Thyroid hormone receptor β agonist

Abstract

Disclosed in the present invention is a thyroid hormone receptor β (THR-β) agonist. The present invention provides a compound as represented by formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. Compared with VK-2809, the compound provided in the present invention has significantly superior agonistic activity against THR-β than VK-2809, or in terms of in vivo organ / tissue distribution, has a liver / heart distribution ratio or plasma / heart distribution ratio superior to that of VK-2809.

Description

A thyroid hormone beta receptor agonist

[0001] This application claims priority to Chinese patent application 2024116363390, filed on 2024 / 11 / 15; Chinese patent application 2025105167663, filed on 2025 / 04 / 23; and Chinese patent application 2025115799439, filed on 2025 / 10 / 30. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a thyroid hormone β-receptor agonist. Background Technology

[0003] Nonalcoholic steatohepatitis (NASH) refers to liver inflammation caused by factors other than alcohol and other known liver-damaging agents. Over the past 20 years, with improvements in economic and living standards, the incidence of NASH has doubled, becoming the leading cause of chronic liver disease and abnormal liver enzymes. The number of NASH patients worldwide is projected to exceed 350 million by 2030. This disease has become a serious threat to human health.

[0004] The thyroxine receptor beta (THR-β) is a nuclear receptor that receives and regulates signals from thyroid hormones within cells. Thyroid hormones primarily include triiodothyronine (T3) and thyroxine (T4), which are secreted by the thyroid gland and are crucial for maintaining metabolism, growth, development, and other physiological processes. THR-β is located in the cell nucleus, and its main function is to act as a transcription factor after binding to thyroid hormones, influencing cellular function by regulating gene expression. When T3 or T4 binds to THR-β, it activates THR-β, enabling it to bind to specific DNA sequences and thereby control the expression levels of related genes. These genes regulate biological processes such as cellular metabolism, growth, and differentiation.

[0005] The expression levels and functions of THR-β vary across different tissues and organs, making it crucial for the regulation of multiple physiological processes, including those in the heart, liver, brain, bones, and other tissues. Studies have found that thyroid hormones play a central role in liver function by activating THR-β receptors in hepatocytes, influencing a range of health parameters from serum cholesterol and triglyceride levels to pathological fat accumulation in the liver. Activated THR-β can promote hepatic fat breakdown and control the levels of normal mitochondria by regulating mitochondrial activity. However, THR-β exhibits low activity in hepatocytes, and activating its activity can promote liver function. Therefore, developing THR-β agonists could be used to treat liver metabolic diseases such as non-alcoholic fatty liver disease. While natural thyroid hormones and their analogues can activate THR-α, this often leads to side effects. Therefore, the discovery of novel THR-β agonists is of great significance.

[0006] Studies have shown that THR-β agonists can significantly reduce lipid accumulation in the liver of a high-fat diet-induced NASH mouse model, decrease body weight, reduce liver inflammation and fibrosis in NASH mice, and improve insulin resistance-related metabolic disorders in NASH mice (AASLD, 2017, Poster 1969). Simultaneously, THR-β agonists have also demonstrated a good effect in reducing hepatic lipid accumulation in phase II clinical trials (Stephen and Mustafa, Lancet, 2019, 394, 2012-2024). Therefore, activating THR-β in hepatocytes is a potential target for the treatment of NASH. Further research is needed in this field to develop more THR-β agonists for the prevention or treatment of THR-β-related diseases.

[0007] VK2809 (CN1882327A) is a THR-β agonist developed by Viking. While VK2809 exhibits some THR-β agonist activity, its distribution in the liver and heart is relatively low in animal tissue distribution studies. This indicates that the compound places a significant burden on the heart and poses potential safety concerns, thus limiting its dosage and application.

[0008] A class of THR-β agonists has also been reported in existing technologies CN112300211A, CN115974925A, CN116199717A, CN118290483A, WO2021032218A1 and WO2021129827A. Summary of the Invention

[0009] To address the problems of existing THR-β agonists, this invention provides a thyroid hormone β receptor agonist represented by Formula I. The compound provided by this invention exhibits significantly superior THR-β agonistic activity compared to VK-2809; or, in terms of in vivo organ and tissue distribution, its liver / heart distribution ratio or plasma / heart distribution ratio is superior to that of VK-2809.

[0010] This invention provides a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0011] Where ring A is

[0012] R 1 and R 2 Independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C1-C6 alkoxy, C6-C 10 Aryl, C6-C 10 Aryloxy or 5-10 heteroaryl groups;

[0013] R 3 R 3 '、R 4 'and R 4 Independently, it is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 aryloxy groups, 5-10 heteroaryl groups, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -S(=O)2NHR c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NR d R e The C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, C2-C6 alkenyl, C2-C6 ynyl, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10The aryl group and the 5-10 heteroaryl group are optionally substituted with one or more halogens or C1-C6 alkyl groups;

[0014] R 5 Hydroxyl, halogen, C1-C6 alkoxy, -NHC(=O)R c -OP(=O)(OR) b2 )2、-OCH2OP(=O)(OR b2 )2、-NHS(=O)2R c or -OC(=O)R b1 ;

[0015] R a R a1 R a2 R a3 R b and R c Independently, it is hydrogen, C1-C6 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocyclic group, wherein the C1-C6 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocyclic group is optionally substituted by one or more hydroxyl groups, halogens or C1-C6 alkyl groups;

[0016] R b1 Hydrogen, C1-C 20 Alkyl, C 15 -C 20 alkenyl or C 15 -C 20 Alkyne group, the C1-C 20 Alkyl, C 15 -C 20 alkenyl and C 15 -C 20 The alkynyl group may optionally be substituted with one or more halogens or C1-C6 alkyl groups;

[0017] R b2 It can be H, Li, Na, K, or NH4;

[0018] R d and R e Independently hydrogen, C1-C6 alkyl, or -(CH2) m -Phenyl;

[0019] m is 1, 2, or 3;

[0020] n is 1, 2, or 3;

[0021] L 1 For -CHR g -, -O-, -S-, -C(=O)-, -NH-, or -N(C1-C4 alkyl)-;

[0022] R gIt is hydrogen or C1-C6 alkyl, or R g R 2 Together with the carbon atoms attached to each other, they form a 5-6 membered carbon ring, which is optionally substituted by one or more C1-C4 alkyl groups;

[0023] L 2 -L 2a -L 2b -, where L 2b The end is connected to the phosphorus;

[0024] L 2a The octet is -CH2-, -CH2CH2-, -CH=CH-, -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-;

[0025] L 2b For connecting key, -CH2-, -CH2CH2- or -C(R) f )2-; and when L 2a When L is -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-, 2b Not a connection key;

[0026] R f Independently hydrogen, C1-C4 alkyl, halogen or -NH2;

[0027] L 3 It can be -CH2-, -O-, or -S-;

[0028] E 1 For connection key, -CR e1 R e2 -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR h -;

[0029] E 2 For -CR e3 R e4 -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR h -;

[0030] R e1 R e2 R e3 and R e4 Independently, it is H, deuterium, F, Cl, Br, I, CN, NO2, -COOH, OH, NH2, -SH or C1-C6 alkyl; or Re1 With R e2 Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups or 5-6 membered heterocyclic groups, or R e3 With R e4 Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups or 5-6 membered heterocyclic groups, or R e1 R e3 Together with their respective attached carbon atoms, they form 3-6 membered cycloalkyl groups;

[0031] R h Independently hydrogen or C1-C4 alkyl;

[0032] R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus.

[0033] R 6a With R 6b Independently C1-C4 alkyl;

[0034] R 6-1 Independently halogenated, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl or C6-C 10 aryloxy;

[0035] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0036] Y 1 -O- or -NR i -, where R i It is H or C1-C4 alkyl;

[0037] Y 2 -CH2-, -CH2CH2-, or -C(R) j )2-;

[0038] Y 3 is -C(=O)-, -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0039] Y 4 It is a C1-C6 alkyl group; the C1-C6 alkyl group is optionally converted by one or more halogens, hydroxyl groups, cyano groups, C1-C6 alkoxy groups, 3-6 membered cycloalkyl groups, C6-C10 Aryl, C6-C 10 Aryloxy or 5-10 heteroaryl substitutions;

[0040] R j It falls into either of the following two categories:

[0041] Case 1: R j Independently hydrogen, halogen, C1-C4 alkyl, C6-C 10 Aryl or -(CH2) p -C6-C 10 Aryl;

[0042] Case 2: One of R j For hydrogen, another R j for

[0043] p is 1, 2, or 3.

[0044] In one possible solution, ring A is...

[0045] R 1 and R 2 Independently hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C1-C6 alkoxy, C6-C 10 Aryl, C6-C 10 Aryloxy or 5-10 heteroaryl groups;

[0046] R 3 R 3 '、R 4 'and R 4 Independently, it is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 aryloxy groups, 5-10 heteroaryl groups, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NRd R e The C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, C2-C6 alkenyl, C2-C6 ynyl, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 The aryl group and the 5-10 heteroaryl group are optionally substituted with one or more halogens or C1-C6 alkyl groups;

[0047] R 5 Hydroxyl, halogen, C1-C6 alkoxy, -NHC(=O)R c -NHS(=O)2R c or -OC(=O)R b1 ;

[0048] R a R a1 R a2 R a3 R b and R c Independently hydrogen or C1-C6 alkyl;

[0049] R b1 Hydrogen, C1-C 20 Alkyl, C 15 -C 20 alkenyl or C 15 -C 20 Alkyne group, the C1-C 20 Alkyl, C 15 -C 20 alkenyl and C 15 -C 20 The alkynyl group may optionally be substituted with one or more halogens or C1-C6 alkyl groups;

[0050] R d and R e Independently hydrogen, C1-C6 alkyl, or -(CH2) m -Phenyl;

[0051] m is 1, 2, or 3;

[0052] n is 1, 2, or 3;

[0053] L 1 For -CHR g -, -O-, -S-, -C(=O)-, -NH-, or -N(C1-C4 alkyl)-;

[0054] R g It is hydrogen or C1-C6 alkyl, or R g R2 Together with the carbon atoms attached to each other, they form a 5-6 membered carbon ring, which is optionally substituted by one or more C1-C4 alkyl groups;

[0055] L 2 -L 2a -L 2b -, where L 2b The end is connected to the phosphorus;

[0056] L 2a The octet is -CH2-, -CH2CH2-, -CH=CH-, -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-;

[0057] L 2b For connecting key, -CH2-, -CH2CH2- or -C(R) f )2-; and when L 2a When L is -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-, 2b Not a connection key;

[0058] R f Independently hydrogen, C1-C4 alkyl, halogen or -NH2;

[0059] L 3 It can be -CH2-, -O-, or -S-;

[0060] E 1 For connection key, -CR e1 R e2 -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR h -;

[0061] E 2 For -CR e3 R e4 -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR h -;

[0062] R e1 R e2 R e3 and R e4 Independently, it is H, deuterium, F, Cl, Br, I, CN, NO2, -COOH, OH, NH2, -SH or C1-C6 alkyl; or R e1 With R e2Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups or 5-6 membered heterocyclic groups, or R e3 With R e4 Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups or 5-6 membered heterocyclic groups, or R e1 R e3 Together with their respective attached carbon atoms, they form 3-6 membered cycloalkyl groups;

[0063] R h Independently hydrogen or C1-C4 alkyl;

[0064] R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus.

[0065] R 6a With R 6b Independently C1-C4 alkyl;

[0066] R 6-1 Independently halogenated, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl or C6-C 10 aryloxy;

[0067] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0068] Y 1 -O- or -NR i -, where R i It is H or C1-C4 alkyl;

[0069] Y 2 -CH2-, -CH2CH2-, or -C(R) j )2-;

[0070] Y 3 is -C(=O)-, -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0071] Y 4 It is a C1-C6 alkyl group; the C1-C6 alkyl group is optionally converted by one or more halogens, hydroxyl groups, cyano groups, C1-C6 alkoxy groups, 3-6 membered cycloalkyl groups, C6-C 10 Aryl, C6-C 10Aryloxy or 5-10 heteroaryl substitutions;

[0072] R j It falls into either of the following two categories:

[0073] Case 1: R j Independently hydrogen, halogen, C1-C4 alkyl, C6-C 10 Aryl or -(CH2) p -C6-C 10 Aryl;

[0074] Case 2: One of R j For hydrogen, another R j for

[0075] p is 1, 2, or 3.

[0076] In one embodiment, the heteroatom of the heteroaryl group is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three.

[0077] The heteroatoms of the heterocycle are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three.

[0078] In one possible solution, ring A is... Preferred More preferably

[0079] In one particular scheme, R 1 and R 2 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; preferably, R 1 and R 2 Independently, it is a C1-C4 alkyl group; more preferably, R 1 and R 2 It is a methyl group.

