Combinations comprising THR-beta agonists and GLP-1R agonists for treatment of liver disorders or cardiac metabolic diseases

Abstract

Provided herein are combinations comprising a glucagon-like peptide-1 receptor (GLP-1R) agonist and a thyroid hormone receptor beta (THRbeta) agonist, and methods comprising administering such combinations to a subject in need thereof.

Description

Cross Reference to Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 495,049, filed April 7, 2023, U.S. Provisional Application No. 63 / 526,362, filed July 12, 2023, and U.S. Provisional Application No. 63 / 615,985, filed December 29, 2023, each of which is incorporated by reference herein in its entirety for all purposes. BACKGROUND

[0002] GLP-1 is an incretin hormone of 30 amino acids long that is secreted by L cells in the gut in response to food intake. GLP-1 has been shown to stimulate insulin secretion, decrease glucagon secretion, suppress gastric emptying, reduce appetite, and stimulate beta cell proliferation in a physiological and glucose-dependent manner. Commercially available GLP-1R agonists are peptides that are typically administered by subcutaneous injection. Liraglutide and semaglutide are among the first GLP-1 peptides approved for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Semaglutide is also approved as a bioavailable oral formulation for the treatment of T2DM.

[0003] In healthy subjects, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating the pancreas to secrete glucose-dependent insulin, resulting in increased peripheral glucose uptake. GLP-1 also suppresses glucagon secretion, resulting in decreased hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small intestinal motility, thereby delaying food absorption.

[0004] Thyroid hormone (TH) is synthesized in the thyroid gland in response to pituitary secretion of thyroid-stimulating hormone (TSH). Thyroid hormone exerts its effects by binding to thyroid hormone receptors (THR). Thyroid hormone receptors belong to the nuclear receptor family and regulate target gene expression. There are two distinct subtypes of thyroid hormone receptors, THR alpha and THR beta. THR alpha is mainly distributed in cardiac tissue and plays an important role in regulating cardiac function. The THR beta subtype is mainly expressed in the liver and pituitary and regulates cholesterol metabolism and the secretion of thyroid-stimulating hormone.

[0005] At normal levels, thyroid hormone TH maintains body weight, metabolic rate, body temperature, and mood, and is responsible for regulating serum cholesterol. Attempts have been made to use thyroid hormone to regulate serum cholesterol. However, given the potential for side effects on the heart (e.g., tachycardia and arrhythmias, heart failure, and thyroid axis function, muscle metabolism, and osteoporosis) from taking natural thyroid hormone, they are not suitable for treating high cholesterol and obesity. Results from studies of selective THR knockout animals, as well as some selective THR ligands, suggest that these side effects of thyroid hormone on the heart can be attributed to THRa, and not THRb. Thus, a THRb selective ligand can provide the benefits of a THR agonist (e.g., lowering cholesterol) without the adverse effects associated with THRa.

[0006] Combination therapy with known agonists can produce unexpected synergistic effects and have a greater degree of improved effect than either agent used alone, but the effects of combination therapy are difficult to predict. Developing new combination therapies to treat various liver disorders and cardiometabolic diseases, including obesity, remains a key unmet clinical need.

[0007] GLP-1R regulates postprandial glycemia and satiety, leading to weight loss, but its efficacy is limited by metabolic adaptation, a compensatory process that reduces energy expenditure (EE). Moreover, the high dose levels of GLP-1R required to achieve clinically meaningful weight loss are associated with more severe and frequent GI-related side effects, including nausea and vomiting, which negatively impact patient compliance. In a meta-analysis evaluating the efficacy and safety of orforglipron as a weight loss drug, the results showed that the overall incidence of adverse events was significantly higher with all doses of orforglipron compared to placebo, and the higher the dose, the higher the risk ratio. Gastrointestinal side effects were the main side effects, with dose dependence, which mainly included nausea, vomiting, constipation, and gastroesophageal reflux (Dutta et al., Obes Sci Pract. April 2024; 10(2):e743 PMID: 38414573). The incidence of total adverse events was significantly higher with orforglipron at daily doses of 12 mg, 24 mg, 36 mg, and 45 mg compared to placebo. (Frias et al., Lancet . 2023;402(10400):472-483, Wharton et al., N Engl J Med . 2023;389(10):877-888, Pratt et al., Diabetes Obes Metabol .2023;25:2642-2649). Thus, dose-dependent gastrointestinal side effects are a persistent challenge in the GLP-1 treatment field.

[0008] Mechanisms to improve the effectiveness of low-dose GLP-1 based therapies can reduce GI-related side effects and improve patient compliance and treatment efficacy. SUMMARY

[0009] In one aspect, the present disclosure relates to a combination of a THRbeta agonist, or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of a liver disorder or a cardiometabolic disease in a patient in need thereof.

[0010] In one aspect, the present disclosure relates to a method of administering a THRbeta agonist, or a pharmaceutically acceptable salt thereof, and administering a GLP-1R agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of a liver disorder or a cardiometabolic disease in a patient in need thereof.

[0011] In one aspect, the present disclosure relates to a method of administering a pharmaceutical composition comprising a THRbeta agonist, or a pharmaceutically acceptable salt thereof, and administering a pharmaceutical composition comprising a GLP-1R agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of a liver disorder or a cardiometabolic disease in a patient in need thereof.

[0012] In one aspect, the present disclosure relates to a method of administering a pharmaceutical composition comprising a THRbeta agonist, or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of a liver disorder or a cardiometabolic disease in a patient in need thereof.

[0013] In some embodiments, the THRbeta agonist of the combination of the present disclosure is a compound of formula (II-1) (II-1) wherein: R1is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted C 3-6 cycloalkyl, the substituents being selected from the group consisting of a halogen atom, a hydroxyl group and C 1-6 alkoxy; R2and R3are each independently selected from the group consisting of a halogen atom and substituted or unsubstituted C 1-6 alkyl, the substituents being selected from the group consisting of a halogen atom, a hydroxyl group and C 1-6 alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 aliphatic ring, or a substituted or unsubstituted C 5-10 aromatic ring, the substituents being one or more species selected from the group consisting of hydrogen, a halogen atom, a hydroxyl group, -OCF3, -NH2, -NHC 1-4Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atoms are selected from the group consisting of F, Cl, and Br. Or its pharmaceutically acceptable salt.

[0014] In some embodiments, the combined THRβ agonist of this disclosure is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0015] Or its pharmaceutically acceptable salt.

[0016] In some embodiments, the combined THRβ agonist of this disclosure is compound 9: (9) Or its pharmaceutically acceptable salt.

[0017] In some embodiments, the combined THRβ agonist of this disclosure is a potassium salt of compound 9: In some embodiments, the combined GLP-1R agonist of this disclosure is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0018] In some embodiments, the combined GLP-1R agonist of this disclosure is a compound of formula (I-1a): (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0019] In some implementations, the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3, –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 cycloalkyl or C 6-10 aryl, wherein the alkyl, alkylene, heteroalkyl, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkoxy, hydroxyl, -CN, or oxo group is substituted, and the cycloalkyl, heterocyclic, or aryl group is optionally substituted with one or more halogens, C, or alkyl groups. 1-6 Alkyl or -CN substitution; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 It is a halogen, hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ -(C 2-6 (-(C-)-(O)OH, -(C-) 1-6 alkylene)-C(O)OH, -NR N12 -(C 1-6 alkylene)-C(O)OH, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R N12 and R N12’ Independently H or C 1-6 alkyl; X 1 yes or , Where R 3 and R 3’ Independently H, D or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with deuterium; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 3-10 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl or heterocyclic group, optionally constituting one or more C 1-6 Alkyl, halogen, -CN or oxo groups are substituted.

[0020] In some embodiments, the combined GLP-1R agonist of this disclosure is a compound of formula (I-5). (I-5) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; Branch C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0021] In some embodiments, the combined GLP-1R agonists of this disclosure are compounds 1-2: (1-2) Or its pharmaceutically acceptable salt.

[0022] In some embodiments, the combined GLP-1R agonist of this disclosure is a meglumine salt of compounds 1-2.

[0023] In some embodiments, the combined THRβ agonists of this disclosure are selected from those listed in Tables 6-11.

[0024] In some embodiments, the combined GLP-1R agonists of this disclosure are selected from those listed in Tables 1-5.

[0025] In some embodiments, the combined GLP-1R agonists of this disclosure are selected from those listed in Table 5A.

[0026] In some embodiments, the combined THRβ agonist of this disclosure is compound 9. (9), Furthermore, the GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tirzepatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the combined THRβ agonist of this disclosure is compound 9. (9), Furthermore, the GLP-1R agonist is omeglione or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the combined THRβ agonist of this disclosure is resmetirom, VK2809, sobetirome, eprotirome, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compounds 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0029] In some embodiments, the combined THRβ agonist of this disclosure is compound 9. (9), Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 (1-2), Or its pharmaceutically acceptable salt.

[0030] In one aspect, this disclosure relates to a method of treating a patient with liver disease or cardiometabolic disease, the method comprising administering the combination disclosed herein to the patient.

[0031] In one aspect, this disclosure relates to a method of treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient a therapeutically effective amount of the combination disclosed herein.

[0032] In one aspect, this disclosure relates to a method for increasing the ratio of lean body mass to total weight in a patient in need, the method comprising administering the combination disclosed herein to the patient.

[0033] In one aspect, this disclosure relates to a method for reducing the ratio of fat mass to total body weight in a patient in need, the method comprising administering the combination disclosed herein to the patient.

[0034] In one aspect, this disclosure relates to a method for achieving weight loss in a patient in need, the method comprising administering the combination disclosed herein to the patient.

[0035] In some implementation schemes, the patient's body mass index (BMI) is 20 kg / m².2 Up to 25 kg / m 2 .

[0036] In some implementation schemes, the patient's BMI is 25 kg / m². 2 Up to 30 kg / m 2 .

[0037] In some implementation schemes, the patient's BMI is 20 kg / m². 2 Or higher.

[0038] In some implementation schemes, the patient's BMI is 25 kg / m². 2 Or higher.

[0039] In some implementation schemes, the patient's BMI is 27 kg / m². 2 Or higher.

[0040] In some implementation schemes, the patient's BMI is 30 kg / m². 2 Or higher.

[0041] In some implementations, cardiometabolic disease is defined as obesity.

[0042] In some implementations, the liver condition is NASH.

[0043] In some implementations, the liver condition is liver fibrosis.

[0044] In some implementations, the THRβ agonist and the GLP-1R agonist are administered substantially simultaneously.

[0045] In some implementations, the THRβ agonist is administered after the GLP-1R agonist.

[0046] In some implementations, the THRβ agonist is administered before the GLP-1R agonist.

[0047] In some implementations, the THRβ agonist is selective for THRβ. Attached Figure Description

[0048] Figure 1 A study design for the treatment of NASH using a combination of a THRβ agonist (compound 9) and a GLP-1R agonist (semaglutide) was described.

[0049] Figure 2 A graph depicts the change (%) in body weight relative to baseline in DIO-NASH mice treated with compound 9 alone and in combination with smegglutinin over several days.

[0050] Figure 3A study design for long-term weight management using a combination of a THRβ agonist (compound 9) and a GLP-1R agonist (smegglutinin) was described.

[0051] Figure 4A A graph depicts the changes in weight loss in diet-induced obese (DIO) mice over several days of treatment with smegglutinin alone or in combination with compound 9.

[0052] Figure 4B A graph depicts the changes in weight loss in DIO mice after treatment with smegglutinin alone or in combination with compound 9.

[0053] Figure 5A A graph depicts the daily food intake of DIO mice over several days of treatment with smegglutinin alone or in combination with compound 9.

[0054] Figure 5B A graph depicts the cumulative food intake of DIO mice over several days of treatment with smegglutinin alone or in combination with compound 9.

[0055] Figure 6A A graph depicts the changes in lean body mass in DIO mice after treatment with semaglutide alone or in combination with compound 9. **** indicates a p-value < 0.0001 relative to the treatment. Figure 6B A graph depicts changes in fat mass in DIO mice after treatment with semaglutide alone or in combination with compound 9. **** indicates p-value < 0.0001 relative to the medium; #### The p-value is <0.001 relative to smegglutinin.

[0056] Figure 7A A graph depicts the changes in lean body mass percentage (LBS) in DIO mice after treatment with semaglutide alone or in combination with compound 9. Treatment with semaglutide alone increased LBS by 3.9%, while treatment with semaglutide in combination with compound 9 increased LBS by 13.9%. **Indicates p-value of 0.0028, and ****Indicates p-value < 0.0001.

[0057] Figure 7B A graph depicts the change in the percentage of body fat in DIO mice after treatment with smegglutinin alone or in combination with compound 9.

[0058] Figure 8A graph depicts the percentage change in body weight relative to baseline in DIO mice after treatment with semaglutide alone or in combination with compound 9, where compound 9 was added 14 days after semaglutide monotherapy.

[0059] Figures 9A-9C A graph depicts the percentage change in body weight (BW) relative to baseline in DIO mice after treatment with semaglutide alone or in combination with compound 9. In a post-hoc analysis, mice were divided into two subgroups based on their initial body weight ( Figure 9A The body weight ranged from 50-54.9 grams (low BW) and 55-60 grams (high BW). Compared to mice with lower initial body weight ( Figure 9B Compared to mice with higher initial body weight, compound 9+ smegglutinin showed better results. Figure 9C It has a high therapeutic effect.

[0060] Figure 10 A study design was described to evaluate the effects of treatment with compound 9 alone and in combination with smegglutinin for 6 weeks on metabolic parameters, energy expenditure, and glycemic control in male DIO mice under thermoneutral conditions.

[0061] Figure 11 A graph depicts the percentage change in body weight relative to baseline in DIO mice after treatment with semaglutide alone, compound 9 alone, semaglutide in combination with compound 9, or tesipatide alone. After 6 weeks of treatment, compound 9 + semaglutide induced additional body weight loss comparable to that of tesipatide. ****p < 0.0001; *p < 0.05.

[0062] Figure 12 A graph depicts the percentage change in body weight relative to baseline in DIO mice after treatment with semaglutide alone, compound 9 alone, semaglutide in combination with compound 9, or tesipatide alone. Compared with semaglutide alone, compound 9 + semaglutide induced an additional approximately 7% weight loss.

[0063] Figure 13 A pair of graphs depicting the percentage changes in adipose body mass and lean body mass after treatment with semaglutide alone, compound 9 alone, semaglutide in combination with compound 9, or tesipatide. Body composition of mice was assessed at weeks 1 and 6 of the study using an EchoMRI 3-1 body composition analyzer. Compared to semaglutide alone, compound 9 + semaglutide enhanced adipose reduction, while the reduction in lean body mass was similar between semaglutide alone and the combination of compound 9 + semaglutide. ****p < 0.0001; *p < 0.05.

[0064] Figure 14 A graph depicts the mean food intake in DIO mice after treatment with semaglutide alone, compound 9 alone, semaglutide in combination with compound 9, or tesipatide. Compound 9 normalized the reduction in semaglutide-induced food intake. ****p < 0.0001; ***p < 0.001; **p < 0.01.

[0065] Figure 15 Three graphs depict energy expenditure (EE) in DIO mice assessed 4 weeks after treatment with semaglutide alone, compound 9 alone, semaglutide in combination with compound 9, or tesipatide. Compound 9 plus semaglutide prevented the decrease in energy expenditure (EE) induced by weight loss. Combination of compound 9 with semaglutide restored energy expenditure to normal (DIO Veh) levels. ****p < 0.0001; *p < 0.05.

[0066] Figure 16 A graph depicting uncoupling protein 1 (UCP-1) expression in DIO mice after treatment with smegglutinin alone, compound 9 alone, smegglutinin in combination with compound 9, or tesipatide. Obesity reduced UCP-1 expression in subcutaneous adipose tissue. Compound 9 partially restored the obesity-induced UCP-1 reduction. *p<0.05, one-way ANOVA followed by Fisher's LSD test.

[0067] Figure 17 A graph depicts the results of glucose tolerance tests (GTT) performed 4 weeks after treatment with semaglutide alone, compound 9 alone, semaglutide in combination with compound 9, or tesipatide. Compound 9 + semaglutide further enhanced glucose tolerance compared to semaglutide alone. ***p < 0.001; **p < 0.01; *p < 0.05.

[0068] Figure 18 A graph depicting the change in body weight relative to baseline over time in DIO hGLP-1R mice after treatment with compound 9 alone, omeglione alone, or omeglione in combination with compound 9. Daily changes in body weight (g) relative to baseline are expressed as mean (SE), with n = 6–7 mice per group. The mediator, compound 9 (3 mg / kg), and omeglione (0.2 mg / kg and 2 mg / kg) were administered once daily via oral tube feeding.

[0069] Figure 19A graph depicting the change in body weight (BW) relative to baseline in DIO hGLP-1R mice after treatment with compound 9 alone, omegaliton alone, or omegaliton in combination with compound 9. Change in BW (g) relative to baseline at 20 days is expressed as mean (SD), with n = 6–7 mice per group. Statistical significance was determined by ordinary one-way ANOVA and multiple comparisons correction. *p < 0.05, ***p < 0.001, ****p < 0.0001. ns = not significant.

[0070] Figure 20 A graph depicting daily food intake over time in DIO hGLP-1R mice treated with compound 9 alone, omega-9 alone, or omega-9 in combination with compound 9 is presented. Daily food intake (g) is shown as mean (SE), with n = 6–7 mice per group. Body weight composition was measured on day 19, which resulted in a sharp decrease in food intake.

[0071] Figure 21 A to Figure 21 B depicts two graphs showing the changes in body composition relative to baseline in DIO hGLP-1R mice after treatment with compound 9 alone, omega-1R alone, or omega-1R in combination with compound 9. Day 19 fat mass ( Figure 21 A) and lean body mass ( Figure 21 B) (g) Changes relative to baseline are expressed as mean (SD), n = 6–7 mice per group. Statistical significance was determined by ordinary one-way ANOVA and multiple comparisons correction. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ns = not significant.

[0072] Figure 22 A graph depicting terminal subcutaneous fat in DIO hGLP-1R mice after treatment with compound 9 alone, omegaliton alone, or omegaliton in combination with compound 9. Data represent mean (SD) subcutaneous fat (mg) collected at the end of the study, n = 6–7 mice per group. Statistical significance was determined by ordinary one-way ANOVA and multiple comparisons correction. *p < 0.05. ns = not significant.

[0073] Figure 23A graph depicting the final liver weight of DIO hGLP-1R mice after treatment with compound 9 alone, omega-9 alone, or omega-9 in combination. Data represent the mean (SD) liver weight (mg) collected at the end of the study, with n = 6–7 mice per group. Statistical significance was determined by ordinary one-way ANOVA and multiple comparisons correction. *p < 0.05, **p < 0.01, **p < 0.01, ****p < 0.0001. ns = not significant.

[0074] Figure 24 A to Figure 24 B depicts two graphs showing the concentration-time profile of compound 9 and omega-9 in DIO hGLP-1R mice. Compound concentrations are shown as compound 9 alone. Figure 24 A) or Oglelon ( Figure 24 B) or the average over time (SD) of the combination. Data represent sparse sampling for each treatment group as follows: before dose (0 hours after dose), n = 3; 2 hours after dose, n = 3; 4 hours after dose, n = 4; 8 hours after dose, n = 4; 24 hours after dose, n = 7. Nominal dose and time are shown.

