JP Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432–441 (2013)). The activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, converting them into their active forms and releasing them extracellularly. This recruits inflammatory cells to aggregate and amplifies the inflammatory response.ASC speckle-like proteins can also recruit and activate caspase-8, cleaving precursor forms of IL-1β and IL-18 to their mature forms and inducing pyroptosis. Non-canonical NLRP3 inflammasome activation is independent of TLR4 signaling pathway activation; it is initiated by caspase-11 directly recognizing intracellular LPS, promoting NLRP3 inflammasome activation, promoting the activation and release of Gasdermin D, and thus mediating cell death (Lamkanfi, M. & Dixit, VMMechanisms and functions of in flammasomes. Cell 157, 1013–1022 (2014)).

[0003] WO2021093820 describes an amide derivative, its preparation method, and its application in medicine. The compound described in the specification has significant inhibitory activity against NLRP3. Summary of the Invention

[0004] The purpose of this invention is to provide the use of NLRP3 inhibitors in the preparation of drugs for the prevention or treatment of hepatitis, fatty liver, hyperlipidemia, obesity, obesity complications, metabolic disorders, or for the preparation of drugs to enhance exercise capacity, in order to overcome the shortcomings of the prior art.

[0005] In one or more embodiments of this application, the NLRP3 inhibitor is used in the preparation of a medicament for the prevention or treatment of obesity or obesity complications.

[0006] In one or more embodiments of this application, the NLRP3 inhibitor is used in the preparation of a medicament for the prevention or treatment of hepatitis, fatty liver, hyperlipidemia, obesity, or obesity complications.

[0007] In one or more embodiments of this application, the NLRP3 inhibitor is used in the preparation of medicaments for the prevention or treatment of metabolic disorders.

[0008] The use of the NLRP3 inhibitor in the preparation of a medicament for the prevention or treatment of glucose metabolism disorders is described in one or more embodiments of this application.

[0009] The use of the NLRP3 inhibitor in the preparation of a medicament for the prevention or treatment of glucose metabolism disorders caused by obesity is described in one or more embodiments of this application.

[0010] In one or more embodiments of this application, the NLRP3 inhibitor is used in the preparation of a medicament for the prevention or treatment of diabetes caused by obesity.

[0011] The use of the NLRP3 inhibitor and semaglutide in the preparation of a pharmaceutical composition for the prevention or treatment of diabetes caused by obesity in one or more embodiments of this application.

[0012] In one or more embodiments of this application, the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0013] The use of the NLRP3 inhibitor in the preparation of a medicament for enhancing athletic performance is described in one or more embodiments of this application.

[0014] In one or more embodiments of this application, the athletic ability is muscle performance or resistance to exercise fatigue.

[0015] In one or more embodiments of this application, the muscle performance is muscle strength and / or muscle endurance.

[0016] In one or more embodiments of this application, the muscle strength is forelimb gripping force.

[0017] The use of the NLRP3 inhibitor in the preparation of a medicament for the prevention or treatment of diet-induced obesity or obesity complications is described in one or more embodiments of this application.

[0018] In one or more embodiments of this application, the obesity complication is hepatitis.

[0019] In one or more embodiments of this application, the obesity complication is fatty liver.

[0020] In one or more embodiments of this application, the obesity complication is hyperlipidemia.

[0021] In one or more embodiments of this application, the NLRP3 inhibitor includes MCC950, DFV-890, OLT1177, ZYIL-1, VTX-2735, NT-0796, NT-0249, NT-0167, RG-6418, MCC-7840, SB-414, VTX-3232, VENT-02, JTE-162, VENT-01, BGE-100, VENT-05, NT-0527, GDC-2394, MCF-1040, JT002, TTX-01, TT-02332, or CLM-022.

[0022] In one or more embodiments of this application, the NLRP3 inhibitor is selected from compounds represented by general formula (I), or their stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals:

[0023] in:

[0024] Q is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0025] R q0 Whether they are the same or different, each is independently selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, halogen, OH, cyano, nitro, -NH2, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl group, -C(=O)OC 3-8 cycloalkyl, -OC(=O)C 3-8 cycloalkyl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 5-10 heteroaryl, -NHC 1-6 Alkyl, -N(C1) -6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)(C 1-6 Alkyl)2、-NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 2-6 Alkyne group, -NHC(=O)C 2-6 alkenyl, -NH (C=NR) q1 )NR q2 R q3 -C(=O)NR q4 R q5 -SH, -SC1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl or -S(=O)2NR q2 R q3 Each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms selected from N, O, or S, and the alkyl, alkoxy, -NH2, alkenyl, alkynyl, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl groups may optionally be further selected from one or more of deuterium, OH, halogen, cyano, =O, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further divided by one to three elements selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or it is replaced by a substituent of =O;

[0026] Or at least one pair of R q0 The carbon ring and its associated atoms form a 4- to 10-membered carbon ring or a 5- to 10-membered heterocycle, wherein the heterocycle contains 1 to 2 heteroatoms selected from N, O, or S, and the carbon ring or heterocycle is optionally further surrounded by one or more atoms selected from OH, halogens, C, and N. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl or -C(=O)NR q4 R q5 The substituent is replaced by the substituent C. 1-6 Alkyl or C 1-6 The alkoxy group may be further selected from OH, halogen, =O, -NR. q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl or -C(=O)NR q4 R q5 The substituents are replaced;

[0027] R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl;

[0028] R q2 R q3 Selected from H or C 1-6 alkyl;

[0029] Rq4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 Alkyl groups may optionally be further selected from OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 and N atoms form 3 to 8-membered heterocycles, wherein the heterocycles contain 1 to 3 heteroatoms selected from N, O or S;

[0030] R q6 C 1-6 alkyl;

[0031] W is selected from O or NHR a ;

[0032] W1 is 0;

[0033] R a Selected from H, cyano, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy;

[0034] X is NH;

[0035] Y is CR b R c ;

[0036] R b R c Each is independently selected from H and C 1-6 Alkyl or 3 to 10-membered carbocyclic group, wherein the C 1-6 Alkyl groups are optionally further surrounded by 1 to 4 elements selected from F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 The substituted group is replaced by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O, or S;

[0037] Or R b With Rc Formation of double bonds;

[0038] R and R1 are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH2, OH, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -O(C=O)-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered heterocyclic, -(C=O)O-3 to 10-membered carbon cycloyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 4- to 10-membered heterocyclic, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2 or (C=O)NR a1 R a2 The heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR. a1 R a2 =O,C 1-6 Alkyl, C1 -6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -(C=O)O-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered heterocyclic, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, -NHCOC 1-6 Alkyl groups, -NH(C=O)-3 to 10-membered carbocyclic groups, -NH(C=O)-3 to 10-membered heterocyclic groups, or -(C=O)NR a1 R a2 The substituents are replaced;

[0039] Alternatively, R and R1 together with their attached atoms form a 4- to 8-membered ring, the 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O, or S, the 4- to 8-membered ring optionally further surrounded by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR. a1 R a2 =O,C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)OC 1-6 Substituents of alkyl, 3- to 10-membered carbocyclic or 5- to 10-membered heterocyclic groups;

[0040] C is a 3- to 10-membered cycloalkyl group;

[0041] R2 is selected from H, F, Cl, Br, I, OH, -NR a1 R a2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0042] G1, G2, and G3 are each independently selected from N or CH;

[0043] q and r are selected from 0, 1, or 2;

[0044] n can be selected from 0, 1, 2, or 3.

[0045] The compounds in one or more embodiments of this application, or their stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compounds are selected from those represented by general formula (II) or (II-1):

[0046] or

[0047] in:

[0048] The definitions of Q, R, R1, R2, C, G1, G2, G3, r, q, and n are the same as those in general formula (I).

[0049] The compounds in one or more embodiments of this application, or their stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compounds are selected from those represented by general formula (II-2):

[0050] Q, W, R, R1, R b R c The definitions of r and q are the same as those in general formula (I);

[0051] m can be selected from 1, 2, or 3.