[0080] In one particular scheme, R 3 R 3 '、R 4 'and R 4 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -C(=O)OR c -NRa S(=O)2R c -C(=O)NR d R e or -NR d R e The C1-C6 alkyl, C1-C6 alkoxy, -(CR a 2) m -C6-C 10 The aryl group may optionally be substituted with one or more halogens or C1-C4 alkyl groups; preferably, R 3 '、R 4 'and R 4 R is either hydrogen or halogen. 3 Independently, it is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy; more preferably, R 3 'and R 4 For hydrogen, R 4 'For hydrogen or halogen, R 3 It is a C1-C4 alkyl group (e.g., isopropyl).

[0081] In one particular scheme, R 3 '、R 4 'and R 4 It is independently hydrogen or halogen, preferably hydrogen;

[0082] R 3 It is a C1-C6 alkyl, C1-C6 alkoxy, -S(=O)2R c or -S(=O)2NHR c Preferably isopropyl;

[0083] R 5 It is a hydroxyl group.

[0084] In one particular scheme, R 5 It is hydroxyl, halogen, C1-C3 alkoxy, -OP(=O)(ONa)2 or -OCH2OP(=O)(ONa)2, preferably hydroxyl, -OP(=O)(ONa)2 or -OCH2OP(=O)(ONa)2.

[0085] In one particular scheme, R 5 It is a hydroxyl group.

[0086] In one particular scheme, R a R a1 R a2 R a3 R b and R c It is independently hydrogen or C1-C4 alkyl.

[0087] In one particular scheme, R cIt is a C1-C6 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocyclic group, wherein the C1-C6 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocyclic group is optionally substituted with one or more hydroxyl groups, halogens or C1-C6 alkyl groups.

[0088] In one particular scheme, R b1 It is hydrogen, C1-C6 alkyl, C 15 -C 20 Alkyl, C 15 -C 20 alkenyl or C 15 -C 20 Alkyne group; preferably, R b1 It is hydrogen or C1-C4 alkyl.

[0089] In one particular scheme, R b2 It can be Li, Na, or K, preferably Na.

[0090] In one particular scheme, R d and R e It is independently hydrogen or C1-C4 alkyl.

[0091] In a certain scheme, m is 1 or 2.

[0092] In a certain scheme, n is 1 or 2, preferably 1.

[0093] In one of the schemes, L 1 For -CHR g -, preferably -CH2-.

[0094] In one particular scheme, R g It is hydrogen or C1-C4 alkyl, or R g R 2 And together with the carbon atoms attached to each other, they form a 5-6 membered carbon ring; preferably, R g It is hydrogen.

[0095] In one of the schemes, L 2a It can be -CH2-, -O-, -S- or -NH-, preferably -O-.

[0096] In one of the schemes, L 2b It is -CH2- or -CH2CH2-, preferably -CH2-.

[0097] In one of the schemes, L 3 It is -CH2-.

[0098] In one of the schemes, E 1 For connection keys.

[0099] In one of the schemes, E 2 For -CRe3 R e4 -

[0100] In one particular scheme, R e3 and R e4 Independently, it is H, F, Cl, Br, I, or a C1-C6 alkyl group; or R e3 With R e4 Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups.

[0101] In one particular scheme, R 6a With R 6b It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl, more preferably methyl.

[0102] In one particular scheme, R 6 for Or a 4-10 membered heterocyclic group; preferably, R 6 for 4-7-membered heterocyclic alkyl, 4-7-membered heterocyclic alkenyl or benzo5-6-membered heterocyclic alkyl; more preferably, R 6 for Or 4-7 membered heterocyclic alkyl; more preferably, R 6 for Or a 5-6 membered heterocyclic alkyl group, wherein the 5-6 membered heterocyclic alkyl group, in addition to the N atom bonded to phosphorus, contains 0-1 heteroatoms optionally selected from N, O, and S; more preferably, R 6 for Most preferably, R 6 for

[0103] In one particular scheme, R 6-1 It is independently a halogen or a C1-C6 alkyl group, preferably a C1-C4 alkyl group, such as methyl.

[0104] In one of the schemes, Y 1 It can be -O- or -NH-.

[0105] In one of the schemes, Y 2 -CH2- or -C(R) j )2-, preferably -CH2-, Among them, the a end and the Y 1 Connected.

[0106] In one of the schemes, Y 3 It is -OC(=O)-, -C(=O)O- or -OC(=O)O-.

[0107] In one of the schemes, Y 4It is a C1-C6 alkyl group, preferably methyl, ethyl or isopropyl.

[0108] In one particular scheme, R j Independently hydrogen, halogen, C1-C4 alkyl, C6-C 10 Aryl or -(CH2) p -C6-C 10 Aryl group, preferably hydrogen, C1-C4 alkyl or -CH2-phenyl, more preferably hydrogen or C1-C4 alkyl, and even more preferably hydrogen or methyl.

[0109] In a certain scheme, when Y 1 For NR i - At that time, R j This is case 2.

[0110] In one particular scheme, p is 1.

[0111] In one embodiment, the halogen is F, Cl, Br, or I.

[0112] In one embodiment, the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0113] In a certain scheme, when R 3 When the alkyl group is C1-C6, the C1-C6 alkyl group is preferably isopropyl.

[0114] In one embodiment, the C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0115] In one embodiment, the C2-C6 alkenyl group is a C2-C4 alkenyl group.

[0116] In one embodiment, the C2-C6 ynyl group is a C2-C4 ynyl group.

[0117] In one embodiment, the 3-7 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0118] In one embodiment, the heteroatom of the 3-7 membered heterocyclic group is selected from one or two of N, O and S, and the number of heteroatoms is one or two.

[0119] In one embodiment, the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic alkyl group or a 3-7 membered heterocyclic alkenyl group, preferably a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkenyl group, and more preferably a 5-6 membered heterocyclic alkyl group.

[0120] In one embodiment, the C6-C 10 The aryl group is phenyl or naphthyl, preferably phenyl.

[0121] In one embodiment, the C6-C 10 The aryl group is -O-phenyl or -O-naphthyl.

[0122] In one embodiment, the heteroatom of the 5-10 aryl group is selected from one or two of N, O and S, and the number of heteroatoms is one or two.

[0123] In one embodiment, the 5-10 aryl group is a monocyclic, bridged, fused, or spirocyclic ring.

[0124] In one embodiment, the 5-10 member heteroaryl group is a 5-6 member monocyclic heteroaryl group or a 9-10 member bicyclic heteroaryl group, preferably a 5-6 member monocyclic heteroaryl group.

[0125] In one scheme, the C1-C 20 The alkyl group is C1-C6 alkyl or C 15 -C 20 Alkyl group, preferably C 15 -C 20 alkyl.

[0126] In one scheme, the C1-C 20 The alkyl group is a straight-chain or branched alkyl group, preferably a straight-chain alkyl group.

[0127] In one scheme, the C 15 -C 20 The alkenyl group can be a straight-chain or branched alkenyl group, preferably a straight-chain alkenyl group.

[0128] In one embodiment, the heteroatom of the 4-10 member heterocyclic group is selected from one or two of N, O and S, and the number of heteroatoms is one or two.

[0129] In one embodiment, the 4-10 membered heterocyclic group is a 4-7 membered heterocyclic alkyl group, a 4-7 membered heterocyclic alkenyl group, or a benzo5-6 membered heterocyclic alkyl group, preferably a 5-6 membered heterocyclic alkyl group, a 5-6 membered heterocyclic alkenyl group, or a benzo5-6 membered heterocyclic alkyl group, and more preferably a 5-6 membered heterocyclic alkyl group;

[0130] The 4-7 membered heterocyclic alkyl group, for example

[0131] The benzo5-6 membered heterocyclic alkyl group, for example

[0132] In one scheme, when the R g R 2 When the carbon atoms attached to each other form a 5-6 membered carbon ring, the 5-6 membered carbon ring is non-aromatic; preferably, the 5-6 membered carbon ring is...

[0133] In one particular scheme, Y is Preferred

[0134] In one particular scheme, R 6 for Preferred More preferably

[0135] In one particular scheme, R 6 for

[0136] In one of the schemes, L 2 for The a-terminus is connected to a phenyl group.

[0137] In one possible solution, ring A is... Preferred

[0138] In one possible solution, ring A is...

[0139] In one scheme, structural fragments for Preferred

[0140] In one possible solution, ring A is...

[0141] R 1 and R 2 It is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0142] R 3 R 3` R 4 'and R 4 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NR d Re The C1-C6 alkyl, C1-C6 alkoxy, -(CR a 2) m -C6-C 10 The aryl group may be optionally substituted with one or more halogens or C1-C4 alkyl groups;

[0143] R 5 Hydroxyl, halogen, C1-C6 alkoxy, -NHC(=O)R c -NHS(=O)2R c or -OC(=O)R b1 ;

[0144] R a R a3 R b and R c Independently hydrogen or C1-C6 alkyl;

[0145] R b1 It is hydrogen or C1-C6 alkyl;

[0146] R d and R e Independently hydrogen, C1-C6 alkyl, or -(CH2) m -Phenyl;

[0147] m is 1, 2, or 3;

[0148] n is 1, 2, or 3;

[0149] L 1 For -CHR g -, -O-, -S-, -C(=O)-, -NH-, or -N(C1-C4 alkyl)-;

[0150] R g It is hydrogen or C1-C6 alkyl, or R g R 2 And together with the carbon atoms attached to each other, they form a 5-6 membered carbon ring, which is optionally substituted by one or more C1-C4 alkyl groups;

[0151] L 2 -L 2a -L 2b -, where L 2b The end is connected to the phosphorus;

[0152] L 2a The octet is -CH2-, -CH2CH2-, -CH=CH-, -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-;

[0153] L 2b For connecting key, -CH2-, -CH2CH2- or -C(R) f )2-; and when L 2a When L is -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-, 2b Not a connection key;

[0154] R f Independently hydrogen, C1-C4 alkyl, halogen or -NH2;

[0155] L 3 It is -CH2-;

[0156] R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus.

[0157] R 6a With R 6b Independently C1-C4 alkyl;

[0158] R 6-1 Independently halogenated, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl or C6-C 10 aryloxy;

[0159] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0160] Y 1 -O- or -NR i -, where R i It is H or C1-C4 alkyl;

[0161] Y 2 -CH2-, -CH2CH2-, or -C(R) j )2-;

[0162] Y 3 is -C(=O)-, -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0163] Y 4It is a C1-C6 alkyl group; the C1-C6 alkyl group is optionally substituted with one or more halogens, C1-C6 alkoxy groups or 3-6 membered cycloalkyl groups;

[0164] R j It falls into either of the following two categories:

[0165] Case 1: R j Independently hydrogen, halogen, C1-C4 alkyl, C6-C 10 Aryl or -(CH2) p -C6-C 10 Aryl;

[0166] Case 2: One of R j For hydrogen, another R j for

[0167] p is 1, 2, or 3.

[0168] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (IA).

[0169] in,

[0170] R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus.

[0171] R 6a With R 6b Independently C1-C4 alkyl;

[0172] R 6-1 Independently halogenated, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl or C6-C 10 aryloxy;

[0173] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0174] Y 1 -O- or -NR i -, where R i It is H or C1-C4 alkyl;

[0175] Y 2 -CH2-, -CH2CH2-, or -C(R) j )2-;

[0176] Y 3 is -C(=O)-, -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0177] Y 4 It is a C1-C6 alkyl group; the C1-C6 alkyl group is optionally substituted with one or more halogens, C1-C6 alkoxy groups or 3-6 membered cycloalkyl groups;

[0178] R j It falls into either of the following two categories:

[0179] Case 1: R j Independently hydrogen, halogen, C1-C4 alkyl, C6-C 10 Aryl or -(CH2) p -C6-C 10 Aryl;

[0180] Case 2: One of R j For hydrogen, another R j for

[0181] p is 1, 2, or 3.

[0182] In one possible solution, ring A is...

[0183] R 1 R 2 and R 3 Independently C1-C4 alkyl;

[0184] R 4 It is hydrogen or halogen;

[0185] R a3 It is hydrogen or C1-C6 alkyl;

[0186] L 1 For -CHR g -;

[0187] R g It is hydrogen or C1-C4 alkyl, or R g R 2 Together with the carbon atoms they are attached to, they form a 5-6 membered carbon ring;

[0188] L 2 for Where L2b The end is connected to the phosphorus;

[0189] R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-1 heteroatoms, optionally selected from N, O and S, in addition to the N atom connected to phosphorus.

[0190] R 6a With R 6b Independently C1-C4 alkyl;

[0191] R 6-1 It is independently a halogen or a C1-C4 alkyl group;

[0192] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0193] Y 1 It can be -O- or -NH-;

[0194] Y 2 -CH2- or -C(R) j )2-;

[0195] Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0196] Y 4 It is a C1-C6 alkyl group;

[0197] R j Independently hydrogen or C1-C4 alkyl;

[0198] Ideally, R 6 for

[0199] In one possible solution, ring A is...

