A combination of THR beta-agonists and GLP-1R agonists for use in the treatment of liver damage or cardiovascular metabolic diseases.

Abstract

This specification provides combinations comprising a glucagon-like peptide-1 receptor (GLP-1R) agonist and a thyroid hormone receptor beta (THRβ) agonist, as well as methods comprising administering such combinations to subjects requiring them.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest to U.S. Provisional Applications No. 63 / 495,049 filed on 7 April 2023, No. 63 / 526,362 filed on 12 July 2023, and No. 63 / 615,985 filed on 29 December 2023, which are incorporated herein by reference in their entirety for all purposes. [Background technology]

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

[0003] In healthy individuals, GLP-1 plays a crucial role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, thereby increasing peripheral glucose absorption. GLP-1 also suppresses glucagon secretion, leading to a decrease in hepatic glucose production. Furthermore, GLP-1 slows gastric emptying and intestinal motility, thereby delaying food absorption.

[0004] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormones function by binding to thyroid hormone receptors (THRs). Thyroid hormone receptors belong to the family of nuclear receptors and regulate the expression of target genes. There are two distinct subtypes of thyroid hormone receptors: THRα and THRβ. THRα is mainly distributed in cardiac tissue and plays an important role in regulating cardiac function. The THRβ subtype is mainly expressed in the liver and pituitary gland and regulates cholesterol metabolism and thyrotropin secretion.

[0005] At normal levels, the thyroid hormone THR is involved in maintaining body weight, metabolic rate, body temperature, and mood, and regulating serum cholesterol. Attempts have been made to regulate serum cholesterol using thyroid hormones. However, given the potential cardiac side effects of taking natural thyroid hormones (e.g., tachycardia and arrhythmias, heart failure, as well as thyroid system function, muscle metabolism, and osteoporosis), they are not suitable for treating high cholesterol and obesity. Research findings from animal studies involving selective knockout of the THR gene, and studies of several selective THR ligands, have shown that the cardiac side effects caused by these thyroid hormones may be due to THRα but not THRβ. Therefore, THRβ-selective ligands may offer the benefits of THR agonist activity (e.g., cholesterol reduction) without the undesirable effects associated with THRα.

[0006] While combination therapies with known agonists can yield significantly higher levels of unexpected synergistic and improved effects than the administration of any single drug, the effects of combination therapies are highly unpredictable. The development of new combination therapies for the treatment of various liver disorders and cardiovascular metabolic diseases, including obesity, remains a significant clinical unmet need.

[0007] GLP-1Rs regulate postprandial blood glucose levels and satiety, which can induce weight loss, but their effectiveness is limited by metabolic adaptations, which are surrogate processes that reduce energy expenditure (EE). Furthermore, the high dose levels of GLP-1R required to achieve clinically meaningful weight loss are associated with more serious and frequent GI-related side effects, including nausea and vomiting, which can negatively impact patient compliance. A meta-analysis evaluating the efficacy and safety of orfolglipron as an anti-obesity agent showed that total adverse events were significantly higher at all doses of orfolglipron compared to placebo, with higher doses resulting in higher hazard ratios. Gastrointestinal side effects were the most common and dose-dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the most frequent side effects (Dutta et al., Obes Sci Pract. 2024 Apr;10(2):e743 PMID:38414573). Compared to placebo, the incidence of total adverse events was significantly higher with olfolglipron daily doses of 12 mg, 24 mg, 36 mg, and 45 mg (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). Therefore, dose-dependent gastrointestinal side effects remain a persistent challenge in the field of GLP-1 therapeutics.

[0008] Mechanisms that improve the efficacy of low-dose GLP-1-based therapy may reduce GI-related side effects and improve patient compliance and outcomes. [Overview of the project]

[0009] In one embodiment, the disclosure relates to a combination of a THRβ agonist or a pharmaceutically acceptable salt thereof and a GLP-1R agonist or a pharmaceutically acceptable salt thereof for the treatment of patients requiring treatment for hepatic impairment or cardiovascular metabolic disease.

[0010] In one embodiment, the present disclosure relates to a method for administering a THRβ agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for the treatment of patients requiring treatment for hepatic impairment or cardiovascular metabolic disease.

[0011] In one embodiment, the present disclosure relates to a method for administering a pharmaceutical composition comprising a THRβ agonist or a pharmaceutically acceptable salt thereof for the treatment of patients requiring treatment for hepatic impairment or cardiovascular metabolic disease, and a pharmaceutical composition comprising a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment, the disclosure relates to a method for administering a pharmaceutical composition 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 a patient requiring treatment for hepatic impairment or cardiovascular metabolic disease.

[0013] In some embodiments, the THRβ agonist of the combination disclosed herein is a compound of formula (II-1), [ka] During the ceremony, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10 Aliphatic rings, or substituted or unsubstituted C 5~10It is an aromatic ring, and the substituents are hydrogen, a halogen atom, hydroxy, -OCF3, -NH2, -NHC 1~4 alkyl, -N(C 1~4 alkyl)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 is one or more substances selected from the group consisting of, and when two substituents are contained, the two substituents may form a ring structure together with the carbon to which they are attached, a compound in which the halogen atom is selected from the group consisting of F, Cl, and Br, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the THRβ agonist of the combination of the present disclosure is a compound of formula (II-1a),

Chemical formula

[0016] In some embodiments, the THRβ agonist of the combinations disclosed herein is the potassium salt of compound 9.

[0017] In some embodiments, the GLP-1R agonist combination of the present disclosure is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 is -C1-C6 alkylene-R 5 And, R 2 is hydrogen, oxo, or C1-C6 alkyl, R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl which may be substituted with a halo or a C1-C3 alkyl, R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom of is S, and further R 5 Hello, -OC 1-6 Alkyl, C1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 member heterocyclene or a 5-12 member heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1-C6 alkylene-**, then the C1-C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon or atom to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon or atom to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or C1-C6 alkyl, Ring B is C3-C 10 Cycloalkyl, C6-C 14 The molecules are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0018] In some embodiments, the GLP-1R agonist of the combination disclosed herein is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] That is the case.

[0019] In some embodiments, the GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, halogen, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5-CH3, -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 cycloalkyl, or C 6-10 aryl, where the alkyl, alkylene, heteroalkyl, or haloalkyl group is optionally substituted with one or more deuteriums, C 1-6 alkoxy, hydroxyl, -CN, or oxo, and the cycloalkyl, heterocyclyl, or aryl group is optionally substituted with one or more halogens, C 1-6 alkoxy, or -CN, R 6 is hydrogen, halogen, or -O-R 7 and R 7 and R 2 are combined together with the atoms to which they are attached to form a 6-membered heterocyclyl, R 8 and R 9 are each independently hydrogen, C 1-6 alkyl, or -S(O)2-C 1-6 alkyl, or R 8 and R 9 are combined together with the atoms to which they are attached to form a 6-membered heterocyclyl, C 1-6 alkyl is optionally substituted with one or more oxos, n is 0, 1, 2, 3, 4, 5, or 6, R 2 is hydrogen, C optionally substituted with deuterium, 1-6 alkyl, C 1-6 haloalkyl, -(O)-C 1-6 alkyl, -CN, one or more -CN, C 1-6 haloalkyl, or C optionally substituted with one or more -CN, 1-6 alkyl optionally substituted with C 3-10 cycloalkyl, A 4- or 5-membered heterocyclyl containing at least one oxygen or at least one sulfur atom, optionally substituted with one or more oxo,

Chem.

Chem.

[0020] In some embodiments, the GLP-1R agonist combination of the present disclosure is a compound of formula (I-5), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms they are bonded to to form a 6-membered heterocycline, C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, Branched C 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arirene, 6-10 membered heteroarirene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0021] In some embodiments, the GLP-1R agonist combination of compounds 1-2 of the present disclosure is [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the GLP-1R agonist of the combination disclosed herein is the meglumine salt of compound 1-2.

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

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

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

[0026] In some embodiments, the THRβ agonist of the combination of the present disclosure is compound 9. [ka] GLP-1R agonists are orfolglipron, danuglobrine, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or pharmaceutically acceptable salts thereof.

[0027] In some embodiments, the THRβ agonist of the combination of the present disclosure is compound 9. [ka] GLP-1R agonists are orfolglipron or its pharmaceutically acceptable salts.

[0028] In some embodiments, the THRβ agonist of the combination of the disclosed herein is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 [ka] or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the THRβ agonist of the combination of the present disclosure is compound 9, [ka] or a pharmaceutically acceptable salt thereof, the GLP-1R agonist is compound 1-2, [ka] or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the present disclosure relates to a method for treating a patient who requires treatment for hepatic impairment or cardiovascular metabolic disease, the method comprising administering to the patient a combination disclosed herein.

[0031] In one embodiment, the present disclosure relates to a method for treating a patient in need of treatment for hepatic impairment or cardiovascular metabolic disease, comprising administering to the patient a therapeutically effective dose of a combination disclosed herein.

[0032] In one embodiment, the present disclosure relates to a method for doing so in a patient who requires an increase in the ratio of lean body mass to total body mass, the method comprising administering to the patient a combination disclosed herein.

[0033] In one embodiment, the present disclosure relates to a method for doing so in a patient who requires a reduction in the ratio of body fat to total body weight, the method comprising administering to the patient a combination disclosed herein.

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

[0035] In some embodiments, the patient is 20 kg / m 2 ~25kg / m 2 They have a body mass index (BMI).

[0036] In some embodiments, the patient is 25 kg / m 2 ~30kg / m 2 He has a BMI of [value missing].

[0037] In some embodiments, the patient is 20 kg / m 2 They have the above BMI.

[0038] In some embodiments, the patient is 25 kg / m 2 They have the above BMI.