[0052] The compounds in one or more embodiments of this application, or their stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compounds are selected from those represented by general formula (III) or (III-1):

[0053] or

[0054] The definitions of Q, R, R1, G1, G2, G3, r, and q are the same as those in general formula (I).

[0055] The compounds, or their stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, in one or more embodiments of this application, wherein:

[0056] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0057] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced;

[0058] R q4 R q5 Selected from H or C 1-4 alkyl;

[0059] W is selected from O or NH;

[0060] R and R1 are each independently selected from deuterium, H, F, CN, OH, and C. 1-6 Alkyl or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl or heterocycle is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, CN or C. 1-6 Substituents of alkoxy groups;

[0061] Alternatively, R and R1 together with the atoms they are attached to form a 4-membered ring or a 5-membered ring;

[0062] G1, G2, and G3 are each independently selected from CH;

[0063] q and r are selected from 0, 1, or 2.

[0064] The compound in one or more embodiments of this application, or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (IV):

[0065] The definitions of Q, W, R, R1, r, and q are the same as those in general formula (I);

[0066] m can be selected from 1, 2, or 3.

[0067] The compounds, or their stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, in one or more embodiments of this application, wherein:

[0068] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0069] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl, -NR q4 R q5 C 3-6 cycloalkyl or C 3-6 Substituents of heterocyclic alkyl groups;

[0070] R q4 R q5 Selected from H or C 1-4 alkyl;

[0071] W is selected from O or NH;

[0072] R and R1 are each independently selected from deuterium, H, F, CN, OH, and C. 1-6 Alkyl or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl or heterocycle is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, CN or C. 1-6 Substituents of alkoxy groups;

[0073] Alternatively, R and R1 together with the atoms they are attached to form a 4-membered ring or a 5-membered ring;

[0074] q and r are selected from 0, 1, or 2;

[0075] m can be selected from 1, 2, or 3.

[0076] The compound in one or more embodiments of this application, or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (V):

[0077] Q, W, R b R c The definition is the same as that described in general formula (I);

[0078] m can be selected from 1, 2, or 3.

[0079] The compounds, or their stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, in one or more embodiments of this application, wherein:

[0080] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0081] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced;

[0082] R q4 R q5 Selected from H or C 1-4 alkyl;

[0083] W is selected from O or NH;

[0084] R b R c Each is independently selected from H and C 1-4 Alkyl or 3- to 5-membered carbon cycloyl groups, or R b With R c Formation of double bonds;

[0085] q and r are selected from 0, 1, or 2;

[0086] m can be selected from 1, 2, or 3.

[0087] The compound in one or more embodiments of this application, or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (VI):

[0088] Q, W, R b R c The definition is the same as that described in general formula (I);

[0089] m can be selected from 1, 2, or 3.

[0090] The compounds, or their stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, in one or more embodiments of this application, wherein:

[0091] Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace;

[0092] R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5The substituents are replaced;

[0093] R q4 R q5 Selected from H or C 1-4 alkyl;

[0094] W is selected from O or NH;

[0095] R b R c Each is independently selected from H and C 1-4 Alkyl or 3- to 5-membered carbon cyclogroups;

[0096] q and r are selected from 0, 1, or 2;

[0097] m can be selected from 1, 2, or 3.

[0098] The compounds, or their stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, in one or more embodiments of this application, wherein:

[0099] Q is selected from

[0100] Selected from or

[0101] The compounds in one or more embodiments of this application, or their stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein said compounds are selected from one of the following structures:

[0102] In one or more embodiments of this application, the compound is selected from the following structures: These two structures are tautomers, but are essentially the same substance.

[0103] In one or more embodiments of this application, the compound is selected from one of the following structures:

[0104] This invention also provides NLRP3 inhibitors for the prevention or treatment of hepatitis, fatty liver, hyperlipidemia, obesity, obesity complications, metabolic disorders, or for enhancing exercise capacity.

[0105] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat obesity or obesity complications.

[0106] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat hepatitis, fatty liver, hyperlipidemia, obesity, or obesity complications.

[0107] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat metabolic disorders.

[0108] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat glucose metabolism disorders.

[0109] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat glucose metabolism disorders caused by obesity.

[0110] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat diabetes caused by obesity.

[0111] In one or more embodiments of this application, the pharmaceutical composition of the NLRP3 inhibitor and semaglutide is used to prevent or treat diabetes caused by obesity.

[0112] In one or more embodiments of this application, the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0113] In one or more embodiments of this application, the NLRP3 inhibitor is used to enhance athletic performance.

[0114] In one or more embodiments of this application, the athletic ability is muscle performance or resistance to exercise fatigue.

[0115] In one or more embodiments of this application, the muscle performance is muscle strength and / or muscle endurance.

[0116] In one or more embodiments of this application, the muscle strength is forelimb gripping force.

[0117] In one or more embodiments of this application, the NLRP3 inhibitor is used to prevent or treat diet-induced obesity or obesity complications.

[0118] In one or more embodiments of this application, the obesity complication is hepatitis.

[0119] In one or more embodiments of this application, the obesity complication is fatty liver.

[0120] In one or more embodiments of this application, the obesity complication is hyperlipidemia.

[0121] In one or more embodiments of this application, the NLRP3 inhibitor is as defined above. Attached Figure Description

[0122] Figure 1 shows the weight change curves of each group in the diet-induced obesity model in Example 1.

[0123] Figure 2 shows the weight change rate curves of each group in the diet-induced obesity model in Example 1.

[0124] Figure 3 shows the food intake change curve of the diet-induced obesity model in Example 1 after 58 days of drug administration.

[0125] Figure 4 shows the epididymal fat wet weight results in the diet-induced obesity model of Example 1.

[0126] Figure 5 shows the perirenal fat wet weight results of the diet-induced obesity model in Example 1.

[0127] Figure 6 shows the total fat wet weight results of the diet-induced obesity model in Example 1.

[0128] Figure 7 is a graph showing the weight results of the DIO obesity pharmacological model experiment in Example 2.

[0129] Figure 8 is a curve showing the rate of weight change in the DIO obesity pharmacological model experiment in Example 2.

[0130] Figure 9 is a bar chart of Lee's index results from the DIO obesity pharmacological model experiment in Example 2.

[0131] Figure 10 is a bar chart of the inflammatory factor IL-1β in the diet-induced obesity model of Example 1.

[0132] Figure 11 is a bar chart of the inflammatory factor IL-6 in the diet-induced obesity model of Example 1.

[0133] Figure 12 is a bar chart of the gastrocnemius muscle / body weight ratio in the diet-induced obesity model of Example 1.

[0134] Figure 13 is a bar chart of triglycerides (TG) in the diet-induced obesity model of Example 1.

[0135] Figure 14 is a bar chart of the diet-induced obesity model AST in Example 1.

[0136] Figure 15 is a bar chart of ALT in the diet-induced obesity model of Example 1.

[0137] Figure 16 is a bar chart of the inflammatory factor IL-1β in the DIO obesity pharmacological model experiment in Example 2.

[0138] Figure 17 is a bar chart of the inflammatory factor IL-6 in the DIO obesity pharmacological model experiment in Example 2.

[0139] Figure 18 shows the fasting blood glucose results of the diet-induced obesity model in Example 1.

[0140] Figure 19 shows the results of the diet-induced obesity model DCCT-HbA1c (%) in Example 1.

[0141] Figure 20 shows the results of insulin (INS) levels in the plasma of the diet-induced obesity model in Example 1.

[0142] Figure 21 is a bar chart of fasting blood glucose in the DIO obesity pharmacokinetics model D27-28 in Example 2.

[0143] Figure 22 is a line graph of blood glucose concentration at each time point after the DIO obesity pharmacodynamic model was established by gavage glucose administration at times D27-28 in Example 2.

[0144] Figure 23 is a bar chart of the area under the blood glucose curve (AUC) of the DIO obesity pharmacodynamic model D27-28 after gavage glucose in Example 2.