[0075] Figure 25 A graph depicts the weight loss induced by combination therapy of compound 9 + compounds (1-2) compared to monotherapy in diet-induced obese transgenic hGLP1R mice.

[0076] Figure 26 A graph depicts the weight loss induced by combination therapy of compound 9 + compounds (1-2) compared to monotherapy in diet-induced obese transgenic hGLP1R mice. Percentage change in body weight after 15 days of treatment is shown. Detailed Implementation

[0077] definition As used herein, unless otherwise stated, the following definitions shall apply. Furthermore, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0078] The term "comprising" is intended to mean that a composition and method include the stated elements, but does not exclude other elements. When used to define compositions and methods, "consistently composed of" should mean excluding other elements that are of any significant importance to the composition. For example, a composition consisting essentially of elements as defined herein will not exclude other elements that will not materially affect the essential and novel features of the claimed invention. "Constitutes of" should mean excluding other ingredients and substantial method steps in trace amounts, such as those listed. Embodiments defined by each of these transitional terms are within the scope of this invention.

[0079] "Combination therapy" or "combination treatment" (also referred to herein as combination therapy) refers to the use of two or more drugs or agents in treatment, such as those expressed in formulas (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX). The use of compounds (IY), (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-P01), (II**), (II*), (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6) in combination with another agent (e.g., an agent used to treat liver conditions such as NAFLD, NASH, and their respective symptoms and manifestations) constitutes combination therapy.

[0080] "Combined" administration refers to the administration of two agents in any manner (e.g., formulas (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX) as used herein). Compounds (IY), (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-P01), (II**), (II*), (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6), and another pharmaceutical agent), so that the pharmacological effects of both are simultaneously manifested in the patient. Therefore, combination administration does not require the administration of a single pharmaceutical composition, the same dosage form, or even the same route of administration for the two pharmaceutical agents, or the two pharmaceutical agents being administered exactly simultaneously. These pharmaceutical agents can be formulated into two separate pharmaceutically acceptable compositions. Two pharmaceutical agents can also be formulated into a single pharmaceutically acceptable composition. Non-limiting examples of such single compositions are oral compositions or oral dosage forms. For example, but not limited to, it is contemplated that formulas (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g) , (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX), (IY (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-P01), (II**), (II*), (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5) or (II-6) compounds are administered in combination therapy with another pharmaceutical agent according to the invention.

[0081] As used herein, the term "excipient" means an inert or inactive substance that can be used in the production of a pharmaceutical or medical product, such as tablets containing compounds of the present invention as active ingredients. The term "excipient" can include a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating agent, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include... For example Carbomer, povidone, xanthan gum, etc.; coating agents include For example Phthalate, cellulose acetate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation aids include For example Calcium carbonate, dextrose, fructose DC (DC = "directly compressible"), honey DC, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch DC, sucrose, etc.; disintegrants include For example Cross-linked sodium carboxymethyl cellulose, gellan gum, sodium glycolate starch, etc.; creams or lotions include For example Maltodextrin, carrageenan, etc.; lubricants include For example Magnesium stearate, stearic acid, sodium stearoyl fumarate, etc.; materials used in chewable tablets include For example Dextran, fructose DC, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include For example Carrageenan, sodium glycolate, xanthan gum, etc.; sweeteners include For example Aspartame, dextrose, fructose DC, sorbitol, sucrose DC, etc.; and wet granulation agents include For example Calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0082] "Patient" refers to a mammal, including both humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some implementations, "patient" refers to a human.

[0083] As used herein, “patient response” refers to the magnitude of a treatment effect (e.g., the amount of weight loss, the percentage of fat reduction, etc.). Improving a “patient response to treatment” may include, but is not limited to, increasing the magnitude of a treatment effect (e.g., increasing weight loss, increasing fat reduction, etc.). In some embodiments, improving a patient response to treatment (e.g., the combinations and methods of this disclosure) includes maintaining efficacy while reducing side effects.

[0084] "Pharmaceutically acceptable" means that the preferred option is...In vivo More preferably, it is safe and non-toxic for human use.

[0085] "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. The compounds described herein can be administered as pharmaceutically acceptable salts.

[0086] "Salt" refers to an ionic compound formed between an acid and a base. When the compounds described herein contain acidic functional groups, such salts include, but are not limited to, alkali metal salts, alkaline earth metal salts, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary and non-limiting cations that can be used for pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds described herein contain basic functional groups, such salts include, but are not limited to, salts of organic acids, such as carboxylic acids and sulfonic acids, and salts of inorganic acids, such as hydrogen halides, sulfuric acid, phosphoric acid, etc. Exemplary and non-limiting anions that can be used for pharmaceutically acceptable salts include oxalate, fumarate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, hydrogen sulfate, monovalent, divalent, and trivalent phosphates, methanesulfonate, toluenesulfonate, etc.

[0087] The "therapeutic effective amount" or dose of a compound or composition refers to the amount of a compound or composition that results in the reduction or suppression of symptoms or the prolongation of survival in a patient. Multiple doses of the compound or composition may be required to achieve the desired effect.

[0088] "Treatment" refers to a method for achieving a beneficial or desired outcome (including clinical outcomes). For the purposes of this invention, beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the disease or condition, alleviating the severity of the disease or condition, stabilizing the disease or condition. For example Treatment can prevent or delay the worsening of a disease or condition, delay the onset or recurrence of a disease or condition, delay or slow the progression of a disease or condition, improve the state of a disease or condition, provide relief from a disease or condition (whether partial or complete), reduce the dosage of one or more other drugs required to treat a disease or condition, enhance the effect of another drug used to treat a disease or condition, delay the progression of a disease or condition, improve quality of life, and / or prolong patient survival. "Treatment" also encompasses reducing the pathological consequences of a disease or condition. The methods of this invention cover any or more of these therapeutic aspects.

[0089] As used herein, “delaying” disease development means postponing, hindering, slowing, blocking, stabilizing, and / or facilitating the development of a disease and / or slowing its progression, or altering the underlying disease process and / or course following its development. Such delay can vary in length, depending on the patient’s medical history and / or the subject being treated. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively encompass prevention, as the subject does not develop disease-related clinical symptoms. A method for “delaying” disease development is a method of reducing the probability of disease development and / or the severity of disease within a given timeframe compared to not using said method, said method including stabilizing one or more symptoms caused by the disease.

[0090] Subjects at “risk” may or may not have a detectable disease, and may or may not have shown a detectable disease prior to receiving the treatments described herein. “At risk” means that a subject has one or more so-called risk factors, which are measurable parameters associated with disease development. Subjects with one or more of these risk factors are more likely to develop the described disease than subjects without these risk factors. These risk factors include, but are not limited to, age, sex, race, diet, medical history, presence of pre-existing conditions, and genetics. That is Genetic factors. In some implementations, the compound may be administered to subjects (including humans) who are at risk of developing a disease or condition or who have a family history of a disease or condition.

[0091] "Stereoisomers" refer to compounds whose constituent atoms exhibit stereoisomerism, such as, but not limited to, the chirality of one or more stereocenters or the cis or trans configurations of carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0092] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. This term includes, for example, straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), etc. Positive Propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), Positive Butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), Secondary Butyl((CH3)(CH3CH2)CH-), Tertiary Butyl((CH3)3C-), Positive Pentyl (CH3CH2CH2CH2CH2-) and neopentyl ((CH3)3CCH2-). C xAn alkyl group is an alkyl group having x carbon atoms.

[0093] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, such as 1 to 10 carbon atoms and 1 to 6 carbon atoms. The term includes, for example, straight-chain and branched hydrocarbon groups, such as methylene (-CH2-), ethylene (-CH2CH2- or –CH(Me)-), propylene (-CH2CH2CH2- or –CH(Me)CH2- or –CH(Et)-), etc.

[0094] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, for example 2 to 4 carbon atoms, and having at least 1, or 1 to 2, vinyl (>C=C<) unsaturated sites. Such groups are exemplified, for example, vinyl, allyl, and but-3-en-1-yl. This term includes... Cis and Trans Isomers, or mixtures of these isomers. C x An alkenyl group refers to an alkenyl group having x carbon atoms.

[0095] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, for example 2 to 3 carbon atoms, and having at least 1, or 1 to 2, alkynyl (-C≡C-) unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH). x An alkynyl group is an alkynyl group that has x carbon atoms.

[0096] "Alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, ... Positive propoxy, isopropoxy, Positive Butoxyl Tertiary Butoxyl Secondary butoxy and Positive Pentoyl group.

[0097] "Aryl" refers to a compound with a single ring ( For example Phenyl (Ph)) or multiple fused rings ( For example A monovalent aromatic carbocyclic group of 6 to 14 carbon atoms (naphthyl or anthracene), wherein the fused ring may or may not be aromatic. For example 2-Benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc., provided that the attachment site is on an aromatic carbon atom. Exemplary aryl groups include phenyl and naphthyl. Divalent aryl groups are referred to herein as "arylene". Divalent phenyl groups are referred to herein as "phenylene".

[0098] "Cyano" refers to the group -C≡N.

[0099] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cyclic alkyl group having, for example, 3 to 10 carbon atoms, 3 to 8 carbon atoms, or 3 to 6 carbon atoms, having a single or multiple cyclic rings, including fused rings, bridged rings, and spirocyclic systems. x A cycloalkyl group is a cycloalkyl group having x ring carbon atoms. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided that the attachment point is a saturated carbon ring through a non-aromatic, non-heterocyclic ring. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 or 1 to 3 substituents selected from the group consisting of: oxo, thion, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester. (Carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioyl, mercapto, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0100] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine, and in some embodiments, fluorine or chlorine.

[0101] "Hydroxy" refers to the -OH group.

[0102] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups can have a monocyclic ring (…). For example pyridyl or furanyl) or multiple fused rings ( For example(e.g., indolazinyl or benzothiopheneyl), wherein the fused ring may or may not be an aromatic ring and / or contain heteroatoms, provided that the attachment point passes through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Exemplary heteroaryl groups include 5- or 6-membered heteroaryl groups, such as pyridyl, pyrroleyl, thiopheneyl, and furanyl. Other exemplary heteroaryl groups include 9- or 10-membered heteroaryl groups, such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl. Divalent heteroaryl groups are referred to herein as "hybrid heteroaryl".

[0103] "Heterocyclic" or "heterocyclic" or "heterocyclic alkyl" or "heterocyclic group" means a saturated or partially saturated, but not aromatic, group having 1 to 10 cyclic carbon atoms, 1 to 8 carbon atoms, and 1 to 6 carbon atoms, and 1 to 4 cyclic heteroatoms, 1 to 3 heteroatoms, and 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. C x Heterocyclic alkyl groups refer to heterocyclic alkyl groups having x ring atoms (including cyclic heteroatoms). Heterocycles encompass monocyclic or multiple fused rings, including fused bridged rings and spirocyclic systems. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the linking point is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety. Divalent heterocyclic groups are referred to herein as "hypo-heterocyclic groups".

[0104] Examples of heterocyclic and heteroaryl groups include, but are not limited to, azacyclic butyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, indoleyl, dihydroindolyl, indazolyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnamolinel, pteridinyl, carbazole, carbolinyl, phenanthridine, acridinel, phenanthrolyl, isothiazolyl, phenazinyl, and others. Isoxazolyl, phenoxazinyl, phenthiazinyl, imidazoalkyl, imidazolinyl, piperidinyl, piperazinyl, indololinyl, phthalimide, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazoalkyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also known as thiomorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0105] "O-group" refers to an atom (=O) or (O).

[0106] The terms “optional” or “optionally” as used throughout this specification mean that an event or condition described below may, but not necessarily, occur, and that the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, “nitrogen atoms are optionally oxidized to provide an N-oxide (N→O) moiety” means that nitrogen atoms may, but do not need to, be oxidized, and that the description includes both cases in which nitrogen atoms are not oxidized and cases in which nitrogen atoms are oxidized.

[0107] The dosage of the compounds described herein is determined appropriately based on whether the compound is a free acid or a free base.

[0108] This document provides compositions and methods for treating obesity and / or related comorbidities. The methods include administering to a patient a glucagon-like peptide-1 receptor (GLP-1R) agonist and a thyroid hormone receptor β (THRβ) agonist as described herein. In some embodiments, this document provides a method for treating cardiovascular metabolic disease in a subject of need (e.g., a human patient), the method comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0109] GLP-1R agonists Suitable GLP-1R agonists that may be used according to the combinations and / or methods described herein include, but are not limited to, ocglitazone, dapaglitazone, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, ocglitazone, or smegglutide, or pharmaceutically acceptable salts of GLP-1R agonists, or pharmaceutically acceptable solvates of GLP-1R agonists or salts of GLP-1R agonists. Suitable GLP-1R agonists that can be used according to the combinations and / or methods described herein also include dapagliflozin tromethamine, SAL-0112, exenatide biobetter, E-2HSA, ECC-5004, dapiglutide, HDM-1002, AZD-9550, BGM-0504, VK2735, AMG-133, HL-08, HZ-010, exenatide SR, DD-01, CT-388, CT-868, CT-996, GL-0034, GMA-105, GMA-106, GLP-06, SCO-094, CagriSema, and amycretin. For exampleOral amylin), ZT-002, DR-10624, DR-10627, retatrutide, NN-6177, NN-9490, NN-9847, NN-9904, efocipegtrutide, GSBR-1290, HB-1085, 4P-004, HM15211, survodutide, froniglutide, efinopegdutide, PF-06954522, YH-25724, YN-012, YN-015, mazdutide, MDR-001, KN-056, MWN-101, emvidutide ALT-801, AP-026, PEG-loxenatide, PEGylated exenatide, ITCA 650, XW-004, XW-014 or efpeglenatide, or a pharmaceutically acceptable salt of a GLP-1R agonist, or a pharmaceutically acceptable solvate of a GLP-1R agonist or a salt of a GLP-1R agonist.

[0110] Suitable GLP-1R agonists that may be used in the combinations and / or methods described herein are also described, for example, in PCT Publications WO / 2023 / 049518, WO / 2022 / 040600, WO / 2023 / 076237, WO / 2023 / 164050, PCT Applications PCT / US2022 / 047687, PCT / US2023 / 013700, PCT / US2024 / 022311 or U.S. Provisional Application No. 63 / 492,895, which are incorporated herein by reference.

[0111] In some implementations, the GLP-1R agonist is a compound of formula (I-1). (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0112] In some implementations, the GLP-1R agonist is a compound of formula (I-1a). (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0113] In some implementations, the GLP-1R agonist is a compound of formula (I-2). (I-2) Or a stereoisomer, tautomer, or pharmaceutically acceptable salt of any of the above, wherein: X is N or CH; Y is N or CR 4 , where R 4 It is hydrogen, OH, or C1-C6 alkyl; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 , where R 5 It is a 3- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein each is independently and optionally substituted with a C1-C6 alkyl group, or R 1 Together with R and the intervening atom, they form a ring C, wherein the ring C is a 5- to 7-membered heterocyclic group optionally substituted with a C1-C6 alkyl group; R 2 and R 3 It is independently a hydrogen, oxo, or C1-C6 alkyl group, wherein when Y is CR 4 At that time, R 3 and R 4 Optionally, they can form C3-C6 cycloalkyl groups together with the carbon atoms to which they are attached; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B. When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene is optionally replaced by R. L Replace, of which: Each R L Independently C1-C6 alkyl or halogroup, or Two Rs L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups. When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally subjected to R. L1 Replace, of which: Each R L1 Independently a halogroup, OH, or C1-C6 alkyl group; or Two Rs L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic, or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three independently selected substituents from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3, and phenyl. The attached conditions are When R 1 It is a -C1-C6 alkylene-R 5 , where R 5 It is a 3- to 6-membered heterocyclic group or a 3- to 6-membered heteroaryl group, wherein each is optionally substituted with a C1-C6 alkyl group, Y is N or CH, n is 1, and R is 1. 2 and R 3Independently hydrogen or C1-C6 alkyl, ring A is a 6-membered heteroaryl group optionally substituted by one or two substituents independently selected from the group consisting of F, Cl and CN, and when L is *-OCH2-**, ring B is not a phenyl group optionally substituted by one or two substituents independently selected from the group consisting of halogroup, CN and C1-C6 alkyl. When R 1 It is a -C1-C6 alkylene-R 5 , where R 5 It is a 3- to 6-membered heterocyclic group or a 3- to 6-membered heteroaryl group, wherein each is optionally substituted with a C1-C6 alkyl group, Y is N or CH, n is 1, and R is 1. 2 and R 3 Independently hydrogen or C1-C6 alkyl, ring A is When Q is H or CH3 and L is a bond, ring B is neither phenyl nor pyridyl, wherein each is optionally substituted by one or two substituents independently selected from the group consisting of a halogroup, CN, and C1-C6 alkyl groups; and When R 1 It is a -C1-C6 alkylene-R 5 , where R 5 It is a 4-membered heterocyclic group or a 5-membered heteroaryl group, wherein each is optionally substituted with a C1-C6 alkyl group, X is N, Y is N or CH, n is 1, and R 2 and R 3 If it is independently a hydrogen or oxo group, then ring B is not a hydrogen or oxo group. In some such implementations of equation (I-2), ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic, or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three independently selected substituents from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, and phenyl. In some such embodiments of formula (I-2), when L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene is optionally substituted by R. L Replace, where each R L Independently C1-C6 alkyl, or two R L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 3- to 6-membered heterocyclic groups. In some such embodiments of formula (I-2), when L is a C1-C6 alkylene group, the C1-C6 alkylene group is not substituted.

[0114] In some implementations, the GLP-1R agonist is a compound of formula (I-3). (I-3), Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl. Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 3- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein R 5 The 3- to 6-membered heterocyclic group or the 5- to 6-membered heteroaryl group is independently and optionally substituted with a halogroup, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkenyl group or a C1-C6 haloalkyl group; R 7 Choose from the following groups: , , , , , and .

[0115] or R 7 It is -C(O)NH-R 8 , where R 8 It is hydrogen, -OH, -S(O)2-C1-C6 alkyl or -C1-C6 alkyl, optionally substituted with a halogroup; Ring A is a 5- to 12-membered heterocyclic group, a 5- to 12-membered heterocyclic group, or a C6-C ring. 14 arylene, wherein each of them is optionally substituted by: halogroup, oxogroup, -CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by halogroup or OH; L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR. 6 -C1-C6 alkylene-**, where: * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene, the C1-C6 alkylene is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic, or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three independently selected substituents from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, cyclopropyl, and phenyl. The attached conditions are: When R 7 It is -C(O)NH-R 8 R 1 yes X is N, Y is CH, n is 1, R 2 and R 3 If each ring is hydrogen, ring A is a 6-membered heteroaryl group, and L is *-OCH2-**, then ring B is not. .