[0200] R 1 and R 2 Independently C1-C4 alkyl;

[0201] R 3 It is a C1-C6 alkyl, C1-C6 alkoxy, -S(=O)2R c or -S(=O)2NHR c Preferably, it is a C1-C6 alkyl group;

[0202] R c Independently, it is a C1-C6 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocyclic group, wherein the C1-C6 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocyclic group is optionally substituted by one or more hydroxyl groups, halogens or C1-C6 alkyl groups;

[0203] R 4 It is hydrogen or halogen;

[0204] R a3 It is hydrogen or C1-C6 alkyl;

[0205] L 1 For -CHR g -;

[0206] R g It is hydrogen or C1-C4 alkyl, or R g R 2 Together with the carbon atoms they are attached to, they form a 5-6 membered carbon ring;

[0207] L 2 for Where L 2b The end is connected to the phosphorus;

[0208] R 6 for 4-7 membered heterocyclic alkyl groups or those containing one or more R groups 6-1 The substituted 4-7-membered heterocyclic alkyl group; the 4-7-membered heterocyclic alkyl group contains at least one N atom and is connected to phosphorus through the N atom; the 4-7-membered heterocyclic alkyl group contains 0-1 heteroatoms, optionally selected from N, O and S, in addition to the N atom connected to phosphorus.

[0209] R 6a With R 6b Independently C1-C4 alkyl;

[0210] R 6-1 It is independently a halogen or a C1-C4 alkyl group;

[0211] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0212] Y 1 It can be -O- or -NH-;

[0213] Y 2 -CH2- or -C(R) j )2-;

[0214] Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0215] Y 4 It is a C1-C6 alkyl group;

[0216] R j It can be hydrogen, C1-C4 alkyl, or -CH2-phenyl independently;

[0217] Ideally, R 6 for

[0218] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (IB).

[0219] in,

[0220] R 1 R 2 and R 3 Independently C1-C4 alkyl;

[0221] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0222] Y 1 It can be -O- or -NH-;

[0223] Y 2 -CH2- or -C(R) j )2-;

[0224] Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0225] Y 4 It is a C1-C6 alkyl group;

[0226] R j Independently hydrogen or C1-C4 alkyl;

[0227] R 6 for 4-7 membered heterocyclic alkyl groups or those containing one or more R groups 6-1 The substituted 4-7-membered heterocyclic alkyl group; the 4-7-membered heterocyclic alkyl group contains at least one N atom and is connected to phosphorus through the N atom; the 4-7-membered heterocyclic alkyl group contains 0-1 heteroatoms, optionally selected from N, O and S, in addition to the N atom connected to phosphorus.

[0228] R 6a With R 6b Independently C1-C4 alkyl;

[0229] R6-1 It is independently a halogen or a C1-C4 alkyl group;

[0230] Ideally, R 6 for

[0231] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (IB).

[0232] in,

[0233] R 1 R 2 and R 3 Independently C1-C4 alkyl;

[0234] Y is -Y 1 -Y 2 -Y 3 -Y 4 ;

[0235] Y 1 It can be -O- or -NH-;

[0236] Y 2 -CH2- or -C(R) j )2-;

[0237] Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-;

[0238] Y 4 It is a C1-C6 alkyl group;

[0239] R j Independently hydrogen or C1-C4 alkyl;

[0240] R 6 for

[0241] In one embodiment, the compound represented by formula (I) is any of the following compounds:

[0242] In one embodiment, the compound represented by formula (I) is any of the following compounds:

[0243] The present invention also provides a compound of formula (II),

[0244] Among them, rings A and R 1 R 2 R 6 L 1 and L 2 The definition is as described above.

[0245] In one embodiment, the compound represented by formula (II) is any of the following compounds:

[0246] In one embodiment, the compound represented by formula (II) is an intermediate of the compound represented by formula (I) above.

[0247] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula (I) above, its stereoisomer or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0248] The present invention also provides the use of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

[0249] The present invention also provides the use of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing THR-β related diseases.

[0250] In one embodiment, the THR-β-related disease is a liver metabolism-related disease, such as non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

[0251] The present invention also provides the use of the compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a THR-β agonist.

[0252] The present invention also provides a pharmaceutical composition comprising compound A and at least one GLP-1 agonist;

[0253] The compound A is the compound shown in formula (I) above, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0254] In one embodiment, the GLP-1 agonist is semaglutide.

[0255] In one embodiment, the GLP-1 agonist is semaglutide, telpolide, or orforglipron.

[0256] In one embodiment, the GLP-1 agonist is orforglipron. In another embodiment, the GLP-1 agonist is telpolide.

[0257] In one embodiment, the GLP-1 agonist is a peptide GLP-1 agonist or a small molecule GLP-1 agonist;

[0258] The polypeptide GLP-1 agonists may include smegglutide, telpogglutide, liraglutide, lixisenatide, exenatide, mastodextrin, retaglutide, or abiglutide.

[0259] The small molecule GLP-1 agonist may include oxaliplatin or Danuglipron.

[0260] In one embodiment, the administration regimens (including route of administration, frequency of administration, dosage, and interval of administration) of compound A and the GLP-1 agonist in the pharmaceutical composition may be the same or different, and may be adjusted by those skilled in the art as needed to provide optimal therapeutic effects.

[0261] In one embodiment, the compound A and the GLP-1 agonist in the pharmaceutical composition may be administered simultaneously or separately.

[0262] The term "simultaneous administration" refers to, for example, the simultaneous administration of "a single pharmaceutical composition containing compound A" and "a single pharmaceutical composition containing a GLP-1 agonist".

[0263] The term "separate administration" refers to, for example, the administration of a "single pharmaceutical composition containing compound A" and a "single pharmaceutical composition containing a GLP-1 agonist" at different times. For instance, one of the "single pharmaceutical composition containing compound A" and the "single pharmaceutical composition containing a GLP-1 agonist" may be administered first, followed by the other. The separate administration may be administered close in time or far in time.

[0264] Whether administered simultaneously or separately, the administration regimens (including route of administration, frequency of administration, dosage, and interval of administration) of the compound A and the GLP-1 agonist may be the same or different, and may be adjusted by those skilled in the art as needed to provide optimal therapeutic effects.

[0265] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutical excipient.

[0266] In some embodiments, the compound A and the GLP-1 agonist are in therapeutically effective amounts.

[0267] In some embodiments, the pharmaceutical composition is used to prepare a drug for treating diabetes, a weight loss drug, or a fat reduction drug.

[0268] In some implementations, the weight loss or fat reduction medication is used for weight management or to treat diabetes, overweight, or obesity.

[0269] The present invention also provides the use of the above-described composition in the preparation of a drug for treating diabetes, a weight loss drug, or a fat reduction drug.

[0270] In some embodiments, the present invention also provides a compound A for weight management or treatment of diabetes, overweight or obesity, wherein compound A is used in combination with a GLP-1 agonist;

[0271] The compound A is the compound shown in formula (I) above, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0272] In some implementations, the administration method and the definition of the GLP-1 agonist are as described above.

[0273] In some embodiments, the present invention also provides a GLP-1 agonist for weight management or treatment of diabetes, overweight or obesity, wherein the GLP-1 agonist is used in combination with compound A;

[0274] The compound A is the compound shown in formula (I) above, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0275] In some implementations, the administration method and the definition of the GLP-1 agonist are as described above.

[0276] In some embodiments, the present invention also provides a combination of compound A and a GLP-1 agonist for weight management or treatment of diabetes, overweight or obesity;

[0277] The compound A is the compound shown in formula (I) above, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0278] In some implementations, the administration method and the definition of the GLP-1 agonist are as described above.

[0279] In some embodiments of the present invention, the forms "Compound Number-P1" and "Compound Number-P2" are used to name two different stereoconfigurations of compounds having a set of stereoisomers. Unless otherwise specified, the suffixes "P1" and "P2" above indicate that, after chiral resolution of the corresponding compounds using the chiral HPLC conditions described in the present invention, the compound eluted first is designated as P1, and the compound eluted later is designated as P2.

[0280] Unless otherwise specified, the following terms have the meanings shown below.

[0281] In this invention, "stereoisomers" refers to compounds that have the same molecular formula and atomic connection sequence (structure), but whose atoms are arranged differently in three-dimensional space. Stereoisomers include, but are not limited to, enantiomers, diastereomers, and transisomers.

[0282] In this invention, certain chemical groups are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl or C 1-6 Alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5 or 6 carbon atoms as defined below.

[0283] In this invention, the numerical range defined in the substituent, such as 5-10, 3-7, 1-6, 1-4, etc., indicates the integers within that range, such as 1-6 being 1, 2, 3, 4, 5 or 6.

[0284] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group R is linked to other fragments or groups in the compound through this site.

[0285] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C1-C6 alkyl" is not limited to "substituted or unsubstituted", it refers only to "C1-C6 alkyl" itself or "unsubstituted C1-C6 alkyl".

[0286] The term "multiple" refers to 2, 3, 4, or 5.

[0287] When the term "one or more" is used to define the number of a certain group, it means 1, 2, 3, 4 or more.

[0288] In the claims, "one or more" in "satisfies one or more of the following conditions" means 1, 2, 3, 4 or more, and the maximum value of "more" is the largest number of conditions recorded in each claim. For example, if a claim records 8 conditions, then "one or more" in "satisfies one or more of the following conditions" in that claim is any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0289] "Halogens" refer to F, Cl, Br, and I.

[0290] In this invention, the term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). For example, C1-C6 alkyl refers to an alkyl group having 1-6 carbon atoms, preferably a C1-C4 alkyl group having 1-4 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0291] In this invention, the term "alkoxy" refers to -O-alkyl, wherein the definition of alkyl is the same as that of the term "alkyl group". The alkoxy group includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0292] The term "alkenyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6, C2-C4) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond.

[0293] The term "alkynyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6, C2-C4) and having one or more (e.g., 1, 2 or 3) carbon-carbon sp triple bonds.

[0294] The term "cycloalkyl" refers to a saturated monocyclic, spirocyclic, bridged, or fused cyclic group having a specified number of carbon atoms in the ring (e.g., 3-7 members) and whose ring atoms consist solely of carbon atoms. The cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0295] The term "heterocyclic group" refers to a saturated or partially unsaturated cyclic group having a specified number of ring atoms (e.g., 3-7, 4-10, or 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., 1, 2, or 3 of N, O, and S). The heterocyclic group can be monocyclic or polycyclic, and the polycyclic group can have fused, spirocyclic, or bridged ring structures. The heterocyclic group can be a heterocyclic alkyl group, a heterocyclic alkenyl group, or an aromatic fused heterocyclic alkyl group, wherein the aromatic fused heterocyclic alkyl group is linked to other groups via a heterocyclic alkyl group. The heterocyclic group can be monocyclic or polycyclic, and the polycyclic group can have fused, spirocyclic, or bridged ring structures. Preferably, all rings of the heterocyclic group are non-aromatic.

[0296] The term "heterocyclic alkyl" refers to a saturated monocyclic, spirocyclic, bridged, or fused cyclic group having a specified number of ring atoms (e.g., 3-7, 4-10, or 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., 1, 2, or 3 of N, P, O, and S). When it is polycyclic, each ring is saturated. Heterocyclic alkyl groups include, but are not limited to: azirrobutyl, oxobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, and piperazineyl, for example...

[0297] The term "heterocyclic alkenyl" refers to an unsaturated monocyclic, spirocyclic, bridged, or fused cyclic group having a specified number of ring atoms (e.g., 3-7, 4-10, or 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (e.g., one or more of N, P, O, and S), and is not aromatic.

[0298] The term "aromatic cyclic heterocyclic alkyl" refers to a heterocyclic alkyl group and an aromatic ring linked by a fused ring. The aromatic cyclic heterocyclic alkyl group is linked to other groups via the heterocyclic alkyl group. The aromatic ring can be aryl or heteroaryl. In this invention, the aromatic cyclic heterocyclic alkyl group can be a benzo[a]heterocyclic alkyl group, such as a benzo[5-6]-membered heterocyclic alkyl group. The aromatic cyclic heterocyclic alkyl group includes, but is not limited to, […].

[0299] The term "aryl" refers to an aryl group having a specified number of carbon atoms in its ring (e.g., C6-C). 10 The aromatic group of aryl. Examples of aryl include, but are not limited to, phenyl or naphthyl.

[0300] The term "oxyaryl" refers to -O-aryl, where the definition of aryl is the same as that of the term "aryl". The oxyaryl includes, but is not limited to, -O-phenyl or -O-naphthyl.

[0301] The term "heteroaryl" refers to a monocyclic or polycyclic cyclic group having a specified number of ring atoms (e.g., 5-10, 9-10, or 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (e.g., one, two, or three of N, O, and S), and having aromaticity.

[0302] In this invention, the term "carbocyclic ring" refers to a cyclic group formed from carbon atoms that is saturated, unsaturated, or partially unsaturated. In a saturated carbocyclic ring, each carbon atom in the ring is saturated; examples of saturated carbocyclic rings include, but are not limited to, those listed below. In aromatic carbocyclic rings, each ring is aromatic, and examples of aromatic carbocyclic rings include, but are not limited to, those mentioned above. In a partially unsaturated carbide ring, at least one carbon atom is saturated and at least one carbon atom is unsaturated or aromatic. Examples of partially unsaturated carbide rings include, but are not limited to, those mentioned above. The 5-6 membered carbon ring can specifically be a 5- or 6-membered carbon ring. In some embodiments, the 5- or 6-membered carbon ring can specifically be a 5- or 6-membered saturated monocyclic carbon ring, for example...