[0145] Figure 24 is a bar chart of glycated hemoglobin in the DIO obesity pharmacological model in Example 2.

[0146] Figure 25 is a bar chart of plasma insulin in the DIO obesity pharmacological model in Example 2.

[0147] Figure 26 shows the forelimb grip strength test results of the diet-induced obesity model.

[0148] Figure 27 shows the results of the treadmill test of the diet-induced obesity model.

[0149] Figure 28 shows the results of the rotator test in the diet-induced obesity model. Detailed Implementation

[0150] Compound 1 is the compound in Example 38 of WO2021093820, and compound 1 was prepared according to its preparation method.

[0151] Example 1

[0152] Preventive and therapeutic efficacy experiments in a C57 mouse diet-induced obesity model

[0153] 1. Experimental Procedure

[0154] 1.1 Experimental Animals and Reagents

[0155] SPF-grade 5-week-old male C57BL / 6J mice were purchased from Chengdu Yaokang Biotechnology Co., Ltd.

[0156] Feed: High-fat feed 60% kcal, product number: XTHF60; maintenance feed, product number: 1010088. All feeds were purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd.

[0157] Vehicle: DMSO: 0.5% MC=5:95 (v / v).

[0158] Compound 1 solution: Compound 1 is dissolved in the above solvent, and the concentration of Compound 1 is 20 mg / ml.

[0159] 1.2 Establishment of a diet-induced obesity model:

[0160] Animals in the blank control group were fed maintenance feed. Eight animals in the blank control group were selected based on their body weight and continued to be fed maintenance feed until the end of the experiment.

[0161] The model control group and the drug-treated group (compound 1 group) were fed a high-fat diet. After transitioning between the maintenance diet and the high-fat diet at ratios of 3:7, 5:5, and 7:3, the animals were fed the high-fat diet to induce an obesity model. One week after dietary induction, the animals' weight levels were measured. Compared with the animals fed the maintenance diet, the animals' weights were significantly higher, and the difference was statistically significant. The animals were then divided into groups. First, the animals fed the high-fat diet were sorted by weight, and one-quarter of the lower-weight animals that resisted the diet-induced obesity were removed. Then, they were randomly divided into two groups of eight each according to their weight using an S-shaped grouping method. After drug administration, the animals continued to be fed the high-fat diet until the end of the experiment.

[0162] 1.3 Administration method:

[0163] Animals were modeled and grouped according to the protocol in 1.2 and then administered the drugs. The groups included: G1 blank control group (maintenance diet, Vehicl e), G2 model control group (high-fat diet, Vehicle), and G3 compound 1 group (high-fat diet, 100 mg / kg).

[0164] The administration volume of compound 1 solution was 5 mL / kg. The normal control group and the model control group were administered the same volume of solvent by gavage twice daily, BID, for 58 days.

[0165] 2. Detection indicators

[0166] 2.1 Animal weight

[0167] Monitor animal weight changes once a week and calculate the rate of weight change.

[0168] 2.2 Food intake

[0169] Twice a week, monitor changes in animal feed intake. Feed intake is measured per cage, with n animals per cage. On the test day, a fixed weight W0 of feed is added, and the remaining feed weight W is measured 24 hours later. 24 .

[0170] Formula for calculating food intake (g / D / animal): (W0-W 24 ) / n.

[0171] 2.3 Wet weight of epididymal fat

[0172] At the end of the experiment, the animals were euthanized, and the bilateral epididymal fat was dissected and weighed by wet weight.

[0173] 2.4 Perinephric fat wet weight

[0174] At the end of the experiment, the animals were euthanized, and the perirenal fat of both sides was dissected and weighed by wet weight.

[0175] 2.5 Total fat wet weight

[0176] At the end of the experiment, the total wet weight of bilateral epididymal fat and bilateral perirenal fat was measured.

[0177] 2.6 Gastrocnemius muscle / body weight ratio

[0178] At the end of the experiment, the gastrocnemius muscle was dissected, weighed wet, and the gastrocnemius muscle / body weight ratio was calculated.

[0179] 2.7 Triglyceride (TG) Detection

[0180] At the end of the experiment, blood was collected to separate plasma, and blood biochemistry was used to detect triglyceride levels.

[0181] 2.8 Content of inflammatory factors IL-1β and IL-6 in liver tissue

[0182] At the end of the experiment, liver tissue was taken and IL-1β and IL-6 were quantitatively detected using an ELISA kit.

[0183] 2.9 ALT and AST detection

[0184] At the end of the experiment, blood was collected to separate plasma, and blood biochemistry was used to detect AST and ALT levels.

[0185] 2.10 Liver tissue pathological examination

[0186] At the end of the experiment, after euthanasia of the animals, the liver was dissected, fixed with paraformaldehyde (4%), embedded in paraffin, sectioned, stained with hematoxylin and eosin, and the liver tissue damage was scored (using the liver NAS scoring criteria, including indicators of steatosis, lobular inflammation, ballooning degeneration, and fibrosis).

[0187] 2.11 Data Analysis

[0188] All data were analyzed using Graphpad Prism 8 software. The mean and standard error (Mean ± SEM) of all results for each group of animals were calculated. The t-test was used to compare adipose tissue weight and inflammatory factor data. P < 0.05 was considered statistically significant. # indicates P < 0.05 compared to the blank control group (# indicates P < 0.05, ## indicates P < 0.01, ### indicates P < 0.001), and * indicates P < 0.05 compared to the model control group (* indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001).

[0189] 3. Experimental Results

[0190] 3.1 Effect of Compound 1 on Body Weight in Diet-Induced Obesity Model Mice

[0191] Figure 1 shows the weight change curves of each group in the diet-induced obesity model, and Figure 2 shows the weight change rate curves of each group in the diet-induced obesity model.

[0192] The results showed that before administration (D0), there was no significant difference in body weight between the model control group and the compound 1 group. Compared with the G1 blank control group, both the model control group and the compound 1 group showed a significant increase in body weight, which was statistically significant. At the experimental endpoint (D58), the body weight of the G2 model control group increased by 41.80% compared with the initial body weight, and the body weight of the G3 compound 1 group increased by 14.41% compared with the initial body weight. Compared with the G2 model control group, the body weight of the G3 compound 1 group decreased after administration, which was statistically significant.

[0193] At the end of the experiment, all groups showed an increasing weight trend compared to their initial weight. However, the weight change rate of compound 1 group was significantly lower than that of the model control group, and the weight change rate of compound 1 group was basically the same as that of the blank control group. Therefore, compound 1 group has a controlling effect on the weight of obese mice induced by a high-fat diet.

[0194] 3.2 Effect of Compound 1 on Food Intake in Diet-Induced Obesity Model Mice

[0195] Figure 3 shows the change curve of food intake in the diet-induced obesity model after 58 days of drug administration.

[0196] The results showed that there was no significant difference in feed intake among the groups until the last observation (D57-58) before the end of the experiment, indicating that the administration of the drug did not affect the animals' feed intake.

[0197] 3.3 Effect of Compound 1 on the wet weight of epididymal fat in diet-induced obesity model mice

[0198] Figure 4 shows the results of epididymal fat wet weight in the diet-induced obesity model.

[0199] The results showed that, compared with the G1 blank control group, the epididymal fat in the G2 model control group was significantly increased, with a statistically significant difference; compared with the G2 model control group, the wet weight of epididymal fat in the G3 compound 1 group was decreased, with a statistically significant difference.

[0200] 3.4 Effect of Compound 1 on Perirhinal Fat Wet Weight in Diet-Induced Obesity Model Mice

[0201] Figure 5 shows the perirenal fat wet weight results of the diet-induced obesity model.

[0202] The results showed that, compared with the G1 blank control group, the perirenal fat of the G2 model control group was significantly increased, with a statistically significant difference; compared with the G2 model control group, the perirenal fat wet weight of the G3 compound 1 group was decreased, with a statistically significant difference.