[0116] In some implementations, the GLP-1R agonist is a compound of formula (I-4). (I-4), Or pharmaceutically acceptable salts, wherein: R 13 -C(O)OH or ; X is N or CR x , where R x It is hydrogen, OH, or C1-C6 alkyl; Y is N or CR y , where R y It is hydrogen, OH, or C1-C6 alkyl; n is 0 or 1; Q is free – C(R) 7 (R) 8 )-、-O-、-N(R 9 The group consisting of - and -S-, where R 7 and R 8 Independently hydrogen, halogen, or C1-C6 alkyl; and R 9 It is hydrogen or C1-C6 alkyl; R 1 It is an optionally substituted -C1-C6 alkyl or -C1-C6 alkylene-R 5 , where R 5 It is a C3-C6 cycloalkyl, a 3- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein each is independently and optionally substituented by one to three independently selected from the group consisting of: halogroup, oxogroup, CN, C1-C6 alkyl, C3-C6 cycloalkyl and –OC1-C6 alkyl, wherein each C1-C6 alkyl, C3-C6 cycloalkyl and –OC1-C6 alkyl substituent is independently and optionally substituted by a halogroup or CN; R 2 and R 3 Together with the carbon atoms to which they are attached, they form optionally substituted C3-C4 cycloalkyl rings; or R 2 and R x When present, they form optionally substituted C3-C5 cycloalkyl rings together with the carbon atoms to which they are attached, and R 3 It is a hydrogen, oxo group, or C1-C6 alkyl group; m can be 0, 1, 2, or 3; R 4 It is an oxo group or a C1-C6 alkyl group; Ring A is C6-C 14 arylene, 5 to 12-membered heterocyclic or 5 to 12-membered heteroarylene, wherein each is optionally substituted by: halogroup, OH, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by halogroup or OH; L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment site with ring A, and ** represents the attachment site with ring B, and where: When L is C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR 6When -C1-C6 alkylene-**, L is optionally surrounded by one to three Rs. L Substituent substitution, where each R L Independently a halogroup, OH, or C1-C6 alkyl group; or two R groups. L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; R 6 When present, it is hydrogen or a C1-C6 alkyl group; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl optionally substituted by halogroup or CN, -OC1-C6 alkyl optionally substituted by halogroup or CN, –COCH3, –CONH2, –S(O)2CH3 and phenyl optionally substituted by halogroup or CN.

[0117] In some implementations, the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3, –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C3-10 cycloalkyl or C 6-10 aryl, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkoxy, hydroxyl, -CN, or oxo group is substituted, and the cycloalkyl, heterocyclic, or aryl group is optionally substituted with one or more halogens, C, or alkyl groups. 1-6 Alkyl or -CN substitution; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4It is a halogen, hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ -(C 2-6 (-(C-)-(O)OH, -(C-) 1-6 alkylene)-C(O)OH, -NR N12 -(C 1-6 alkylene)-C(O)OH, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R N12 and R N12’ Independently H or C 1-6 alkyl; X 1 yes or , Where R 3 and R 3’ Independently H, D or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with deuterium; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 3-10 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl or heterocyclic group, optionally constituting one or more C 1-6 Alkyl, halogen, -CN or oxo groups are substituted.

[0118] In some implementations, the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkyl or heterocyclic group is substituted with an alkoxy, hydroxy, -CN, or oxo group, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN. R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 It is hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, or a 5-10 heteroaryl group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl group, optionally constituting one or more C 1-6 Alkyl, halogen or oxo group substitution.

[0119] In some implementations, the GLP-1R agonist is a compound of formula I*: (I*) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0120] In some embodiments, the compound of formula (I*) has formula (I'): (I') Or its pharmaceutically acceptable salt; wherein: X 3 It is CH or N; R 1 It is -C 1-6 Halogenated alkyl or -OX 4 ; Where X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl), –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more -CN groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 It is hydrogen; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; or A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attach, and Where X 2 It is CH or N; Cycle B is a 6-10 membered heteroaryl group or a 3-10 membered heterocyclic group, optionally surrounded by one or more C groups. 1-6 Alkyl substitution; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or replace; A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0121] In some implementations, the GLP-1R agonist is a compound of formula I'': (I'') Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; Where X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C 1-6 alkyl; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form C 2-9 Heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attached, X 5 It is CH or N, and X 2 It is CH or N; Cycle B is a 6-10 membered heteroaryl group or a 3-10 membered heterocyclic group, optionally surrounded by one or more C groups. 1-6 Alkyl substitution; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; and Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0122] In some implementations, the GLP-1R agonist is a compound of formula (I'''*): (I'''*) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR X3 Or N; Where R X3 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkoxy groups, -O-(CH2CH2-O) 1-5 -CH3 or C 1-6 Alkoxy; X 5’ It is CR 5’ R 1 It is -C 1-6 Halogenated alkyl or -OX 4 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; Where X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, halogen, or -CN, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogen or -CN; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; halogen; Branch C 3-6 alkyl; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; or A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 5’ It is hydrogen or -C(O)-OH; R 4 It is hydrogen, halogen, -C(O)-OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attached, Where X 5 It is CH or N, and X 2 It is CH or N; Cycle B is a 6-10 membered heteroaryl group or a 3-10 membered heterocyclic group, optionally surrounded by one or more C groups. 1-6 Alkyl substitution; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0123] In some implementations, the GLP-1R agonist is a compound of formula (I'''). (I''') Or its pharmaceutically acceptable salt; wherein: X 3 It is CR X3 Or N; Where R X3 It is H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkoxy or C 1-6 Alkoxy; R 1 It is -C 1-6 Halogenated alkyl or -OX 4 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; Where X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium or -CN, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; halogen; C 3-6 alkyl; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attached, Where X 5 It is CH or N, and X 2 It is CH or N; Cycle B is a 6-10 membered heteroaryl group or a 3-10 membered heterocyclic group, optionally surrounded by one or more C groups. 1-6 Alkyl substitution; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or replace; A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0124] In some embodiments of formula (I''') or its pharmaceutically acceptable salts X 3 It is CH or N; R 1 It is -C 1-6 Halogenated alkyl or -OX 4 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; Where X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium or -CN, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C 3-6 alkyl; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5At least one heteroatom is S; or R 2 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attached, Where X 5 It is CH or N, and X 2 It is CH or N; Cycle B is a 6-10 membered heteroaryl group or a 3-10 membered heterocyclic group, optionally surrounded by one or more C groups. 1-6 Alkyl substitution; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or replace; A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0125] In some embodiments, the compound of formula (I''') has formula (I): (I) Or its pharmaceutically acceptable salt; wherein R1 It is -C 1-6 Halogenated alkyl or -OX 4 ; Where X 4 It is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), -(-CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more -CN groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; or A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attach, and Where X 2 It is CH or N; Ring B is: A nitrogen-containing 6-membered heteroaryl group; A 9-membered subheterocyclic group containing two oxygen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl substitution; or A 10-membered subheterocyclic group containing two oxygen atoms; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or replace; A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0126] In some implementations, the GLP-1R agonist is a compound of formula (I-5). (I-5) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O)1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; Branch C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0127] In some implementations, the GLP-1R agonist is a compound of formula (I-PO1): (I-P01) Or its pharmaceutically acceptable salt; wherein: X 3 It is CH or N; R 1 It is -C 1-6 Halogenated alkyl or -OX 4 ; Where X 4 It is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more -CN groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; or A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is or , Among them, * indicates and X 1 Attach, and Where X 2 It is CH or N; Cycle B is a 6-10 membered heteroaryl group or a 3-10 membered heterocyclic group, optionally surrounded by one or more C groups. 1-6 Alkyl substitution; L is a bond or *-O-(C 1-6 Alkylene)-, where * indicates attachment to ring B; Ring C is: A 6-aryl group, optionally bonded by one or more halogens, -OCH3, -CN, or C. 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or replace; A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0128] In some embodiments, the compound of formula (I-5) has formula (I-5a): (I-5a) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 Rings A and C are as defined with respect to equation (I-5).

[0129] In some embodiments, the compound of formula (I-5) has formula (I-5b): (I-5b) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 Rings A and C are as defined with respect to equation (I-5).

[0130] In some embodiments, the compound of formula (I-5) has formula (I-5c): (I-5c) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 Rings A and C are as defined with respect to equation (I-5).

[0131] In some embodiments, the compound of formula (I-5) has formula (I-5d): (I-5d) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 X 2 And the ring C is as defined for equation (I-5).

[0132] In some embodiments, the compound of formula (I-5) has formula (I-5e): (I-5e) Or its pharmaceutically acceptable salt; Where X 4 n, R 2 X 1 Rings A, B, and C are as defined with respect to equation (I-5).

[0133] In some embodiments, the compound of formula (I-5) has formula (I-5f): (I-5f) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 And the ring C is as defined for equation (I-5).

[0134] In some embodiments, the compound of formula (I-5) has formula (I-5g): (I-5g) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 Rings A and C are as defined with respect to equation (I-5).

[0135] In some embodiments, the compound of formula (I-5) has formula (I-5h): (I-5h) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 Rings A and C are as defined with respect to equation (I-5).

[0136] In some embodiments, the compound of formula (I-5) has formula (I-5i): (I-5i) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 Rings A and C are as defined with respect to equation (I-5).

[0137] In some embodiments, the compound of formula (I-5) has the formula (I-5j). (I-5j) Or its pharmaceutically acceptable salt; Where R 1 n, R 2 X 1 And the ring C is as defined for equation (I-5).

[0138] In some embodiments, the compound of formula (I-5) has the formula (I-5k). (I-5k) Or its pharmaceutically acceptable salt; Where X 4 R 2 X 1 , n, ring A, ring B, L and ring C are as defined with respect to equation (I-5).

[0139] In some embodiments, the compound of formula (I-5) has the formula (I-5l). (I-5l) Or its pharmaceutically acceptable salt; Where R 1 R 2 X 1 And the ring C is as defined for equation (I-5).

[0140] In some embodiments, the compound of formula (I-5) has the formula (I-5m). (I-5m) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0141] In some embodiments, the compound of formula (I-5) has the formula (I-5n). (I-5n) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0142] In some embodiments, the compound of formula (I-5) has the formula (I-5o). (I-5o) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0143] In some embodiments, the compound of formula (I-5) has the formula (I-5p). (I-5p) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0144] In some embodiments, the compound of formula (I-5) has the formula (IQ). (IQ) Or its pharmaceutically acceptable salt; Where R 1 R 2 , n, ring B, L and ring C are as defined with respect to equation (I-5).

[0145] In some embodiments, the compound of formula (I-5) has the formula (IR). (IR) Or its pharmaceutically acceptable salt; Where R 1 R 2 , n, ring B, L and ring C are as defined with respect to equation (I-5).

[0146] In some embodiments, the compound of formula (I-5) has the formula (IS). (IS) Where R 1 R 2 , n, ring B, L and ring C are as defined with respect to equation (I-5).

[0147] In some embodiments, the compound of formula (I-5) has the formula (IT). (IT) Or its pharmaceutically acceptable salt; Where X 1 X 3 Rings A, B, L and C are as defined with respect to equation (I-5).

[0148] In some embodiments, the compound of formula (I-5) has the formula (IU). (IU) Or its pharmaceutically acceptable salt; Where X 3 X 1 Rings A, B, L and C are as defined with respect to equation (I-5).

[0149] Or its pharmaceutically acceptable salt; Where X 3 R 4 R 1 , n and R 2 As defined for equation (I-5).

[0150] In some embodiments, the compound of formula (I-5) has the formula (IX). (IX) Or its pharmaceutically acceptable salt; Where X 3 n, R 2 X 1 Rings A, B, L and C are as defined with respect to equation (I-5).

[0151] In some embodiments, the compound of formula (I-5) has the formula (IY). (IY) Or its pharmaceutically acceptable salt; Where X 3 n, R 2X 1 Rings A, B, L and C are as defined with respect to equation (I-5).

[0152] In some embodiments, the compound of formula (I-5) has the formula (IZ). (IZ) Or its pharmaceutically acceptable salt; Where X 3 n, R 2 X 1 Rings A, B, L and C are as defined with respect to equation (I-5).

[0153] In some embodiments, the compound of formula (I''') has formula (IAA). (IAA) Or its pharmaceutically acceptable salt; Where X 3 n, R 2 X 1 Rings A, B, L and C are as defined with respect to equation (I-5).

[0154] In some embodiments, the compound of formula (I-5) has formula (IAB). (IAB) Or its pharmaceutically acceptable salt; X6, R8, R9, n, R2, X1, ring A, ring B, L and ring C are as defined with respect to equation (I-5).

[0155] In some embodiments, the compound of formula (I-5) has formula (IAC). (IAC) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0156] In some embodiments, the compound of formula (I-5) has formula (IAD). (IAD) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0157] In some embodiments, the compound of formula (I-5) has formula (IAE). (IAE) Or its pharmaceutically acceptable salt; Rings B, L, and C are defined as in equation (I-5).

[0158] In some embodiments, the compound of formula (I-5) has formula (IAG). (IAG) Or its pharmaceutically acceptable salt; X3, X1, ring A, L and ring C are defined as in equation (I-5).

[0159] In some embodiments, the compound of formula (I-5) has formula (IAH): (IAH) Or its pharmaceutically acceptable salt; Where n, R2, X1, ring A, L and ring C are as defined with respect to equation (I-5).

[0160] In some embodiments, the compound of formula (I-5) has formula (IAI): (IAI) Where R 1 It is -O-(C 1-6 (Halogenated alkyl); X3, X1, ring A, ring B, L and ring C are as defined with respect to equation (I-5); Or its pharmaceutically acceptable salt.

[0161] In some embodiments, the compound of formula (I-5) has formula (IAJ): (IAJ) in R2 It can be hydrogen, thiazolyl, oxetane, cyclopropyl or methoxy, optionally substituted with cyano; n is 1 or 2; R 1 Yes - OC 1-6 Alkyl, -OH or -NH2, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogroups or deuterium; X 3 It is CR 6 , where R 6 It is a halogenated group or hydrogen; L is *-O-(C 1-6Alkylene), wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; R 10 It is a halogenated group; and R 11 It is a halogenated group or a cyano group; Or its pharmaceutically acceptable salt.

[0162] In some embodiments, the compound of formula (I**) has the following formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 Alkyl; and R 1** Is it H or C? 1-2 Alkyl groups, optionally substituted with one or more deuterium or halogens.

[0163] In some embodiments, the compound of formula (I**) has the formula (II*): (II*) Or its pharmaceutically acceptable salt; Each R f1 Independently selected from halogens R f4 and R f5Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, or 3; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 alkyl; Each R f6 Selected independently from H, D, or F.

[0164] In some implementation schemes, R f4 and R f5 Each is independently selected from CH3, H and D.

[0165] In some implementations, each R f1 It's fluorine.

[0166] In some implementation schemes, X 3 It is N. In some implementations, X 3 It is CH.

[0167] In some implementation schemes, X 6 It is N. In some implementations, X 6 It is CR 4 .

[0168] In some implementation schemes, R 1 It is R 1 Yes - OC 1-6 Alkyl group. In some embodiments, the alkyl group is straight-chain. In some embodiments, the alkyl group is branched. In some embodiments, the alkyl group is straight-chain and optionally contains one or more deuterium, -CN, or -OC groups. 1-6 Alkyl substitution. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is substituted with one or more -CN or -OC compounds. 1-6 Alkyl substitution. In some embodiments, R 1 It is -O-CH2-CH3, -O-CH3, -O-CH2-CN, -O-CH2-CH2-O-CH3, or -O-CH2CH(-O-CH3)-CH3. In some implementations, R 1It is branched and optionally replaced by one or more -CN. In some implementations, R 1 yes or .

[0169] In some implementation schemes, R 1 Yes - OC 1-6 The alkyl halogroup is linear. In some embodiments, the alkyl halogroup is substituted with one or more fluorine molecules. In some embodiments, R... 1 is -O-CHF2, -O-CF3, -O-CH2-CH2F, -O-CH2-CF3, -O-CH2-CHF-CH3, -O-CHF-CH3, -O-CHF-CH2F, or -O-CH2-CH2F.

[0170] In some implementation schemes, R 1 It is arbitrarily C 1-6 alkoxy or halogen-substituted -OC 3-10 Cycloalkyl. In some embodiments, R 1 It is -O-cyclopropyl or -O-cyclobutyl, wherein the cyclopropyl or cyclobutyl group is optionally substituted with fluorine or methoxy. In some embodiments, R 1 -OC is optionally replaced by one or more halogens (e.g., fluorine), -OCH3, or -CN. 3-10 Cycloalkyl.

[0171] In some implementation schemes, R 1 It is -O- (3 to 8-membered heterocyclic group). In some embodiments, the 3 to 8-membered heterocyclic group contains one oxygen atom. In some embodiments, the 3 to 8-membered heterocyclic group contains two oxygen atoms. In some embodiments, R 1 It is -O-CH2-(1,4-dioxane-2-yl) or -O-CH2-tetrahydrofuran-2-yl.

[0172] In some implementation schemes, R 1 It is -O–(C 1-6 alkylene)-(C 3-10 (Cycloalkyl). In some embodiments, R 1 It is -O–(C) that is optionally substituted with one or more halogens, cyano groups, or -OCH3. 1-6 alkylene)-(C 3-10 (Cycloalkyl). In some embodiments, R 1 yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, R 1 yes or .

[0173] In some implementation schemes, R 1 It is -O-(C 1-6 (alkylene)-(3 to 8-membered heterocyclic group). In some embodiments, -O-(C 1-6 The alkylene group (3 to 8-membered heterocyclic group) is optionally substituted with one or more halogens, cyano groups, or -OCH3. In some embodiments, R 1 yes , , , , , , , , , , or In some implementations, R 1 yes or .

[0174] In some implementation schemes, R 1 yes , , , or .

[0175] In some implementation schemes, R 1 It is C 1-6 Halogenated alkyl groups. In some embodiments, R 1 It is -CF2-CH3.

[0176] In some implementation schemes, R 1 It is -O- (3 to 8-membered heterocyclic group). In some implementations, R 1 It is an oxetane-butyl group. In some embodiments, R 1 It is oxetane-3-yl.

[0177] In some implementation schemes, R 1 It is -O-(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3. In some implementations, R 1 yes or .

[0178] In some implementation schemes, R 1 Yes -NR 8 R 9 In some implementations, R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group. In some embodiments, R 8 and R 9 They combine with the atoms to which they are attached to to form morpholine. In some embodiments, R 8 and R 9 It is hydrogen. In some implementations, R 1 It is NH2. In some implementations, R 1 It is NR 8 R 9 , where R 8 It is H and R 9 C is a C that is optionally substituted with an oxygen group. 1-6 alkyl.

[0179] In some implementation schemes, R 2 C is optionally replaced by one or more -CN. 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 Alkyl group. In some embodiments, R 2 It is a cyclopropyl group optionally substituted with one or more -CN groups, C 1-6Halogenated alkyl or C substituted with one or more -CN 1-6 Alkyl group. In some embodiments, R 2 yes , or .

[0180] In some implementation schemes, R 2 It is a 4- or 5-membered heterocyclic group containing at least one oxygen or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution. In some embodiments, R 2 (i) optionally constituting one or more oxo groups or Substituted thioheterobutanes, (ii) oxoheterobutanes, or (iii) optionally with one or more C... 1-6 Alkyl-substituted tetrahydrofurans. In some embodiments, R 2 yes , , or .