[0039] In some embodiments, the patient weighs 27 kg / m². 2 They have the above BMI.

[0040] In some embodiments, the patient is 30 kg / m 2 They have the above BMI.

[0041] In some embodiments, cardiovascular metabolic disease is obesity.

[0042] In some embodiments, the liver damage is NASH.

[0043] In some embodiments, the liver damage is hepatic fibrosis.

[0044] In some embodiments, the THRβ agonist is administered substantially concurrently with the GLP-1R agonist.

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

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

[0047] In some embodiments, THRβ agonists are selective for THRβ. [Brief explanation of the drawing]

[0048] [Figure 1] This document presents a study design for using a combination of a THRβ agonist (compound 9) and a GLP-1R agonist (semaglutide) to treat NASH.

[0049] [Figure 2] The graph shows the percentage change in body weight from baseline in DIO-NASH mice, corresponding to the number of treatment days with compound 9 alone and in combination with semaglutide.

[0050] [Figure 3] This paper presents a study design for using a combination of a THRβ agonist (compound 9) and a GLP-1R agonist (semaglutide) for long-term weight management.

[0051] [Figure 4A] The graph shows the change in weight loss in diet-induced obesity (DIO) mice as a result of the number of treatment days with semaglutide alone or in combination with compound 9.

[0052] [Figure 4B] The graph shows the changes in weight loss in DIO mice after treatment with semaglutide alone or in combination with compound 9.

[0053] [Figure 5A] The graph shows the daily food intake of DIO mice in relation to the number of treatment days with semaglutide alone or in combination with compound 9.

[0054] [Figure 5B] The graph shows the cumulative food intake of DIO mice in relation to the number of treatment days with semaglutide alone or in combination with compound 9.

[0055] [Figure 6A] The graph shows the change in lean body mass of DIO mice after treatment with semaglutide alone or in combination with compound 9. **** indicates a p-value < 0.0001 relative to the vehicle.

[0056] [Figure 6B] The graph shows the changes in body fat mass in DIO mice after treatment with semaglutide alone or in combination with compound 9. **** indicates a p-value < 0.0001 for the vehicle, and #### indicates a p-value < 0.001 for semaglutide.

[0057] [Figure 7A] This graph shows the change in lean body mass as a percentage of total body weight in DIO mice after treatment with semaglutide alone or in combination with compound 9. The percentage of lean body mass as a percentage of total body weight increased by 3.9% after treatment with semaglutide alone and by 13.9% after treatment with semaglutide in combination with compound 9. ** indicates a p-value of 0.0028, and **** indicates a p-value of <0.0001.

[0058] [Figure 7B] The graph shows the change in body fat mass as a percentage of body weight in DIO mice after treatment with semaglutide alone or in combination with compound 9.

[0059] [Figure 8]The graph shows the percentage change from baseline in body weight of DIO mice after treatment with semaglutide alone or in combination with compound 9, with compound 9 added after 14 days of semaglutide monotherapy.

[0060] [Figure 9A] [Figure 9B] [Figure 9C] This graph shows the percentage change from baseline in body weight (BW) of DIO mice after treatment with semaglutide alone or in combination with compound 9. In the post-hoc analysis, mice were divided into two subgroups based on their initial start weight. Body weight ranged from 50–54.9 g (low BW) to 55–60 g (high BW). Compound 9 + semaglutide showed higher efficacy in mice with higher start weight (Figure 9C) compared to mice with lower start weight (Figure 9B).

[0061] [Figure 10] This study design evaluates the effects of six weeks of treatment with compound 9 alone and in combination with semaglutide on metabolic parameters, energy expenditure, and blood glucose control in male DIO mice with heatstroke.

[0062] [Figure 11] The graphs show the percentage change from baseline in body weight of DIO mice after treatment with semaglutide alone, compound 9 alone, semaglutide and compound 9 in combination, or tirzepatide alone. After 6 weeks of treatment, compound 9 + semaglutide caused an additional weight loss comparable to that of tirzepatide. ****p values ​​< 0.0001, *p values ​​< 0.05.

[0063] [Figure 12] The graph shows the percentage change from baseline in DIO mice after treatment with semaglutide alone, compound 9 alone, a combination of semaglutide and compound 9, or tilzepatide alone. Compound 9 + semaglutide resulted in an additional approximately 7% weight loss compared to semaglutide treatment alone.

[0064] [Figure 13] Paired graphs show the percentage change in body fat mass and lean body mass after treatment with semaglutide alone, compound 9 alone, semaglutide and compound 9 in combination, or tilzepatide. Mouse body composition was evaluated at weeks 1 and 6 of the study using an EchoMRI 3-1 body composition analyzer. Compound 9 + semaglutide improved fat reduction compared to semaglutide alone, and lean body mass reduction was similar between semaglutide alone and the compound 9 + semaglutide combination. ****p-value < 0.0001, *p-value < 0.05.

[0065] [Figure 14] The graphs show the mean food intake of DIO mice after treatment with semaglutide alone, compound 9 alone, a combination of semaglutide and compound 9, or tilzepatide. Compound 9 normalized the decrease in food intake caused by semaglutide. ****p value < 0.0001, ***p value < 0.001, **p value < 0.01.

[0066] [Figure 15] Three graphs are shown illustrating energy expenditure (EE) assessed after 4 weeks of treatment with semaglutide alone, compound 9 alone, semaglutide and compound 9 in combination, or tilzepatide in DIO mice. Compound 9 + semaglutide prevented the decrease in energy expenditure (EE) caused by weight loss. Compound 9, when combined with semaglutide, restored energy expenditure to a normal (DIO Veh) level. ****p values ​​< 0.0001, *p values ​​< 0.05.

[0067] [Figure 16]Graphs showing the expression of uncoupling protein 1 (UCP-1) in DIO mice after treatment with semaglutide alone, compound 9 alone, semaglutide and compound 9 in combination, or tilzepatide. Obesity reduced the expression of uncoupling protein 1 (UCP-1) in subcutaneous adipose tissue. Compound 9 partially restored the obesity-induced reduction in UCP-1. *p<0.05, one-way ANOVA followed by Fisher's LSD test.

[0068] [Figure 17] The graph shows the results of a glucose tolerance test administered to DIO mice at week 4 after treatment with semaglutide alone, compound 9 alone, a combination of semaglutide and compound 9, or tilzepatide. Compound 9 + semaglutide further improved glucose tolerance compared to semaglutide treatment alone. ***p value < 0.001, **p value < 0.01, *p value < 0.05.

[0069] [Figure 18] The graph shows the time course of body weight from baseline in DIO hGLP-1R mice after treatment with compound 9 alone, or orfolglipron alone, or a combination of orfolglipron and compound 9. The daily change in body weight (g) from baseline is shown as the mean (SE) of n=6-7 mice per group. The vehicle, compound 9 (3 mg / kg), and orfolglipron (0.2 mg / kg and 2 mg / kg) were administered once daily by forced oral administration.

[0070] [Figure 19] Graphs show the change in body weight from baseline in DIO hGLP-1R mice after treatment with compound 9 alone, or orfolglipron alone, or a combination of orfolglipron and compound 9. The change in body weight (g) from baseline at day 20 is shown as the mean (SD) of n=6-7 mice per group. Statistical significance was determined by standard one-way ANOVA with corrections for multiple comparisons. *p<0.05, ***p<0.001, ****p<0.0001. ns = not significant.

[0071] [Figure 20] This graph shows the daily food intake as a percentage of time in DIO hGLP-1R mice after treatment with compound 9 alone, or orfolglipron alone, or a combination of orfolglipron and compound 9. Daily food intake (g) is shown as the mean (SE) of n=6-7 mice per group. Body weight composition measurements on day 19, which indicate an acute decrease in food intake, are also shown.

[0072] [Figure 21] Two graphs are shown illustrating the changes in body weight composition from baseline in DIO hGLP-1R mice after treatment with compound 9 alone, or orfolglipron alone, or a combination of orfolglipron and compound 9. Changes in body fat mass (A) and lean body mass (B) (g) from baseline at day 19 are shown as mean (SD) values ​​for n=6-7 mice per group. Statistical significance was determined by standard one-way ANOVA with corrections for multiple comparisons. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. ns = not significant.

[0073] [Figure 22] This graph shows the final subcutaneous fat in DIO hGLP-1R mice after treatment with compound 9 alone, or orfolglipron alone, or a combination of orfolglipron and compound 9. Data represent the mean (SD) subcutaneous fat (mg) of n=6-7 mice per group at the end of the study. Statistical significance was determined by standard one-way ANOVA with corrections for multiple comparisons. *p<0.05. ns = not significant.

[0074] [Figure 23]This graph shows the final liver weight in DIO hGLP-1R mice after treatment with compound 9 alone, or orfolglipron alone, or a combination of orfolglipron and compound 9. Data represent the mean (SD) liver weight (mg) of n=6-7 mice per group at the end of the study. Statistical significance was determined by standard one-way ANOVA with corrections for multiple comparisons. *p<0.05, **p<0.01, **p<0.01, ****p<0.0001. ns = not significant.

[0075] [Figure 24] Two graphs are shown showing the concentration-time profiles of compound 9 and orfolglipron in DIO hGLP-1R mice. Compound concentrations are shown as the standard deviation (SD) over time for compound 9 (A) or orfolglipron (B) alone and in combination. Data represent sparse sampling across each treatment cohort as follows: before administration (0 hours after administration), n=3; 2 hours after administration, n=3; 4 hours after administration, n=4; 8 hours after administration, n=4; 24 hours after administration, n=7. Nominal dose and time are shown.

[0076] [Figure 25] This graph shows the weight loss induced by combination therapy with compound 9 + compound (1-2) compared to monotherapy in diet-induced obesity transgenic hGLP1R mice.