[0203] 3.5 Effect of Compound 1 on Total Fat Wet Weight in Diet-Induced Obesity Model Mice

[0204] Figure 6 shows the total fat wet weight results of the diet-induced obesity model.

[0205] The results showed that, compared with the G1 blank control group, the total fat in the G2 model control group was significantly increased, with a statistically significant difference; compared with the G2 model control group, the total fat wet weight in the G3 compound 1 group was decreased, with a statistically significant difference.

[0206] 3.6 Effect of Compound 1 on the ratio of gastrocnemius muscle to body weight in fat in a diet-induced obesity model mouse

[0207] Figure 12 is a bar chart of the gastrocnemius muscle / body weight ratio in the diet-induced obesity model of Example 1.

[0208] Experimental results: The results showed that at the end of the experiment, compared with the normal control group, the gastrocnemius muscle / body weight ratio of the model group was decreased, while the gastrocnemius muscle / body weight ratio of the compound 1 administration group was increased compared with the model group.

[0209] 3.7 Effect of Compound 1 on Triglycerides (TG) in Fat of Diet-Induced Obesity Model Mice

[0210] Figure 13 is a bar chart of triglycerides (TG) in the diet-induced obesity model of Example 1.

[0211] Experimental results: The results showed that at the end of the experiment, compared with the normal control group, the TG in the model group was increased, while the TG in the compound 1 administration group was decreased compared with the model group, indicating that compound 1 has the effect of reducing TG.

[0212] 3.8 Effects of Compound 1 on Inflammatory Factors in Fat of Diet-Induced Obesity Model Mice

[0213] Figure 10 shows the inflammatory factor IL-1β in the diet-induced obesity model. Figure 11 shows the results of the inflammatory factor IL-6 in the diet-induced obesity model.

[0214] The results showed that compared with the G1 blank control group, the G2 model control group had increased IL-1β and IL-6, with statistically significant differences; compared with the G2 model control group, the G3 compound 1 group had decreased IL-1β and IL-6, with statistically significant differences.

[0215] 3.9 Effect of Compound 1 on ALT and AST levels in fat of diet-induced obesity model mice

[0216] Figure 14 is a bar chart of AST in the diet-induced obesity model of Example 1. Figure 15 is a bar chart of ALT in the diet-induced obesity model of Example 1.

[0217] Experimental results: The results showed that at the end of the experiment, compared with the normal control group, the AST and ALT levels in the model group were increased, while the levels in the compound 1 administration group showed a decreasing trend compared with the model group, indicating that compound 1 has the effect of reducing AST and ALT.

[0218] 3.10 Pathological examination of liver tissue in a diet-induced obesity model using compound 1

[0219] Table 1 shows the pathological examination of liver tissue in each group of the diet-induced obesity model. The specific HE staining scores of the liver tissue are as follows:

[0220] Table 1

[0221] Experimental results: The results showed that at the end of the experiment, compared with the normal control group, the HE staining score of liver tissue in the model group was increased, while that in the compound 1 administration group was decreased compared with the model group, indicating that compound 1 has the effect of alleviating liver tissue damage.

[0222] In summary, the compounds of this invention can effectively control weight gain in mice in a high-fat diet-induced obesity model, reduce epididymal fat weight, perirenal fat wet weight and total fat wet weight, and improve inflammation in the liver tissue of obese mice. They can be used to prepare drugs for the prevention and treatment of diet-induced obesity and other complications.

[0223] Example 2

[0224] DIO Obesity Pharmacodynamic Model

[0225] 1. Experimental Design

[0226] 1.1 Laboratory Animals

[0227] SPF grade 18-week-old male C57BL / 6J and DIO C57BL / 6J mice (purchased DIO obese pharmacological efficacy model mice, Chengdu Yaokang Biotechnology Co., Ltd.)

[0228] 1.2 Experimental grouping and drug administration

[0229] After acclimatization to the laboratory environment, 8 C57BL / 6J mice were fed a normal maintenance diet, and 40 DIO C57BL / 6J mice were fed a high-fat diet. The DIO C57BL / 6J mice were divided into 5 groups of 8 mice each using an S-shaped grouping method based on their body weight. The day of grouping was designated as day 0 of the experiment (D0), and drug administration began on day 1 (D1).

[0230] Compound 1 was administered in DMSO + HS-15 + 0.5% MC (v / v / v = 5:10:85) as the solvent. Semaglutide (C AYMAN CHEMICAL COMPANY) was administered in DMSO + PBS buffer (v / v = 10:90) as the solvent. The Vehicle and Model groups were administered DMSO + HS-15 + 0.5% MC (v / v / v = 5:10:85) via ig and BID.

[0231] The group dosing regimen is detailed in Table 2.

[0232] Table 2 Dosage Regimen Note: ig refers to gavage administration; sc refers to subcutaneous injection; QD refers to once-daily administration; BID refers to twice-daily administration.

[0233] 1.3 Detection Indicators

[0234] 1.3.1 Weight: Weigh animals three times a week, on Mondays, Wednesdays, and Fridays, between 09:00 and 11:00, to monitor changes in animal weight, plot weight curves, and calculate the rate of weight change.

[0235] 1.3.2 Lee's Index: The experimental endpoint, the animal was weighed and its body length was measured. Body length was defined as the distance from the tip of the mouse's nose to the base of its tail. The mouse was immobilized during body length measurement to prevent it from arching its back. Lee's Index was then calculated. (Lee's Index = 1 / 3 of body weight (g) * 1000 / body length (cm))

[0236] 1.3.3 Content of inflammatory factors IL-1β and IL-6 in liver tissue: At the end of the experiment, liver tissue was taken and IL-1β and IL-6 were quantitatively detected using an ELISA kit.

[0237] 1.3.4 Liver tissue pathological examination: At the end of the experiment, after euthanasia of the animals, the liver was dissected, fixed with paraformaldehyde (4%), embedded in paraffin, sectioned, stained with hematoxylin and eosin, and the liver tissue damage was scored (using the liver NAS scoring standard, including indicators of steatosis, lobular inflammation, ballooning degeneration, and fibrosis).

[0238] 1.3.5 Data Analysis: All data were analyzed using SPSS 16.0 software. One-way ANOVA was used for data comparison. P < 0.05 was considered statistically significant. # indicates comparison with the control group, and * indicates comparison with the model group. The statistical mean and standard error (Mean ± SEM) of all results for each group of animals were also included.

[0239] 2. Experimental Results

[0240] 2.1. Body weight and rate of change in body weight

[0241] Figure 7 shows the weight loss curves from the DIO obesity pharmacodynamic model experiment. Weight was recorded up to day 31. Compared with the G1 blank control group, the G2 model control group showed a continuous increase in weight, indicating a statistically significant difference and successful model construction. Compared with the G2 model control group, the weight loss in different dosage groups of compound 1 was dose-dependent. The G3 group (compound 1 at 100 mpk) showed a slight weight loss with no statistically significant difference. The G4 group (compound 1 at 200 mpk) showed a significant weight loss with a statistically significant difference. The G5 group (semaglutide 0.01 mpk) and the G6 group (compound 1 at 100 mpk + semaglutide 0.01 mpk) showed significant weight loss with statistically significant differences. The weight loss in the G6 group was more significant than that in the G5 group. The weight loss results suggest that compound 1 may have a weight-loss effect at a single dose of 200 mpk, and that compound 1 at a dose of 100 mpk combined with semaglutide may have a synergistic effect.

[0242] Figure 8 shows the weight change rate curves in the DIO obesity pharmacodynamic model experiment. Statistics up to D31 show a slight decrease in weight change rate in the G1 blank control group, with a more significant decrease in G1#3600 rats due to injury from fighting. The weight changes in other animals were minimal, suggesting that the solvent had no significant effect on animal weight. The weight change rate in the G2 model control group continued to increase. Compared to the G2 model control group, the weight change rate in the G3-compound 1 100mpk group showed no significant increase, indicating that this dosage could control the weight gain trend. The weight change rates in the G4-compound 1 200mpk, G5-semaglutide 0.01mpk, and G6-compound 1 100mpk + semaglutide 0.01mpk combination groups showed a significant decrease. These weight change rate results suggest that compound 1 at single-drug doses of 100mpk and above may have a certain weight control effect, and that compound 1 at 100mpk dose combined with semaglutide may have a synergistic effect.