[0181] In some implementation schemes, R 2 It is a 5-membered heteroaryl group, which contains one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S. In some embodiments, R 2 It is a thiazole. In some implementations, R 2 yes .

[0182] In some implementation schemes, R 2 It is H. In some implementations, R 2 It is -OCH3.

[0183] In some implementations, n is 1.

[0184] In some implementation schemes, X 1 yes In some implementations, X 1 yes In some implementations, X 1 yes In some implementations, R 3 It is methyl. In some embodiments, R 3 It is hydrogen. In some implementations, R 3 and R 3’ Independently, it can be CH3, CD3, deuterium, or hydrogen. In some embodiments, X 1 yes In some implementations, X 1 yes In some implementations, X 1 yes In some implementations, X 1 yes .

[0185] In some implementations, ring A is or The * indicates the same as X. 1 Attached. In some implementations, ring A is or The * indicates the same as X. 1 Attached. In some embodiments, ring A is optionally surrounded by one or more halogens or C. 1-6 Alkyl-substituted phenylene ring. In some embodiments, ring A is... , , , , , or ,in Instructions and X 1 Appendix. In some embodiments, ring A is a 6-membered heteroaryl group optionally substituted with one or more halogens. In some embodiments, ring A is In some implementations, ring A is , , , , , or ,in Instructions and X 1 Attached.

[0186] In some embodiments, ring B is a nitrogen-containing 6-membered heteroaryl group. In some embodiments, ring B is a pyridyl or pyrimidinyl group optionally substituted with one or more halogens. In some embodiments, ring B is a pyridyl group. In some embodiments, ring B is... The asterisk (*) indicates attachment to ring A or L'. In some embodiments, ring B is... , , , , , or , where * indicates attachment to ring A or L'.

[0187] In some embodiments, ring B is a 9-membered subheterocyclic group containing two oxygen atoms, optionally separated by one or more C atoms.1-6 Alkyl substitution. In one embodiment, ring B is optionally replaced by one or more C. 1-6 Alkyl-substituted benzoindolinyl group. In some embodiments, ring B is... The asterisk (*) indicates attachment to ring A or L'. In some embodiments, ring B is a 10-membered heterocyclic group containing two oxygen atoms. In some embodiments, ring B is a benzo[a]dioxane. In some embodiments, ring B is... The asterisk (*) indicates attachment to ring A or L'. In some embodiments, ring B is... , where * indicates attachment to ring A or L'.

[0188] In some embodiments, ring B is a 10-membered subheterocyclic group comprising one oxygen atom and one nitrogen atom. In some embodiments, ring B is... , where * indicates attachment to ring A or L'.

[0189] In some implementations, L is a bond. In some implementations, ring B is *-O-CH2-, where * indicates attachment to ring B.

[0190] In one embodiment, ring C is optionally surrounded by one or more halogens, -CN, -OCH3, Or a cyclopropyl-substituted phenyl group. In some embodiments, the ring C is... , , , , , , , , , , , , , , or .

[0191] In some embodiments, the cyclic C is a 6-membered heteroaryl group containing a nitrogen atom, optionally surrounded by one or more halogens, -CN, -OC. 1-6 Alkyl, -C(=O)-(C 3-10 cycloalkyl) or C 3-10 Cycloalkyl substitution. In one embodiment, the ring C is optionally replaced by one or more halogens: -Cl, -F, -CN, -OCH3, cyclopropyl, ... , , or Substituted pyridinyl group. In some embodiments, the ring C is... , , , , , , , , or .

[0192] In some embodiments, the ring C is a bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally surrounded by one or more C atoms. 1-6 Alkyl or oxo-substituted compounds. In some embodiments, the ring C is pyrazolopyridine, triazolopyridine, or 2,3-dihydropyridine. -1H -Pyrrolopyridine, 1,2-dihydrooxazolopyridine, 1,2,3,4-tetrahydronaphthylidine, 2,3-dihydro-pyridoxazine, 2,3-dihydro- 1H -pyrrolopyridine or 2,3-dihydrooxazolopyridine, wherein the pyrrolopyridine, triazolopyridine, 2,3-dihydrooxazolopyridine -1H -Pyrrolopyridine, 1,2-dihydrooxazolopyridine, 1,2,3,4-tetrahydronaphthylidine, 2,3-dihydro-pyridoxazine, 2,3-dihydro- 1H -Pyrrolopyridine or 2,3-dihydrooxazolopyridine is optionally mixed with one or more C 1-6 Alkyl or oxo-substituted. In some embodiments, the cyclic C is... , , , , , , , , or .

[0193] In some implementation schemes, yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0194] In some implementation schemes, R 12 It is -COOH. In some implementations, R 12 yes , , , , , , , , , or .

[0195] This disclosure covers the following Combinations of any of the following expressions in the part: (I-5e), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (I-5q), (I-5r), (I-5s), (I-5t), (I-5u), (I-5v), (I-5w), (I-5x), (I-5y), (I-5z), (I-5aa), (I-5ab), (I-5ac), or (I-5af): , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0196] This disclosure covers the following Combinations of any of the following expressions in the part: (I-5e), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (I-5q), (I-5r), (I-5s), (I-5t), (I-5u), (I-5v), (I-5w), (I-5x), (I-5y), (I-5z), (I-5aa), (I-5ab), (I-5ac), or (I-5af): , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0197] In some implementations, the GLP-1R agonist is It is 2-((4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1R agonist is 2-((4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid meglumine salt.

[0198] In some implementations, the GLP-1R agonist is selected from those listed in Table 1 below, or a pharmaceutically acceptable salt thereof: Table 1

[0199] In some implementations, the GLP-1R agonist is selected from those listed in Table 2 below, or a pharmaceutically acceptable salt thereof: Table 2

[0200] In some implementations, the GLP-1R agonist is selected from those listed in Table 3 below, or a pharmaceutically acceptable salt thereof: Table 3

[0201] In some implementations, the GLP-1R agonist is selected from those listed in Table 4 below, or a pharmaceutically acceptable salt thereof: Table 4 In some implementations, the GLP-1R agonist is selected from those listed in Table 5 below, or a pharmaceutically acceptable salt thereof: Table 5

[0202] In some implementations, the GLP-1R agonist is selected from those listed in Table 5A below, or a pharmaceutically acceptable salt thereof: Table 5A

[0203] THR beta agonists In some embodiments, the THRβ agonist administered to patients in need is retinoic acid (MGL-3196, Madrigal Therapeutics). In some embodiments, the THRβ agonist administered to patients in need is VK2809 (Viking Therapeutics). In some embodiments, the THRβ agonist administered to patients in need is sodexem. In some embodiments, the THRβ agonist administered to patients in need is ilottilo. In some embodiments, the THRβ agonist administered to patients in need is ALG-055009 (Aligo). In some embodiments, the THRβ agonist administered to patients in need is CNPT-101101. In some embodiments, the THRβ agonist administered to patients in need is CNPT-101207. In some embodiments, the THRβ agonist administered to patients in need is ASC41 (Ascletis).

[0204] Suitable THRβ agonists that can be used according to the methods described herein are also described, for example, in PCT publications WO / 2020 / 123827, WO / 2020 / 041741, WO / 2020 / 077123, WO / 2021 / 041237, WO / 2021 / 050945 or WO / 2022 / 187403, which are incorporated herein by reference.

[0205] In some embodiments, the THRβ agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C)1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atoms are selected from the group consisting of F, Cl, and Br. Or its pharmaceutically acceptable salt.

[0206] In some implementations, the THRβ agonist administered to patients in need is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0207] Or its pharmaceutically acceptable salt.

[0208] In some implementations, R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; and m is an integer in the range of 1 to 3.

[0209] In some embodiments, R1 is selected from hydrogen, cyano, and substituted or unsubstituted C. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. 1-6 The group consisting of alkoxy groups; and the halogen atoms are selected from the group consisting of F, Cl, and Br.

[0210] In some implementations, the THRβ agonist administered to patients in need is a compound of formula (II-2). (II-2) Or its pharmaceutically acceptable salt, wherein: Ring A together with the carbonyl (ketone) group within the ring forms a 5-membered heterocycle containing 1-3 cyclic heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted by 1-2 C1-C3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (ketone) group is not adjacent to the atom attached to X. R 1 It is a C1-C4 alkyl, C3-C5 cycloalkyl, or CON(R) group optionally substituted with 1-5 halogroups or hydroxyl groups. 10 )2 or NR 10 COR 10 ; R 2 It is an H or C1-C3 alkyl group; L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 CN, CHR 11 or C(R) 11 )R 11 ; R 3 and R 4 Independently, it can be Cl, Br, methyl, or ethyl; R 5 It is H, halogroup, C1-C4 alkyl or C3-C4 cycloalkyl; or R 5 With R 4 Together with the intervening atoms, they form 5-7 membered cycloalkyl groups or 5-7 membered heterocycles containing 1-2 cyclic heteroatoms; X represents non-existent, O, or NR. 12 C(O)NR 12 NR 12 C(O), CR 12 R 12 OCR 12 R 12 CR 12 R 12 O, NR 12 CR 12 R 12 CR 12 R 12 NR 12 、 SO2NR 12 or NR 12 SO2; Each R 10 Independently, it is a C1-C3 alkyl group or H; Each R 11 Independently, it is a C1-C2 alkyl group optionally substituted with 1-5 halogroups. Or two Rs 11 The groups, together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl rings; and Each R 12 It can be H or methyl on its own.

[0211] In some implementations, the THRβ agonist administered to patients in need is a compound of formula (II-3). (II-3) in: R1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, -C(O)N(R7)(R8), or -N(R9)C(O)(R 10 ) or halogenated group; R2 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group; R3 is an H or a halogenated group; R4 is H or a straight-chain C1-C3 alkyl group, whether substituted or unsubstituted; L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-; R5 and R6 are independently H, halogroup, -CN or substituted or unsubstituted C1-C6 alkyl groups, or R5 and R6 together with the carbon atoms to which they are attached form substituted or unsubstituted C3-C6 cycloalkyl groups. R7 and R8 are independently H or substituted or unsubstituted C1-C6 alkyl groups, or R7 and R8 together with the nitrogen atom to which they are attached form substituted or unsubstituted 3- to 7-membered heterocyclic alkyl groups; R9 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group; R 10 It is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -N(R7)(R8) or -O(R 11 ); R 11 It is a substituted or unsubstituted C1-C6 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl; M1 and M2 are independently halogroups or substituted or unsubstituted C1-C6 alkyl groups; and M3 is H, a halogroup, or a substituted or unsubstituted C1-C6 alkyl group, or M3 together with M2 and the carbon atoms to which they are attached form a 5- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. Or its pharmaceutically acceptable salt.

[0212] In some implementations, the THRβ agonist administered to patients in need is a compound of formula (II-4). (II-4) Or its tautomers or N-oxides, or their respective isotopic isomers, or the aforementioned stereoisomers, or pharmaceutically acceptable salts of each of the foregoing, or solvates of each of the foregoing, wherein: A is ; It is a 5-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein each optionally contains 1-2 additional cyclic heteroatoms selected from the group consisting of N and O. Wherein, if desired, each heteroatom of the heterocyclic or heteroaryl group is associated with an R 1 Group bonding completes the valence of heteroatoms, and Wherein, if desired, each carbon atom of the heterocyclic or heteroaryl group is associated with an R 2 Group bonding completes the valence of a carbon atom, provided that no more than one R is required. 2 Groups complete the valence of each carbon atom; Z 1 Z 2 and Z 3 Independently N or CH; Y is either N or C; Each R 1 Independently, it is H, C1-C6 alkyl, or C3-C6 cycloalkyl. Each C1-C6 alkyl or C3-C6 cycloalkyl group is optionally surrounded by 1-5 R groups. 3 Group substitution; Each R 2 Independently, it can be H, C1-C6 alkyl, C3-C6 cycloalkyl, -O (C1-C6 alkyl), -O (C3-C6 cycloalkyl), hydroxyl, or oxo group. Each C1-C6 alkyl, C3-C6 cycloalkyl, -O (C1-C6 alkyl), or -O (C3-C6 cycloalkyl) group is optionally surrounded by 1-5 R... 3 Group substitution; or R 1 and R 2 Together they form 5- to 6-membered heteroaryl groups or 5- to 7-membered heterocyclic groups; Or two Rs 2 The groups together form 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic, C5-C7 cycloalkyl, or C6 aryl groups; Each R 3 It can be independently a halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -NH2, -CN or hydroxyl.

[0213] In some implementations, the THRβ agonist administered to patients in need is a compound of formula (II-5). (II-5) Or its tautomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 1 It is H or -CH3; X 1 X 2 X 3 and X 4 Each independently for CR 2 Or N, where X 1 X 2 X 3 and X 4 At least two of them are CR 2 ; Each R 2 Independently, it is H, a halogroup, a C1-C6 alkyl group, a C1-C6 alkyl-CN group, a C1-C6 alkyl-OH group, a C1-C6 haloalkyl group, -CN, a hydroxyl group, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O(C1-C6 alkyl), C3-C6 cycloalkyl, a 5- to 6-membered heteroaryl group, a 5- to 7-membered heterocyclic group, or a C6 aryl group, wherein each C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic group, or C6 aryl group is optionally surrounded by 1 to 5 R groups. 3 Group substitution; Or two Rs 2 The groups, together with the carbon atoms to which they are attached, form 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclic, C5-C7 cycloalkyl, or C6 aryl groups, each optionally surrounded by 1-5 R groups. 3 Group substitution; and Each R 3 It can be independently C1-C6 alkyl, -O(C1-C6 alkyl), halogroup, -CN, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or CO2H.

[0214] In some implementations, the THRβ agonist administered to patients in need is a compound of formula (II-6). (II-6) Or its tautomers or stereoisomers, or pharmaceutically acceptable salts of each of the foregoing, wherein: A is , where R A It is H or -CN; L 1 It is a bond, -NR'-, -O-, -S- or -S(O)2-, where R' is H or a C1-C6 alkyl group; L 2 It is a bond or -S(O)2-; R 1 It is H, C1-C6 alkyl, C6-C 10 aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C6-C 10 Aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, and C3-C6 cycloalkyl groups are each independently and optionally bound by 1-5 R groups. 2 Group substitution; R is H, C1-C6 alkyl, C6-C 10 aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C6-C 10 Aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, and C3-C6 cycloalkyl groups are each independently and optionally bound by 1-5 R groups. 2 Group substitution; and Each R 2 Independently, it is a halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -NH2, -CN, or hydroxyl group, provided that... When L 1 If A is a bond and R is H, then A is... or ,and When L 1 It is -O-, R is H, and A is When, then R 1 It is a C2-C6 alkyl, C6-C 10 aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl or C3-C6 cycloalkyl, wherein the C2-C6 alkyl, C6-C 10 Aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, and C3-C6 cycloalkyl groups are each independently and optionally bound by 1-5 R groups. 2 Group substitution.

[0215] In some implementations, the THRβ agonist is selected from those listed in Table 6 below, or a pharmaceutically acceptable salt thereof: Table 6 In some implementations, the THRβ agonist is (Compound 9) is 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the THRβ agonist is the potassium salt of 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile. In some embodiments, the THRβ agonist is sodium 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile).

[0216] In some implementations, the THRβ agonist is selected from those listed in Table 7 below, or a pharmaceutically acceptable salt thereof: Table 7 In some implementations, the THRβ agonist is selected from those listed in Table 8 below, or a pharmaceutically acceptable salt thereof: Table 8 In some implementations, the THRβ agonist is selected from those listed in Table 9 below, or a pharmaceutically acceptable salt thereof: Table 9 In some implementations, the THRβ agonist is selected from those listed in Table 10 below, or a pharmaceutically acceptable salt thereof: Table 10 In some implementations, the THRβ agonist is selected from those listed in Table 11 below, or a pharmaceutically acceptable salt thereof: Table 11 Pharmaceutically acceptable compositions and formulations This invention covers pharmaceutically acceptable compositions of any compounds detailed herein, or simply "pharmaceutical compositions". Therefore, this invention includes pharmaceutical compositions comprising GLP-1R agonists (such as formulas (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX), (IY), (I... (II) compounds of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6) or pharmaceutically acceptable salts thereof, THRβ agonists (such as compounds of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6) or pharmaceutically acceptable salts thereof), and pharmaceutically acceptable carriers or excipients. In some embodiments, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical compositions according to the invention are available in forms suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or in forms suitable for inhalation administration.

[0217] In one aspect, the compounds detailed herein may be in purified form, and compositions comprising compounds in purified form are also detailed herein. Compositions comprising the compounds detailed herein or salts thereof are provided, such as compositions of substantially pure compounds. In some embodiments, compositions comprising compounds as detailed herein or salts thereof are in substantially pure form. In some embodiments, “substantially pure” means a composition containing no more than 35% impurities, where impurities represent compounds other than the compound or salt thereof constituting the majority of the composition. For example, a composition of substantially pure compounds is intended to contain no more than 35% impurities, where impurities represent compounds other than said compound or salt thereof. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, wherein said composition contains no more than 25% impurities. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, wherein said composition contains no more than 20% impurities. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, wherein said composition contains no more than 10% impurities. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, wherein said composition contains no more than 5% impurities. In some embodiments, compositions of substantially pure compounds or salts thereof are provided, wherein said composition contains no more than 3% impurities. In some embodiments, a composition of substantially pure compound or its salt is provided, wherein the composition contains no more than 1% impurities. In some embodiments, a composition of substantially pure compound or its salt is provided, wherein the composition contains no more than 0.5% impurities. In some embodiments, a composition of substantially pure compound means that the composition contains no more than 15%, in some embodiments no more than 10%, in some embodiments no more than 5%, in some embodiments no more than 3%, and in some embodiments no more than 1%, the impurities being compounds in different stereochemical forms.

[0218] In some embodiments, the compounds described herein are synthetic compounds prepared for administration to a subject (such as a human). In some embodiments, compositions comprising compounds in substantially pure form are provided. In some embodiments, the invention covers pharmaceutical compositions comprising the compounds detailed herein and pharmaceutically acceptable carriers or excipients. In some embodiments, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0219] The compound can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery. The compound can be formulated with a suitable carrier to provide a delivery form, including but not limited to tablets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), flat capsules, lozenges, sugar lozenges, gums, dispersions, suppositories, ointments, poultices (pastes), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs.

[0220] The compounds described herein can be used to prepare formulations, such as pharmaceutical preparations, by combining the compound as the active ingredient with a pharmaceutically acceptable carrier (such as those described above). The carrier can take various forms depending on the therapeutic form of the system (e.g., transdermal patches versus oral tablets). Additionally, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for adjusting osmotic pressure. Formulations containing the compounds may also contain other substances with valuable therapeutic properties. Pharmaceutical preparations can be prepared using known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0221] The compounds described herein can be administered to subjects (e.g., humans) in the form of generally acceptable oral compositions, such as tablets, coated tablets, and hard-shell or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions are lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, etc. Acceptable carriers for soft-shell gel capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for adjusting osmotic pressure.