[0077] [Figure 26] This graph shows the weight loss induced by combination therapy with compound 9 + compound (1-2) compared to monotherapy in diet-induced obesity transgenic hGLP1R mice. The percentage change in body weight after 15 days of treatment is shown. [Modes for carrying out the invention]

[0078] definition When used herein, unless otherwise indicated, the following definitions shall apply. Furthermore, if any term or symbol used herein is not defined as described below, it shall have the meaning it ordinarily has in the art.

[0079] "Comprising" is intended to mean that compositions and methods include the enumerated elements but do not exclude others. When used to define compositions and methods, "essentially consisting of" shall mean excluding other elements that have any essential importance to the combination. For example, a composition essentially consisting of the elements defined herein does not exclude other elements that do not substantially affect the basic and novel features(s) of the claimed invention. "Consists of" shall mean excluding, for example, trace amounts or more of other components described and substantial method steps. Embodiments defined by each of these transitional clauses are within the scope of the present invention.

[0080] "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, for example, with another agent (e.g., one useful for treating liver disorders such as NAFLD and NASH, and their respective symptoms and signs) as used herein, 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- The use of compounds 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) constitutes combination therapy.

[0081] "Combined administration" refers to the administration of two drugs (e.g., using the 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) in any manner in which both pharmacological effects appear simultaneously in the patient. This refers to the administration of a compound of (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) and another drug. Therefore, concomitant administration does not require that a single pharmaceutical composition, the same dosing form, or even the same route of administration be used for the administration of both drugs, or that the two drugs be administered at exactly the same time. A drug can be formulated in two separate pharmaceutically acceptable compositions. Both drugs can also be formulated in a single pharmaceutically acceptable composition. Non-limiting examples of such a single composition are oral compositions or oral dosage forms.For example, although not limited to, 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), ( The compounds 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) are intended to be administered in combination therapy with other agents of the present invention.

[0082] The term “additive” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical (such as a tablet containing the compound of the present invention as an active ingredient). A variety of substances may be included in the term additive, including, but are not limited to, any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring, suspension / gelling agent, or wet granulator. Binders include, for example, carbomer, povidone, xanthan gum; coatings include, for example, cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, enteric coatings; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, starch glycolate sodium, etc.; creams or lotions include, for example The ingredients include maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspension / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0083] "Patient" refers to a mammal, including 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 embodiments, patient refers to a human.

[0084] As used herein, “patient response” refers to the magnitude of the therapeutic effect (e.g., the amount of weight loss, the percentage of fat loss, etc.). Improving the “patient response” to treatment may include, but is not limited to, increasing the degree of therapeutic efficacy (e.g., increasing weight loss, increasing fat loss, etc.). In some embodiments, improving the patient response to treatment (e.g., combinations and methods of the disclosure) includes maintaining efficacy while reducing side effects.

[0085] "Pharmacologically acceptable" means that it is safe and non-toxic, preferably in vivo, and more preferably in human administration.

[0086] "Pharmacologically acceptable salt" refers to a pharmaceutically acceptable salt. The compounds described herein may be administered as pharmaceutically acceptable salts.

[0087] "Salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain an acidic functional group, such salts include, but are not limited to, alkali metals, alkaline earth metals, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include naturally occurring amino acid-based cations of Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations. When the compounds used herein contain a basic functional group, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, as well as mineral acids such as hydrogen halides, sulfuric acid, and phosphoric acid. Examples and non-limiting anions useful for pharmaceutically acceptable salts include oxalates, fumarates, maleates, acetates, propions, succinates, tartrates, chlorides, sulfates, bisulfates, monobasic, dibasic, and tribasic phosphates, mesylates, and tosylates.

[0088] The “therapeutic dose” or dosage of a compound or composition refers to the amount of the compound or composition that results in a reduction or inhibition of symptoms or an extension of survival in a patient. Results may require multiple doses of the compound or composition.

[0089] "Treatment" or "treating" refers to an approach to obtain a beneficial or desired outcome, encompassing clinical outcomes. For the purposes of the present invention, beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms of a disease or disorder; reducing the severity of a disease or disorder; stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder); delaying the onset or recurrence of a disease or disorder; delaying or slowing the progression of a disease or disorder; improving the state of a disease or disorder; providing remission (partial or complete) of a disease or disorder; reducing the dose of one or more other drugs required to treat a disease or disorder; enhancing the effect of another drug used to treat a disease or disorder; delaying the progression of a disease or disorder; improving quality of life; and / or extending the patient's survival time. Reduction of the pathological consequences of a disease or disorder is also covered by "treatment." The methods of the present invention aim to achieve any one or more of these aspects of treatment.

[0090] As used herein, “delaying” the onset of a disease means delaying, preventing, slowing, stabilizing, and / or postponing the onset of a disease, and / or slowing its progression once it has occurred, or altering the underlying disease process and / or course. This delay may be of varying lengths depending on the history of the disease being treated and / or the subject. As will be apparent to those skilled in the art, a sufficient or significant delay may effectively cover prevention in such a way that the subject does not develop clinical symptoms associated with the disease. A method for “delaying” the onset of a disease is a method that reduces the probability of disease onset in a given time frame and / or reduces the severity of the disease in a given time frame compared to not using the method, and includes stabilizing one or more symptoms resulting from the disease.

[0091] Subjects “at risk” of developing the disease may or may not have a detectable disease, and may or may not be presented with a detectable disease prior to the treatment described herein. “At risk” means that a subject has one or more so-called risk factors (which are measurable parameters that correlate with the development of the disease). Subjects having one or more of these risk factors have a higher probability of developing the disease than subjects without these risk factors. These risk factors include, but are not limited to, age, sex, race, diet, medical history of previous diseases, presence of progenitor diseases, and genetic (i.e., heritability) considerations. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing or have a family history of a disease or condition.

[0092] "Stereoisomers" refer to compounds that differ in the stereogenicity of their constituent atoms, such as, but not limited to, the chirality of one or more stereocenters or the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoiomers include enantiomers and diastereomers.

[0093] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. This term includes, for example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group having x carbon atoms.

[0094] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, for example, 1 to 10 carbon atoms, and 1 to 6 carbon atoms. This term includes, as examples, linear and branched hydrocarbyl groups, such as methylene (-CH2-), ethylene (-CH2CH2- or -CH(Me)-), and propylene (-CH2CH2CH2- or -CH(Me)CH2-, or -CH(Et)-).

[0095] "Alkenyl" refers to a monovalent hydrocarbyl group, either linear or branched, having 2 to 6 carbon atoms, for example, 2 to 4 carbon atoms, and possessing at least one or 1 to 2 vinyl (>C=C<) unsaturated sites. Such groups are exemplified by vinyl, allyl, and buta-3-en-1-yl. This term includes cis and trans isomers, or mixtures thereof. x An alkenyl refers to an alkenyl group that has x carbon atoms.

[0096] "Alkynyl" refers to a monovalent hydrocarbyl group, either linear or branched, having 2 to 6 carbon atoms, for example, 2 to 3 carbon atoms, and possessing at least one or 1 to 2 acetylene (-C≡C-) unsaturated sites. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH). x Alkynyl refers to an alkynyl group having x carbon atoms.

[0097] "Alkoxy" refers to the -O-alkyl group, where alkyl is defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0098] "Aryl" refers to a monovalent aromatic carbocyclic group consisting of 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple fused rings (e.g., naphthyl or anthryl) (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-on-7-yl, etc.), where these fused rings may or may not be aromatic, provided that the bond site is located on an aromatic carbon atom. Exemplary aryl groups include phenyl and naphthyl. Divalent aryl groups are referred to herein as "arylenes." Divalent phenyl groups are referred to herein as "phenylenes."

[0099] "Cyano" refers to the group -C≡N.

[0100] "Cycloalkyl" refers to, for example, saturated or unsaturated non-aromatic cyclic alkyl groups having 3 to 10 carbon atoms, 3 to 8 carbon atoms, or 3 to 6 carbon atoms, and having one or more cyclic rings, including fused ring systems, bridging ring systems, and spiro ring systems. xA cycloalkyl group refers to a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided that the bonding site is via a non-aromatic ring or a non-heterocyclic saturated carbon ring. "Substitutive cycloalkyl groups" include oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, and substituted cyano. This refers to a cycloalkyl group having 1 to 5 or 1 to 3 substituents selected from the group consisting of cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, where such substituents are defined herein.

[0101] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine, and in some embodiments, it is fluoro or chloro.

[0102] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0103] A "heteroaryl" refers to an aromatic group consisting of 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such a heteroaryl group may have a monocyclic ring (e.g., pyridinyl or furyl) or a plurality of fused rings (e.g., indolidinyl or benzothienyl), the fused rings may be aromatic or non-aromatic, and / or may contain heteroatoms, provided that the bonding site is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms(s) of the heteroaryl group may be optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Exemplary heteroaryls include 5- or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other exemplary heteroaryls include 9- or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl. A divalent heteroaryl group is referred to as "heteroarylene" in this specification.

[0104] A "heterocyclic" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, non-aromatic group having 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, and 1 to 6 carbon atoms, 1 to 4 ring heteroatoms, 1 to 3 heteroatoms, and 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. x A heterocycloalkyl group refers to a heterocycloalkyl group having x ring atoms, including a ring heteroatom. Heterocycles include monocycles or multiple fused rings, and fused rings include fused-ring systems, bridging-ring systems, and spirocycle systems. In fused-ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the bonding site is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms(s) of the heterocyclic group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety. A divalent heterocyclyl group is referred to herein as "heterocyclene".