[0243] 2.2. Lee's Index

[0244] Figure 9 is a bar chart showing the Lee's index results of the DIO obesity pharmacodynamic model experiment. Compared with the G1 blank control group, the Lee's index of the G2 model control group increased significantly, showing a statistically significant difference, consistent with the weight trend, indicating that the obesity model was successfully constructed. Compared with the G2 model control group, the Lee's index decreased in the groups treated with G3-compound 1 100mpk, G4-compound 1 200mpk, G5-semaglutide 0.01mpk, and G6-compound 1 100mpk + semaglutide 0.01mpk. Among them, the combination group of G5-semaglutide 0.01mpk and G6-compound 1 100mHpk + semaglutide 0.01mpk showed a statistically significant difference. The decrease in Lee's index between G3-compound 1 100mpk and G4-compound 1 200mpk was dose-dependent, and the decrease in Lee's index between G6-compound 1 100mpk + semaglutide was dose-dependent. The decrease in Lee's index was more significant in the 0.01 mpk combination group than in the G5-semaglutide 0.01 mpk group. The Lee's index results suggest that compound 1 at doses of 100 mpk or higher may have a weight-loss effect, and that combination of compound 1 at a dose of 1100 mpk with se-maglutide may have a synergistic effect.

[0245] 2.3. Changes in the levels of inflammatory factors IL-1β and IL-6 in liver tissue

[0246] Figure 16 is a bar chart of the inflammatory factor IL-1β in the DIO obesity pharmacological model experiment in Example 2. Figure 17 is a bar chart of the inflammatory factor IL-6 in the DIO obesity pharmacological model experiment in Example 2.

[0247] The results showed that compared with the G1 blank control group, IL-1β and IL-6 were significantly increased in the G2 model control group. Compared with the G2 model control group, IL-1β and IL-6 were decreased in the groups treated with G3-compound 1100mpk, G4-compound 1200mpk, G5-semaglutide 0.01mpk, and the combination group of G6-compound 1 100mpk + semaglutide 0.01mpk. The decrease in IL-1β and IL-6 with G3-compound 1 100mpk and G4-compound 1 200mpk was dose-dependent, and the decrease in IL-1β and IL-6 with the combination group of G6-compound 1 100mpk + semaglutide 0.01mpk was more significant than that with G5-semaglutide 0.01mpk. These results suggest that compound 1 at a single dose of 100mpk or higher has a liver-inducing effect, and the combination of compound 1 at a dose of 1100mpk with semaglutide may have a synergistic effect.

[0248] 2.4. Pathological changes in liver tissue

[0249] Table 3 shows the liver tissue pathological examination of each group in the DIO obesity pharmacodynamic model. The specific NAS scores of the liver groups are as follows:

[0250] Table 3

[0251] The results showed that at the end of the experiment, compared with the normal control group, the liver NAS score of the model group was increased, while that of the compound 1 administration group was decreased compared with the model group, indicating that compound 1 has the effect of alleviating liver tissue damage while reducing weight.

[0252] In summary, the compounds of this invention can effectively control weight gain in mice in the DIO obesity pharmacological model and can be used to prepare drugs for the prevention and treatment of diet-induced obesity and other complications.

[0253] Example 3

[0254] Preventive and therapeutic efficacy experiments in a C57 mouse diet-induced obesity model

[0255] 1. Experimental Procedure

[0256] 1.1 Experimental Animals and Reagents

[0257] SPF-grade 5-week-old male C57BL / 6J mice were purchased from Chengdu Yaokang Biotechnology Co., Ltd.

[0258] Feed: High-fat feed 60% kcal, product number: XTHF60; maintenance feed, product number: 1010088. All feeds were purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd.

[0259] Vehicle: DMSO: 0.5% MC=5:95 (v / v).

[0260] Compound 1 solution: Compound 1 is dissolved in the above solvent, and the concentration of Compound 1 is 20 mg / ml.

[0261] 1.2 Establishment of a diet-induced obesity model:

[0262] Animals in the blank control group were fed maintenance feed. Eight animals in the blank control group were selected based on their body weight and continued to be fed maintenance feed until the end of the experiment.

[0263] The model control group and the drug-treated group (compound 1 group) were fed a high-fat diet. After transitioning between the maintenance diet and the high-fat diet at ratios of 3:7, 5:5, and 7:3, the animals were fed the high-fat diet to induce an obesity model. One week after dietary induction, the animals' weight levels were measured. Compared with the animals fed the maintenance diet, the animals' weights were significantly higher, and the difference was statistically significant. The animals were then divided into groups. First, the animals fed the high-fat diet were sorted by weight, and one-quarter of the lower-weight animals that resisted the diet-induced obesity were removed. Then, they were randomly divided into two groups of eight each according to their weight using an S-shaped grouping method. After drug administration, the animals continued to be fed the high-fat diet until the end of the experiment.

[0264] 1.3 Administration method:

[0265] Animals were randomly assigned to groups and administration began. The groups included: blank control group (maintenance diet, vehicle), model control group (high-fat diet, vehicle), and compound 1 group (high-fat diet, 100 mg / kg). The administration volume of compound 1 solution was 5 mL / kg. The control group and model control group were administered the same volume of solvent by gavage twice daily, BID, for 65 days.

[0266] 2. Detection indicators

[0267] 2.1 Fasting blood glucose (FBG)

[0268] On day 43 of drug administration, blood was collected from the tail tip of the animals after fasting for 6 hours to test fasting blood glucose.

[0269] 2.2 Glycated hemoglobin (DCCT-HbA1c)

[0270] At the end of the experiment, the animals were fasted overnight. The next day, blood was collected by enucleating the eyeballs. After centrifugation, the lower red blood cell layer was collected and purified water was added to prepare a blood-lysed sample. Glycated hemoglobin was detected using a kit.

[0271] 2.3 Insulin (INS)

[0272] At the end of the experiment, after the animals fasted overnight, blood was drawn from their eye sockets, and plasma was collected for insulin (INS) testing.

[0273] 3.1 Effect of Compound 1 on Fasting Blood Glucose in Diet-Induced Obesity Model Mice

[0274] Figure 18 shows the fasting blood glucose results of the diet-induced obesity model.

[0275] The results showed that, compared with the blank control group, the fasting blood glucose level in the G2 model control group was significantly increased, with a statistically significant difference.

[0276] Compared with the G2 model control group, the fasting blood glucose level in the G3 compound 1 group was significantly lower, showing a statistically significant difference. Furthermore, the blood glucose concentration in the compound 1 group was essentially the same as that in the blank control group, indicating that compound 1 can significantly reduce blood glucose in diet-induced obese model mice, demonstrating a hypoglycemic effect.

[0277] 3.2 Effect of Compound 1 on Glycated Hemoglobin in Diet-Induced Obesity Model Mice

[0278] Figure 19 shows the results of the diet-induced obesity model DCCT-HbA1c (%).

[0279] The results showed that compared with the G1 blank control group, the DCCT-HbA1c (%) in the G2 model control group was significantly increased, with a statistically significant difference; compared with the G2 model control group, the DCCT-HbA1c (%) in the G3 compound 1 group was decreased, with a statistically significant difference. This indicates that compound 1 can reduce glycated hemoglobin and has an ameliorative effect on diet-induced type 2 diabetes.

[0280] 3.3 Effect of Compound 1 on Insulin in Diet-Induced Obesity Model Mice

[0281] Figure 20 shows the results of insulin (INS) levels in the plasma of a diet-induced obesity model.