[0303] As used in this invention, "stereoisomer" refers to all molecules composed of identical atoms linked by the same chemical bond sequence, but whose atoms are arranged differently in three-dimensional space. These isomers have one or more chiral centers and cannot overlap with each other.

[0304] The term "weight management" as used in this invention refers to a comprehensive health intervention strategy whose core objective is to maintain an appropriate body weight and body fat level based on the user's wishes. This strategy encompasses one or more aspects of preventing weight gain and losing weight, and is applicable to various populations. The implementation and evaluation of "weight management" are based on objective, quantifiable medical and physiological indicators, and its specific objectives include, but are not limited to:

[0305] (1) Preventive goal: For individuals who are not obese or overweight, prevent them from developing into an “overweight” or “obese” state.

[0306] (2) Weight Loss Goals: For individuals who have reached the "overweight" or "obese" state, the aim is to achieve clinically significant weight loss through intervention. Effective "weight management" can be manifested in, for example:

[0307] • Weight loss from baseline ≥5%, preferably ≥10%, more preferably ≥15%;

[0308] • Reduce BMI to a healthier range (e.g., from “obese” to “overweight”, or from “overweight” to the normal range);

[0309] • Central obesity indicators such as waist circumference have decreased significantly.

[0310] (3) Controlled goals: For individuals who intend to adjust their weight and body shape, the goal is to achieve changes in their weight, body fat percentage, etc. through intervention. The above interventions can be for therapeutic or non-therapeutic purposes.

[0311] The weight management program can be implemented independently or as part of a comprehensive health management plan that includes dietary adjustments, physical exercise, and behavioral interventions.

[0312] As used in this invention, "overweight" refers to a pre-disease state or mild disease state characterized by an individual's weight exceeding the healthy standard corresponding to their height, or the presence of early signs of abnormal fat accumulation. This state is defined by objective medical indicators, including but not limited to:

[0313] (1) Body Mass Index (BMI) is 25.0 kg / m² 2 Up to 29.9 kg / m 2 Within the range;

[0314] (2) and / or, waist circumference exceeds the health threshold (e.g., according to Asian population standards, ≥90 cm for men and ≥80 cm for women).

[0315] As used in this invention, "obesity" refers to a chronic disease characterized by abnormal or excessive fat accumulation that can impair health. This disease is graded according to its severity and defined by objective medical indicators, such as a BMI of 30.0 kg / m² or higher. 2 The confirmation of the "obesity" status can also be based on or supplemented by other indicators, such as waist-to-hip ratio or body fat percentage.

[0316] The term "obesity" further includes the following subtypes (according to World Health Organization standards):

[0317] Grade I obesity: BMI ≥ 30.0 kg / m² 2 Up to 34.9 kg / m 2 between;

[0318] Grade II obesity: BMI ≥ 35.0 kg / m² 2 Up to 39.9 kg / m 2 between;

[0319] Grade III obesity (severe obesity): BMI of 40.0 kg / m² or higher. 2 .

[0320] As used in this invention, the term "diabetes" refers to a metabolic disease characterized by hyperglycemia, the causes of which include insufficient insulin secretion, impaired insulin action, or both. This term includes type 1 diabetes, type 2 diabetes, and gestational diabetes mellitus. In this invention, diabetic patients can be identified using standards recognized in the art, such as fasting plasma glucose ≥7.0 mmol / L, or 2-hour plasma glucose ≥11.1 mmol / L in an oral glucose tolerance test, or glycated hemoglobin ≥6.5%.

[0321] As used in this invention, the term "therapeutic effective amount" refers to the amount of a compound sufficient to effectively treat the disease or condition described in this invention when administered to a subject. The amount of compound constituting a "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, but may be adjusted as needed by those skilled in the art.

[0322] The subject of application in this invention refers to any animal that needs to receive treatment or prevention of disease, typically a mammal, such as a human. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0323] The term "pharmaceutical excipients" as used in this invention refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. It encompasses all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0324] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0325] The reagents and raw materials used in this invention are all commercially available.

[0326] The positive and progressive effects of this invention are that the compounds provided by this invention have at least one of the following advantages:

[0327] (1) The compound of the present invention has a better THR-β agonist effect compared with the comparative compound VK-2809;

[0328] (2) Compared with the comparative compound VK-2809, the compound of the present invention has a better tissue distribution effect, especially the plasma / cardiac AUC ratio;

[0329] (3) When the compounds of the present invention are used in combination with GLP-1 agonists (such as smegglutide or ozogluconol), they have better effects on weight loss, fat / muscle reduction ratio, and / or LDL-c or TC reduction.

[0330] (4) The compounds of the present invention have good stability, especially under acidic, neutral and alkaline conditions. Attached Figure Description

[0331] Figure 1 shows the change in the average body weight of mice in each group over time during the drug administration period in Test Example 4;

[0332] Figure 2 shows the average triglyceride content in the livers of mice in each group in test example 4;

[0333] Figure 3 shows the results of the glucose tolerance test in each group of mice in test example 4;

[0334] Figure 4 shows the change in the average body weight of mice in each group over time during the drug administration period in Test Example 5.

[0335] Figure 5 shows the average TC content in the plasma of mice in each group before and 2 weeks after drug administration in Test Example 5.

[0336] Figure 6 shows the average triglyceride content in the livers of mice in each group in Test Example 5;

[0337] Figure 7 shows the change in average body weight of mice in each group in Test Example 6 over time. Detailed Implementation

[0338] LCMS conditions:

[0339] Instrument 1: Shimadzu equipped with a PDA or ELSD detector; Column: Chrom Core 120 C18 3um, 3.0*30mm; Mobile phase: 0.04% TFA aqueous solution (A) and 0.02% TFA acetonitrile solution (B); Gradient: ACN from 10% to 80% in 0 min to 6 min, ACN at 80% in 6 min to 6.5 min, ACN from 80% to 10% in 6.5 min to 6.51 min, and ACN at 10% in 6.51 min to 7 min;

[0340] Instrument 2: Agilent 1 with DAD detector; Column: Waters, Xbridge C18 30*2.1mm, 3.5um; Mobile phase: 1.5mL / 4L TFA / H2O solution (A) and 1.5mL / 4L TFA / ACN solution (B); Gradient: ACN from 0% to 95% in 5.8 min, ACN to 100% in 5.8 min to 6.6 min, ACN from 100% to 0% in 6.61 min to 7 min; Column temperature: 40℃; Detection wavelength: 220 / 254nm; Flow rate: 1.0mL / min; Injection volume: 1μL.

[0341] HPLC analysis conditions:

[0342] Instrument: Shimadzu; Column: WelCh XB-C18 3.0*50mm, 3um; Mobile phase: 1.5mL / 4L TFA / H2O solution (A) and 0.75mL / 4L TFA / ACN solution (B); Gradient: ACN from 1% to 5% in 1 minute, ACN from 5% to 100% in 1 minute to 6 minutes, ACN at 100% in 6 minutes to 8 minutes, ACN from 100% to 1% in 8 minutes to 8.01 minutes, ACN at 1% in 8.01 minutes to 10 minutes; Column temperature: 50℃; Detection wavelength: 220 / 254nm; Flow rate: 1.2mL / min; Injection volume: 1μL.

[0343] Chiral HPLC analysis conditions:

[0344] Instrument: PDA Ch2 254nm@4.8nm-Compens; Column: Chiralpak AD-3 50×4.6mm ID, 3um; Mobile phase: A: CO2, B: ethanol (0.2% NH3); Column temperature: 35℃; Detection wavelength: 254nm; Flow rate: 4.0mL / min; Run time: 3min.

[0345] Preparative HPLC (reversed-phase) conditions:

[0346] Instrument: CASSH-Prep-CA; Column: 41-WePure Biotech XP tC18 150×40mm, 7μm; Mobile phase: 0.225% FA in H2O / ACN solution; Gradient: ACN from 10% to 60% over 1 min to 12 min, ACN from 60% to 100% over 12 min to 13 min, ACN at 100% over 13 min to 15 min; Column temperature: 25℃; Detection wavelength: 220 / 254nm; Flow rate: 30mL / min; Injection volume: 0.5mL (sample concentration 25mg / mL).

[0347] Chiral preparative HPLC conditions:

[0348] Instruments: Shimadzu LC8AP PREP-HPLC system; Column: DAIICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase: CO2-EtOH (0.1% NH3H2O); Column temperature: 40℃; Detection wavelength: 254nm; Flow rate: 150mL / min; Run time: 40min.

[0349] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0350] I. Synthesis of intermediate S2

[0351] S1 (500.0 mg, 1.4 mmol) was dissolved in ACN (15 mL) solution, and DIEA (886.7 mg, 6.9 mmol) and S2-1 (398.6 mg, 1.7 mmol) were added. The mixture was stirred at 25 °C for 16 hours and concentrated to dryness. The residue was purified by reverse-phase column chromatography to obtain S2 (320.0 mg, 48%) as a white solid.

[0352] LCMS:[MH] - =477.2

[0353] 1 H NMR (400MHz, CD3OD) δ6.82(d,J=1.8Hz,1H),6.69(s,2H),6.61-6.57(m,1H),6.55-6.50(m,1H),5.68( d,J=12.4Hz,2H),4.12-4.08(m,2H),3.89(s,2H),3.25-3.20(m,1H),2.20(s,6H),1.16-1.10(m,15H).

[0354] The following intermediates are synthesized using methods similar to those described above:

[0355] Intermediate S201:

[0356] LCMS:[M+H] + =453.0.

[0357] II. Synthesis of intermediate S3

[0358] S1 (700.0 mg, 1.9 mmol) was dissolved in ACN (10 mL) solution, and S3-1 (562.6 mg, 2.3 mmol) and DIEA (1.2 g, 9.6 mmol) were added. The mixture was stirred at 25 °C for 16 hours and concentrated to dryness. The residue was purified by reverse-phase column chromatography to obtain S3 (430.0 mg, 47%) as a brown solid, which was directly used in the next step of the reaction.

[0359] LCMS:[M+H] + =481.1

[0360] Synthesis of intermediate s4:

[0361] S1 (1.0 g, 2.7 mmol) and D-alanine ethyl ester (HCl salt) (1.3 g, 8.2 mmol) were dissolved in DCM (30 mL), and PPh3 (899.8 mg, 3.4 mmol), DIEA (2.1 g, 16.5 mmol), and DIAD (693.7 mg, 3.4 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by reverse-phase column chromatography to give S4 (1.0 g, 79%) as a white solid, which could be used directly in the next reaction.

[0362] LCMS:[M+H] + =464.1.

[0363] The following intermediates are synthesized using methods similar to those described above:

[0364] Intermediate s5:

[0365] LCMS:[M+H] + =478.2

[0366] Intermediate s6:

[0367] LCMS: [M+H]+=478.2

[0368] Intermediate s7:

[0369] LCMS: [M+H]+=492.3

[0370] Intermediate s8:

[0371] LCMS: [M+H]+=464.1

[0372] Example 1: Synthesis of Compound 2

[0373] To a solution of s2 (320.0 mg, 0.7 mmol) in DMF (10 mL), dimethylamine (HCl salt) (545.3 mg, 6.7 mmol), BOP (1.2 g, 2.7 mmol), and DIEA (518.6 mg, 4.0 mmol) were added. The mixture was stirred at 25 °C for 3 hours. The residue was diluted with H2O (40 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase column chromatography to give compound 2 (128.0 mg, 38%) as a brown solid.

[0374] LCMS:[M+H] + =506.3

[0375] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),6.83(d,J=1.8Hz,1H),6.72(s,2H),6.61(d,J=8.1Hz,1H),6.46(dd,J=2.0,8.1Hz,1H),5.65-5. 55(m,2H),4.43-4.29(m,2H),3.80(s,2H),3.16-3.09(m,1H),2.65(d,J=9.2Hz,6H),2.16(s,6H),1.17(s,9H),1.09(d,J=7.0Hz,6H).

[0376] Compound 2 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0377] Example 2 Synthesis of Compound 3

[0378] Morpholine (637.2 mg, 7.3 mmol), BOP (1.3 g, 2.9 mmol), and DIEA (567.2 mg, 4.4 mmol) were added to a DMF (10 mL) solution of s2 (350.0 mg, 0.7 mmol). The mixture was stirred at 25 °C for 2 hours. The residue was diluted with H2O (30 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase column chromatography to give compound 3 (189.3 mg, 47%) as a white solid. LCMS: [M+H] + =548.4

[0379] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),6.84(d,J=1.8Hz,1H),6.73(s,2H),6.61(d,J=8.1Hz,1H),6.45(dd,J=1.9,8.2Hz,1H),5.69-5. 53(m,2H),4.45-4.25(m,2H),3.81(s,2H),3.54(d,J=3.0Hz,4H),3.17-3.10(m,5H),2.17(s,6H),1.17(s,9H),1.10(d,J=7.0Hz,6H).