[0105] Examples of heterocyclyls and heteroaryls include azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazyl, pyrimidyl, pyridazyl, indolidyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, carbazolyl, carborinyl, phenantridinyl, acridinyl, phenantrolinyl, isothiazolyl, phenadinyl, and isoxazolyl. Examples include, but are not limited to, phenoxazinyl, phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranil.

[0106] "Oxo" refers to an atom (=O) or (O).

[0107] When the terms “optional” or “optionally” are used throughout this specification, the following events or circumstances may occur, but are not necessarily required, and the description includes both cases in which the events or circumstances occur and cases in which they do not. For example, “The nitrogen atom may be optionally oxidized to provide an N-oxide (N→O) moiety” means that the nitrogen atom may be oxidized, but is not required, and this description includes both cases in which the nitrogen atom is not oxidized and cases in which the nitrogen atom is oxidized.

[0108] The dosage of compounds described herein shall be determined as appropriate based on the free acid or free base of the compound.

[0109] This specification 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, what is provided herein is a method for treating cardiovascular metabolic disorders in subjects (e.g., human patients) requiring treatment of such disorders, the method comprising administering to a subject a therapeutically effective amount of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0110] GLP-1R Agonist Suitable GLP-1R agonists that can be used in combination and / or by the methods described herein include, but are not limited to, orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or orfolglipron, or semaglutide, or pharmaceutically acceptable salts of the GLP-1R agonists, or pharmaceutically acceptable solvates of any of the GLP-1R agonists or salts of the GLP-1R agonists. Suitable GLP-1R agonists that can be used in combination and / or methods described herein also include danuglypron 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, amicretin (e.g., oral amicretin), ZT-002, DR-10624, DR-10627, letatoltide, NN-6177, NN-949. 0, NN-9847, NN-9904, Efosipegdultide, GSBR-1290, HB-1085, 4P-004, HM15211, Sulvodutide, Froniglutide, Efinopegdutide, PF-06954522, YH-25724, YN-012, YN-015, Mazdutide, MDR-001, KN-056, MWN-101, Emvidutide This includes ALT-801, AP-026, PEG-loxenatide, PEGylated exenatide, ITCA650, XW-004, XW-014, or efpeglenatide, or a pharmaceutically acceptable salt of the GLP-1R agonist, or a pharmaceutically acceptable solvate of either the GLP-1R agonist or a salt of the GLP-1R agonist.

[0111] Suitable GLP-1R agonists that can be used in combination and / or by method as 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 63 / 492,895, which are incorporated herein by reference.

[0112] In some embodiments, the GLP-1R agonist is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 is -C1-C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl, R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl which may be substituted with a halo or a C1-C3 alkyl, R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom of is S, and further R 5 Hello, -OC1-6 Alkyl, C 1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 member heterocyclene or a 5-12 member heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1-C6 alkylene-**, then the C1-C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon or atom to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon or atom to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or C1-C6 alkyl, Ring B is C3-C 10 Cycloalkyl, C6-C 14The molecules are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0113] In some embodiments, the GLP-1R agonist is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] That is the case.

[0114] In some embodiments, the GLP-1R agonist is a compound of formula (I-2), [ka] Alternatively, it may be a stereoisomer, a tautomer, or any of the aforementioned pharmaceutically acceptable salts, in which, X is either N or CH. Y is N or CR 4 And here, R 4 is hydrogen, OH, or C1-C6 alkyl, n is either 0 or 1. R is hydrogen, R 1 -C1~C6 alkylene-R 5 And R 5 These are 3-6 membered heterocyclyls or 5-6 membered heteroaryls, each of which can be independently optionally substituted with a C1-C6 alkyl group, or R 1However, together with R and intervening atoms, they form a ring C, where the ring C is a 5-7 member heterocycline that can be optionally substituted with C1-C6 alkyl groups. R 2 and R 3 These are independently hydrogen, oxo, or C1-C6 alkyl, where Y is CR 4 If R 3 and R 4 They can optionally form a C3-C6 cycloalkyl group together with the carbon atoms to which they are bonded. Ring A is a 5-12 member heterocyclene or a 5-12 member heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1-C6 alkylene-**, then C1-C6 alkylene is R of any choice. L It is replaced by, in the formula, Each R L These are independently either C1-C6 alkyl or halo, or Two R's L However, together with the carbon atom or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then R is of optional choice. L1 It is replaced by, in the formula, Each R L1 These are independently a halo, an OH group, or a C1-C6 alkyl group, or Two R's L1 However, together with the carbon atom or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R6 is hydrogen or C1-C6 alkyl, Ring B is C3-C 10 Cycloalkyl, C6-C 14 These are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl groups, each independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl. however, R 1 -C1~C6 Alkylene-R 5 (In the formula, R 5 (where is a 3-6 member heterocyclyl or 3-6 member heteroaryl, each of which is optionally substituted with a C1-C6 alkyl group), Y is N or CH, n is 1, and R 2 and R 3 If L is independently hydrogen or a C1-C6 alkyl group, and ring A is a 6-membered heteroaryl group optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, and CN, then ring B is not a phenyl group optionally substituted with one or two substituents independently selected from the group consisting of halo, CN, and C1-C6 alkyl groups, R 1 -C1~C6 Alkylene-R 5 (In the formula, R 5 (where is a 3-6 member heterocyclyl or 3-6 member heteroaryl, each of which is optionally substituted with a C1-C6 alkyl group), Y is N or CH, n is 1, and R 2 and R 3 These are independently hydrogen or C1-C6 alkyl, and ring A is [ka] In the formula (wherein Q is H or CH3), if L is a bond, then ring B is not a phenyl or pyridinyl which is optionally substituted by one or two substituents independently selected from the group consisting of halo, CN, and C1-C6 alkyl groups, respectively. R 1 However, -C1~C6 alkylene-R 5 (In the formula, R 5 (where is a 4-membered heterocyclyl or 5-membered heteroaryl, each of which is optionally substituted with a C1-C6 alkyl group), X is N, Y is N or CH, n is 1, R 2 and R 3 If they are independently hydrogen or oxo, then ring B is [ka] No. In some such embodiments of formula (I-2), ring B is C3-C 10 Cycloalkyl, C6-C 14 The substituents are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl, in some such embodiments of formula (I-2), where L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene is optionally R L It may also be substituted by, where each R L They are independently C1-C6 alkyl or two R L However, together with the carbon atom or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycline. In some such embodiments of formula (I-2), if L is a C1-C6 alkylene, the C1-C6 alkylene is unsubstituted.

[0115] In some embodiments, the GLP-1R agonist is a compound of formula (I-3), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 is -C1-C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl, R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl which may be substituted with a halo or a C1-C3 alkyl, R 5 R is a 3-6 member heterocyclyl or a 5-6 member heteroaryl, 5 The 3-6 member heterocyclyl or 5-6 member heteroaryl is independently and optionally substituted with a halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. R 7 teeth, [ka] Selected from the group consisting of, Or, R 7 is -C(O)NH-R 8 And R 8 These are hydrogen, -OH, -S(O)2-C1~C6 alkyl, or optionally a -C1~C6 alkyl substituted with a halo. Ring A is a 5-12 member heterocyclene, a 5-12 member heteroarylene, or C6-C 14They are allylenes, each independently substituted with a halo, oxo, -CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1-C6 alkylene-**, then C1-C6 alkylene is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon atom or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon atom or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or C1-C6 alkyl, Ring B is C3-C 10 Cycloalkyl, C6-C 14 These are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl groups, each independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -C(O)NH2, -S(O)2CH3, cyclopropyl, and phenyl. however, R 7 -C(O)NH-R 8 And R1 but [ka] And X is N, Y is CH, n is 1, R 2 and R 3 If each of them is hydrogen, ring A is a 6-membered heteroaryl, and L is *-OCH2-**, then ring B is, [ka] isn't it.

[0116] In some embodiments, the GLP-1R agonist is a compound of formula (I-4), [ka] or a pharmaceutically acceptable salt, in the formula, R 13 is -C(O)OH or [ka] And, X is N or CR x And here, R x is hydrogen, OH, or C1-C6 alkyl, Y is N or CR y And here, R y is hydrogen, OH, or C1-C6 alkyl, n is either 0 or 1. Q is -C(R 7 )(R 8 )-, -O-, -N(R 9 Selected from the group consisting of )-, and -S-, where, R 7 and R 8 These are independently hydrogen, halogen, or C1-C6 alkyl. R 9 is hydrogen or a C1-C6 alkyl group. R 1 This is an optionally substituted -C1~C6 alkyl or -C1~C6 alkylene-R5 And here, R 5 Each of these is a C3-C6 cycloalkyl, a 3-6 membered heterocyclyl, or a 5-6 membered heteroaryl, each of which is independently and optionally substituted with 1-3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each of the C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituents is independently and optionally substituted with halo or CN. R 2 and R 3 These, together with the carbon atoms to which they are bonded, form an optionally substituted C3-C4 cycloalkyl ring, or R 2 and R x If present, they, together with the carbon atoms to which they are bonded, form an optionally substituted C3-C5 cycloalkyl ring, R 3 These are hydrogen, oxo, or C1-C6 alkyl groups. m is 0, 1, 2, or 3. R 4 These are oxo or C1-C6 alkyl groups. Ring A is C6-C 14 Allirene, 5-12 membered heterocyclene, or 5-12 membered heteroarylene, each independently substituted with halo, OH, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with halo 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 a bond to ring A and ** represents a bond to ring B. L is C1~C6 alkylene, *-O-C1~C6 alkylene**, *-C1~C6 alkylene-O-**, or *-NR 6 -If it is a C1-C6 alkylene-**, then L is any one to three R L Substituting with substituents, where each RL These are independently a halo, OH, or C1-C6 alkyl, or two R groups. L These, together with the carbon atoms or multiple carbon atoms to which they are bonded, form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 If present, it is hydrogen or a C1-C6 alkyl group. Ring B is C3~C 10 Cycloalkyl, C6~C 14 The molecules are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently and optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, optionally halo or CN-substituted C1-C6 alkyl, optionally halo or CN-substituted -OC1-C6 alkyl, -COCH3, -CONH2, -S(O)2CH3, and optionally halo or CN-substituted phenyl.