[0282] The results showed that compared with the G1 blank control group, insulin levels were significantly increased in the G2 model control group, and compared with the G2 model control group, insulin levels were decreased in the G3 compound 1 group. This indicates that compound 1 can reduce insulin levels and may have an ameliorative effect on insulin resistance in diet-induced obese mice.

[0283] Example 4

[0284] DIO Obesity Pharmacodynamic Model

[0285] 1. Experimental Design

[0286] 1.1 Laboratory Animals

[0287] SPF grade 18-week-old male C57BL / 6J and DIO C57BL / 6J mice (purchased DIO obese pharmacological efficacy model mice, Chengdu Yaokang Biotechnology Co., Ltd.)

[0288] 1.2 Experimental grouping and drug administration

[0289] After acclimatization to the laboratory environment, 8 C57BL / 6J mice were fed a normal maintenance diet, and 40 DIO C57BL / 6J mice were fed a high-fat diet. The DIO C57BL / 6J mice were divided into 5 groups of 8 mice each using an S-shaped grouping method based on their body weight. The day of grouping was designated as day 0 of the experiment (D0), and drug administration began on day 1 (D1).

[0290] Compound 1 was administered in DMSO + HS-15 + 0.5% MC (v / v / v = 5:10:85) as the solvent. Semaglutide (CAYMAN CHEMICAL COMPANY) was administered in DMSO + PBS buffer (v / v = 10:90) as the solvent. The Vehicle and Model groups were administered DMSO + HS-15 + 0.5% MC (v / v / v = 5:10:85) by gavage, twice daily, for 32-33 consecutive days.

[0291] The group dosing regimen is detailed in Table 4.

[0292] Table 4 Dosage Regimen Note: ig refers to gavage administration; sc refers to subcutaneous injection; QD refers to once-daily administration; BID refers to twice-daily administration.

[0293] 1.3 Detection Indicators

[0294] 1.3.1 Fasting blood glucose (FBG)

[0295] Fasting blood glucose: Animals are fasted overnight, and blood is collected from the tip of their tails on the second day. To reduce the impact of animal stress, the first drop of blood is discarded, and subsequent blood is collected using blood glucose test strips. The blood glucose meter reading is then read to monitor fasting blood glucose.

[0296] 1.3.2 Oral Glucose Tolerance Test (OGTT)

[0297] Before the OGTT test, animals were fasted overnight, and the drug was administered the next day. 30 minutes later, glucose solution was administered at 2 g / kg to establish the model. Blood was collected from the tail tip at 0 min, 15 min, 30 min, 60 min and 120 min after modeling to record blood glucose changes and calculate the area under the blood glucose curve (AUC).

[0298] AUC(t 15min +t 0min )x0.25 / 2+(t 30mi n+t 15min )x0.25 / 2+(t 30min +t 60min )x0.5 / 2+(t 120min +t 60min )x1 / 2.

[0299] 1.3.3 Glycated hemoglobin (DCCT-HbA1c)

[0300] At the end of the experiment, the animals were fasted overnight, blood was collected from the orbital cavity, and the lower red blood cell layer was collected after centrifugation. Purified water was added to prepare a blood-lysed sample, and glycated hemoglobin was detected using a kit.

[0301] 1.3.4 Insulin (INS)

[0302] At the end of the experiment, after the animals fasted overnight, blood was drawn from their eye sockets, and plasma was collected for insulin (INS) testing.

[0303] 1.3.5 Data Analysis

[0304] All data were analyzed using SPSS 16.0 software. One-way ANOVA was used for data comparison. P < 0.05 was considered statistically significant. # indicates comparison with the control group, and * indicates comparison with the model group. The statistical mean and standard error (Mean ± SEM) of all results for each group of animals were also included.

[0305] 2. Experimental Results

[0306] 2.1 Fasting blood glucose

[0307] The fasting blood glucose test results (overnight fasting) on ​​days 27-28 (Figure 21) showed that, compared with the G1 blank control group, the fasting blood glucose of the G2 model control group was significantly higher, with a statistically significant difference, indicating that the model mice had hyperglycemia. Compared with the G2 model control group, the fasting blood glucose of each treatment group showed a decreasing trend. The fasting blood glucose results suggest that compound 1 has a certain ameliorative effect on hyperglycemia in obese animals, and there is a dose-response relationship.

[0308] 2.2. Oral glucose tolerance test

[0309] The OGTT test results on days 27-28 (Figures 22-23) showed that, compared with the G1 blank control group, the blood glucose and AUC values ​​at all time points after glucose gavage modeling in the G2 model control group were significantly increased, and the differences were statistically significant, indicating that the model animals' ability to regulate blood glucose was impaired. Compared with the G2 model control group, the AUC values ​​at all time points and in the G3-compound 1-L group and the G4-compound 1-H group showed a decreasing trend, with a statistically significant difference in blood glucose at 15 min. The AUC values ​​of compound 1 at each dose group were dose-dependent. In the G5-semaglutide group, except for the blood glucose at 30 min, the blood glucose and AUC values ​​at all other time points showed a decreasing trend, with statistically significant differences in blood glucose and AUC values ​​at 0 min, 15 min, and 120 min. In the G6-compound 1L + semaglutide combination group, the blood glucose and AUC values ​​at all time points showed a decreasing trend, with statistically significant differences in blood glucose and AUC values ​​at 15 min and 30 min.

[0310] The OGTT results indicated that compound 1 had an improving effect on the body's ability to regulate blood glucose after glucose ingestion.

[0311] 2.3. Glycated hemoglobin (DCCT-HbA1c)

[0312] The glycated hemoglobin (HbA1) results (Figure 24) showed that, compared with the G1 blank control group, the HbA1 absorbance in the G2 model control group increased. Compared with the model group, HbA1 decreased in all treatment groups, with the G6-compound 1-L + semaglutide combination group showing a statistically significant difference and superior effect compared with the G5-semaglutide monotherapy group. This indicates that compound 1 can reduce HbA1 in a dose-dependent manner and has a synergistic effect with semaglutide.

[0313] 2.4. Insulin (INS)

[0314] Plasma insulin results (Figure 25) showed that, compared with the G1 blank control group, the G2 model control group had a statistically significant increase in plasma insulin levels. Compared with the model group, plasma insulin levels decreased in all treatment groups, with the G6-compound 1-L + semaglutide combination group showing a statistically significant difference, exceeding the effect of the G5-semaglutide monotherapy group. These results suggest that compound 1 monotherapy can improve insulin resistance and increase insulin sensitivity, and its combination with semaglutide is more effective than monotherapy.

[0315] In summary, compound 1 of the present invention can effectively control blood glucose in mice in a high-fat diet-induced obesity model, and can be used to prepare drugs for the prevention and treatment of metabolic disorders, type 2 diabetes and other complications caused by diet-induced obesity.

[0316] Example 5

[0317] Preventive and therapeutic efficacy experiments in a C57 mouse diet-induced obesity model

[0318] 1. Experimental Procedure

[0319] 1.1 Experimental Animals and Reagents

[0320] SPF-grade 5-week-old male C57BL / 6J mice were purchased from Chengdu Yaokang Biotechnology Co., Ltd.

[0321] Feed: High-fat feed 60% kcal, product number: XTHF60; maintenance feed, product number: 1010088. All feeds were purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd.

[0322] Vehicle: DMSO: 0.5% MC=5:95 (v / v).

[0323] Compound 1 solution: Compound 1 is dissolved in the above solvent, and the concentration of Compound 1 is 20 mg / ml.

[0324] 1.2 Establishment of a diet-induced obesity model:

[0325] Animals in the blank control group were fed maintenance feed. Eight animals in the blank control group were selected based on their body weight and continued to be fed maintenance feed until the end of the experiment.