[0222] Methods of use and uses The combinations described herein can be used in some respects to treat or prevent liver conditions. In some embodiments, methods of treating or preventing liver conditions in patients in need include administering a GLP-1R agonist and a THRβ agonist to the patient.

[0223] Liver conditions include, but are not limited to, liver inflammation, fibrosis, and fatty liver disease. In some embodiments, the liver condition is selected from liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). In some embodiments, the liver condition is selected from: liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the liver condition is NASH. In another embodiment, the liver condition is liver inflammation. In another embodiment, the liver condition is liver fibrosis. In another embodiment, the liver condition is alcoholic fibrosis. In another embodiment, the liver condition is steatosis. In another embodiment, the liver condition is alcoholic steatosis. In another embodiment, the liver condition is NAFLD. In one embodiment, the treatment methods provided herein inhibit or slow the progression of NAFLD to NASH. In one embodiment, the treatment methods provided herein inhibit or slow the progression of NASH. NASH can progress to one or more of the following: cirrhosis, liver cancer, etc. In some embodiments, the liver condition is NASH. In some embodiments, the patient has undergone a liver biopsy. In some embodiments, the method further includes obtaining the results of the liver biopsy.

[0224] In some implementations, a method for treating liver conditions in patients in need, wherein the liver condition is selected from the group consisting of: liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0225] In some implementation schemes, the disease or ailment to be treated and / or prevented is a cardiometabolic disorder. For exampleDiabetes mellitus (T1D and / or T2DM, including prediabetes)), idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent-onset atypical diabetes mellitus (YOAD), adolescent-to-adult diabetes mellitus (MODY), malnutrition-associated diabetes, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy (e.g., acute kidney injury, renal tubular dysfunction, proximal tubular pro-inflammatory changes), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urinary incontinence), overweight but not obese (e.g., BMI between 25 kg / m²). 2 With 30 kg / m 2 (between), eating disorders (including bulimia syndrome, bulimia nervosa, and syndromic obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome)), excessive sugar intake, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, liver disease (such as NAFLD, fatty degeneration, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke Wind, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral artery disease, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, or hyperapolipoprotein B hyperlipoproteinemia.

[0226] In some implementations, the disease or disorder to be treated includes sleep apnea, weight gain due to the use of other agents (e.g., steroids and antipsychotics), traumatic brain injury, Parkinson's disease, macular degeneration, cataracts, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and addiction (e.g., alcohol and / or substance abuse), prevention or treatment of polycystic ovary syndrome, or treatment of addiction (e.g., alcohol and / or substance abuse).

[0227] In some embodiments, this disclosure relates to co-administering a GLP-1R agonist and a THRβ agonist to a subject, resulting in a reduction in the subject's fat mass while the subject's lean mass is barely reduced or not reduced at all. In some embodiments, this document provides a method for treating cardiovascular metabolic disorders in a subject of need (e.g., a human patient), the method comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0228] In one implementation, the methods and combinations of this disclosure relate to a) reducing HbA1c; b) preventing or treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin-dependent diabetes; or c) preventing or treating obesity, for the purpose of reducing weight and / or food intake, or for the purpose of inducing satiety in subjects in need.

[0229] In some implementations, the combinations and methods of this disclosure relate to treating or preventing obesity, reducing body fat percentage, increasing lean body mass percentage of total body weight, or inducing satiety in subjects in need.

[0230] In some implementations, the combinations and methods of this disclosure relate to treating or preventing obesity, reducing body fat percentage, increasing lean body mass percentage of total body weight, or inducing satiety in subjects in need.

[0231] In some implementations, the combinations and methods of this disclosure relate to treating obesity in subjects in need.

[0232] In some implementations, the combinations and methods of this disclosure relate to treating or preventing obesity in subjects in need.

[0233] In some implementations, the combinations and methods of this disclosure involve reducing body fat, increasing the percentage of lean body mass in total weight, or inducing satiety in subjects in need.

[0234] In some embodiments, this disclosure provides methods for treating or preventing obesity in subjects of need, reducing body fat, and / or increasing the percentage of lean body mass in total weight, said methods comprising administering a THR-B agonist ( For example Compound 9 and the GLP-1R agonist produced a synergistic effect compared to the administration of the GLP-1R agonist alone.

[0235] In some embodiments, this disclosure provides methods for treating obesity in subjects of need, reducing body fat, and / or increasing the percentage of lean body mass in total weight, said methods comprising administering a THR-B agonist ( For example Compound 9 and the GLP-1R agonist produced a synergistic effect compared to the administration of the GLP-1R agonist alone.

[0236] In some embodiments, this document provides a method for treating a liver condition in a subject (e.g., a human patient) of need, the method comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. Exemplary liver conditions include, but are not limited to, liver inflammation, fibrosis, and steatohepatitis. In some embodiments, the liver condition is selected from the list comprising: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft-versus-host disease, transplanted liver regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and Otti antitrypsin deficiency. In some embodiments, the liver condition is selected from the list comprising: liver inflammation, liver fibrosis, alcoholic fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). In some embodiments, the liver condition is selected from the group consisting of liver fibrosis, alcoholic fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the liver condition is NASH. In another embodiment, the liver condition is liver inflammation. In another embodiment, the liver condition is liver fibrosis. In another embodiment, the liver condition is alcoholic fibrosis. In another embodiment, the liver condition is steatosis. In another embodiment, the liver condition is alcoholic steatosis. In another embodiment, the liver condition is NAFLD. In one embodiment, the treatment method provided herein inhibits or slows the progression of NAFLD to NASH. In one embodiment, the treatment method provided herein inhibits or slows the progression of NASH. NASH can progress to one or more of, for example, cirrhosis, liver cancer, etc. In some implementations, the liver condition is NASH. In some implementations, the patient has undergone a liver biopsy. In some implementations, the method further includes obtaining the results of the liver biopsy.

[0237] In some embodiments, this disclosure provides a method for reducing food intake in a subject in need, the method comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions disclosed herein. In some embodiments, the administration of the compounds disclosed herein results in a reduction of the subject's food intake by at least 10% relative to the food intake of a subject in the absence of the compounds disclosed herein, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the reduction in the subject's food intake, for example, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, continues for at least 1 hour after administration, for example, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 1 day, or at least 2 days after administration.

[0238] In some embodiments, this disclosure provides a method for improving glucose tolerance in a subject in need. In some embodiments, after glucose intake (e.g., glucose intake from food) and administration of the compound disclosed herein, the blood glucose concentration in the subject is reduced, for example, by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or 1000%, compared to the blood glucose concentration without administration of the compound disclosed herein.

[0239] According to this application, the compounds described herein or pharmaceutically acceptable salts thereof may be administered via any suitable route, in the form of a pharmaceutical composition suitable for such route, and at a dose intended to be therapeutically effective. In some embodiments, it is a compound of any embodiment of formula (I) or a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. The compounds and / or compositions described herein may be administered orally, rectally, vaginally, parenterally, or topically.

[0240] In some embodiments, the compound and / or composition can be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, or it may be administered via buccal or sublingual administration, thereby allowing the compound to enter the bloodstream directly from the mouth.

[0241] In some embodiments, the compound and / or composition can be administered directly into the bloodstream, muscle, or visceral organs. Suitable methods of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0242] In some embodiments, the compound and / or composition may be applied topically to the skin or mucous membranes, i.e., transdermal or percutaneous administration. In some embodiments, the compound and / or composition may be administered intranasally or by inhalation. In some embodiments, the compound and / or composition may be administered rectally or vaginally. In some embodiments, the compound and / or composition may be applied directly to the eyes or ears.

[0243] The dosage regimens of the compounds and / or compositions described herein are based on a variety of factors, including patient type, age, weight, sex, and medical condition; severity of the disease; route of administration; and the activity of the specific compound used. Therefore, dosage regimens can vary considerably. In some embodiments, for the treatment of the specified diseases discussed herein, the total daily dose of the compounds of this application is typically from about 0.001 to about 100 mg / kg (i.e., mg compound / kg body weight). In one embodiment, the total daily dose of the compounds of this application is from about 0.01 to about 30 mg / kg, and in another embodiment, from about 0.03 to about 10 mg / kg, and in yet another embodiment, from about 0.1 to about 3 mg / kg. It is not uncommon for the compounds of this application to be administered multiple times a day (typically not exceeding four times). Multiple daily doses can typically be used to increase the total daily dose if desired.

[0244] The appropriate dosage of the THRβ agonist described herein is also described in, for example, PCT publications WO2021231646, WO2023086561 and WO2023083288, which are incorporated herein by reference.

[0245] In some embodiments, a THRβ agonist is administered to the subject at a dose of about 0.5 mg to about 100 mg. In some embodiments, a compound is administered to the subject at a dose of about 0.5 mg to about 90 mg. In some embodiments, a compound is administered to the subject at a dose of about 1 mg to about 90 mg. In some embodiments, a compound is administered to the subject at a dose of about 3 mg to about 90 mg. In some embodiments, a compound is administered to the subject at a dose of about 0.5 mg to about 30 mg. In some embodiments, a compound is administered to the subject at a dose of about 1 mg to about 30 mg. In some embodiments, a compound is administered to the subject at a dose of about 3 mg to about 90 mg. In some embodiments, a compound is administered to the subject at a dose of about 1 mg to about 5 mg. In some embodiments, a compound is administered to the subject at a dose of about 1 mg to about 3 mg. In some embodiments, a compound is administered to the subject at a dose of about 5 mg to about 10 mg. In some embodiments, a compound is administered to the subject at a dose of about 10 mg to about 15 mg. In some embodiments, a compound is administered to the subject at a dose of about 15 mg to about 20 mg. In some embodiments, a compound is administered to the subject at a dose of about 20 mg to about 25 mg. In some embodiments, the subject is administered about 25 mg to about 30 mg of the compound. In some embodiments, the subject is administered about 1 mg of the compound. In some embodiments, the subject is administered about 2 mg of the compound. In some embodiments, the subject is administered about 3 mg of the compound. In some embodiments, the subject is administered about 4 mg of the compound. In some embodiments, the subject is administered about 5 mg of the compound. In some embodiments, the subject is administered about 6 mg of the compound. In some embodiments, the subject is administered about 7 mg of the compound. In some embodiments, the subject is administered about 8 mg of the compound. In some embodiments, the subject is administered about 9 mg of the compound. In some embodiments, the subject is administered about 10 mg of the compound. In some embodiments, the subject is administered about 15 mg of the compound. In some embodiments, the subject is administered about 20 mg of the compound. In some embodiments, the subject is administered about 25 mg of the compound. In some embodiments, the subject is administered about 30 mg of the compound. In some embodiments, the compound is compound 9 as described herein.

[0246] Combinations In further embodiments, the pharmaceutical compositions provided herein may be co-formulated with other active ingredients or substances that do not impair the desired therapeutic effect or complement the desired effect. In some embodiments, the GLP-1R agonist and the THRβ agonist are administered close together in time (e.g., the GLP-1R agonist and the THRβ agonist may be administered simultaneously). Therefore, this disclosure provides a method for treating or preventing cardiometabolic disorders, the method comprising administering a GLP-1R agonist and a THRβ agonist close together in time.

[0247] In some embodiments, a GLP-1R agonist of formula (I-1), (I-1a), (I-5), (I**) or (II*) or a pharmaceutically acceptable salt thereof is administered close in time to a THRβ agonist of formula (II-1) or (II-1a) or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, a GLP-1R agonist of formula (I-1), (I-1a), (I-5), (I**) or (II*) or a pharmaceutically acceptable salt thereof is administered close in time to a THRβ agonist (such as a compound of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5) or (II-6) or a pharmaceutically acceptable salt thereof).

[0249] In some embodiments, a GLP-1R agonist of formula (II**) or a pharmaceutically acceptable salt thereof is administered close in time to a THRβ agonist of formula (II-1) or (II-1a) or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, a GLP-1R agonist of formula (II**) or a pharmaceutically acceptable salt thereof is administered close in time to a THRβ agonist (such as a compound of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5) or (II-6) or a pharmaceutically acceptable salt thereof).

[0251] In some embodiments, a THRβ agonist of formula (II-1) or (II-1a) or a pharmaceutically acceptable salt thereof is combined with a GLP-1R agonist (such as formula (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n ...b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5d), (I-5b), (I-5c), (I-5b), (I-5c), (I-5c), (I-5b), (I-5c), (I-5c), (I-5b), Compounds of (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX), (IY), (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I), (I-P01), (II**) or (II*) or pharmaceutically acceptable salts thereof are administered close together in time.

[0252] In some implementations, "temporally proximate" means that the administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that the therapeutic effects of one therapeutic agent overlap with those of the other. In some implementations, the therapeutic effects of one therapeutic agent completely overlap with those of the other. In some implementations, "temporally proximate" means that the administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the two therapeutic agents. "Temporally proximate" can vary depending on various factors, including but not limited to the age, sex, weight, genetic background, medical condition, disease history, and treatment history of the subject to be administered the therapeutic agent; the disease or ailment to be treated or improved; the therapeutic outcome to be achieved; the dose, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some implementations, "time proximity" means within 15 minutes, 30 minutes, one hour, two hours, four hours, six hours, eight hours, 12 hours, 18 hours, 24 hours, 36 hours, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, six weeks, or eight weeks. In some implementations, multiple administrations of one therapeutic agent may be performed within time proximity to a single administration of another therapeutic agent. In some implementations, time proximity may vary during a treatment cycle or within a dosing regimen.

[0253] In some embodiments, the THRβ agonist is administered to the patient prior to the GLP-1R agonist. In some embodiments, the THRβ agonist is administered to the patient 0-1 hour, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, or 5-6 hours prior to the GLP-1R agonist. In some embodiments, the THRβ agonist is administered to the patient 0-1 day, 1-2 days, 2-3 days, 3-4 days, 4-5 days, or 5-6 days prior to the GLP-1R agonist. In some embodiments, the THRβ agonist has reached a stable state in the patient prior to administration of the GLP-1R agonist. In some embodiments, the GLP-1R agonist is administered to the patient prior to the THRβ agonist. In some embodiments, the GLP-1R agonist is administered to the patient 0-1 day, 1-2 days, 2-3 days, 3-4 days, 4-5 days, or 5-6 days prior to the THRβ agonist. In some implementations, the GLP-1R agonist has reached a stable state in the patient before the THRβ agonist is administered. In some implementations, the THR-β agonist and the GLP-1R agonist are administered to the patient substantially simultaneously.

[0254] Articles of manufacture and kits This disclosure further provides articles comprising, in suitable packaging, the compounds described herein or salts thereof, compositions described herein, or one or more unit doses described herein. In some embodiments, the articles are used in any of the methods described herein. Suitable packaging (e.g., containers) is known in the art and includes, for example, vials, dishes, ampoules, bottles, wide-mouth bottles, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0255] This disclosure further provides a kit for carrying out the methods of this disclosure, the kit comprising at least two compounds described herein or pharmaceutically acceptable salts thereof, or a composition comprising compounds described herein or pharmaceutically acceptable salts thereof. The kit may employ any of the compounds disclosed herein or pharmaceutically acceptable salts thereof. In some embodiments, the kit employs GLP-1R agonists described herein (such as formulas (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX), ( (IY), (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-PO1), (II**) or (II*) compounds or pharmaceutically acceptable salts thereof and THRβ agonists (such as (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5) or (II-6) compounds or pharmaceutically acceptable salts thereof). The kit may be used for any one or more of the purposes described herein and may therefore contain the therapeutic instructions as described herein.

[0256] Kits typically include suitable packaging. A kit may include one or more containers containing any of the compounds described herein or their pharmaceutically acceptable salts. Each component may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container. In some embodiments, the kit includes a container containing a GLP-1R agonist (such as formula (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX). (IY), (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-P01), (II**) or (II*) compounds or pharmaceutically acceptable salts thereof) and THRβ agonists (such as (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5) or (II-6) compounds or pharmaceutically acceptable salts thereof). In other embodiments, the kit includes a first container containing a GLP-1R agonist (such as formula (I-1), (I-1a), (I-2), (I-3), (I-4), (I-5), (I-5a), (I-5b), (I-5c), (I-5d), (I-5e), (I-5f), (I-5g), (I-5h), (I-5i), (I-5j), (I-5k), (I-5l), (I-5m), (I-5n), (I-5o), (I-5p), (IQ), (IR), (IS), (IT), (IU), (IX), (IY). (IZ), (IAA), (IAB), (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-P01), (II**) or (II*) compounds or pharmaceutically acceptable salts thereof; and a second container containing a THRβ agonist (such as (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5) or (II-6) compounds or pharmaceutically acceptable salts thereof).

[0257] The reagent kit can be in unit dosage form or in bulk packaging. For example (Multi-dose packaging) or subunit doses. For example, kits may be provided containing sufficient doses of a compound such as disclosed herein (e.g., compound 9) or a pharmaceutically acceptable salt thereof and / or additional pharmaceutically active compounds applicable to the diseases detailed herein, to be administered to subjects for an extended period of time through effective treatment, such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. Kits may also include multiple unit doses of the compound and instructions for use, and be available in a quantity sufficient for use in pharmacies ( For example For example The amount stored and used in hospital pharmacies and compound pharmacies is packaged.

[0258] The kit may optionally include a set of instructions relating to the use of the components of the methods of this disclosure, generally in written form, but containing an electronic storage medium of the instructions. General biological protocols Disks or CDs are also acceptable. The instructions included with the kit typically contain information about the components and their administration to the subject.

[0259] Nonalcoholic steatohepatitis (NASH) mouse model Liver biopsies The mouse model was fed a high-fat diet, which resulted in non-alcoholic fatty liver disease (NASH) and weight gain.

[0260] Blood sampling and plasma preparation Mice were anesthetized, and a small abdominal incision was made along the midline to expose the left lobe of the liver. A cone-wedge-shaped section of liver tissue was excised from the distal end of the lobe and fixed in 10% neutral buffered formalin for histological analysis. The liver section was immediately electrocoagulated using bipolar electrocoagulation.

[0261] In vivo Tissue sampling Blood samples: Collect samples at week 8, 30 minutes after dose, 1 hour after dose, 2 hours after dose, 4 hours after dose, 6 hours after dose, and 24 hours after dose (before the next dose). Collect blood from the tail vein, tongue, or cheek into appropriately sized Microvette tubes containing anticoagulant and mix. Centrifuge the blood. Transfer the plasma supernatant to a new tube and freeze immediately on dry ice. Termination of blood sample collection: During anesthesia, open the abdominal cavity and aspirate blood from the heart using a syringe containing anticoagulant and mix. Centrifuge the blood and transfer the plasma supernatant to a new tube and freeze immediately on dry ice.

[0262] Liver (NASH) Post-biopsy After the animal is killed, its liver is collected and weighed.

[0263] The liver is divided into the left lobe, medial lobe, right lobe, and caudate lobe.

[0264] Liver sponsorship The tissue was cut from the left lobe, 4 mm from the pre-biopsy site, with margins. The tissue was collected in paraformaldehyde.

[0265] Dissection from the left inner lobe Liver RNA sequencing (RNAseq) The film was placed in a tube and then directly into liquid nitrogen.