[0117] In some embodiments, the GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, halogen, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 Cycloalkyl, or C 6-10 It is an aryl group, where alkyl, heteroalkyl, alkylene, or haloalkyl is optionally one or more deuterium, C 1-6 Substituted with alkoxy, hydroxyl, -CN, or oxo groups, and optionally with one or more halogens, C 1-6 Substituted with alkoxy or -CN, R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms they are bonded to to form a 6-membered heterocycline, C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C is optionally substituted with deuterium. 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, -CN, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is a halogen, hydrogen, -C(O)OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 12 These are hydrogen, -C(O)OH, and -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ ,-(C 2-6 Alkynylene)-C(O)OH, -(C 1-6 Alkylene)-C(O)OH, -NR N12 -(C 1-6 Alkylene)-C(O)OH, 5-10 member heteroaryl, or one or more oxo compounds of any choice. 1-6 Alkyl, or C 1-6 It is a 5-10 member heterocycline substituted with a haloalkyl group. R N12 and RN12’ H or C 1-6 It is alkyl, X 1 teeth, [ka] And, In the formula, R 3 and R 3’ These are independently H, D, or C 1-6 It is alkyl, C 1-6 The alkyl group is optionally substituted with deuterium. Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterocyclenes, where C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterosicurenes may be optionally selected from one or more oxo and C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-(C 1-6 Alkylene)-, *-NR L -(C 1-6 Alkylene)-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and C 1-6Alkylenes are optionally substituted with deuterium. In the formula, R L is H or C 1-6 It is alkyl, Ring C is, Choose one or more C's at your discretion. 3-10 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-10 membered heterocyclyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, C 3-10 A cycloalkyl or a 6-membered aryl substituted with -C(O)NR'2, In the formula, R' is either H or C 1-6 Alkyl, 6-membered aryl, Optionally, one or more halogens, -CN, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 These are bicyclic 9- or 10-membered heteroaryl or heterocyclyl compounds substituted with alkyl, halogen, -CN, or oxo.

[0118] In some embodiments, the GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6Haloalkyl, halogen, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where alkyl, heteroalkyl, alkylene, or haloalkyl is optionally one or more deuterium, C 1-6 Substituted with alkoxy, hydroxyl, -CN, or oxo, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms they are bonded to to form a 6-membered heterocycline, C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C is optionally substituted with deuterium. 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, -CN, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen, -C(O)OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 12 is hydrogen, -C(O)OH, or one or more oxos of any choice, C 1-6 Alkyl, or C 1-6 It is a 5-10 member heteroaryl substituted with a haloalkyl group. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is a six-membered heteroaryl substituted with alkyl, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterocyclenes, where C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterosicurenes may be optionally selected from one or more oxo and C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-(C 1-6 Alkylene)-, *-NR L -(C 1-6 Alkylene)-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and C 1-6 Alkylenes are optionally substituted with deuterium. In the formula, R L is H or C 1-6 It is alkyl, Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, C 1-6 Haloalkyl, 3-10 membered heterocyclyl, halogen, C1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, C 3-10 A cycloalkyl or a 6-membered aryl substituted with -C(O)NR'2, In the formula, R' is either H or C 1-6 Alkyl, 6-membered aryl, Optionally, one or more halogens, -CN, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl substituted with an alkyl, halogen, or oxo molecule.

[0119] In some embodiments, the GLP-1R agonist is a compound of formula I*, [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms they are bonded to to form a 6-membered heterocycline, C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arirene, 6-10 membered heteroarirene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0120] In some embodiments, the compound of formula (I*) is the same as the one of formula (I'), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 is CH or N, R 1is -C 1-6 Haloalkyl or -OX 4 And, X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more -CN groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. n is 0, 1, 2, 3, 4, 5, or 6. R 2 is hydrogen, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, or A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl compound in which at least one heteroatom is S, X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] And, In the formula, * represents X 1 This shows a connection to, X 2 is CH or N, Ring B is a 6-10 member heteroarylene, or one or more C rings of any choice. 1-6 These are alkyl-substituted 3- to 10-membered heterocyclenes. L is a bond or *-O-(C 1-6 It is an alkylene, and in the formula, * indicates a bond to ring B. Ring C is, Optionally, one or more halogens, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A 6-membered heteroaryl aryl containing a nitrogen atom, which is substituted with Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0121] In some embodiments, the GLP-1R agonist is a compound of formula I'', [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms they are bonded to to form a 6-membered heterocycline, C 1-6The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C 1-6 Alkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 7 These combine together with the atoms they are bonded to, C 2-9 Forming heterocyclines, R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] And, In the formula, * represents X 1 This shows a connection to, X 5 is CH or N, X 2 is CH or N, Ring B is a 6-10 member heteroarylene, or one or more C rings of any choice. 1-6 These are alkyl-substituted 3- to 10-membered heterocyclenes. L is a bond or *-O-(C 1-6 It is an alkylene, and in the formula, * indicates a bond to ring B. Ring C is, Optionally, one or more halogens, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0122] In some embodiments, the GLP-1R agonist is a compound of formula (I'''*), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR X3 or N, In the formula, R X3 H, halogen, C1-6 Alkyl, C 1-6 Haloalkoxy, -O-(CH2CH2-O) 1-5 -CH3, or C 1-6 It is an alkoxy, X 5’ CR 5’ And, R 1 is -C 1-6 Haloalkyl or -OX 4 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, halogen, or -CN, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, halogen, Branched C 3-6 Alkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, or A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 5’ is hydrogen or -C(O)-OH, R 4 is hydrogen, halogen, -C(O)-OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] And, In the formula, * represents X 1 This shows a connection to, X 5 is CH or N, X 2 is CH or N, Ring B is a 6-10 member heteroarylene, or one or more C rings of any choice. 1-6These are alkyl-substituted 3- to 10-membered heterocyclenes. L is a bond or *-O-(C 1-6 It is an alkylene, and in the formula, * indicates a bond to ring B. Ring C is, Optionally, one or more halogens, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0123] In some embodiments, the GLP-1R agonist is a compound of formula (I'''), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR X3 or N, In the formula, R X3 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkoxy, or C 1-6 It is an alkoxy, R 1 is -C 1-6 Haloalkyl or -OX 4 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 is hydrogen, C 1-6Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 Alkylene)-(C 3-10 Cycloalkyl), or -(C 1-6 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium or -CN groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, halogen, C 3-6 Alkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] And, In the formula, * represents X 1 This shows a connection to, X 5 is CH or N, X 2 is CH or N, Ring B is a 6-10 member heteroarylene, or one or more C rings of any choice. 1-6 These are alkyl-substituted 3- to 10-membered heterocyclenes. L is a bond or *-O-(C 1-6 It is an alkylene, and in the formula, * indicates a bond to ring B. Ring C is, Optionally, one or more halogens, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A 6-membered heteroaryl aryl containing a nitrogen atom, which is substituted with Choose one or more C's at your discretion. 1-6It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0124] In some embodiments of formula (I'''), or its pharmaceutically acceptable salt, X 3 is CH or N, R 1 is -C 1-6 Haloalkyl or -OX 4 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium or -CN groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C 3-6 Alkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl, in which at least one heteroatom is S, or R 2 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] And, In the formula, * represents X 1 This shows a connection to, X 5 is CH or N, X 2 is CH or N, Ring B is a 6-10 member heteroarylene, or one or more C rings of any choice. 1-6 These are alkyl-substituted 3- to 10-membered heterocyclenes. L is a bond or *-O-(C 1-6It is an alkylene, and in the formula, * indicates a bond to ring B. Ring C is, Optionally, one or more halogens, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A 6-membered heteroaryl aryl containing a nitrogen atom, which is substituted with Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0125] In some embodiments, the compound of formula (I''') is the same as that of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 is -C 1-6 Haloalkyl or -OX 4 And, X 4 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 Alkylene)-(C 3-10 Cycloalkyl), or -(C 1-6 Alkilen)-(3-8 member heterocyclyl),-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5-CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more -CN groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, or A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 It is a 5-membered heteroaryl compound in which at least one heteroatom is S, X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] And, In the formula, * represents X 1 This shows a connection to, X 2 is CH or N, Ring B is, Nitrogen-containing 6-membered heteroarylene, Choose one or more C's at your discretion. 1-6 A 9-membered heterocyclene containing two oxygen atoms, which is alkyl-substituted, or It is a 10-membered heterocyclene containing two oxygen atoms, L is a bond or *-O-(C 1-6 It is an alkylene, and in the formula, * indicates a bond to ring B. Ring C is, Optionally, one or more halogens, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A 6-membered heteroaryl aryl containing a nitrogen atom, which is substituted with Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0126] In some embodiments, the GLP-1R agonist is a compound of formula (I-5), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4combine with the atoms to which they are attached to form a 6-membered heterocyclyl, X 4 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)-(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, -(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogen or -CN, R 6 is hydrogen, halogen, or -O-R 7 and R 7 and R 2 combine with the atoms to which they are attached to form a 6-membered heterocyclyl, R 8 and R 9 are each independently hydrogen, C 1-6 alkyl, or -S(O)2-C 1-6 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form a 6-membered heterocyclyl, C 1-6 alkyl is optionally substituted with one or more oxo, n is 0, 1, 2, 3, 4, 5, or 6, R 2 is hydrogen, branched C 1-6 alkyl, C 1-6 haloalkyl, -(O)-C 1-6 alkyl, one or more -CN, C 1-6 haloalkyl, or optionally C substituted with one or more -CN 1-6 alkyl optionally substituted with C 3-10 cycloalkyl, a 4- or 5-membered heterocyclyl containing at least one oxygen or at least one sulfur atom, optionally with one or more oxo, [Chemical formula] or C 1-6 alkyl-substituted 4- or 5-membered heterocyclyl, a 5-membered heteroaryl containing one or two heteroatoms independently selected from N and S, where 5 at least one of the heteroatoms of R is S, a 5-membered heteroaryl, or R 2 and R 7 are combined together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl, R 4 is hydrogen or -O-R 8 and R 8 and R 1 are combined together with the atoms to which they are attached to form a 6-membered heterocyclyl, X 1 is [Chemical formula] and wherein R 3 is H or C 1-6 alkyl, ring A is [Chemical formula] optionally phenylene substituted with one or more halo or C 1-6 alkyl, or optionally 6-membered heteroarylene substituted with one or more halo or C 1-6 alkyl, and In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arirene, 6-10 membered heteroarirene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 It is a bicyclic 9- or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0127] In some embodiments, the GLP-1R agonist is a compound of formula (I-P01), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 is CH or N, R 1 is -C 1-6 Haloalkyl or -OX 4 And, X 4 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 Alkylene)-(C 3-10 Cycloalkyl), or -(C 1-6 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more -CN groups, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN groups. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 Alkyl-substituted, 4 or 5-membered heterocyclyl, or A 5-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N and S, where at least one heteroatom of R 5 is S, and is a 5-membered heteroaryl, X 1 is