[0380] The obtained compound 3 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0381] The compounds in the following examples were synthesized by a method similar to that described above:

[0382] Example 3 Compound 16:

[0383] LCMS:[M+H] + =506.1

[0384] 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),6.83(d,J=1.8Hz,1H),6.73(s,2H),6.60(d,J=8.1Hz,1H),6.45(dd,J=2.2,8.1Hz,1H),5.63-5. 53(m,2H),4.44-4.29(m,2H),3.80(s,2H),3.53(d,J=3.3Hz,4H),3.16-3.06(m,5H),2.17(s,6H),2.08(s,3H),1.09(d,J=6.8Hz,6H).

[0385] The obtained compound 16 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0386] Example 4 Compound 4:

[0387] LCMS:[M+H] + =508.1.

[0388] 1 H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 6.83 (d, J = 1.9Hz, 1H), 6.72 (s, 2H), 6. 61(d,J=8.1Hz,1H),6.46(dd,J=2.1,8.2Hz,1H),5.62-5.53(m,2H),4.85-4 .80(m,1H),4.43-4.30(m,2H),3.80(s,2H),3.16-3.09(m,1H),2.64(d,J=9 .5Hz, 6H), 2.17 (s, 6H), 1.24 (dd, J=3.4, 6.2Hz, 6H), 1.10 (d, J=6.9Hz, 6H).

[0389] The obtained compound 4 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0390] Example 5 Compound 5:

[0391] LCMS:[M+H] + =550.2.

[0392] 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),6.85(d,J=2.0Hz,1H),6.73(s,2H),6.61(d,J=8.1Hz,1H),6.45(dd,J=2.0,8.1Hz,1H),5.65-5.57(m,2H),4.85 -4.75(m,1H),4.45-4.33(m,2H),3.81(s,2H),3.58-3.48(m,4H),3.16-3. 08(m,5H),2.17(s,6H),1.25(dd,J=2.6,6.2Hz,6H),1.10(d,J=7.0Hz,6H).

[0393] Compound 5 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0394] Example 6 Compound 15:

[0395] LCMS:[M+H] + =522.3

[0396] 1 H NMR (400MHz, CD3CN) δ6.93 (d, J = 1.3Hz, 1H), 6.74 (s, 2H), 6.67-6.64 (m, 1H), 6.62-6.55 (m, 2H), 5.73-5.59 (m, 2H), 4. 35-4.25(m,2H),3.91(s,2H),3.81(s,3H),3.65-3.55(m,4H),3.23-3.15(m,5H),2.23(s,6H),1.16(d,J=7.0Hz,6H).

[0397] The obtained compound 15 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0398] Example 7 Compound 6:

[0399] LCMS:[M+H] + =491.4

[0400] 1 H NMR(400 MHz, DMSO-d6)δ8.99(s,1H),6.83(s,1H),6.67(s,2H),6.61(d,J=8.4Hz, 1H),6.46(dd,J=1.8,8.1Hz,1H),5.14-4.98(m,1H),4.25-4.13(m,2H),4. 11-3.98(m,2H),3.88-3.73(m,3H),3.20-3.10(m,1H),2.65-2.55(m,6H), 2.17(s,6H),1.35-1.25(m,3H),1.25-1.15(m,3H),1.09(d,J=6.8Hz,6H).

[0401] Example 8 Compound 7:

[0402] LCMS:[M+H] + =533.3

[0403] 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),6.84(d,J=1.7Hz,1H),6.68(s,2H),6.61(d,J =8.2Hz,1H),6.45(d,J=8.2Hz,1H),5.26-5.12(m,1H),4.23-4.13(m,2H),4.12-4. 01(m,2H),3.87-3.81(m,1H),3.80(s,2H),3.55-3.45(m,4H),3.16-3.04(m,5H),2 .17(s,6H),1.30(dd,J=4.0,7.0Hz,3H),1.22-1.14(m,3H),1.10(d,J=7.0Hz,6H).

[0404] Compound 7 was separated by chiral HPLC to obtain a pair of stereoisomers in a ratio of 4:6.

[0405] Example 9 Compound 8:

[0406] LCMS:[M+H] + =505.2.

[0407] 1H NMR(400MHz,DMSO-d6)δ9.23-8.73(br s,1H),6.83(s,1H),6.67(s,2H),6.61(d,J=8.3Hz,1H),6.46(dd,J=1.7,8.3Hz,1H),5.09-4.94(m,1H),4.92-4.78(m,1H),4.25-4.11(m,2 H),3.82-3.73(m,3H),3.16-3.10(m,1H),2.63-2.57(m,6H),2.17(s,6H),1.28(d,J=7.0Hz,3H),1.21-1.16(m,6H),1.09(d,J=6.9Hz,6H).

[0408] Compound 8 was separated by chiral HPLC to obtain a pair of stereoisomers in a ratio of 6:4.

[0409] Example 10 Compound 9:

[0410] LCMS:[M+H] + =547.2.

[0411] 1 H NMR(400MHz,DMSO-d6)δ8.99(s,1H),6.83(s,1H),6.67(s,2H),6.60(d,J=8 .1Hz,1H),6.45(d,J=8.1Hz,1H),5.31-5.02(m,1H),4.92-4.78(m,1H),4.2 3-4.10(m,2H),3.79(s,3H),3.55-3.45(m,4H),3.15-3.04(m,5H),2.16(s, 6H), 1.28 (dd, J=4.3, 7.0Hz, 3H), 1.21-1.14 (m, 6H), 1.09 (d, J=6.9Hz, 6H).

[0412] Compound 9 was separated by chiral HPLC to obtain a pair of stereoisomers in a ratio of 9:11.

[0413] Example 11 Compound 10:

[0414] LCMS:[M+H] + =505.4

[0415] 1H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 6.83 (d, J = 1.8Hz, 1H), 6.68 (s, 2H), 6. 61(d,J=8.1Hz,1H),6.46(dd,J=2.0,8.1Hz,1H),4.77(d,J=13.0Hz,1H),4.2 0-4.05(m,4H),3.80(s,2H),3.20-3.05(m,1H),2.59(d,J=9.5Hz,6H),2.17 (s, 6H), 1.42 (d, J = 3.7Hz, 6H), 1.20 (t, J = 7.2Hz, 3H), 1.10 (d, J = 6.8Hz, 6H).

[0416] The obtained compound 10 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0417] Example 12 Compound 11:

[0418] LCMS:[M+H] + =547.4

[0419] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),6.85(d,J=1.8Hz,1H),6.69(s,2H),6.61(d,J=8.1Hz,1H),6.46(dd,J=1.8,8.3Hz,1H),4.90(d,J=13.9Hz,1 H),4.20-4.04(m,4H),3.81(s,2H),3.55-3.45(m,4H),3.16-3.04(m,5H) ,2.18(s,6H),1.45(s,6H),1.21(t,J=7.1Hz,3H),1.10(d,J=7.0Hz,6H).

[0420] Compound 11 was separated by chiral HPLC, yielding a pair of stereoisomers in a 1:1 ratio. The compound that eluted first from the column during the separation process was designated 11-p1, and the compound that eluted later was designated 11-p2.

[0421] Example 13 Compound 13:

[0422] LCMS:[M+H] + =561.4

[0423] 1H NMR (400MHz, DMSO-d6) δ8.97(s,1H),6.84(d,J=1.6Hz,1H),6.68(s,2H),6.60(d,J=8.3Hz,1H),6.45(dd,J=1.9,8.1Hz,1H),4.94-4.78(m,2H),4. 22-4.02(m,2H),3.80(s,2H),3.58-3.40(m,4H),3.19-2.98(m,5H),2.17 (s,6H),1.43(s,6H),1.20(dd,J=4.6,6.2Hz,6H),1.09(d,J=6.9Hz,6H).

[0424] The obtained compound 13 was chirally resolved using the following conditions:

[0425] ES30390-267-P1A1

[0426] Instrument: Supercritical Preparative Liquid Chromatography

[0427] Column:DAICEL CHIRALPAK AD(250mm*50mm,10um)

[0428] Mobile phase:A for CO2 and B for EtOH(0.1%NH3H2O)

[0429] Gradient:B%=35.00%isocratic elution mode

[0430] Flow rate: 200.00 ml / min

[0431] Monitor wavelength: 220 & 254nm

[0432] Column temperature: 40℃

[0433] System back pressure: 100 bar

[0434] A pair of stereoisomers were obtained. The compound that eluted first from the column during the separation process was designated as 13-p1, and the compound that eluted later was designated as 13-p2.

[0435] Example 14 Compound 12

[0436] LCMS:[M+H] + =519.3

[0437] 1 H NMR (400MHz, CD3CN) δ 7.06 (br s,1H),6.93(d,J=1.6Hz,1H),6.72(s,2H),6.68(d,J=8.1Hz,1H),6.55(dd, J=1.9,8.1Hz,1H),5.05-4.90(m,1H),4.17-4.11(m,2H),3.90(s,2H),3.80 (d,J=12.4Hz,1H),3.25-3.15(m,1H),2.71(s,3H),2.69(s,3H),2.20(s,6H ),1.50(d,J=8.8Hz,6H),1.25(dd,J=2.1,6.2Hz,6H),1.16(d,J=6.9Hz,6H).

[0438] The obtained compound 12 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0439] Example 15 Compound 14:

[0440] LCMS:[M+H] + =480.0.

[0441] 1 H NMR(400MHz,DMSO-d6)δ8.98(br s,1H),6.83(d,J=1.9Hz,1H),6.71(s,2H),6.60(d,J=8.1Hz,1H),6.45(dd,J=1.9,8.2Hz,1H),5.75-5.55(m,2H),4.51 -4.13(m,2H),3.79(s,2H),3.75(s,3H),3.19-3.05(m,1H),2.63(d,J=9.5Hz,6H),2.16(s,6H),1.09(d,J=6.9Hz,6H).

[0442] The obtained compound 14 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0443] Example 16 Compound 17

[0444] LCMS:[M+H] + =491.3

[0445] 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),6.83(d,J=1.8Hz,1H),6.68(s,2H),6.61(d,J=8.2Hz,1H),6.46(dd,J=2.1,8.2Hz,1H),4.82(d,J=13.0Hz,1H ),4.21-4.03(m,2H),3.80(s,2H),3.62(s,3H),3.20-3.15(m,1H),2.58( d,J=9.4Hz,6H),2.17(s,6H),1.42(d,J=3.2Hz,6H),1.09(d,J=7.0Hz,6H)

[0446] The obtained compound 17 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0447] Example 17 Compound 19

[0448] LCMS:[M+H] + =533.3

[0449] 1 H NMR(400MHz,CD3CN)δ6.95(s,1H),6.75-6.71(m,2H),6.68-6.63(m,1H),6.60-6.56(m,1H),4.14(d,J=8.7Hz,2H),3.91(s,2H), 3.86-3.77(m,1H),3.70(s,3H),3.65-3.60(m,4H),3.20-3.15(m,4H),2.23(s,6H),1.54(d,J=7.6Hz,6H),1.16(d,J=7.0Hz,6H)

[0450] The obtained compound 19 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0451] Example 18 Compound 20:

[0452] LCMS:[M+H] + =545.2

[0453] 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),6.84(d,J=2.0Hz,1H),6.68(s,2H),6.61(d,J=8.1Hz,1H),6.46(dd,J=2.0,8.4Hz,1H),4.72(d,J=1 3.4Hz,1H),4.12-4.02(m,4H),3.80(s,2H),3.12-2.98(m,5H),2.17(s,6H),1.40-1.30(m,12H),1.25-1.20(m,3H),1.10(d,J=7.0Hz,6H)

[0454] The obtained compound 20 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0455] Example 19 Compound 21:

[0456] LCMS:[M+H] + =560.4

[0457] 1 H NMR (400MHz, DMSO-d6) δ8.97 (s, 1H), 6.84 (d, J = 1.6Hz, 1H), 6.68 (s, 2H), 6. 61(d,J=8.1Hz,1H),6.47(dd,J=2.0,8.4Hz,1H),4.80(d,J=13.8Hz,1H),4.1 3-4.03(m,4H),3.81(s,2H),3.16-3.04(m,5H),2.25-2.20(m,4H),2.18(s, 6H), 2.14 (s, 3H), 1.44 (s, 6H), 1.21 (t, J = 7.1Hz, 3H), 1.10 (d, J = 6.9Hz, 6H).

[0458] Example 20 Compound 18:

[0459] LCMS:[M+H] + =531.1

[0460] 1H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 6.84 (d, J = 1.5Hz, 1H), 6.69 (s, 2H), 6.61 (d, J=8.1Hz,1H),6.46(dd,J=2.0,8.1Hz,1H),4.70(d,J=11.9Hz,1H),4.14(d,J=8.6 Hz,2H),4.06(q,J=7.0Hz,2H),3.80(s,2H),3.17-3.09(m,5H),2.17(s,6H),1.76 -1.70(m,4H),1.43(d,J=3.3Hz,6H),1.19(t,J=7.0Hz,3H),1.10(d,J=6.8Hz,6H).