[0266] Dissected from the center of the left lobe Liver TG TC The flakes are rapidly frozen (directly placed into liquid nitrogen in a Nunc filter) and collected in a pre-cooled tube placed in liquid nitrogen.

[0267] Dissected from the right medial lobe Liver additional The sample, without edges, is located on the opposite side of the sponsoring sheet. The sample is weighed individually and collected in a test tube, then placed in liquid nitrogen.

[0268] Dissected from the right leaf Biopsy processing The tissue samples were collected in tubes and then placed in liquid nitrogen as spare tissues for use in studies and for reanalysis if necessary.

[0269] Microtome sectioning of formalin-fixed paraffin-embedded (FFPE) biopsy tissue NAFLD activity score (NAS) and fibrosis stage FFPE biopsy tissue was placed in 10% neutral buffered formalin and then transferred to 70% EtOH. The FFPE biopsy tissue was then infiltrated in a Histokinette and embedded in a tissue block. The biopsy tissue was cut into 3 μm sections using a microtome and mounted on Superfrost Plus slides.

[0270] et al. Liver samples stained with hematoxylin and eosin (H&E) or Picro Sirius red (PSR) were scored according to NAS and fibrosis stage, respectively, using Kleiner's method. et al. The clinical criteria were proposed in 2005. The total NAS represents the sum of scores for steatosis, inflammation, and ballooning degeneration, and ranges from 0 to 8. (Adapted from: Design and validation of ahistological scoring system for nonalcoholic fatty liver disease, Kleiner) et al. Histological staining proceduresHepatology 41; 2005 Gene expression analysis using RNAseq The paraffin-embedded sections were dewaxed in xylene and then rehydrated in a series of gradients of ethanol.

[0271] Hematoxylin and eosin (H&E) staining: Incubate the slide in Mayer hematoxylin (Dako), wash in tap water, stain in eosin Y solution (Sigma-Aldrich), dehydrate and cover with a coverslip.

[0272] Sirius Red (PSR) staining: Incubate the slide in Weigert iron hematoxylin (Sigma-Aldrich), wash in tap water, stain in Picro-Sirius Red (Sigma-Aldrich), and wash twice in acidified water. Remove excess water by shaking the slide, then dehydrate the slide with 100% ethanol (three times), wash with xylene, and cover with a coverslip.

[0273] Immunohistochemistry using a single chromophore: IHC was performed using standard procedures. Briefly, after antigen retrieval and blockade of endogenous peroxidase activity, slides were incubated with the primary antibody. The primary antibody was detected using a polymerized HRP-linker antibody conjugate. Next, DAB was used as the chromophore to visualize the primary antibody. Finally, the sections were counterstained in hematoxylin and covered with coverslips. The slides were scanned under a 20x objective lens on a ScanScope AT slide scanner (Aperio).

[0274] RNA isolation Library preparation and sequencing Collect tissue and rapidly freeze in liquid nitrogen. Store samples at -70°C until processing. Isolate RNA using the NucleoSpin® kit (MACHEREY-NAGEL).

[0275] Data analysis A total of 10 ng–1 μg of purified RNA was extracted from each sample to generate a cDNA library using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina (New England Biolabs). The cDNA libraries were then sequenced on a NextSeq 500 using the NextSeq 500 / 550 High Output Kit V2 (Illumina).

[0276] Serum and plasma assaysSequencing data were aligned with animal species genomes obtained from the Ensembl database using the Spliced ​​Transcript Alignment Reference (STAR) software. For bioinformatics analysis, data quality was assessed using standard RNA sequencing quality control parameters, inter- and intra-group variability was evaluated using principal component analysis and hierarchical clustering, and differentially expressed genes were identified using the R package DESeq2. Downstream analyses, such as pathway analysis or target identification, were performed according to agreements with sponsors.

[0277] Tissue assays Alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), and total cholesterol (TC): Blood samples were collected in heparinized tubes, and plasma was separated and stored at -70°C until analysis. Samples were measured using commercial kits.

[0278] Cytokeratin 18 (CK18-M30): Blood samples were collected in EDTA tubes, and plasma was separated and stored at -70°C until analysis. CK18 was measured using a commercial ELISA kit.

[0279] Insulin: Blood samples were collected in heparinized tubes, and plasma was separated and stored at -70°C until analysis. Insulin was measured using a commercial MSD platform.

[0280] TIMP-1: Collect blood samples in EDTA tubes, separate the plasma, and store at -70°C until analysis. Measure TIMP-1 using a commercial ELISA kit.

[0281] PIIINP: Blood samples are collected in EDTA tubes, and plasma is separated and stored at -70°C until analysis. PIIINP is measured using a commercial ELISA kit.

[0282] Oral glucose tolerance test (OGTT) Triglycerides (TG) and total cholesterol (TC): Liver samples were homogenized and TG and TC were extracted. The samples were centrifuged and the TG and TC content in the supernatant was measured using a commercial kit.

[0283] Terminal plasma and tissue collection On the day of the OGTT, random blood glucose and body weight were measured in mice. The mice were administered the corresponding compound or mediator before fasting in the morning, followed by a 6-hour fast. Basal fasting blood glucose was then measured via a tail vein incision. Glucose was administered orally via tube at a dose of 2 g / kg, with a volume of 5 mL / kg. Blood glucose levels were measured at 0 min (before dose), 15 min, 30 min, 60 min, and 120 min after glucose administration. A second dose was administered after the OGTT treatment.

[0284] Hypothalamic collection procedure All mice were measured for body weight and food intake, then fasted for 6 hours, euthanized with CO2, and bled out via cardiac puncture. Blood samples were centrifuged to obtain serum, which was stored for TC / TG / LDL / HDL / AST / ALT analysis. Blood samples were mixed with K2EDTA anticoagulant and centrifuged to obtain plasma, which was then stored for insulin and other possible analyses.

[0285] The weight of the entire liver and epididymal fat was weighed and recorded. The left lobule of the liver was fixed in formalin. The remaining liver was rapidly frozen and stored. The pancreas was collected and fixed in formalin. Brown fat, subcutaneous white fat, epididymal white fat tissue, and the hypothalamic region of the brain were frozen, preserved, and stored in liquid nitrogen for optional qPCR analysis.

[0286] Weight loss analysis The brain tissue was placed in a mold, with the olfactory bulb positioned in the center of the groove. The brain tissue was cut into eight coronal sections, spaced 2 mm apart and evenly distributed. The third section (6-8 mm) of the coronal brain tissue was taken, and the section was cut along the boundary of the purple part with a scalpel to separate the cerebral cortex. The remaining tissue was the hypothalamus.

[0287] Embodiments 1-169 Weight, food, and water intake were measured daily. Body composition was measured using EchoMRI. Subcutaneous fat was collected and weighed at the end of the study. UCP-1 expression in subcutaneous adipose tissue samples was assessed by qPCR and Western blot analysis.

[0288] Implementation plan with numbering Embodiments A1-A48. 1. A combination comprising a THRβ agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for the treatment of liver disease or cardiometabolic disease in patients in need.

[0289] 2. A combination of a THRβ agonist or a pharmaceutically acceptable salt thereof with a GLP-1R agonist or a pharmaceutically acceptable salt thereof, said combination for achieving weight loss in patients in need.

[0290] 3. The combination as described in embodiment 1 or 2, wherein the THRβ agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atom is selected from the group consisting of F, Cl and Br; Or its pharmaceutically acceptable salt.

[0291] 4. The combination of any one of the foregoing embodiments, wherein the THRβ agonist is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0292] Or its pharmaceutically acceptable salt.

[0293] 5. The combination of any one of the foregoing embodiments, wherein the THRβ agonist is compound 9: (9) Or its pharmaceutically acceptable salt.

[0294] 6. The combination as described in any of the foregoing embodiments, wherein the THRβ agonist is a potassium salt of compound 9.

[0295] 7. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0296] 8. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a): (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0297] 9. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3, –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 cycloalkyl or C 6-10 aryl, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkoxy, hydroxyl, -CN, or oxo group is substituted, and the cycloalkyl, heterocyclic, or aryl group is optionally substituted with one or more halogens, C, or alkyl groups. 1-6 Alkyl or -CN substitution; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 It is a halogen, hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ -(C 2-6 (-(C-)-(O)OH, -(C-) 1-6 alkylene)-C(O)OH, -NR N12 -(C 1-6 alkylene)-C(O)OH, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R N12 and R N12’ Independently H or C 1-6 alkyl; X 1 yes or , Where R 3 and R 3’ Independently H, D or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with deuterium; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 3-10 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl or heterocyclic group, optionally constituting one or more C 1-6 Alkyl, halogen, -CN or oxo groups are substituted.

[0298] 10. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-5). (I-5) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5-CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; Branch C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0299] 11. The combination of any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 Alkyl; and R 1** Is it H or C? 1-2 Alkyl groups, optionally substituted with one or more deuterium or halogens.

[0300] 12. The combination of any of the foregoing embodiments, wherein the GLP-1R agonist is compound 1-2: (1-2) Or its pharmaceutically acceptable salt.

[0301] 13. The combination of any of the foregoing embodiments, wherein the GLP-1R agonist is a meglumine salt of compounds 1-2.

[0302] 14. The combination of any of the foregoing embodiments, wherein the THRβ agonist is selected from those listed in Tables 6-11.

[0303] 15. The combination of any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1-5.

[0304] 16. The combination of any of the foregoing embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0305] 17. The combination of any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0306] 17a. The combination of any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0307] 17b. The combination of any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0308] 17c. The combination of any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0309] 18. The combination of any of the foregoing embodiments, wherein the THRβ agonist is retmetiro, VK2809, sofoteram, ilottiro, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0310] 19. The combination of any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0311] 20. A method for treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient a combination of any of the preceding embodiments.

[0312] 21. A method for treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient a therapeutically effective amount of any of the preceding embodiments.

[0313] 22. A method for increasing the lean body mass relative to total weight of a patient in need, the method comprising administering to the patient a combination of any of the preceding embodiments.

[0314] 23. A method for reducing the ratio of fat mass to total body weight in a patient in need, the method comprising administering to the patient a combination of any of the preceding embodiments.

[0315] 24. A method for achieving weight loss in a patient in need, the method comprising administering to the patient a combination of any of the preceding embodiments.

[0316] 25. The method as described in any of the foregoing embodiments, wherein the patient's body mass index (BMI) is 20 kg / m². 2 Up to 25 kg / m 2 .

[0317] 26. The method as described in any of the foregoing embodiments, wherein the patient's BMI is 25 kg / m². 2 Up to 30kg / m 2 .

[0318] 27. The method as described in any of the foregoing embodiments, wherein the patient's BMI is 30 kg / m². 2 Or higher.

[0319] 28. The method as described in any of the foregoing embodiments, wherein the cardiometabolic disease is obesity.

[0320] 29. The method as described in any of the preceding embodiments, wherein the liver condition is NASH.

[0321] 30. The method as described in any of the preceding embodiments, wherein the liver condition is liver fibrosis.

[0322] 31. The method as described in any of the preceding embodiments, wherein the GLP-1R agonist element of the combination is administered to the subject more than once.

[0323] 32. The method as described in any of the preceding embodiments, wherein the THR-β agonist element of the combination is administered to the subject more than once.

[0324] 33. The method as described in any of the preceding embodiments, wherein the combination of the GLP-1R agonist and THRβ agonist elements is administered to the subject more than once.

[0325] 34. The method of any of the foregoing embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0326] 35. The method of any of the foregoing embodiments, wherein the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0327] 36. The method as described in any of the foregoing embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0328] 37. The method as described in any of the foregoing embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered substantially simultaneously.

[0329] 38. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0330] 39. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0331] 40. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0332] 41. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered prior to the initial dose of the GLP-1R agonist.

[0333] 42. The method of embodiment 40, wherein the subsequent dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0334] 43. The method as described in embodiment 41 or 42, wherein the subsequent dose of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0335] 44. The method of any one of embodiments 41 to 43, wherein the subsequent dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0336] 45. A method for improving the response of patients in need to administration of a GLP-1R agonist, the method comprising: (i) Administering compound 9 to the patient (9), Or its pharmaceutically acceptable salt, and (ii) Administer a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0337] 46. ​​The method of embodiment 45, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases the fat reduction associated with administration of the GLP-1R agonist.

[0338] 47. The method of embodiment 45, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases fat reduction associated with administration of the GLP-1R agonist while maintaining lean body mass.

[0339] 48. The method of embodiment 45, wherein the administration of compound 9 or a pharmaceutically acceptable salt thereof is performed before or simultaneously with the administration of the GLP-1R agonist.

[0340] 49. The method of embodiment 45, wherein the administration of compound 9 or a pharmaceutically acceptable salt thereof is performed prior to the administration of the GLP-1R agonist.

[0341] 50. The method as described in any of the preceding embodiments, wherein the subject is administered the GLP-1R agonist more than once.

[0342] 51. The method as described in any of the preceding embodiments, wherein the subject is administered the THRβ agonist element more than once.

[0343] 52. The method as described in any of the preceding embodiments, wherein the subject is administered the GLP-1R agonist and THR-β agonist more than once.

[0344] 53. The method as described in any of the preceding embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0345] 54. The method of any of the foregoing embodiments, wherein the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0346] 55. The method as described in any of the preceding embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0347] 56. The method as described in any of the preceding embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered substantially simultaneously.

[0348] 57. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0349] 58. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0350] 59. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0351] 60. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered prior to the initial dose of the GLP-1R agonist.

[0352] 61. The method as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0353] 62. The method as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0354] 63. The method as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0355] 64. A combination therapy comprising a THRβ agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for the treatment of obesity in patients of need.

[0356] 65. The combination therapy as described in embodiment 64, wherein the THRβ agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atoms are selected from the group consisting of F, Cl, and Br. Or its pharmaceutically acceptable salt.

[0357] 66. The combination therapy as described in embodiment 64 or 65, wherein the THRβ agonist is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0358] Or its pharmaceutically acceptable salt.

[0359] 67. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0360] 67a. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0361] 67b. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0362] 67c. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0363] 68. The combination therapy as described in any of the preceding embodiments, wherein the THRβ agonist is a potassium salt of compound 9.

[0364] 69. The combination therapy as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0365] 70. The combination therapy as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a): (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0366] 71. The combination therapy as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3, –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 cycloalkyl or C 6-10 aryl, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkoxy, hydroxyl, -CN, or oxo group is substituted, and the cycloalkyl, heterocyclic, or aryl group is optionally substituted with one or more halogens, C, or alkyl groups. 1-6 Alkyl or -CN substitution; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 It is a halogen, hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ -(C 2-6 (-(C-)-(O)OH, -(C-) 1-6 alkylene)-C(O)OH, -NR N12 -(C 1-6 alkylene)-C(O)OH, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R N12 and R N12’ Independently H or C 1-6 alkyl; X 1 yes or , Where R 3 and R 3’ Independently H, D or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with deuterium; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 3-10 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl or heterocyclic group, optionally constituting one or more C 1-6 Alkyl, halogen, -CN or oxo groups are substituted.

[0367] 72. The combination therapy according to any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-5). (I-5) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; Branch C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0368] 73. The combination therapy as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6Alkyl; and R 1** Is it H or C? 1-2 Alkyl groups, optionally substituted with one or more deuterium or halogens.

[0369] 74. The combination therapy as described in any of the foregoing embodiments, wherein the GLP-1R agonist is compound 1-2: (1-2) Or its pharmaceutically acceptable salt.

[0370] 75. The combination therapy as described in any of the preceding embodiments, wherein the GLP-1R agonist is a meglumine salt of compounds 1-2.

[0371] 76. The combination therapy as described in any of the preceding embodiments, wherein the THRβ agonist is selected from those listed in Tables 6-11.

[0372] 77. The combination therapy as described in any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1-5.

[0373] 78. The combination therapy as described in any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0374] 79. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0375] 79a. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0376] 79b. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0377] 79c. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0378] 80. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is retemetil, VK2809, sofoteram, ilottil, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0379] 81. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0380] 82. The combination therapy as described in any of the foregoing embodiments, wherein the patient's body mass index (BMI) is 25 kg / m². 2 Up to 30 kg / m 2 .

[0381] 83. The combination therapy as described in any of the foregoing embodiments, wherein the patient's BMI is 30 kg / m². 2 Or higher.

[0382] 84. The combination therapy as described in any of the preceding embodiments, wherein the GLP-1R agonist element of the combination therapy is administered to the subject more than once.

[0383] 85. The combination therapy as described in any of the preceding embodiments, wherein the THRβ agonist element of the combination therapy is administered to the subject more than once.

[0384] 86. The combination therapy as described in any of the preceding embodiments, wherein the subject is administered the GLP-1R agonist and THR-β agonist elements of the combination therapy more than once.

[0385] 87. The combination therapy as described in any of the preceding embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0386] 88. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is administered at a time adjacent to the time of the GLP-1R agonist.

[0387] 89. The combination therapy as described in any of the preceding embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0388] 90. The combination therapy as described in any of the preceding embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered substantially simultaneously.

[0389] 91. The combination therapy as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0390] 92. The combination therapy as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0391] 93. The combination therapy as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0392] 94. The combination therapy as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered prior to the initial dose of the GLP-1R agonist.

[0393] 95. The combination therapy as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0394] 96. The combination therapy as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0395] 97. The combination therapy as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0396] 98. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, in combination therapy for treating obesity in patients in need.

[0397] 99. A THR-β agonist or a pharmaceutically acceptable salt thereof used as in embodiment 98, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atoms are selected from the group consisting of F, Cl, and Br. Or its pharmaceutically acceptable salt.

[0398] 100. A THR-β agonist or a pharmaceutically acceptable salt thereof used as in embodiment 98 or 99, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0399] Or its pharmaceutically acceptable salt.

[0400] 101. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is compound 9 (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0401] 101a. A THR-β agonist or a pharmaceutically acceptable salt thereof, or a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used as in any of the foregoing embodiments, wherein the THR-β agonist is compound 9. (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0402] 101b. A THR-β agonist or a pharmaceutically acceptable salt thereof, or a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used as in any of the foregoing embodiments, wherein the THR-β agonist is compound 9. (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0403] 101c. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0404] 102. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THRβ agonist is a potassium salt of compound 9.

[0405] 103. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0406] 104. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is a compound of formula (I-1a): (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0407] 105. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3, –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 cycloalkyl or C 6-10 aryl, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkoxy, hydroxyl, -CN, or oxo group is substituted, and the cycloalkyl, heterocyclic, or aryl group is optionally substituted with one or more halogens, C, or alkyl groups. 1-6 Alkyl or -CN substitution; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 It is a halogen, hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ -(C 2-6 (-(C-)-(O)OH, -(C-) 1-6 alkylene)-C(O)OH, -NR N12 -(C 1-6 alkylene)-C(O)OH, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6Halogenated alkyl substitution; R N12 and R N12’ Independently H or C 1-6 alkyl; X 1 yes or , Where R 3 and R 3’ Independently H, D or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with deuterium; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 3-10 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl or heterocyclic group, optionally constituting one or more C 1-6 Alkyl, halogen, -CN or oxo groups are substituted.