Chemical formula

Chemical formula

Chemical formula

[0128] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5a), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 Rings A and C are defined for equation (I-5).

[0129] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5b), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 Rings A and C are defined for equation (I-5).

[0130] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5c), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 Rings A and C are defined for equation (I-5).

[0131] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5d), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 , X 2 And ring C is defined as in equation (I-5).

[0132] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5e), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 4 , n, R 2 , X 1 Rings A, B, and C are defined for equation (I-5).

[0133] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5f), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 And ring C is defined as in equation (I-5).

[0134] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5g), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 Rings A and C are defined for equation (I-5).

[0135] In some embodiments, the compound of formula (I-5) is the same as the compound of formula (I-5h), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 Rings A and C are defined for equation (I-5).

[0136] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5i), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 And rings A and C are defined as shown for equation (I-5).

[0137] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5j), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , n, R 2 , X 1 And ring C is defined as in equation (I-5).

[0138] In some embodiments, the compound of formula (I-5) is the same as the compound of formula (I-5k), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 4 , R 2 , X 1 , n, ring A, ring B, L, and ring C are defined for equation (I-5).

[0139] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5l), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , X 1n and ring C are defined for equation (I-5).

[0140] In some embodiments, the compound of formula (I-5) is the same as the compound of formula (I-5m), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0141] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5n), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0142] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5o), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0143] In some embodiments, the compound of formula (I-5) is the same as the one of formula (I-5p), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0144] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IQ), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , n, rings B, L, and C are defined for equation (I-5).

[0145] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IR), [ka] or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , n, rings B, L, and C are defined for equation (I-5).

[0146] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IS), [ka] In the formula, R 1 , R 2 , n, rings B, L, and C are defined for equation (I-5).

[0147] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IT), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 1 , X 3 Rings A, B, L, and C are defined for equation (I-5).

[0148] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IU), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 , X 1Rings A, B, L, and C are defined as shown in formula (I-5), or a pharmaceutically acceptable salt thereof, In the formula, X 3 , R 4 , R 1 , n, and R 2 This is as defined for equation (I-5).

[0149] In some embodiments, the compounds of formula (I-5) are the same as those of formula (IX), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 , n, R 2 , X 1 Rings A, B, L, and C are defined for equation (I-5).

[0150] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IY), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 , n, R 2 , X 1 Rings A, B, L, and C are defined for equation (I-5).

[0151] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IZ), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 , n, R 2 , X 1 Rings A, B, L, and C are defined for equation (I-5).

[0152] In some embodiments, the compound of formula (I''') is the same as the one of formula (IAA), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X 3 , n, R 2 , X 1 Rings A, B, L, and C are defined for equation (I-5).

[0153] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IAB), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X6, R8, R9, n, R2, X1, ring A, ring B, L, and ring C are defined as in formula (I-5).

[0154] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IAC), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0155] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IAD), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0156] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IAE), [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings B, L, and C are defined as defined for formula (I-5).

[0157] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IAG), [ka] or a pharmaceutically acceptable salt thereof, In the formula, X3, X1, rings A, L, and C are defined as in formula (I-5).

[0158] In some embodiments, the compound of formula (I-5) is the same as the one of formula (IAH), [ka] or a pharmaceutically acceptable salt thereof, In the formula, n, R2, X1, ring A, L, and ring C are defined as in formula (I-5).

[0159] In some embodiments, the compound of formula (I-5) is of formula (IAI), [ka] In the formula, R 1 is -O-(C 1-6 (Haloalkyl) X3, X1, ring A, ring B, L, and ring C are defined for equation (I-5), or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the compound of formula (I-5) is the compound of formula (IAJ), [ka] In the formula, R 2 These are hydrogen, thiazolyl, oxetanyl, optionally cyano-substituted cyclopropyl, or methoxy. n is either 1 or 2. R 1 is, -OC 1-6 It is alkyl, -OH, or -NH2, where C 1-6 The alkyl group is optionally substituted with one or more halos or deuterium atoms. X 3 CR 6 And in the formula, R 6 is a halo or hydrogen, L is *-O-(C 1-6 It is an alkylene)-, where * indicates a bond to ring B, and C 1-6 Alkylenes are optionally substituted with deuterium. R 10 It is a halo, R 11 is halo or cyano, or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound of formula (I**) is the same as the one of formula (II**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, R 3 and R 3’ These are independently H or D, X 1 * is N or CR f1 And, X 2* and X 3* They are independently CH or CF, Each R f3 These are, independently, halogen, -CN, and C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, R 1** is either H, or C which is optionally substituted with one or more deuterium or halogens. 1-2 It is alkyl.

[0162] In some embodiments, the compound of formula (I**) is the same as the one of formula (II*), [ka] or a pharmaceutically acceptable salt thereof, Each R f1 These are independently selected from halogens. R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, Each R f3 These are, independently, halogen, -CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, Each R f6 It is independently selected from H, D, or F.

[0163] In some embodiments, R f4 and R f5 Each of these is independently selected from CH3, H, and D.

[0164] In some embodiments, R f1 It is fluorine.

[0165] In some embodiments, X 3 In some embodiments, X 3 It is CH.

[0166] In some embodiments, X 6 In some embodiments, X 6 CR 4 That is the case.

[0167] In some embodiments, R 1 R 1 is, -OC 1-6 It is alkyl. In some embodiments, the alkyl group is linear. In some embodiments, the alkyl group is branched. In some embodiments, the alkyl group is linear and optionally contains one or more deuterium, -CN, or -OC 1-6 It is substituted with an alkyl group. In some embodiments, the alkyl group is not substituted. In some embodiments, the alkyl group is one or more -CN or -OC 1-6 It is substituted with alkyl. In some embodiments, R 1 is -O-CH2-CH3, -O-CH3, -O-CH2-CN, -O-CH2-CH2-O-CH3, or -O-CH2CH(-O-CH3)-CH3. In some embodiments, R 1 It is branched and optionally replaced with one or more -CNs. In some embodiments, R 1 teeth, [ka] That is the case.

[0168] In some embodiments, R 1は -OC 1-6It is a haloalkyl group, where the haloalkyl group is linear. In some embodiments, the haloalkyl group is substituted with one or more fluorine atoms. In some embodiments, R 1 These are -O-CHF2, -O-CF3, -O-CH2-CH2F, -O-CH2-CF3, -O-CH2-CHF-CH3, -O-CHF-CH3, -O-CHF-CH2F, or -O-CH2-CH2F.

[0169] In some embodiments, R 1 C is optional. 1-6 -OC substituted with alkoxy or halogen 3-10 It is cycloalkyl. In some embodiments, R 1 is -O-cyclopropyl or -O-cyclobutyl, where cyclopropyl or cyclobutyl is optionally substituted with fluorine or methoxy. In some embodiments, R 1 -OC is optionally substituted with one or more halogens (e.g., fluorine), -OCH3, or -CN. 3-10 It is a cycloalkyl group.

[0170] In some embodiments, R 1 is -O- (3-8 membered heterocyclyl). In some embodiments, the 3-8 membered heterocyclyl contains one oxygen atom. In some embodiments, the 3-8 membered heterocyclyl contains two oxygen atoms. In some embodiments, R 1 This is -O-CH2-(1,4-dioxan-2-yl) or -O-CH2-tetrahydrofuran-2-yl.

[0171] In some embodiments, R 1 is -O-(C 1-6 Alkylene)-(C 3-10 It is a cycloalkyl. In some embodiments, R 1 -O-(C) is optionally substituted with one or more halogens, cyanosides, or -OCH3. 1-6 Alkylene)-(C 3-10 It is a cycloalkyl. In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0172] In some embodiments, R 1 is -O-(C 1-6 It is an alkylene)-(3-8 membered heterocycline). In some embodiments, -O-(C 1-6 The alkylene-(3-8 member heterocyclyl) is optionally substituted with one or more halogens, cyanosides, or -OCH3 groups. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0173] In some embodiments, R 1 teeth, [ka] That is the case.