[0461] The obtained compound 18 was separated by chiral HPLC to obtain a pair of stereoisomers in a 1:1 ratio.

[0462] The compounds listed in Table 1 below were synthesized using a method similar to the one described above:

[0463] Table 1

[0464] Test Example 1: Activity assay of TRβ (LBD) luciferase reporter gene based on HEK293T cells:

[0465] Each hole has been laid with 2x10 holes. 4 In 96-well plates containing HEK293T cells, three DNA plasmids encoding THRβ(LBD)-GAL4, UAS-Luciferase reporter genes, and the control Renilla luciferase were simultaneously transfected using transfection reagents (Fugene, Promega) at a ratio of 20:50:5. After incubating the DNA plasmid mixture with Fugene reagent at room temperature for 15 minutes, 10 μL of the mixture was added to each well, and the cells were incubated at 37°C, 5% CO2 for 6 hours. The test compound was serially diluted 3-fold with DMSO, starting at a concentration of 5 mM, resulting in a total of 8 dilutions. The diluted test compound was added to the transfected cells at a ratio of 1:500, and the cells were incubated at 37°C, 5% CO2 for 24 hours. Firefly luciferase and Renilla luciferase luciferase readings were measured according to the Dual-Glo luciferase kit (Promega) instructions.

[0466] Each plate included control wells for thyroxine T3 treatment (HC) and DMSO treatment (LC). The ratio R of the Firefly luciferase reading to the Renilla luciferase reading in each well was first calculated. The activity level of the test compound was calculated using the following formula: Activity Effect = (R[test compound] - R[LC]) / (R[HC] - R[LC]) × 100%

[0467] The data was fitted with four parameters using GraphPad Prism 7 software, and EC was calculated. 50 The test results are shown in Table 2.

[0468] Test Example 2: Activity assay of TRβ(FL) luciferase reporter gene based on HepG2 cells:

[0469] Each hole has been laid with 4x10mm holes. 4 In 96-well plates containing HepG2 cells, four DNA plasmids encoding THRβ, 2XDR4-p43 reporter genes, Renilla luciferase, and RXRα were simultaneously transfected using transfection reagents (Fugene, Promega) at a ratio of 20:50:5:20. After incubating the DNA plasmid mixture with Fugene reagent at room temperature for 15 minutes, 10 μL of the mixture was added to each well, and the cells were incubated at 37°C, 5% CO2 for 6 hours. The test compound was serially diluted 3-fold with DMSO, starting at a concentration of 5 mM, to a total of 8 dilutions. The diluted test compound was added to the transfected cells at a ratio of 1:500, and the cells were incubated at 37°C, 5% CO2 for 24 hours. Firefly luciferase and Renilla luciferase luciferase readings were measured according to the Dual-Glo luciferase kit (Promega) instructions.

[0470] Each plate included control wells for thyroxine T3 treatment (HC) and DMSO treatment (LC). The ratio R of the Firefly luciferase reading to the Renilla luciferase reading in each well was first calculated. The activity level of the analyte was calculated using the following formula:

[0471] Activity Effect (%) = (R[analyte] - R[LC]) / (R[HC] - R[LC]) × 100%

[0472] The data was fitted with four parameters using GraphPad Prism 7 software, and the EC was calculated.50 The test results are shown in Table 2.

[0473] Table 2

[0474] EC50: A: <100nM, B: 100~500nM, C: 500~1000nM, D: >1000nM.

[0475] As shown in Table 2, the compounds in the embodiments of the present invention have better THR-β agonist effects compared with the comparative compound VK-2809.

[0476] Test Example 3: Absorption and Tissue Distribution of Compounds in Rats

[0477] SPF-grade male SD rats were used, with 12 rats in each group. The compound (1 mg / kg) from the examples or comparative examples was administered sequentially by gavage. Blood samples were collected from 3 rats in each group at 1, 3, 8, and 24 hours post-administration, and the rats were euthanized. Heart, liver, and whole blood were collected. The collected whole blood was immediately transferred to blood collection tubes containing EDTA-K2, inverted at least 5 times to mix thoroughly, and stored on crushed ice. Plasma was separated by centrifugation at 2000g and 4°C for 10 min within 0.5 hours. Plasma samples from each collection point were immediately stored at -70°C or below for later use after centrifugation.

[0478] Tissue samples were processed on dry ice throughout the process. Tissue samples (liver and heart) were removed and placed in homogenization tubes. Four times the weight (w / v) of the tissue was added to 80% acetonitrile homogenate (5 mM PMSF) after an ice bath, and homogenized at 4°C. 800 μL of the sample was centrifuged at 14000 g for 15 min at 4°C, and 300 μL of the supernatant was blown with nitrogen. After drying, the sample was reconstituted with 200 μL of 60% acetonitrile aqueous solution. LC-MS analysis was performed to determine the concentration of compound s1 and calculate the corresponding Cmax value. The AUC value within the 0–8 h interval was calculated using the trapezoidal rule method. The results obtained are the AUC and Cmax values ​​for liver and heart, respectively. The AUC and Cmax ratios for liver and heart were calculated, and the results are shown in Table 3.

[0479] A plasma sample of 80 μL was collected and precipitated with 320 μL of methanol. The sample was centrifuged at 14000 g for 15 min at 4 °C, and 300 μL of the supernatant was removed and purged with nitrogen. After drying, the sample was reconstituted with 100 μL of 60% acetonitrile aqueous solution. LC-MS analysis was performed to determine the concentration of compound s1 and calculate the corresponding Cmax value. The AUC value within the 0–8 h interval was calculated using the trapezoidal rule method. The obtained result is the plasma AUC. The AUC ratio between plasma and heart was calculated, and the results are shown in Table 4.

[0480] Table 3

[0481] Ratio: A: >80; B: 40-80; C: <40.

[0482] Table 4

[0483] Ratio: A:>10; B:5~10; C:<5.

[0484] As can be seen from Tables 3 and 4, the compounds of the present invention have better liver / heart and plasma / heart distribution ratios compared with the comparative compounds, thereby resulting in a lower cardiac burden.

[0485] Test Example 4: Weight Loss Experiment After Combining Compound with GLP-1 Agonist

[0486] 1. Model Building

[0487] Male C57BL / 6J mice aged 5–6 weeks were divided into two groups. One group was given a free diet of 60 kcal% High Fat Diet (HFD) (#D12492) (DIO group), while the other group was fed a normal diet (B6J group). After 19 weeks, all mice underwent an acclimatization diet for 2 weeks, and their body weight was measured weekly. This weight was used for subsequent drug administration.

[0488] 2. Administration

[0489] Mice were grouped according to the table below, and then administered the drugs according to the dosages listed in the table. The day of administration was designated as day 0. Administration methods: Compound 13 and solvent were administered by gavage, while smegglutinin and saline were administered subcutaneously; Dosage frequency: QD; Dosage volume: 5 uL / g (mice body weight); Dosage period: 28 days (4 weeks).

[0490] Table 5

[0491] 3. Data Collection

[0492] During the administration period, the body weight of mice in each group was measured daily and the mice's condition was observed; the body weight of mice in each group was measured once a day, and the corresponding results are shown in Figure 1 and Table 6.

[0493] Table 6

[0494] Two weeks after administration, mice in each group were fasted for 5-6 hours, and anticoagulated whole blood was collected. Plasma was separated, and total cholesterol (TC) was measured using a fully automated blood biochemistry analyzer (HITACHI 3500). The corresponding plasma TC results are shown in Table 9.

[0495] Three weeks after drug administration, an IPGTT test was performed. Mice in each group were fasted for 5-6 hours and injected intraperitoneally with 20% glucose solution. Blood glucose levels were measured at 0 min, 15 min, 30 min, 60 min, 90 min, and 120 min. Line graphs were plotted and the area under the line (AUC) was calculated using Graphpad Prism software. The corresponding results are shown in Figure 3.

[0496] Before grouping and 3 weeks after administration, body composition was measured in all mice using qNMR (Suzhou Numai Analytical Instruments Co., Ltd.) to obtain muscle weight and fat weight values, and the proportion of each to body weight was calculated (formula: muscle or fat proportion to body weight = muscle or fat weight / mouse body weight) and the change after administration relative to before administration (formula: change in muscle or fat = muscle or fat weight after administration - muscle or fat weight before administration).

[0497] The corresponding results are shown in Tables 7 and 8.

[0498] Table 7

[0499] Table 8

[0500] Table 9

[0501] Three weeks after drug administration, liver tissue was collected from mice in each group and weighed. The tissue was homogenized with isopropanol, and the supernatant was collected after standing overnight. Triglyceride levels were measured using a fully automated blood biochemistry analyzer (HITACHI 3500). The corresponding results are shown in Figure 2.

[0502] As can be seen from Figure 1 and Table 6, the weight-reducing effect of the combination of compound 13 and smegglutide is better than that of the smegglutide monotherapy group and the compound 13 monotherapy group.

[0503] As can be seen from Tables 7 and 8, the combination of compound 13 and smegglutide has a higher fat loss effect and a similar muscle loss effect compared with the smegglutide monotherapy group, thus achieving a higher fat loss / muscle loss ratio.

[0504] As shown in Figures 2 and 3 and Table 9, the combination of compound 13 and smegglutide showed better effects on reducing total cholesterol, liver triglycerides, and glucose tolerance compared with the smegglutide monotherapy group and the compound 13 monotherapy group.

[0505] Test Example 5: Weight Loss Experiment After Combination of Compound and GLP-1 Agonist - 2

[0506] 1. Model Building

[0507] 33-week-old mice were divided into two groups: the C57 group and the DIO group. Mice in the C57 group were fed a normal diet, while mice in the DIO group were fed a high-fat diet (Research Diets, D12492i, 60% kcal of fat). After acclimatization, the mice were administered a solvent via gavage for one week to ensure stable weight gain. Drug administration was initiated after the gavage acclimatization period.

[0508] 2. Administration

[0509] Mice were grouped according to the table below, and then administered the drugs according to the dosages listed in the table. The day of the first administration was designated as Day 1. Administration route: PO, administration frequency: QD, for a total of 28 administrations.

[0510] Table 10

[0511] The solvent is a solution of 10% Solutol HS15 and 90% dd water.

[0512] During the drug administration period, the weight and food intake of each mouse were recorded daily. The corresponding results are shown in Figure 4 and Table 11.

[0513] Table 11

[0514] Mice were assessed for fat and muscle mass using a Bruker's minispec LF90II body fat analyzer one day before and 29 days after drug administration. The results are shown in Table 12.

[0515] Table 12

[0516] Two weeks after administration, mice in each group were fasted for 5-6 hours, and anticoagulated whole blood was collected. Plasma was separated, and LDL-c and TC were detected using a fully automated blood biochemistry analyzer (HITACHI 3100). The corresponding results are shown in Figures 5 and 6.

[0517] As can be seen from Figure 4 and Table 11, the weight loss effect of the combination of compound 13 and Orforglipron was better than that of the Orforglipron alone group.

[0518] As shown in Table 12, the combination of compound 13 and Orforglipron had a higher fat loss effect and a similar muscle loss effect compared with the Orforglipron monotherapy group, thus achieving a higher fat loss / muscle loss ratio.

[0519] As can be seen from Figures 5 and 6, the combination of compound 13 and Orforglipron showed better LDL-c and TC reduction effects compared with the Orforglipron alone group.

[0520] Test Example 6: Weight Loss Experiment After Combination of Compound and GLP-1 Agonist - 2

[0521] 1. Model Building

[0522] Male C57BL / 6J mice aged 5–6 weeks were divided into two groups. One group was given a free diet of 60 kcal% High Fat Diet (HFD) (#D12492) (DIO group), while the other group was fed a normal diet (B6J group). After 19 weeks, all mice underwent an acclimatization diet for 2 weeks, and their body weight was measured weekly. This weight was used for subsequent drug administration.

[0523] 2. Administration

[0524] Mice were grouped according to the table below, and then administered the drugs according to the dosages listed in the table. The day of administration was designated as day 0. Administration methods: Compound 13-P1, control compound 1, and Vehicle were administered by gavage; Semaglutide and Tirzepatide were administered subcutaneously. Dosage frequency: QD; Dosage volume: 5 uL / g (mice body weight); Dosage period: 28 days.

[0525] Table 13

[0526] Comparative compound 1

[0527] During the drug administration period, the body weight of mice in each group was measured daily and their condition was observed; the body weight of mice in each group was measured once a day. The corresponding results are shown in Table 14 and Figure 7 below.

[0528] Table 14

[0529] As can be seen from Table 14 above, the compounds in the embodiments of this application, when used in combination with telpolide, also achieve better weight loss effects than the telpolide monotherapy group. Furthermore, compared with comparative compound 1, the compounds in the embodiments of this application, when used in combination with the same dose of smegglutide, achieve better weight loss effects.

[0530] Two weeks after administration, mice in each group were fasted for 5-6 hours, and anticoagulated whole blood was collected. Plasma was separated, and blood lipids (TC) were measured using a fully automated blood biochemistry analyzer (HITACHI 3500).