[0408] 106. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is a compound of formula (I-5): (I-5) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5-CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; Branch C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0409] 107. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is a compound of formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 Alkyl; and R 1** Is it H or C? 1-2 Alkyl groups, optionally substituted with one or more deuterium or halogens.

[0410] 108. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2: (1-2) Or its pharmaceutically acceptable salt.

[0411] 109. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is a meglumine salt of compounds 1-2.

[0412] 110. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THRβ agonist is selected from those listed in Tables 6-11.

[0413] 111. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is selected from those listed in Tables 1-5.

[0414] 112. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0415] 113. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is compound 9 (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0416] 113a. A THR-β agonist or a pharmaceutically acceptable salt thereof, or a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used as in any of the foregoing embodiments, wherein the THR-β agonist is compound 9 (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0417] 113b. A THR-β agonist or a pharmaceutically acceptable salt thereof, or a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the THR-β agonist is compound 9 (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0418] 113c. A THR-β agonist or a pharmaceutically acceptable salt thereof, or a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the THR-β agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0419] 114. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the THR-β agonist is retmetiro, VK2809, sofetem, ilottiro, ALG-055009, CNPT-101101, CNPT-101207, ASC41 or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compounds 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0420] 115. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is compound 9 (9), Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0421] 116. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the patient's body mass index (BMI) is 25 kg / m². 2 Up to 30kg / m 2 .

[0422] 117a. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the patient's BMI is 27 kg / m². 2 Or higher.

[0423] 117b. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the patient's BMI is 30 kg / m². 2 Or higher.

[0424] 118. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the subject is administered the GLP-1R agonist more than once.

[0425] 119. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the subject is administered the THRβ agonist more than once.

[0426] 120. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the subject is administered both the GLP-1R agonist and the THR-β agonist more than once.

[0427] 121. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is administered before or simultaneously with the GLP-1R agonist.

[0428] 122. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0429] 123. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the THR-β agonist and the GLP-1R agonist are administered on the same day.

[0430] 124. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the THR-β agonist and the GLP-1R agonist are administered substantially simultaneously.

[0431] 125. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the initial dose of the THR-β agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0432] 126. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the initial dose of the THR-β agonist and the GLP-1R agonist are administered on the same day.

[0433] 127. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the initial dose of the THR-β agonist is administered substantially simultaneously with the GLP-1R agonist.

[0434] 128. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the initial dose of the THR-β agonist is administered prior to the initial dose of the GLP-1R agonist.

[0435] 129. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein the subsequent dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0436] 130. The THR-β agonist or a pharmaceutically acceptable salt thereof used in any of the foregoing embodiments, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, wherein subsequent doses of the THR-β agonist and the GLP-1R agonist are administered on the same day.

[0437] 131. The THR-β agonist or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein subsequent doses of the THR-β agonist are administered substantially simultaneously with the GLP-1R agonist.

[0438] 132. A method for treating obesity in a patient in need, the method comprising administering to the patient a THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0439] 133. The method of embodiment 132, wherein the THRβ agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atoms are selected from the group consisting of F, Cl, and Br. Or its pharmaceutically acceptable salt.

[0440] 134. The method as described in embodiment 132 or 133, wherein the THRβ agonist is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0441] Or its pharmaceutically acceptable salt.

[0442] 135. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0443] 135a. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0444] 135b. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0445] 135c. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0446] 136. The method of any one of the foregoing embodiments, wherein the THRβ agonist is a potassium salt of compound 9.

[0447] 137. The method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0448] 138. The method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a): (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0449] 139. The method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I**): (I**) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R 1 It is -C 1-6 Halogenated alkyl groups, halogens, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3, –(CH2-CH(-OCH3)-CH2-O)1-5 -CH3, C 3-10 cycloalkyl or C 6-10 aryl, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally oxidized by one or more deuterium, C 1-6 The alkoxy, hydroxyl, -CN, or oxo group is substituted, and the cycloalkyl, heterocyclic, or aryl group is optionally substituted with one or more halogens, C, or alkyl groups. 1-6 Alkyl or -CN substitution; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; C can be arbitrarily replaced by deuterium 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; -CN; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6 alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R4 It is a halogen, hydrogen, -C(O)OH or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 12 It is hydrogen, -C(O)OH, -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ -(C 2-6 (-(C-)-(O)OH, -(C-) 1-6 alkylene)-C(O)OH, -NR N12 -(C 1-6 alkylene)-C(O)OH, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, optionally surrounded by one or more oxo groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R N12 and R N12’ Independently H or C 1-6 alkyl; X 1 yes or , Where R 3 and R 3’ Independently H, D or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be substituted with deuterium; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 5-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10arylene, 5-10 heteroarylene, or 3-10 heterocyclic group optionally substituted with one or more halogenated groups, C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a key, *-(C 1-6 alkylene)-, *-NR L –(C 1-6 alkylene)-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6 Alkylenes may optionally be substituted with deuterium; Where R L Is it H or C? 1-6 Alkyl; and Ring C is: 6-aryl, optionally bounded by one or more C 3-10 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3-10 membered heterocyclic groups, halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -CN, C 3-10 Cycloalkyl or -C(O)NR'2 substitution; Where R' is H or C 1-6 alkyl A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or Bicyclic 9- or 10-membered heteroaryl or heterocyclic group, optionally constituting one or more C 1-6 Alkyl, halogen, -CN or oxo groups are substituted.

[0450] 140. The method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-5): (I-5) Or its pharmaceutically acceptable salt; wherein: X 3 It is CR 6 Or N; X 6 It is CR 4 Or N; R1 It is -C 1-6 Halogenated alkyl groups, -OX 4 or -NR 8 R 9 , or R 1 and R 4 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 4 It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-10 cycloalkyl) or –(C 1-6 Alkylene group (3 to 8-membered heterocyclic group), 3 to 8-membered heterocyclic group, -(CH2CH2-O) 1-5 -CH3 or –(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, wherein the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halogens or -CN; R 6 Is it hydrogen, halogen, or -OR? 7 ; Where R 7 and R 2 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; R 8 and R 9 Each is independently selected from hydrogen and C. 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, or R 8 and R 9 They combine with the atoms to which they are attached to form a 6-membered heterocyclic group; wherein the C 1-6 The alkyl group may optionally be substituted with one or more oxo groups; n is 0, 1, 2, 3, 4, 5, or 6; R 2 yes: hydrogen; Branch C 1-6 alkyl; C 1-6 Halogenated alkyl groups; -(O)-C 1-6 alkyl; C can be optionally replaced by one or more -CN 3-10 cycloalkyl, C 1-6 Halogenated alkyl or C substituted with one or more -CN 1-6alkyl; A 4- or 5-membered heterocyclic group comprising at least one oxygen atom or at least one sulfur atom, wherein the 4- or 5-membered heterocyclic group is optionally surrounded by one or more oxo groups. Or C 1-6 Alkyl substitution; A 5-membered heteroaryl group comprising one or two heteroatoms independently selected from N and S, wherein R 5 At least one heteroatom is S; or R 2 and R 7 They combine with the atoms to which they are attached to form 5- or 6-membered heterocyclic groups; R 4 Is it hydrogen or -OR 8 , Where R 8 and R 1 They combine with the atoms to which they are attached to form 6-membered heterocyclic groups; X 1 yes or , Where R 3 Is it H or C? 1-6 alkyl; Ring A is , Optionally substituted with one or more halogenated groups or C 1-6 Alkyl-substituted phenylene or optionally substituted with one or more halogen groups or C 1-6 Alkyl-substituted 6-membered heteroaryl groups; Among them, * indicates and X 1 Attached, X 5 It is CR 3 Or N, and X 2 It is CR 3 Or N; L' is a key or -O-; Ring B is C 6-10 arylene, 6-10-membered heteroarylene or 3-10-membered heterocyclic, wherein the C 6-10 arylene, 6-10 heteroarylene, or 3-10 heterocyclic group optionally bounded by one or more C 1-6 Alkyl, C 1-6 Alkyl or halogen substitution; L is a bond, *-CH2-, *-O-(C 1-6 alkylene)- or *–(C 1-6 (alkylene)-O-, wherein * indicates attachment to ring B, and the C 1-6The alkylene group is optionally substituted with deuterium; and Ring C is: 6-aryl, optionally bounded by one or more C 1-6 Alkyl, 3-10 membered heterocyclic groups, halogens, -OCH3, -CN or C 3-10 Cycloalkyl substitution; A 6-membered heteroaryl group containing a nitrogen atom, optionally bonded by one or more halogens, -CN, or -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 cycloalkyl) , or Replace; or A bicyclic 9- or 10-membered heteroaryl group containing two nitrogen atoms, optionally bonded by one or more C atoms. 1-6 Alkyl or oxo group substitution.

[0451] 141. The method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 Alkyl; and R 1** Is it H or C? 1-2Alkyl groups, optionally substituted with one or more deuterium or halogens.

[0452] 142. The method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is compound 1-2: (1-2) Or its pharmaceutically acceptable salt.

[0453] 143. The method as described in any of the preceding embodiments, wherein the GLP-1R agonist is a meglumine salt of compounds 1-2.

[0454] 144. The method as described in any of the preceding embodiments, wherein the THRβ agonist is selected from those listed in Tables 6-11.

[0455] 145. The method of any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1-5.

[0456] 146. The method of any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0457] 147. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0458] 147a. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0459] 147b. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is smegglutinin or a pharmaceutically acceptable salt thereof.

[0460] 147c. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9 (9), Furthermore, the GLP-1R agonist is dagliflozin or a pharmaceutically acceptable salt thereof.

[0461] 148. The method as described in any of the preceding embodiments, wherein the THRβ agonist is retmetiro, VK2809, sofoteram, ilottiro, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0462] 149. The method as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0463] 150. The method as described in any of the foregoing embodiments, wherein the patient's body mass index (BMI) is 25 kg / m². 2 Up to 30 kg / m 2 .

[0464] 151. The method as described in any of the foregoing embodiments, wherein the patient's BMI is 30 kg / m². 2 Or higher.

[0465] 152. The method as described in any of the preceding embodiments, wherein the subject is administered the GLP-1R agonist more than once.

[0466] 153. The method as described in any of the preceding embodiments, wherein the subject is administered the THRβ agonist more than once.

[0467] 154. The method as described in any of the preceding embodiments, wherein the subject is administered the GLP-1R agonist and THR-β agonist more than once.

[0468] 155. The method of any of the foregoing embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0469] 156. The method of any of the foregoing embodiments, wherein the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0470] 157. The method as described in any of the preceding embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0471] 158. The method as described in any of the preceding embodiments, wherein the THRβ agonist and the GLP-1R agonist are administered substantially simultaneously.

[0472] 159. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0473] 160. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0474] 161. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0475] 162. The method as described in any of the preceding embodiments, wherein the initial dose of the THRβ agonist is administered prior to the initial dose of the GLP-1R agonist.

[0476] 163. The method as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist is administered at a time adjacent to that of the GLP-1R agonist.

[0477] 164. The method as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist and the GLP-1R agonist are administered on the same day.

[0478] 165. The method as described in any of the preceding embodiments, wherein the subsequent dose of the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0479] 166. The combination of any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0480] 167. The combination therapy as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9. (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0481] 168. A THR-β agonist or a pharmaceutically acceptable salt thereof, or a GLP-1R agonist or a pharmaceutically acceptable salt thereof, used in any of the foregoing embodiments, wherein the THR-β agonist is compound 9. (9), Furthermore, the GLP-1R agonist is omega-1 or a pharmaceutically acceptable salt thereof.

[0482] 169. The method as described in any of the preceding embodiments, wherein the GLP-1R agonist is omega-1 agonist or a pharmaceutically acceptable salt thereof.

[0483] Sample preparation A1. A combination comprising a THRβ agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0484] A2. The combination as described in embodiment A1, wherein the THRβ agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atom is selected from the group consisting of F, Cl and Br; Or its pharmaceutically acceptable salt.

[0485] A3. The combination as described in embodiment A1 or A2, wherein the THRβ agonist is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br.

[0486] Or its pharmaceutically acceptable salt.

[0487] A4. The combination as described in any of the foregoing embodiments, wherein the THRβ agonist is compound 9: (9) Or its pharmaceutically acceptable salt.

[0488] A5. The combination as described in any of the foregoing embodiments, wherein the THRβ agonist is a potassium salt of compound 9.

[0489] A6. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

[0490] A7. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a): (I-1a) Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

[0491] A8. The combination of any of the foregoing embodiments, wherein the GLP-1R agonist is a compound of formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 Alkyl; and R 1** Is it H or C? 1-2 Alkyl groups, optionally substituted with one or more deuterium or halogens.

[0492] A9. The combination as described in any of the foregoing embodiments, wherein the GLP-1R agonist is compound 1-2: (1-2) Or its pharmaceutically acceptable salt.

[0493] A10. The combination of any one of the foregoing embodiments, wherein the GLP-1R agonist is a meglumine salt of compounds 1-2.

[0494] A11. The combination of any of the preceding embodiments, wherein the THRβ agonist is selected from those listed in Tables 6-11, or pharmaceutically acceptable salts thereof.

[0495] A12. The combination of any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1-5, or pharmaceutically acceptable salts thereof.

[0496] A13. The combination of any of the preceding embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A below, or a pharmaceutically acceptable salt thereof.

[0497] A14. The combination as described in any of the preceding embodiments, wherein the THRβ agonist is compound 9. (9), The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

[0498] A15. The combination as described in any of the preceding embodiments, wherein the THRβ agonist is compound 9. (9), Furthermore, the GLP-1R agonist is omega-1, dapagliflozin, or smegglutinin, or a pharmaceutically acceptable salt thereof.

[0499] A16. The combination of any of the foregoing embodiments, wherein the THRβ agonist is retmetiro, VK2809, sofoteram, ilottiro, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0500] A17. The combination as described in any of the preceding embodiments, wherein the THRβ agonist is compound 9. (9), Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2), Or its pharmaceutically acceptable salt.

[0501] A18. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is from about 0.5 mg to about 25 mg.

[0502] A19. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is from about 1 mg to about 15 mg.

[0503] A20. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is from about 2 mg to about 10 mg.

[0504] A21. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is about 1 mg.

[0505] A22. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is about 3 mg.

[0506] A23. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is about 6 mg.

[0507] A24. The combination as described in any of the foregoing embodiments, wherein the amount of the THRβ agonist is about 10 mg.

[0508] A25. The combination of any of the foregoing embodiments is used to treat liver disease or cardiometabolic disease in patients in need.

[0509] A26. The combination of any one of the foregoing embodiments is used to achieve weight loss in patients in need.

[0510] A27. The combination of any of the foregoing embodiments, used in combination therapy for treating obesity in patients in need.

[0511] A28. A method for treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient a combination of any of the foregoing embodiments.

[0512] A29. A method for treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient a therapeutically effective amount of any of the preceding embodiments.

[0513] A30. A method for increasing the ratio of lean body mass to total body weight in a patient in need, the method comprising administering to the patient a combination of any of the preceding embodiments.

[0514] A31. A method for reducing the ratio of fat mass to total body weight in a patient in need, the method comprising administering to the patient a combination of any of the preceding embodiments.

[0515] A32. A method for achieving weight loss in a patient in need, the method comprising administering to the patient the combination of any one of the foregoing embodiments.

[0516] A33. The method as described in any of the foregoing embodiments, wherein the patient's body mass index (BMI) is 27 kg / m². 2 Or higher.

[0517] A34. The method as described in any of the foregoing embodiments, wherein the patient's BMI is 30 kg / m². 2 Or higher.

[0518] A35. The method as described in any of the foregoing embodiments, wherein the administration of the THRβ agonist allows for the administration of a reduced dose of the GLP-1R agonist while maintaining an equivalent weight loss.

[0519] A36. The method as described in any of the preceding embodiments, wherein administration of the THRβ agonist increases weight loss compared to administration of an equivalent dose of a GLP-1R agonist.

[0520] A37. The method as described in any of the foregoing embodiments, wherein the cardiometabolic disease is obesity or an obesity-related disorder.

[0521] A38. The method as described in any of the foregoing embodiments, wherein the cardiometabolic disease is diabetes.

[0522] A39. The method as described in any of the foregoing embodiments, wherein the combination or method improves glycemic control in adults with type 2 diabetes.

[0523] A40 A method for treating obesity or achieving weight loss in patients in need, the method comprising: (i) Administering compound 9 to the patient (9), Or its pharmaceutically acceptable salt, and (ii) Administer a GLP-1R agonist, or a pharmaceutically acceptable salt thereof, to the patient; Administering compound 9 or a pharmaceutically acceptable salt thereof to the patient improves the patient's response to the GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0524] A41. The combination or method as described in any of the foregoing embodiments, wherein the THRβ agonist is administered once or twice daily.

[0525] A42. The combination or method as described in any of the foregoing embodiments, wherein the THRβ agonist is administered orally.

[0526] A43. The combination or method as described in any of the foregoing embodiments, wherein the GLP-1R agonist is administered orally.

[0527] A44. The method of embodiment A40, wherein the GLP-1R agonist comprises compounds 1-2, omega-1, semaglutide, tesipatide, or dapagliflozin.

[0528] A45. The method as described in any of the preceding embodiments, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases fat reduction associated with administration of the GLP-1R agonist.

[0529] A46. The method as described in any of the preceding embodiments, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases fat reduction associated with administration of the GLP-1R agonist while maintaining lean body mass.

[0530] A47. The combination of any one of embodiments A1 to A27, used to prepare a medicament for use in any one of embodiments A28 to A46.

[0531] A48. Use of the combination of any one of embodiments A1 to A27 in the method of any one of embodiments A28 to A46.

[0532] Example The combination therapies presented in this article can be tested by administering the combination of drugs to well-known mouse models and evaluating the results. Methods for such testing can be adapted from those already known.

[0533] Example 1. Evaluation of the combination of THR-B agonist compound 9 and GLP-1R agonist (e.g., smegglutinin). To evaluate the effects of compound 9 alone and in combination with smegglutinin for 12 weeks on metabolic parameters, liver pathology, and NAFLD activity scores (including fibrosis stage) in male biopsy-confirmed GANDIO-NASH mice.

[0534] Study groups *Titration: Day 1: 0.12 nmol / ml; Day 2: 0.24 nmol / ml; Day 3: 0.48 nmol / ml; Day 4: 0.96 nmol / ml; Day 5: 2.4 nmol / ml; Day 6: 6 nmol / ml Measurement (in vivo pharmacology) *Titration: Day 1: 0.6 nmol / kg; Day 2: 1.2 nmol / kg; Day 3: 2.4 nmol / kg; Day 4: 4.8 nmol / kg; Day 5: 12 nmol / kg; Day 6: 30 nmol / kg.

[0535] Measurement (histology) Measurement (assays) Nonalcoholic steatohepatitis (NASH) mouse model Liver biopsies The mouse model was fed a high-fat diet, resulting in non-alcoholic fatty liver disease (NASH). NASH mice were based on male C57BL / 6JRj mice, which were fed a diet of 40% fat, 22% fructose, and 2% cholesterol (D09100310, SSNIFF, Germany) for at least 28 weeks prior to the experiment.