[0174] In some embodiments, R 1 C 1-6 In some embodiments, R 1 It is -CF2-CH3.

[0175] In some embodiments, R 1 is -O- (3-8 member heterocyclyl). In some embodiments, R 1 is oxetanil. In some embodiments, R 1It is oxetane-3-yl.

[0176] In some embodiments, R 1 is -O-(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3 is the case in some embodiments. 1 teeth, [ka] That is the case.

[0177] In some embodiments, R 1 -NR 8 R 9 In some embodiments, R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline. In some embodiments, R 8 and R 9 These combine with the atoms to which they are bonded to form morpholine. In some embodiments, R 8 and R 9 is hydrogen. In some embodiments, R 1 is NH2. In some embodiments, R 1 , NR 8 R 9 And here, R 8 H is R 9 This is C, which has been optionally replaced with an oxo. 1-6 It is alkyl.

[0178] In some embodiments, R 2 is one or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 It is cycloalkyl. In some embodiments, R 2 is one or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6It is a cyclopropyl that is optionally substituted with alkyl. In some embodiments, R 2 teeth, [ka] That is the case.

[0179] In some embodiments, R 2 is a 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, and the 4 or 5-membered heterocycline optionally contains one or more oxo, [ka] or C 1-6 It is substituted with alkyl. In some embodiments, R 2 (i) one or more oxo or [ka] (ii) thietan replaced by (ii) oxetane, or (iii) one or more C of any choice 1-6 It is an alkyl-substituted tetrahydrofuran. In some embodiments, R 2 teeth, [ka] That is the case.

[0180] In some embodiments, R 2 R is a 5-membered heteroaryl compound containing one or two heteroatoms independently selected from N and S, 5 At least one heteroatom of is S. In some embodiments, R 2 is a thiazole. In some embodiments, R 2 teeth, [ka] That is the case.

[0181] In some embodiments, R2 H is H. In some embodiments, R 2 It is -OCH3.

[0182] In some embodiments, n is 1.

[0183] In some embodiments, X 1 teeth, [ka] In some embodiments, X 1 teeth, [ka] In some embodiments, X 1 teeth, [ka] In some embodiments, R 3 is methyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 and R 3’ X is independently CH3, CD3, deuterium, or hydrogen. In some embodiments, X 1 teeth, [ka] In some embodiments, X 1 teeth, [ka] In some embodiments, X 1 teeth, [ka] In some embodiments, X 1 teeth, [ka] That is the case.

[0184] In some embodiments, ring A is [ka] And in the formula, * represents X 1 This shows bonding to. In some embodiments, ring A is [ka] And in the formula, * represents X 1 This shows bonding to a halogen. In some embodiments, ring A is optionally one or more halogens or C 1-6 It is a phenylene ring substituted with an alkyl group. In some embodiments, ring A is [ka] And in the formula, [ka] X 1 This shows bonding to. In some embodiments, ring A is a 6-membered heteroarylene ring that is optionally substituted with one or more halogens. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] And in the formula, [ka] X 1 This indicates a connection to [the specified location].

[0185] In some embodiments, ring B is a nitrogen-containing 6-membered heteroarylene. In some embodiments, ring B is a pyridinylene or pyrimidinylene optionally substituted with one or more halogens. In some embodiments, ring B is pyridinylene. In some embodiments, ring B is [ka] In the formula, * indicates a bond to ring A or L'. In some embodiments, ring B is [ka] In the formula, * indicates a bond to ring A or L'.

[0186] In some embodiments, ring B is optionally one or more C 1-6 It is a 9-membered heterocyclene containing two oxygen atoms, which is alkyl-substituted. In some embodiments, ring B is optionally one or more C 1-6 It is an alkyl-substituted benzoidoxolylene. In some embodiments, ring B is [ka] In the formula, * indicates a bond to ring A or L'. In some embodiments, ring B is a 10-membered heterocyclene containing two oxygen atoms. In some embodiments, ring B is a benzodioxanylene. In some embodiments, ring B is [ka] In the formula, * indicates a bond to ring A or L'. In some embodiments, ring B is [ka] In the formula, * indicates a bond to ring A or L'.

[0187] In some embodiments, ring B is a 10-membered heterocyclene containing one oxygen atom and one nitrogen atom. In some embodiments, ring B is [ka] In the formula, * indicates a bond to ring A or L'.

[0188] In some embodiments, L is a bond. In some embodiments, L is *-O-CH2-, where * indicates a bond to ring B.

[0189] In some embodiments, ring C is optionally one or more halogens, -CN, -OCH3, [ka] or a phenyl substituted with cyclopropyl. In some embodiments, ring C is [ka] That is the case.

[0190] In some embodiments, ring C is optionally one or more halogens, -CN, -OC 1-6 Alkyl, -C(=O)-(C 3-10 Cycloalkyl, or C 3-10 It is a 6-membered heteroaryl containing a nitrogen atom, substituted with a cycloalkyl group. In some embodiments, the ring C is optionally one or more -Cl, -F, -CN, -OCH3, cyclopropyl, [ka] It is a pyridinyl substituted with. In some embodiments, the ring C is [ka] That is the case.

[0191] In some embodiments, the ring C may optionally be one or more C1-6 The ring C is a bicyclic 9 or 10-membered heteroaryl containing two nitrogen atoms, substituted with alkyl or oxo. In some embodiments, ring C is pyrazolopyridine, triazolopyridine, 2,3-dihydro-1H-pyrrolopyridine, 1,2-dihydrooxazolopyridine, 1,2,3,4-tetrahydronaphthiridine, 2,3-dihydropyridoxazine, 2,3-dihydro-1H-pyrrolopyridine, or 2,3-dihydrooxazolopyridine, and pyrazolopyridine, triazolopyridine, 2,3-dihydro-1H-pyrrolopyridine, 1,2-dihydrooxazolopyridine, 1,2,3,4-tetrahydronaphthiridine, 2,3-dihydropyridoxazine, 2,3-dihydro-1H-pyrrolopyridine, or 2,3-dihydrooxazolopyridine may optionally contain one or more C 1-6 It is substituted with alkyl or oxo. In some embodiments, ring C is [ka] That is the case.

[0192] In some embodiments, [ka] teeth, [ka] [ka] That is the case.

[0193] In some embodiments, R 12 is -COOH. In some embodiments, R 12 teeth, [ka] That is the case.

[0194] This disclosure relates to one of the following formulas: (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), and the following [ka] Intend to combine with any one of the parts: [ka] [ka]

[0195] This disclosure relates to one of the following formulas: (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), and the following [ka] Intend to combine with any one of the parts: [ka] [ka]

[0196] In some embodiments, the GLP-1R agonist is [ka] This is 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)piperidine-1-yl)methyl)-1-(thiazole-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1R agonist is the magnesium salt of 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)piperidine-1-yl)methyl)-1-(thiazole-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0197] In some embodiments, the GLP-1R agonist is selected from those listed in Table 1 below, or from pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0198] In some embodiments, the GLP-1R agonist is selected from those listed in Table 2 below, or from pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2] Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 [Table 2-20] [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29] [Table 2-30] [Table 2-31] [Table 2-32]

[0199] In some embodiments, the GLP-1R agonist is selected from those listed in Table 3 below, or from pharmaceutically acceptable salts thereof. [Table 3-1] [Table 3-2] [Table 3-3]

[0200] In some embodiments, the GLP-1R agonist is selected from those listed in Table 4 below, or from pharmaceutically acceptable salts thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12]

[0201] In some embodiments, the GLP-1R agonist is selected from those listed in Table 5 below, or from pharmaceutically acceptable salts thereof. Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 5-12 Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23 Table 5-24 Table 5-25 Table 5-26 Table 5-27 Table 5-28 Table 5-29 Table 5-30 Table 5-31 Table 5-32 Table 5-33 Table 5-34 Table 5-35 Table 5-36 Table 5-37 Table 5-38 Table 5-39 Table 5-40 Table 5-41 Table 5-42 Table 5-43 Table 5-44 Table 5-45 Table 5-46 Table 5-47 Table 5-48 Table 5-49 Table 5-50 Table 5-51 [Table 5-52]

[0202] In some embodiments, the GLP-1R agonist is selected from those listed in Table 5A below, or from pharmaceutically acceptable salts thereof. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] [Table 6-19] [Table 6-20] [Table 6-21] [Table 6-22] [Table 6-23] [Table 6-24] [Table 6-25] [Table 6-26] [Table 6-27] [Table 6-28] [Table 6-29] [Table 6-30]

[0203] THRβ agonist In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is resmethirome (MGL-3196, Madrigal Therapeutics). In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is VK2809 (Viking Therapeutics). In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is sovethyrom. In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is eprothyrom. In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is ALG-055009 (Aligo). In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is CNPT-101101. In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is CNPT-101207. In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is ASC41 (Ascletis).

[0204] Suitable THRβ agonists that can be used in accordance with 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). [ka] (In the formula, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10 Aliphatic rings, or substituted or unsubstituted C 5~10 It is an aromatic ring, and its substituents are hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, and -NHC. 1~4 Alkyl, -N(C 1~4 Alkyl)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 One or more substances selected from the group consisting of cycloalkyls, and if they contain two substituents, the two substituents may form a ring structure together with the carbons linked to them. (The halogen atom is selected from the group consisting of F, Cl, and Br.) or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is a compound of formula (II-1a). [ka] (In the formula, R1 to R3 are defined as described in detail herein with respect to formula (II-1), R4 is hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2,-CONH2,-CONHC 1~4Alkyl, -CON(C 1~4 Alkyl)2,-NHCOC 1~4 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and C 3~6 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, R4 is hydrogen, a halogen atom, hydroxyl, -OCF3, C 1~6 Alkyl, C 1~6 Alkoxy and C 3~6 It is selected from the group consisting of cycloalkyls, and m is an integer in the range of 1 to 3.