[0326] The model control group and the drug-treated group (compound 1 group) were fed a high-fat diet. After transitioning between the maintenance diet and the high-fat diet at ratios of 3:7, 5:5, and 7:3, the animals were fed the high-fat diet to induce an obesity model. One week after dietary induction, the animals' weight levels were measured. Compared with the animals fed the maintenance diet, the animals' weights were significantly higher, and the difference was statistically significant. The animals were then divided into groups. First, the animals fed the high-fat diet were sorted by weight, and one-quarter of the lower-weight animals that resisted the diet-induced obesity were removed. Then, they were randomly divided into two groups of eight each according to their weight using an S-shaped grouping method. After drug administration, the animals continued to be fed the high-fat diet until the end of the experiment.

[0327] 1.3 Administration method:

[0328] Animals were randomly assigned to groups and administration was initiated. The groups included: blank control group (maintenance diet, Vehicle), model control group (high-fat diet, Vehicle), and compound 1 group (high-fat diet, 100 mg / kg). The administration volume of compound 1 solution was 5 mL / kg. The control group and model control group were administered the same volume of solvent by gavage twice daily, BID, for 58 days.

[0329] 2. Detection indicators

[0330] 2.1 Forelimb grip strength

[0331] Forelimb grip strength tests were performed on day 36 of drug administration. Before the test, the animals were weighed, gently removed from their cages, and their tails were grasped, allowing them to grip the digital dynamometer. Simultaneously, the dynamometer was gently pulled parallel to the bar with the tail. The reading on the dynamometer was recorded when the maximum force was applied to the experimental mouse. Multiple measurements were repeated to ensure accurate results, and the force / body weight (g / g) was calculated.

[0332] 2.2 Treadmill Test

[0333] Before the formal experiment, the mice were trained to run under the following conditions:

[0334] Day 1 training: 10 minutes of free movement on a stationary track; 5 m / min, 5 minutes; 8 m / min, 5 minutes;

[0335] D2 training: 5m / min, 4min; 8m / min, 3min; 12m / min, 3min;

[0336] D3 training: 5m / min, 4min; 10m / min, 3min; 15m / min, 3min;

[0337] During training, the number of electric shocks shall not exceed 5 times and the duration shall not exceed 1 second. If the animal leaves the track, it shall be forced back onto the track to continue training.

[0338] After training, the formal experimental conditions were as follows: 10 m / min, acceleration for 3 min, maintenance for 5 min, then directly to 18 m / min, acceleration for 15 min, maintenance for 900 s, electric shock for 10 s, 50 times, 0.4 mA. During this period, each mouse was placed in a separate track, and the track was cleaned with water and alcohol to avoid odors interfering with the mice's behavior. The animals were allowed at least 1 hour of rest between each formal experiment. During the experiment, attention was paid to minimizing talking and walking to avoid noise interference.

[0339] 2.3 Rotating Rod Test

[0340] Before the formal experiment, the mice were trained to rotarod under the following conditions:

[0341] D1 training: 5 r / min, 1 min; 10 r / min, 1 min; 5-20 r / min, 3 min, experiment duration 5 min.

[0342] D2 training: 5 r / min, 1 min; 10 r / min, 1 min; 5-30 r / min, 3 min, experiment duration 5 min.

[0343] If an animal leaves the spinning bar during training, human intervention may be used to get it back onto the spinning bar to continue training.

[0344] After training, the formal experimental conditions are: 5-40 r / min, acceleration time of 5 min, and total experimental time of 10 min. During the experiment, each mouse is placed in a separate rotating bar compartment. The mice are changed at intervals. The apparatus must be cleaned with water and alcohol to avoid odors interfering with the mice's behavior. Animals should rest for at least 1 hour between each formal experiment. During the experiment, attention should be paid to reducing talking and walking to avoid noise interference.

[0345] 3. Experimental Results

[0346] 3.1 Effect of Compound 1 on forelimb grip strength in diet-induced obesity model mice

[0347] Figure 26 shows the forelimb grip strength test results of the diet-induced obesity model.

[0348] The results showed that the grip strength of the G2 model control group decreased compared with the G1 blank control group; compared with the G2 model control group, the G3 compound 1 group improved the grip strength of the mouse forelimbs and increased the grip strength / body weight ratio.

[0349] 3.2 Effect of Compound 1 on Treadmill Test in Diet-Induced Obesity Model Mice

[0350] Figure 27 shows the results of the treadmill test of the diet-induced obesity model.

[0351] The results showed that, compared with the G2 model control group, the G3 compound 1 group exhibited an increasing trend in running distance, time to exhaustion, and speed. Compared with the G1 blank control group, the G3 compound 1 group had a similar running distance on the treadmill, but significantly higher than the G2 model control group. Therefore, the increased running distance, faster running speed, and longer time to exhaustion in the G3 compound 1 group indicate that the animals administered compound 1 have greater exercise endurance and enhanced muscle endurance.

[0352] 3.3 Effect of Compound 1 on Rotarod Test in Diet-Induced Obesity Model Mice

[0353] Figure 28 shows the results of the rotator test in the diet-induced obesity model.

[0354] The results showed that, compared with the G2 model control group, the G3 compound 1 group exhibited an increasing trend in rotarod duration. Compared with the G1 blank control group, the G3 compound 1 group had a longer rotarod duration than the G1 blank control group and significantly longer than the G2 model control group. Since the rotarod test is used to assess the effect of exercise-induced fatigue, compound 1 has an anti-exercise-induced fatigue effect.

[0355] In summary, compound 1 of the present invention can effectively improve the motor performance of mice in a high-fat diet-induced obesity model.

[0356] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. Use of NLRP3 inhibitors in the preparation of drugs for the prevention or treatment of hepatitis, fatty liver, hyperlipidemia, obesity, obesity complications, metabolic disorders, or for the preparation of drugs to enhance exercise capacity.

2. The use according to claim 1, characterized in that: The use of the NLRP3 inhibitor in the preparation of a medicament for the prevention or treatment of hepatitis, fatty liver, hyperlipidemia, obesity, or obesity complications.

3. The use according to claim 1, characterized in that: The use of the NLRP3 inhibitor in the preparation of medicaments for the prevention or treatment of metabolic disorders.

4. The use according to claim 1, characterized in that: The use of the NLRP3 inhibitor in the preparation of drugs to enhance athletic performance.

5. The use according to claim 2, characterized in that: The use of the NLRP3 inhibitor in the preparation of a medicament for the prevention or treatment of diet-induced obesity or obesity complications.

6. The use according to claim 3, characterized in that: The use of the NLRP3 inhibitor in the preparation of medicaments for the prevention or treatment of glucose metabolism disorders.

7. The use according to claim 4, characterized in that: The aforementioned athletic ability refers to muscle performance or resistance to exercise fatigue.

8. The use according to claim 7, characterized in that: The muscle performance refers to muscle strength and / or muscle endurance.

9. The use according to claim 3, characterized in that: The use of the NLRP3 inhibitor in the preparation of a medicament for the prevention or treatment of glucose metabolism disorders caused by obesity.

10. The use according to claim 8, characterized in that: The muscle strength referred to is the forelimb gripping force.

11. The use according to claim 9, characterized in that: The use of the NLRP3 inhibitor in the preparation of a drug for the prevention or treatment of diabetes caused by obesity.

12. The use according to claim 11, characterized in that: Use of the NLRP3 inhibitor and semaglutide in the preparation of a pharmaceutical composition for the prevention or treatment of diabetes caused by obesity.

13. The use according to claim 12, characterized in that: The diabetes referred to is type 1 diabetes, type 2 diabetes, or gestational diabetes.

14. The use according to any one of claims 1-13, characterized in that: The NLRP3 inhibitors include MCC950, DFV-890, OLT1177, ZYIL-1, VTX-2735, NT-0796, NT-0249, NT-0167, RG-6418, MCC-7840, SB-414, VTX-3232, VENT-02, JTE-162, VENT-01, BGE-100, VENT-05, NT-0527, GDC-2394, MCF-1040, JT002, TTX-01, TT-02332, or CLM-022.