[0531] Before grouping and 3 weeks after administration, body composition was measured in all mice using qNMR (Suzhou Numai Analytical Instruments Co., Ltd.) to obtain muscle weight and fat weight values, and the proportion of each to body weight was calculated (formula: muscle or fat proportion to body weight = muscle or fat weight / mouse body weight) and the change after administration relative to before administration (formula: change in muscle or fat = muscle or fat weight after administration - muscle or fat weight before administration).

[0532] Solution stability of compound in Test Example 7 - 1

[0533] 1. Preparation of buffer solution:

[0534] pH=2.00 glycine-hydrochloric acid buffer: Weigh 750.78 mg glycine, add 80 mL of deionized water, dissolve and clarify, then adjust the pH to 2.00 with concentrated hydrochloric acid, and then bring the volume to 100 mL with deionized water to obtain 100 mM pH=2.00 glycine-hydrochloric acid buffer.

[0535] pH=5.00 anhydrous sodium acetate-glacial acetic acid buffer: Weigh 820.23 mg of anhydrous sodium acetate, add 100 mL of deionized water to dissolve and clarify, measure 289 μL of glacial acetic acid, add 50 mL of deionized water to dissolve, mix the two until pH=5.00, to obtain 100 mM pH=5.00 anhydrous sodium acetate-glacial acetic acid buffer.

[0536] Potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution (pH 7.00): Weigh 1.36 g of potassium dihydrogen phosphate and dilute to 100 mL with deionized water to obtain a 100 mM potassium dihydrogen phosphate solution. Weigh 1.74 g of dipotassium hydrogen phosphate and dilute to 100 mL with deionized water to obtain a 100 mM dipotassium hydrogen phosphate solution. Mix the two solutions until pH 7.00 is reached to obtain a 100 mM potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution (pH 7.00).

[0537] pH=10.00 glycine-sodium hydroxide buffer: Weigh 750.61 mg glycine and add it to 80 mL of deionized water. After dissolving and clarifying, adjust the pH to 10.00 with 10 N sodium hydroxide, and then bring the volume to 100 mL with deionized water to obtain 100 mM pH=10.00 glycine-sodium hydroxide buffer.

[0538] 2. Preparation and injection of the analyte solution:

[0539] Weigh 1.00 mg of the test compound (the compound in the examples and comparative examples of this invention) into 10 mL volumetric flasks, add 3.0 mL of acetonitrile, shake to dissolve, and then bring the volume to 10 mL with pH 2.00 / 7.00 / 10.00 buffer solution, shake well, and filter. Immediately dilute and inject the prepared solution as the initial sample. Place the remaining sample in a 37.0°C incubator where the temperature has stabilized, and take samples at 2, 4, 6, and 24 hours, diluting and injecting them using the same method as the initial sample. Injection conditions are as follows:

[0540] Table 15

[0541] Comparative compound 2:

[0542] The corresponding results are shown in the table below:

[0543] Table 16

[0544] Table 17

[0545] Table 18

[0546] Solution stability of compound in Example 8 - 2:

[0547] Comparative compound 3

[0548] 1. Prepare the buffer solution according to the test example above.

[0549] 2. Preparation and injection of the analyte solution:

[0550] Weigh 1.00 mg of the test compound (the compound in the examples and comparative compounds of this invention) into a 10 mL volumetric flask, add 4.0 mL of acetonitrile, shake to dissolve, and then add pH 2.00 / 5.00 / 7.00 / 10.00 buffer solutions to the mark. Shake well and filter. Immediately dilute and inject the prepared solution as the initial sample. Place the remaining sample in a 37.0℃ incubator where the temperature has stabilized, and take samples at 1 hour, 3 hours, 5 hours, and 24 hours, and inject them using the same dilution method as the initial sample. The injection conditions are as follows:

[0551] Table 19

[0552] The corresponding results are shown in the table below.

[0553] Table 20

[0554] Table 21

[0555] Table 22

[0556] Table 23

[0557] As can be seen from the results of test examples 7 and 8, the compounds of the present invention exhibit better chemical stability under acidic, neutral, and alkaline conditions compared to the comparative compounds. This not only allows for better application in formulation production and ensures product quality, but also enables them to remain in the gastrointestinal tract for a longer period, demonstrating better efficacy and safety in practical use.

Claims

1. A compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is R 1 and R 2 are independently hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, C1-C6alkoxy, C6-C 10 aryl, C6-C 10 aryloxy, or 5-10 membered heteroaryl; R 3 R 3 '、R 4 'and R 4 Independently, it is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 aryloxy groups, 5-10 heteroaryl groups, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -S(=O)2NHR c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NR d R e The C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, C2-C6 alkenyl, C2-C6 ynyl, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 The aryl group and the 5-10 heteroaryl group are optionally substituted with one or more halogens or C1-C6 alkyl groups; R 5 is hydroxyl, halogen, C1-C6-alkoxy, -NHC(=O)R c , -OP(=O)(OR b2 )2, -OCH2OP(=O)(OR b2 )2, -NHS(=O)2R c or -OC(=O)R b1 ; R a , R a1 , R a2 , R a3 , R b , and R c are independently hydrogen, C1-C6alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocyclyl, wherein the C1-C6alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocyclyl is optionally substituted with one or more hydroxyl, halogen, or C1-C6alkyl; R b1 Hydrogen, C1-C 20 Alkyl, C 15 -C 20 alkenyl or C 15 -C 20 Alkyne group, the C1-C 20 Alkyl, C 15 -C 20 alkenyl and C 15 -C 20 The alkynyl group may optionally be substituted with one or more halogens or C1-C6 alkyl groups; R b2 is H, Li, Na, K or NH4; R d and R e are independently hydrogen, C1-C6alkyl or -(CH2) m -phenyl; m is 1, 2, or 3; n is 1, 2, or 3; L 1 -CHR g -, -O-, -S-, -C(=O)-, -NH-, or -N(C1-C4alkyl)-; R g is hydrogen or CrC6alkyl, or R g , R 2 and the carbon atom to which each is attached together form a 5-6 membered carbocyclic ring, which is optionally substituted by one or more CrC4alkyl; L 2 -L 2a -L 2b -, wherein L 2b and the phosphorus; L 2a is -CH2-, -CH2CH2-, -CH=CH-, -0-, -S-, -C(=0)-, -NH-, -S(=0)2-, -CH2-C(=0)-, -C(=0)NH-, or -NHC(=0)-; L 2b For connecting key, -CH2-, -CH2CH2- or -C(R) f )2-; and when L 2a When L is -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH-, or -NHC(=O)-, 2b Not a connection key; R f independently hydrogen, C1-C4alkyl, halogen, or -NH2; L 3 is -CH2-, -O- or -S-; E 1 is a bond, -CR e1 R e2 -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR h -; E 2 -CR e3 R e4 -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR h -; R e1 R e2 R e3 and R e4 Independently, it is H, deuterium, F, Cl, Br, I, CN, NO2, -COOH, OH, NH2, -SH or C1-C6 alkyl; or R e1 With R e2 Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups or 5-6 membered heterocyclic groups, or R e3 With R e4 Together with the carbon atoms attached to them, they form 3-6 membered cycloalkyl groups or 5-6 membered heterocyclic groups, or R e1 R e3 Together with their respective attached carbon atoms, they form 3-6 membered cycloalkyl groups; R h independently hydrogen or C1-C4alkyl; R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus. R 6a with R 6b independently C1-C4alkyl; R 6-1 Independently halogenated, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl or C6-C 10 aryloxy; Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NR i wherein R i is H or C1-C4 alkyl; Y 2 is -CH2-, -CH2CH2- or -C(R j )2-; Y 3 -C(=O)-, -OC(=O)-, -C(=O)O-, or -OC(=O)O-; Y 4 It is a C1-C6 alkyl group; the C1-C6 alkyl group is optionally converted by one or more halogens, hydroxyl groups, cyano groups, C1-C6 alkoxy groups, 3-6 membered cycloalkyl groups, C6-C 10 Aryl, C6-C 10 Aryloxy or 5-10 heteroaryl substitutions; R j is either of the following two cases: Case 1 : R j independently hydrogen, halogen, C1-C4alkyl, C6-C10aryl, or -(CH2)0-4-C6-C10aryl; 10 independently hydrogen, halogen, C1-C4alkyl, C6-C10aryl, or -(CH2)0-4-C6-C10aryl; p -C6-C 10 aryl; Case 2: one of R j is hydrogen, the other R j is p is 1, 2, or 3.

2. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R 3 R 3 '、R 4 'and R 4 Independently, it is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 aryloxy groups, 5-10 heteroaryl groups, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NR d R e The C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, C2-C6 alkenyl, C2-C6 ynyl, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, C6-C 10 Aryl, C6-C 10 The aryl group and the 5-10 heteroaryl group are optionally substituted with one or more halogens or C1-C6 alkyl groups; R 5 is hydroxyl, halogen, C1-C6alkoxy, -NHC(=O)R c , -NHS(=O)2R c or -OC(=O)R b1 ; R a , R a1 , R a2 , R a3 , R b and R c are independently hydrogen or C1-C6alkyl.

3. The compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein The compound represented by formula (I) satisfies one or more of the following conditions: (1) Ring A is Preferably More preferably (2) R 1 and R 2 are independently hydrogen, halogen, Ci-C6alkyl or Ci-C6alkoxy; preferably, R 1 and R 2 are independently Ci-C4alkyl; more preferably, R 1 and R 2 are methyl; (3)R 3 R 3 '、R 4 'and R 4 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NR d R e The C1-C6 alkyl, C1-C6 alkoxy, -(CR a 2) m -C6-C 10 The aryl group may optionally be substituted with one or more halogens or C1-C4 alkyl groups; preferably, R 3 '、R 4 'and R 4 R is either hydrogen or halogen. 3 Independently, it is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy; more preferably, R 3 'and R 4 For hydrogen, R 4 'For hydrogen or halogen, R 3 It is a C1-C4 alkyl group (e.g., isopropyl); (4) R 5 is hydroxyl; (5) R a , R a1 , R a2 , R a3 , R b , and R c are independently hydrogen or C1-C4alkyl; (6) R b1 is hydrogen, Ci-C6alkyl, C 15 -C 20 alkyl, C 15 -C 20 alkenyl or C 15 -C 20 alkynyl; preferably, R b1 is hydrogen or Ci-C4alkyl; (7) R d and R e independently hydrogen or C1-C4alkyl; (8) m is 1 or 2; (9) n is 1 or 2, preferably 1; (10) L 1 is -CHR g , preferably -CH2-; (11) R g is hydrogen or CrC4alkyl, or R g , R 2 and the carbon atom to which each is attached together form a 5-6 membered carbocyclic ring; preferably R g is hydrogen; (12) L 2a is -CH2-, -O-, -S- or -NH-, preferably -O-; (13) L 2b is -CH2- or -CH2CH2-, preferably -CH2-; (14) L 3 is -CH2-; (15) E 1 is a bond; (16) E 2 -CR e3 R e4 -; (17) R e3 and R e4 are independently H, F, Cl, Br, I, or Ci-C6alkyl; or R e3 and R e4 and the carbon atom to which they are attached together form a 3-6 membered cycloalkyl; (18) R 6a with R 6b independently of one another are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl; (19) R 6 For or 4-10 membered heterocyclyl; preferably, R 6 is 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkenyl or benzo 5-6 membered heterocycloalkyl; more preferably, R 6 is or 4-7 membered heterocycloalkyl; further preferably, R 6 is or 5-6 membered heterocycloalkyl containing 0-1 heteroatoms other than N attached to the N atom and phosphorus; still further preferably, R 6 is Most preferably, R 6 is (20) R 6-1 independently halogen or Ci-C6alkyl, preferably Ci-C4alkyl, e.g. methyl; (21) Y 1 is -O- or -NH-; (22) Y 2 is -CH2- or -C(R j )2-, preferably -CH2-, wherein a is connected to Y 1 connected; (23) Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-; (24) Y 4 is C1-C6alkyl, preferably methyl, ethyl or isopropyl; (25)R j Independently hydrogen, halogen, C1-C4 alkyl, C6-C 10 Aryl or -(CH2) p -C6-C 10 Aryl, preferably hydrogen or C1-C4 alkyl, more preferably hydrogen or methyl; (26) when Y 1 is NR i -, R j is Case 2; And (27)p is 1.

4. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) The halogen is F, Cl, Br or I; (2) The C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) When R 3 When the alkyl group is C1-C6, the C1-C6 alkyl group is preferably isopropyl. (4) The C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy or isopropoxy; (5) The C2-C6 alkenyl group is a C2-C4 alkenyl group; (6) The C2-C6 ynyl group is a C2-C4 ynyl group; (7) The 3-7 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8) The heteroatoms of the 3-7 membered heterocyclic group are selected from one or two of N, O and S, and the number of heteroatoms is one or two; (9) The 3-7 membered heterocyclic group is a 3-7 membered heterocyclic alkyl group or a 3-7 membered heterocyclic alkenyl group, preferably a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkenyl group, more preferably a 5-6 membered heterocyclic alkyl group; (10) The C6-C 10 The aryl group is phenyl or naphthyl, preferably phenyl; (11) The C6-C 10 The aryl group is -O-phenyl or -O-naphthyl; (12) The heteroatom of the 5-10 member heteroaryl group is selected from one or two of N, O and S, and the number of heteroatoms is one or two; (13) The 5-10 member heteroaryl group is a monocyclic, bridged, fused or spirocyclic ring; (14) The 5-10 member heteroaryl is a 5-6 member monocyclic heteroaryl or a 9-10 member bicyclic heteroaryl, preferably a 5-6 member monocyclic heteroaryl; (15) said C1-C 20 alkyl is C1-C6alkyl or C 15 -C 20 alkyl, preferably C 15 -C 20 alkyl; (16) said C1-C 20 alkyl is straight-chain or branched alkyl, preferably straight-chain alkyl; (17) said C 15 -C 20 Alkenyl is straight-chain or branched alkenyl, preferably straight-chain alkenyl; (18) The heteroatoms of the 4-10 member heterocyclic group are selected from one or two of N, O and S, and the number of heteroatoms is one or two; (19) The 4-10 membered heterocyclic group is a 4-7 membered heterocyclic alkyl, a 4-7 membered heterocyclic alkenyl or a benzo5-6 membered heterocyclic alkyl, preferably a 5-6 membered heterocyclic alkyl, a 5-6 membered heterocyclic alkenyl or a benzo5-6 membered heterocyclic alkyl, and more preferably a 5-6 membered heterocyclic alkyl. The 4-7 membered heterocycloalkyl group is for example The benzo5-6 membered heterocycloalkyl group is for example and (20) in certain embodiments, when R g , R 2 and the carbon atom to which each is attached together form a 5-6 membered carbocyclic ring, the 5-6 membered carbocyclic ring is not aromatic; preferably, the 5-6 membered carbocyclic ring is 5. The compound of formula (I) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) Y is Preferably (2) R 6 To Preferably More preferably (3) L 2 To The a-terminus is connected to a phenyl group; (4) Ring A is Preferably More preferably and (5) structural fragments For Preferably 6. The compound of formula (I) as claimed in claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) R 5 is hydroxyl, halogen, C1-C3alkoxy, -OP(=O)(ONa)2, or -OCH2OP(=O)(ONa)2, preferably hydroxyl, -OP(=O)(ONa)2, or -OCH2OP(=O)(ONa)2; (2) R c Ci-C6alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocyclyl, wherein said Ci-C6alkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocyclyl is optionally substituted with one or more hydroxyl, halogen, or Ci-C6alkyl; (3) R b2 Li, Na or K, preferably Na; (4) R 6a with R 6b independently methyl or ethyl; (5) R j independently hydrogen, C1-C4alkyl, or -CH2-phenyl.

7. The compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein The compound represented by formula (I) satisfies one of the following schemes: Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, and Scheme 6: Option 1: Ring A is R 1 and R 2 independently are hydrogen, halogen, Ci-C6alkyl or Ci-C6alkoxy; R 3 R 3` R 4 'and R 4 Independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, 3-7 membered cycloalkyl, -(CR a 2) m -C6-C 10 Aryl, -C(=O)R b -S(=O)2R c -C(=O)OR c -NR a S(=O)2R c -C(=O)NR d R e or -NR d R e The C1-C6 alkyl, C1-C6 alkoxy, -(CR a 2) m -C6-C 10 The aryl group may be optionally substituted with one or more halogens or C1-C4 alkyl groups; R 5 is hydroxyl, halogen, C1-C6alkoxy, -NHC(=O)R c , -NHS(=O)2R c or -OC(=O)R b1 ; R a , R a3 , R b and R c are independently hydrogen or C1-C6alkyl; R b1 is hydrogen or CrC6alkyl; R d and R e independently are hydrogen, C1-C6alkyl or -(CH2) m -phenyl; m is 1, 2, or 3; n is 1, 2, or 3; L 1 -CHR g -, -O-, -S-, -C(=O)-, -NH-, or -N(C1-C4alkyl)-; R g is hydrogen or CrC6alkyl, or R g , R 2 and the carbon atom to which each is attached together form a 5-6 membered carbocyclic ring said 5-6 membered carbocyclic ring being optionally substituted with one or more CrC4alkyl; L 2 -L 2a -L 2b -, where L 2b The end is connected to the phosphorus; L 2a is -CH2-, -CH2CH2-, -CH=CH-, -0-, -S-, -C(=0)-, -NH-, -S(=0)2-, -CH2-C(=0)-, -C(=0)NH-, or -NHC(=0)-; L 2b is a bond, -CH2-, -CH2CH2- or -C(R f )2-; and L 2a is not a bond when L 2b is -O-, -S-, -C(=O)-, -NH-, -S(=O)2-, -CH2-C(=O)-, -C(=O)NH- or -NHC(=O)-. R f independently hydrogen, C1-C4alkyl, halogen, or -NH2; L 3 is -CH2-; R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus. R 6a with R 6b independently C1-C4alkyl; R 6-1 independently halogen, Ci-C6alkyl, Ci-C6alkoxy, C6-Ci0aryl, or C6-Ci0aryloxy; and 10 Ci-C6alkyl, Ci-C6alkoxy, C6-Ci0aryl, or C6-Ci0aryloxy; and 10 C6-Ci0aryl, or C6-Ci0aryloxy; and Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NR i -; wherein R i is H or C1-C4 alkyl; Y 2 is -CH2-, -CH2CH2- or -C(R j )2-; Y 3 -C(=O)-, -OC(=O)-, -C(=O)O-, or -OC(=O)O-; Y 4 Ci-C6-alkyl; said Ci-C6-alkyl is optionally substituted with one or more halogen, Ci-C6-alkoxy or 3-6 membered cycloalkyl; R j is either of the following two cases: Case 1 : R j independently hydrogen, halogen, C1-C4alkyl, C6-C 10 aryl or -(CH2) p -C6-C 10 aryl; Case 2: one of R j is hydrogen, the other R j is p is 1, 2, or 3; Option 2: The compound of formula (I) is a compound of formula (I-A), in, R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-2 heteroatoms, selected from N, O and S, in addition to the N atom connected to phosphorus. R 6a with R 6b independently C1-C4alkyl; R 6-1 independently halogen, Ci-C6alkyl, Ci-C6alkoxy, C6-Ci0aryl, or C6-Ci0aryloxy; and 10 independently halogen, Ci-C6alkyl, Ci-C6alkoxy, C6-Ci0aryl, or C6-Ci0aryloxy; and 10 independently halogen, Ci-C6alkyl, Ci-C6alkoxy, C6-Ci0 Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NR i wherein R i is H or C1-C4 alkyl; Y 2 is -CH2-, -CH2CH2- or -C(R j )2-; Y 3 -C(=O)-, -OC(=O)-, -C(=O)O-, or -OC(=O)O-; Y 4 Ci-C6-alkyl; said Ci-C6-alkyl is optionally substituted with one or more halogen, Ci-C6-alkoxy or 3-6 membered cycloalkyl; R j is either of the following two cases: Case 1 : R j independently hydrogen, halogen, C1-C4alkyl, C6-C 10 aryl or -(CH2) p -C6-C 10 aryl; Case 2: one of R j is hydrogen, the other R j is p is 1, 2, or 3; Option 3: Ring A is R 1 , R 2 , and R 3 are independently C1-C4alkyl; R 4 R is hydrogen or halogen; R a3 is hydrogen or CrC6alkyl; L 1 -CHR g -; R g is hydrogen or CrC4alkyl, or R g , R 2 and the carbon atom to which each is attached together form a 5-6 membered carbocyclic ring; L 2 for wherein L 2b the end and the phosphorus are connected; R 6 for 4-10 membered heterocyclic groups or those with one or more R groups 6-1 A substituted 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains at least one N atom and is connected to phosphorus through the N atom; the 4-10 membered heterocyclic group contains 0-1 heteroatoms, optionally selected from N, O and S, in addition to the N atom connected to phosphorus. R 6a with R 6b independently C1-C4alkyl; R 6-1 independently halogen or C1-C4alkyl; Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NH-; Y 2 is -CH2- or -C(R j )2-; Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-; Y 4 Ci-C6-alkyl; R j independently hydrogen or C1-C4alkyl; Option 4: Ring A is R 1 and R 2 independently C1-C4alkyl; R 3 is Ci-C6-alkyl, Ci-C6-alkoxy, -S(=0)2R c or -S(=0)2NHR c ; R c independently C1-C6alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocyclyl, wherein the C1-C6alkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocyclyl is optionally substituted with one or more hydroxyl, halogen, or C1-C6alkyl; R 4 R is hydrogen or halogen; R a3 is hydrogen or CrC6alkyl; L 1 -CHR g -; R g is hydrogen or CrC4alkyl, or R g , R 2 and the carbon atom to which each is attached together form a 5-6 membered carbocyclic ring; L 2 For wherein L 2b the end and the phosphorus are connected; R 6 for 4-7 membered heterocyclic alkyl groups or those containing one or more R groups 6-1 The substituted 4-7-membered heterocyclic alkyl group; the 4-7-membered heterocyclic alkyl group contains at least one N atom and is connected to phosphorus through the N atom; the 4-7-membered heterocyclic alkyl group contains 0-1 heteroatoms, optionally selected from N, O and S, in addition to the N atom connected to phosphorus. R 6a with R 6b independently C1-C4alkyl; R 6-1 independently halogen or C1-C4alkyl; Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NH-; Y 2 is -CH2- or -C(R j )2-; Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-; Y 4 Ci-C6-alkyl; R j independently hydrogen, C1-C4alkyl or -CH2-phenyl; Option 5: the compound of formula (I) is a compound of formula (I-B), in, R 1 , R 2 , and R 3 are independently C1-C4alkyl; Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NH-; Y 2 is -CH2- or -C(R j )2-; Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-; Y 4 Ci-C6-alkyl; R j independently hydrogen or C1-C4alkyl; R 6 For 4-7 membered heterocyclic alkyl groups or those containing one or more R groups 6-1 The substituted 4-7-membered heterocyclic alkyl group; the 4-7-membered heterocyclic alkyl group contains at least one N atom and is connected to phosphorus through the N atom; the 4-7-membered heterocyclic alkyl group contains 0-1 heteroatoms, optionally selected from N, O and S, in addition to the N atom connected to phosphorus. R 6a with R 6b independently C1-C4alkyl; R 6-1 independently halogen or C1-C4alkyl; Option Six: the compound of formula (I) is a compound of formula (I-B), in, R 1 , R 2 , and R 3 are independently C1-C4alkyl; Y is -Y 1 -Y 2 -Y 3 -Y 4 ; Y 1 is -O- or -NH-; Y 2 is -CH2- or -C(R j )2-; Y 3 is -OC(=O)-, -C(=O)O- or -OC(=O)O-; Y 4 Ci-C6-alkyl; R j independently hydrogen or C1-C4alkyl; R 6 for 8. The compound of claim 1, represented by formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein, The compound of formula (I) is any one of the following compounds: ​ Preferably, the compound of formula (I) is any one of the following compounds:

9. A compound of formula (II) ###0002### (II) wherein Rings A, R 1 , R 2 , R 6 , L 1 and L 2 are as defined in any one of claims 1-8; Preferably, the compound of formula (II) is any one of the following compounds:

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as claimed in any one of claims 1-8, its stereoisomer or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

11. The use of a compound of formula (I) as claimed in any one of claims 1-8, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 10, wherein the use is at least one of the following: (1) Use in the preparation of medicines for the treatment and / or prevention of THR-β related diseases; (2) Use in the preparation of medicines for the treatment and / or prevention of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis; (3) Application in the preparation of THR-β agonists; Preferably, the THR-β-related disease is a liver metabolism-related disease, such as non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

12. A pharmaceutical composition comprising, for example, compound A and at least one GLP-1 agonist; The compound A is the compound of formula (I) according to any one of claims 1-8, its stereoisomer, or a pharmaceutically acceptable salt thereof; Preferably, the GLP-1 agonist is semaglutide, telpolide, or oxaliplatin.

13. Use of the composition of claim 12 in the preparation of a medicine for treating diabetes, a weight loss medicine or a fat reduction medicine.

14. A compound A for use in weight management or the treatment of diabetes, overweight or obesity, wherein, Compound A was used in combination with a GLP-1 agonist; The compound A is the compound of formula (I) according to any one of claims 1-8, its stereoisomer, or a pharmaceutically acceptable salt thereof.

15. A GLP-1 agonist for use in weight management or the treatment of diabetes, overweight or obesity, wherein, GLP-1 agonist and compound A in combination; The compound A is the compound of formula (I) according to any one of claims 1-8, its stereoisomer, or a pharmaceutically acceptable salt thereof.

16. A compound A in combination with a GLP-1 agonist for weight management or treatment of diabetes, overweight or obesity; The compound A is the compound of formula (I) according to any one of claims 1-8, its stereoisomer, or a pharmaceutically acceptable salt thereof.

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