[0536] Blood sampling and plasma preparation Mice were anesthetized by inhalation anesthesia using isoflurane (2%–3%). A small abdominal incision was made at the midline, exposing the left lobe of the liver. A cone-wedge-shaped section of liver tissue (approximately 50 mg) was excised from the distal end of the liver lobe and fixed in 10% neutral buffered formalin (10% NBF) for histological analysis. The liver section was immediately electrocoagulated using bipolar electrocoagulation (ERBE VIO 100 high-frequency electrosurgical unit). The liver was returned to the abdominal cavity, the abdominal wall was sutured, and the skin was closed with a suture device. For postoperative recovery, mice were administered carbofen (5 mg / kg) subcutaneously on the day of the operation and on days 1 and 2 post-operation.

[0537] In vivo Tissue sampling Blood samples: Collect samples at week 8, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after the next dose (before the next dose). Collect blood from the tail vein, tongue, or cheek into appropriately sized Microvette tubes containing anticoagulant and mix by inverting 5 times. Incubate the blood at 4°C until centrifuged at 3000 g for 10 minutes. Transfer the plasma supernatant to a new tube and freeze immediately on dry ice. Store samples at -70°C.

[0538] Termination of blood sample collection: During isoflurane anesthesia, open the abdominal cavity and use a syringe to draw cardiac blood into appropriately sized microvettes / vacuettes containing anticoagulant, mixing by inverting 5 times. Incubate the blood at 4°C until centrifuged at 3000 g for 10 minutes. Transfer the plasma supernatant to a new test tube and immediately freeze on dry ice. Store the sample at -70°C.

[0539] Liver (NASH) Post-biopsy After euthanizing the animal by cardiac puncture, the liver was collected and weighed. Specific liver samples and biopsy samples were dissected and processed according to the provisions in the "Termination Samples" table, which are further described below.

[0540] The liver is divided into the left lobe, medial lobe, right lobe, and caudate lobe. Unless otherwise specified in the protocol, the remaining lobes are not used.

[0541] Liver sponsorship A slice (~200 mg, less than 0.7 x 0.5 cm) was cut from the left leaf, 4 mm from the pre-biopsy site, with margins. The tissue was collected in paraformaldehyde.

[0542] Dissection from the left inner lobe Liver RNA sequencing (RNAseq)Place the tablet (~150 mg) into a tube and immerse it directly in liquid nitrogen. Store the sample at -70°C. Note that the size of the sponsored tablet varies depending on the size of the left inner leaflet.

[0543] Dissected from the center of the left lobe Liver TG TC Tablets (20±10 mg) were rapidly frozen (directly placed into liquid nitrogen in a Nunc filter) and collected in pre-cooled tubes placed in liquid nitrogen. Samples were stored at -70°C.

[0544] Dissected from the right medial lobe Liver additional Tablets (25±5 mg), without edges, are placed on the opposite side of the sponsor tablet. Samples are weighed individually and collected in test tubes, then placed in liquid nitrogen. Samples are stored at -70°C.

[0545] Dissected from the right leaf Biopsy processing Each tablet (~100-300 mg) was collected in a tube and then placed in liquid nitrogen as a spare tissue for the study and for reanalysis if necessary. Samples were stored at -70°C.

[0546] Microtome sectioning of formalin-fixed paraffin-embedded (FFPE) biopsy tissue NAFLD activity score (NAS) and fibrosis stage FFPE biopsy tissue was placed in 10% neutral buffered formalin (10% NBF) for approximately 24 hours, then transferred to 70% EtOH and stored at 4°C. The FFPE biopsy tissue was then infiltrated in Histokinette and embedded in tissue blocks. The biopsy tissue was cut into 3 μm sections using a microtome, and the sections were mounted on Superfrost Plus slides and stored at 4°C.

[0547] Histological staining procedures Liver samples stained with hematoxylin and eosin (H&E) or Picro Sirius red (PSR) were scored according to NAS and fibrosis stage, using the clinical criteria proposed by Kleiner et al. (2005). Total NAS represented the sum of scores for steatosis, inflammation, and ballooning degeneration, and ranged from 0 to 8. (Adapted from: Design and validation of ahistological scoring system for nonalcoholic fatty liver disease, Kleiner et al., Hepatology 41; 2005) Gene expression analysis using RNAseq In short, the glass slides containing paraffin-embedded sections were dewaxed in xylene and rehydrated in a series of gradients of ethanol.

[0548] Hematoxylin and eosin (H&E) staining: Incubate the slide in Mayer hematoxylin (Dako), wash in tap water, stain in eosin Y solution (Sigma-Aldrich), dehydrate and cover with a coverslip.

[0549] Sirius Red (PSR) staining: Incubate the slide in Weigert iron hematoxylin (Sigma-Aldrich), wash in tap water, stain in Picro-Sirius Red (Sigma-Aldrich), and wash twice in acidified water. Remove excess water by shaking the slide, then dehydrate the slide with 100% ethanol (three times), wash with xylene, and cover with a coverslip.

[0550] Immunohistochemistry using a single chromophore: IHC was performed using standard procedures. Briefly, after antigen retrieval and blockade of endogenous peroxidase activity, slides were incubated with the primary antibody. The primary antibody was detected using a polymerized HRP-linker antibody conjugate. Next, DAB was used as the chromophore to visualize the primary antibody. Finally, the sections were counterstained in hematoxylin and covered with coverslips. The slides were scanned under a 20x objective lens on a ScanScope AT slide scanner (Aperio).

[0551] Serum and plasma assays RNA isolation: Collect tissue and rapidly freeze in liquid nitrogen. Store samples at -70°C until processing. Isolate RNA using the NucleoSpin® kit (MACHEREY-NAGEL).

[0552] Library preparation and sequencing: A total of 10 ng–1 μg of purified RNA was extracted from each sample to generate a cDNA library using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina (New England Biolabs). The cDNA libraries were then sequenced on a NextSeq 500 using the NextSeq 500 / 550 High Output Kit V2 (Illumina).

[0553] Data analysis: Sequencing data were aligned with animal species genomes obtained from the Ensembl database using the Spliced ​​Transcript Alignment Reference (STAR) software. For bioinformatics analysis, data quality was assessed using standard RNA sequencing quality control parameters, inter- and intra-group variability was evaluated using principal component analysis and hierarchical clustering, and differentially expressed genes were identified using the R package DESeq2. Downstream analyses, such as pathway analysis or target identification, were performed as agreed with sponsors.

[0554] Tissue assays Alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), and total cholesterol (TC): Blood samples were collected in heparinized tubes, and plasma was separated and stored at -70°C until analysis. Samples were measured using a commercial kit (Roche Diagnostics) on a cobas c 501 automated analyzer.

[0555] Cytokeratin 18 (CK18-M30): Blood samples were collected in EDTA tubes, and plasma was separated and stored at -70°C until analysis. CK18 was measured using a commercial ELISA kit (Cusabio).

[0556] Insulin: Blood samples were collected in heparinized tubes, and plasma was separated and stored at -70°C until analysis. Insulin was measured using a commercial MSD platform (Meso Scale Diagnostics).

[0557] TIMP-1: Blood samples are collected in EDTA tubes, and plasma is separated and stored at -70°C until analysis. TIMP-1 is measured using a commercial ELISA kit (R&D Systems).

[0558] PIIINP: Blood samples were collected in EDTA tubes, and plasma was separated and stored at -70°C until analysis. PIIINP was measured using a commercial ELISA kit (Cusabio).

[0559] Animal use Triglycerides (TG) and total cholesterol (TC): Liver samples were homogenized and TG and TC were extracted in 5% NP-40 by heating twice to 90°C. The samples were centrifuged and the TG and TC content in the supernatant was measured using a commercial kit (Roche Diagnostics) on a cobas c501 automated analyzer.

[0560] Example 2: In vivo efficacy of compounds (1-2) alone and in combination with compound 9 in reducing body weight in hGLP1R-C57BL / 6J mice in a high-fat diet-induced obesity model. hGLP1R-C57BL / 6J mice that had been fed a high-fat diet for >20 weeks to induce obesity were administered compounds (1-2) alone or in combination with compound 9. Other groups were administered alternative GLP-1R agonists, such as smegglutinin. Body weight and food intake were measured daily.

[0561] Mouse generations Study procedure One hundred and eighteen 6-7 week old h-GLP1R-C57BL / 6J mice were fed a high-fat diet (HFD, study diet D12492i 60% kcal) for approximately 20 weeks to obtain a diet-induced obesity (DIO) phenotype, while n=10 h-GLP1R-C57BL / 6J mice were fed a normal diet as a low-fat control. All animals had free access to food and water. The animal room environment was controlled (target conditions: temperature 20°C to 24°C, relative humidity 30% to 70%). Temperature and relative humidity were monitored daily. A 12-hour light / 12-hour dark cycle was provided using an electronically timed lighting system. Two to three mice were housed in each plastic cage, in accordance with the National Research Council's Guidelines for the Care and Use of Laboratory Animals. Abundant toys were provided. Animals were housed in individual cages and acclimatized to the environment for at least one week prior to the formal experiments. Weight was measured weekly during the modeling period.

[0562] Group design Adaptations 1 Groups 6 and 9 received the test product in the morning (9:30 to 10:30 am) followed by a dose of either the mediator (10% Solutol HS15: 90% sterile water, [v / v]) or saline (semaglutide mediator) in the evening (5:30 to 6:30 pm) to balance the treatment. For combination groups (7 and 8), compounds (1-2) and compound 9 were administered in the morning (9:30 to 10:30 am), followed by compounds (1-2) and the mediator in the evening (5:30 to 6:30 p...

Claims

1. A combination comprising a THRβ agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

2. The combination of claim 1, wherein the THRβ agonist is a compound of formula (II-1). (II-1) in: R1 is selected from the group consisting of: hydrogen, cyano, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C. 1-6 Alkoxy; R2 and R3 are each independently selected from halogen atoms and substituted or unsubstituted carbon atoms. 1-6 The group consisting of alkyl groups, wherein the substituents are selected from the group consisting of halogen atoms, hydroxyl groups, and C atoms. 1-6 Alkoxy; Ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 Aliphatic rings, with or without substituted C 5-10 An aromatic ring, wherein the substituent is one or more substances selected from the group consisting of: hydrogen, halogen atoms, hydroxyl groups, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and when containing two substituents, the two substituents are capable of forming a ring structure together with the carbon to which they are attached; and The halogen atom is selected from the group consisting of F, Cl and Br; Or its pharmaceutically acceptable salt.

3. The combination of claim 1 or 2, wherein the THRβ agonist is a compound of formula (II-1a). (II-1a) in: R1 to R3 are defined in detail in this paper for equation (II-1); R4 is selected from the group consisting of: hydrogen, halogen atom, hydroxyl group, -OCF3, -NH2, -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -CONH2, -CONHC 1-4 Alkyl, -CON(C) 1-4 Alkyl)2、-NHCOC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; m is an integer in the range of 1 to 4; and The halogen atoms are selected from the group consisting of F, Cl and Br. Or its pharmaceutically acceptable salt.

4. The combination of any of the preceding claims, wherein the THRβ agonist is compound 9: (9) Or its pharmaceutically acceptable salt.

5. The combination of any of the preceding claims, wherein the THRβ agonist is a potassium salt of compound 9.

6. The combination of any of the preceding claims, wherein the GLP-1R agonist is a compound of formula (I-1): (I-1) Or its pharmaceutically acceptable salt, wherein: X is N or CH; Y is N or CR 4 ; n is 0 or 1; R is hydrogen; R 1 It is a -C1-C6 alkylene-R 5 ; R 2 It is a hydrogen, oxo group, or C1-C6 alkyl group; R 3 It is a hydrogen, oxo, or C1-C6 alkyl group, and R 4 It is hydrogen, OH, or C1-C6 alkyl; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups that are optionally substituted with halogroups or C1-C3 alkyl groups; R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein each contains 1, 2 or 3 heteroatoms independently selected from O, N and S, wherein R 5 At least one heteroatom is S, and further wherein R 5 Optional halogenated groups, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl or C1-C6 haloalkyl substitution; Ring A is a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein each is optionally substituted independently by a halogroup, CN, C3-C6 cycloalkyl or C1-C6 alkyl, optionally substituted by a halogroup or OH. L represents a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *–NR. 6 -C1-C6 alkylene-**, where * represents the attachment point to ring A, and ** represents the attachment point to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene of L is optionally replaced by R. L Replace, where each R L Independently C1-C6 alkyl or halogroup, or two R groups L Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups; and When L is a C1-C6 alkylene group, the C1-C6 alkylene group is optionally replaced by R. L1 Replace, where each R L1 Independently a halogroup, OH, oxogroup, or C1-C6 alkyl group, or two R groups. L1 Together with one or more carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or 3 to 6-membered heterocyclic groups; R 6 It is hydrogen or C1-C6 alkyl; and Ring B is C3-C 10 cycloalkyl, C6-C 14 Aryl, 4- to 12-membered heterocyclic or 5- to 12-membered heteroaryl, wherein each is independently and optionally substituted by one to three substituents independently selected from the group consisting of: halogroup, CN, oxogroup, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.

7. The combination of any of the preceding claims, wherein the GLP-1R agonist is a compound of formula (I-1a): (I-1a), or a pharmaceutically acceptable salt thereof. Where R 7 It is hydrogen, chlorine, bromine, fluorine, methyl, or vinyl; and R 8 yes , , , , , or .

8. The combination of any of the preceding claims, wherein the GLP-1R agonist is a compound of formula (II**): (II**) Or its pharmaceutically acceptable salt; wherein R f4 and R f5 Each is independently selected from C 1-6 Alkyl, H and D nf1 is 0, 1, 2, 3 or 4; nf3 is 0, 1, 2, 3, 4 or 5; Each R f1 It is halogen; R 3 and R 3’ Independently H or D; X 1 * indicates N or CR f1 ; X 2* and X 3* Independently CH or CF; Each R f3 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy or -C(O)N(R) f3’ )2, Each R f3’ Independently selected from H or C 1-6 Alkyl; and R 1** Is it H or C? 1-2 Alkyl groups, optionally substituted with one or more deuterium or halogens.

9. The combination of any of the preceding claims, wherein the GLP-1R agonist is compound 1-2: (1-2) Or its pharmaceutically acceptable salt.

10. The combination of any of the preceding claims, wherein the GLP-1R agonist is a meglumine salt of compounds 1-2.

11. The combination of any of the preceding claims, wherein the THRβ agonist is selected from those listed in Tables 6-11, or pharmaceutically acceptable salts thereof.

12. The combination of any of the preceding claims, wherein the GLP-1R agonist is selected from those listed in Tables 1-5, or pharmaceutically acceptable salts thereof.

13. The combination of any of the preceding claims, wherein the GLP-1R agonist is selected from those listed in Table 5A below, or a pharmaceutically acceptable salt thereof.

14. The combination of any of the preceding claims, wherein the THRβ agonist is compound 9. (9), or its pharmaceutically acceptable salt. The GLP-1R agonist is omega-1, dapagliflozin, liraglutide, exenatide, dulaglutide, abiglutide, liximab, tesipatide, or smegglutide, or a pharmaceutically acceptable salt thereof.

15. The combination of any of the preceding claims, wherein the THRβ agonist is compound 9. (9), or its pharmaceutically acceptable salt. Furthermore, the GLP-1R agonist is omega-1, dapagliflozin, or smegglutinin, or a pharmaceutically acceptable salt thereof.

16. The combination of any of the preceding claims, wherein the THRβ agonist is retmetiro, VK2809, sofoteram, ilottiro, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2)， Or its pharmaceutically acceptable salt.

17. The combination of any of the preceding claims, wherein the THRβ agonist is compound 9. (9)， Or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2. (1-2)， Or its pharmaceutically acceptable salt.

18. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is from about 0.5 mg to about 25 mg.

19. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is from about 1 mg to about 15 mg.

20. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is from about 2 mg to about 10 mg.

21. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is about 1 mg.

22. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is about 3 mg.

23. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is about 6 mg.

24. The combination of any of the preceding claims, wherein the amount of the THRβ agonist is about 10 mg.

25. The combination of any of the preceding claims, used to treat liver disease or cardiometabolic disease in patients in need.

26. The combination of any of the preceding claims, used to achieve weight loss in patients in need.

27. The combination of any of the preceding claims, used in combination therapy for treating obesity in patients in need.

28. A method of treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient the combination of any one of the preceding claims.

29. A method of treating a patient with liver disease or cardiometabolic disease, the method comprising administering to the patient a therapeutically effective amount of any combination of the preceding claims.

30. A method for increasing the lean body mass relative to total weight of a patient in need, the method comprising administering to the patient the combination of any one of the preceding claims.

31. A method for reducing the ratio of fat mass to total body weight in a patient in need, the method comprising administering to the patient the combination of any one of the preceding claims.

32. A method for achieving weight loss in a patient in need, the method comprising administering to the patient the combination of any one of the preceding claims.

33. The method as described in any of the preceding claims, wherein the patient's body mass index (BMI) is 27 kg / m². 2 Or higher.

34. The method as described in any of the preceding claims, wherein the patient's BMI is 30 kg / m². 2 Or higher.

35. The method of any of the preceding claims, wherein the administration of the THRβ agonist allows for the administration of a reduced dose of the GLP-1R agonist while maintaining an equivalent weight loss.

36. The method as described in any of the preceding claims, wherein administration of the THRβ agonist increases weight loss compared to administration of an equivalent dose of a GLP-1R agonist.

37. The method of any of the preceding claims, wherein the cardiometabolic disease is obesity or an obesity-related disorder.

38. The method as claimed in any of the preceding claims, wherein the cardiometabolic disease is diabetes.

39. The method as described in any of the preceding claims, wherein the combination or method improves glycemic control in adults with type 2 diabetes.

40. A method for treating obesity or achieving weight loss in patients in need, the method comprising: (i) Administering compound 9 to the patient (9)， Or its pharmaceutically acceptable salt, and (ii) Administer a GLP-1R agonist, or a pharmaceutically acceptable salt thereof, to the patient; Administering compound 9 or a pharmaceutically acceptable salt thereof to the patient improves the patient's response to the GLP-1R agonist or a pharmaceutically acceptable salt thereof.

41. The combination or method as described in any of the preceding claims, wherein the THRβ agonist is administered once or twice daily.

42. The combination or method as described in any of the preceding claims, wherein the THRβ agonist is administered orally.

43. The combination or method as described in any of the preceding claims, wherein the GLP-1R agonist is administered orally.

44. The method of claim 40, wherein the GLP-1R agonist comprises compounds 1-2, omeprazole, smegglutide, tesipatide, or dapagliflozin.

45. The method of any of the preceding claims, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases fat reduction associated with administration of the GLP-1R agonist.

46. ​​The method of any of the preceding claims, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases fat reduction associated with administration of the GLP-1R agonist while maintaining lean body mass.

47. The combination of any one of claims 1 to 27, used to prepare a medicament for use in any one of claims 28 to 46.

48. Use of the combination of any one of claims 1 to 27 in the method of any one of claims 28 to 46.

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