15. The use according to any one of claims 1-13, characterized in that: The NLRP3 inhibitor is selected from compounds of general formula (I), or their stereoisomers, tautomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts, or cocrystals: in: Q is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl is optionally surrounded by 0 to 4 R atoms. q0 replace; R q0 Whether they are the same or different, each is independently selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, halogen, OH, cyano, nitro, -NH2, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl group, -C(=O)OC 3-8 cycloalkyl, -OC(=O)C 3-8 cycloalkyl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl, -C(=O)C 6-10 Aryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -C(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 5-10 heteroaryl, -NHC 1-6 Alkyl, -N(C1) -6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)(C 1-6 Alkyl)2、-NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 2-6 Alkyne group, -NHC(=O)C 2-6 alkenyl, -NH (C=NR) q1 )NR q2 R q3 -C(=O)NR q4 R q5 -SH, -SC 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl or -S(=O)2NR q2 R q3 Each of the heterocyclic alkyl or heteroaryl groups contains 1 to 3 heteroatoms selected from N, O, or S, and the alkyl, alkoxy, -NH2, alkenyl, alkynyl, heterocyclic alkyl, cycloalkyl, aryl, or heteroaryl groups may optionally be further selected from one or more of deuterium, OH, halogen, cyano, =O, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further divided by one to three elements selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or it is replaced by a substituent of =O; Or at least one pair of R q0 The carbon ring and its associated atoms form a 4- to 10-membered carbon ring or a 5- to 10-membered heterocycle, wherein the heterocycle contains 1 to 2 heteroatoms selected from N, O, or S, and the carbon ring or heterocycle is optionally further surrounded by one or more atoms selected from OH, halogens, C, and N. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl or -C(=O)NR q4 R q5 The substituent is replaced by the substituent C. 1-6 Alkyl or C 1-6 The alkoxy group may be further selected from OH, halogen, =O, -NR. q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl or -C(=O)NR q4 R q5 The substituents are replaced; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 R q3 Selected from H or C 1-6 alkyl; R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 Alkyl groups may optionally be further selected from OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 and N atoms form 3 to 8-membered heterocycles, wherein the heterocycles contain 1 to 3 heteroatoms selected from N, O or S; R q6 C 1-6 alkyl; W is selected from O or NHR a ; W1 is 0; R a Selected from H, cyano, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy; X is NH; Y is CR b R c ; R b R c Each is independently selected from H and C 1-6 Alkyl or 3 to 10-membered carbocyclic group, wherein the C 1-6 Alkyl groups are optionally further surrounded by 1 to 4 elements selected from F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 The substituted group is replaced by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O, or S; Or R b With R c Formation of double bonds; R and R1 are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH2, OH, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -O(C=O)-3 to 10-membered carbon cycloyl, -O(C=O)-3 to 10-membered heterocyclic, -(C=O)O-3 to 10-membered carbon cycloyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 4- to 10-membered heterocyclic, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2 or (C=O)NR a1 R a2 The heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR. a1 R a2 =O,C 1-6 Alkyl, C1 -6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy group, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 Alkyl, -(C=O)O-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered carbocyclic, -O(C=O)-3 to 10-membered heterocyclic, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, -NHCOC 1-6 Alkyl groups, -NH(C=O)-3 to 10-membered carbocyclic groups, -NH(C=O)-3 to 10-membered heterocyclic groups, or -(C=O)NR a1 R a2 The substituents are replaced; Alternatively, R and R1 together with their attached atoms form a 4- to 8-membered ring, the 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O, or S, the 4- to 8-membered ring optionally further surrounded by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR. a1 R a2 =O,C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -(C=O)OC 1-6 Substituents of alkyl, 3- to 10-membered carbocyclic or 5- to 10-membered heterocyclic groups; C is a 3- to 10-membered cycloalkyl group; R2 is selected from H, F, Cl, Br, I, OH, -NR a1 R a2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy; G1, G2, and G3 are each independently selected from N or CH; q and r are selected from 0, 1, or 2; n can be selected from 0, 1, 2, or 3.

16. The use according to claim 15, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from compounds represented by general formula (II) or (II-1): or in: The definitions of Q, R, R1, R2, C, G1, G2, G3, r, q, and n are the same as those in general formula (I).

17. The use according to claim 15, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (II-2): Q, W, R, R1, R b R c The definitions of r and q are the same as those in general formula (I); m can be selected from 1, 2, or 3.

18. The use according to claim 16 or 17, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from compounds represented by general formula (III) or (III-1): or The definitions of Q, R, R1, G1, G2, G3, r, and q are the same as those in general formula (I).

19. The use according to claim 18, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein: Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace; R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced; R q4 R q5 Selected from H or C 1-4 alkyl; W is selected from O or NH; R and R1 are each independently selected from deuterium, H, F, CN, OH, and C. 1-6 Alkyl or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl or heterocycle is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, CN or C. 1-6 Substituents of alkoxy groups; Alternatively, R and R1 together with the atoms they are attached to form a 4-membered ring or a 5-membered ring; G1, G2, and G3 are each independently selected from CH; q and r are selected from 0, 1, or 2.

20. The use according to claim 17, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (IV): The definitions of Q, W, R, R1, r, and q are the same as those in general formula (I); m can be selected from 1, 2, or 3.

21. The use according to claim 20, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein: Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace; R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl, -NR q4 R q5 C 3-6 cycloalkyl or C 3-6 Substituents of heterocyclic alkyl groups; R q4 R q5 Selected from H or C 1-4 alkyl; W is selected from O or NH; R and R1 are each independently selected from deuterium, H, F, CN, OH, and C. 1-6 Alkyl or 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl or heterocycle is optionally further surrounded by 1 to 4 heteroatoms selected from OH, F, CN or C. 1-6 Substituents of alkoxy groups; Alternatively, R and R1 together with the atoms they are attached to form a 4-membered ring or a 5-membered ring; q and r are selected from 0, 1, or 2; m can be selected from 1, 2, or 3.

22. The use according to claim 17, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (V): Q, W, R b R c The definition is the same as that described in general formula (I); m can be selected from 1, 2, or 3.

23. The use according to claim 22, wherein the compound or its stereoisomers, tautomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein: Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace; R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced; R q4 R q5 Selected from H or C 1-4 alkyl; W is selected from O or NH; R b R c Each is independently selected from H and C 1-4 Alkyl or 3- to 5-membered carbon cycloyl groups, or R b With R c Formation of double bonds; q and r are selected from 0, 1, or 2; m can be selected from 1, 2, or 3.

24. The use according to claim 17, wherein the compound or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from compounds represented by general formula (VI): Q, W, R b R c The definition is the same as that described in general formula (I); m can be selected from 1, 2, or 3.

25. The use according to claim 24, wherein the compound or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein: Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, and the aryl or heteroaryl group is optionally surrounded by 0 to 4 R atoms. q0 replace; R q0 Whether they are the same or different, each is independently selected from C. 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, -NHC 1-4 Alkyl or -N(C) 1-4 Alkyl group 2, wherein each of the heterocyclic alkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocyclic alkyl, or cycloalkyl group is optionally further surrounded by one or more atoms selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 The substituents are replaced; R q4 R q5 Selected from H or C 1-4 alkyl; W is selected from O or NH; R b R c Each is independently selected from H and C 1-4 Alkyl or 3- to 5-membered carbon cyclogroups; q and r are selected from 0, 1, or 2; m can be selected from 1, 2, or 3.

26. The use according to any one of claims 15 to 25, wherein the compound or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein: Q is selected from Selected from or 27. The use according to any one of claims 15 to 26, wherein the compound or its stereoisomers, solvates, metabolites, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from one of the following structures:

28. The use according to any one of claims 1, 2, 5, 14-27, characterized in that: The obesity-related complication is hepatitis.

29. The use according to any one of claims 1, 2, 5, 14-27, characterized in that: The obesity complication mentioned is fatty liver.

30. The use according to any one of claims 1, 2, 5, 14-27, characterized in that: The obesity complication mentioned is hyperlipidemia.

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