[0208] In some embodiments, R1 is hydrogen, cyano, and substituted or unsubstituted C 1~6 Selected from the group consisting of alkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 The group consists of alkoxy atoms, and the halogen atom is selected from the group consisting of F, Cl, and Br.

[0209] In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is a compound of formula (II-2). [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ring A, together with the carbonyl (keto) group within the ring, forms a 5-membered heterocycle containing 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and the heterocycle is optionally substituted with 1 to 2 C1-C3 alkyl groups or C3-C4 cycloalkyl groups, and the carbonyl (keto) group is not adjacent to the atom bonded to X. R 1This includes C1-C4 alkyl, C3-C5 cycloalkyl, and CON(R) elements optionally substituted with 1-5 halo or hydroxyl groups. 10 )2, or NR 10 COR 10 And, R 2 is H or C1-C3 alkyl, L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 )CN, CHR 11 , or C(R 11 )R 11 And, R 3 and R 4 These are independently Cl, Br, methyl, or ethyl. R 5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R 5 However, R 4 Together with intervening atoms, they form a 5-7 membered cycloalkyl group or a 5-7 membered heterocycle containing 1-2 ring heteroatoms. X does not exist, or O, 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 It is SO2, Each R 10 These are independently C1-C3 alkyl or H, Each R 11 These are independently C1-C2 alkyl groups that are optionally substituted with 1-5 halos. or two R's 11The groups, together with the carbon atoms to which they are bonded, form a cyclopropyl or cyclobutyl ring. Each R 12 These are independently either H or methyl.

[0210] In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is a compound of formula (II-3). [ka] (In the formula, R1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, -C(O)N(R7)(R8), -N(R9)C(O)(R 10 ), or halo, R2 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group. R3 is H or halo, R4 is H, or a substituted or unsubstituted linear C1-C3 alkyl group. L is -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, or -C(R5)(R6)-, R5 and R6 are independently H, halo, -CN, or substituted or unsubstituted C1-C6 alkyl, or R5 and R 6は Together with the carbon atoms to which they are bonded, they 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 bonded, form substituted or unsubstituted 3-7 member heterocycloalkyl groups. R9 is H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C3-C6 cycloalkyl group. R 10 These are substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, -N(R7)(R8), or -O(R 11 ) and R 11 These are substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted C3-C6 cycloalkyl groups. M1 and M2 are independently a halo, or a substituted or unsubstituted C1-C6 alkyl group. M3 is either H, a halo, or a substituted or unsubstituted C1-C6 alkyl group, or M3, together with M2 and the carbon atoms to which they are bonded, forms a 5-7 membered ring containing 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S. or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is a compound of formula (II-4). [ka] or its tautomers or N-oxides, or their respective isotopic isomers, or the aforementioned stereoisomers, or the respective pharmaceutically acceptable salts, or the respective solvates, in the formula, A is [ka] And, [ka] These are 5-membered heterocyclyls or 5-6 membered heteroaryls, each of which optionally contains 1-2 additional cyclic heteroatoms selected from the group consisting of N and O. Here, if each heteroatom in a heterocyclyl or heteroaryl must satisfy the valence of the heteroatom, then one R 1 Bonded to the base, Here, if each carbon atom in a heterocycline or heteroaryl must satisfy the valence of a carbon atom, then one R 2 It is bonded to the base, however, one more than R is needed to satisfy the valence of each carbon atom. 2The condition is that the base is not necessary. Z 1 , Z 2 , and Z 3 These are independently N or CH, Y is either N or C. Each R 1 These are independently H, C1-C6 alkyl, or C3-C6 cycloalkyl, Here, each C1~ C6 Alkyl or C3-C6 cycloalkyl groups may optionally contain 1 to 5 R groups. 3 It is substituted with the base, Each R 2 These are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), hydroxyl, or oxo. Here, each C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), or -O(C3-C6 cycloalkyl) group can optionally contain 1 to 5 R groups. 3 It is substituted with the base, Or, R 1 and R 2 They combine to form 5-6 member heteroaryls or 5-7 member heterocyclines. Or, two R's 2 The groups combine to form 5-6 membered heteroaryl, 5-7 membered heterocyclyl, C5-C7 cycloalkyl, or C6 aryl groups. Each R 3 These are independently halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, -NH2, -CN, or hydroxyl.

[0212] In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is a compound of formula (II-5). [ka] or its tautomer, or any of the aforementioned pharmaceutically acceptable salts, in the formula, R 1 is H or -CH3, X 1 , X 2 , X 3 , and X 4 Each of them operates independently, CR 2 or N, where X 1 , X 2 , X 3 , and X 4 At least two of them are CR 2 And, Each R 2 These are independently H, halo, C1-C6 alkyl, C1-C6 alkyl-CN, C1-C6 alkyl-OH, C1-C6 haloalkyl, -CN, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -O(C1-C6 alkyl), C3-C6 cycloalkyl, 5-6 membered heteroaryl, 5-7 membered heterocyclyl, or C6aryl, where each C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, 5-6 membered heteroaryl, 5-7 membered heterocyclyl, or C6aryl optionally contains 1-5 R 3 It is substituted with the base, Or, two R's 2 The groups, together with the carbon atoms to which they are bonded, form 5-6 membered heteroaryls, 5-7 membered heterocyclines, C5-C7 cycloalkyls, or C6 aryls, each of which optionally contains 1-5 R groups. 3 It is substituted by the group, Each R 3 These are independently C1-C6 alkyl, -O(C1-C6 alkyl), halo, -CN, hydroxyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or CO2H.

[0213] In some embodiments, the THRβ agonist administered to patients requiring THRβ agonist administration is a compound of formula (II-6). [ka] or its tautomers or stereoisomers, or each of the aforementioned pharmaceutically acceptable salts, in the formula, A is [ka] And in the formula, R A is H or -CN, L 1 The bond is -NR'-, -O-, -S-, or -S(O)2-, where R' is H or C1-C6 alkyl. L 2 is a bond or -S(O)2-, R 1 H, C1-C6 alkyl, C6-C 10 The C3-C6 cycloalkyl groups are aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, or C3-C6 cycloalkyl groups, where C1-C6 alkyl and C6-C6 alkyl groups are C3-C6. 10 Aryls, 3-12 membered heterocyclyls, 5-12 membered heteroaryls, and C3-C6 cycloalkyls each independently have 1-5 R groups of their choice. 2 It is substituted with the base, R is H, C1-C6 alkyl, C6-C 10 The C3-C6 cycloalkyl groups are aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, or C3-C6 cycloalkyl groups, where C1-C6 alkyl and C6-C6 alkyl groups are C3-C6. 10 Aryls, 3-12 membered heterocyclyls, 5-12 membered heteroaryls, and C3-C6 cycloalkyls each independently have 1-5 R groups of their choice. 2 It is substituted with the base, Each R 2 These are independently halogens, C1-C6 alkyls, C3-C6 cycloalkyls, C1-C6 haloalkyls, C1-C6 alkyl-OHs, -NH2, -CN, or hydroxyls, however, L 1 If it is a bond and R is H, then A is [ka] And, L 1is -O-, R is H, and A is [ka] If R 1 C2-C6 alkyl, C6-C 10 The C3-C6 cycloalkyl groups are aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, or C3-C6 cycloalkyl groups, where C2-C6 alkyl and C6-C6 alkyl groups are C3-C6 cycloalkyl groups. 10 Aryls, 3-12 membered heterocyclyls, 5-12 membered heteroaryls, and C3-C6 cycloalkyls each independently have 1-5 R groups of their choice. 2 It is substituted with the base.

[0214] In some embodiments, THRβ agonists are selected from those listed in Table 6 below, or from pharmaceutically acceptable salts thereof. [Table 7]

[0215] In some embodiments, the THRβ agonist is [ka] (Compound 9) is (2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazine-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitriel), or a pharmaceutically acceptable salt thereof. In some embodiments, the THRβ agonist is 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazine-1-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitriel potassium salt. In some embodiments, the THRβ agonist is 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazine-1-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitride sodium salt.

[0216] In some embodiments, THRβ agonists are selected from those listed in Table 7 below, or from pharmaceutically acceptable salts thereof. [Table 8-1] [Table 8-2] [Table 8-3]

[0217] In some embodiments, THRβ agonists are selected from those listed in Table 8 below, or from pharmaceutically acceptable salts thereof. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0218] In some embodiments, THRβ agonists are selected from those listed in Table 9 below, or from pharmaceutically acceptable salts thereof. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0219] In some embodiments, the THRβ agonist is selected from those listed in Table 10 below, or from pharmaceutically acceptable salts thereof. [Table 11]

[0220] In some embodiments, the THRβ agonist is selected from those listed in Table 11 below, or from pharmaceutically acceptable salts thereof. [Table 12-1] [Table 12-2] [Table 12-3]

[0221] Pharmaceutically acceptable compositions and formulations Any pharmaceutically acceptable composition or simply “pharmaceutical composition” of any of the compounds detailed herein is encompassed by the present invention. Therefore, the present invention relates to GLP-1R agonists (for example, 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) The present invention includes a pharmaceutical composition comprising 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, and a pharmaceutically acceptable carrier or additive. In some embodiments, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the present invention may take form suitable for oral, oral, parenteral, nasal, topical or rectal administration, or form suitable for inhalation administration.

[0222] The compounds detailed herein may, in one embodiment, be in a purified form, and compositions containing the purified compounds are detailed herein. Compositions containing the compounds or salts thereof, for example, substantially pure compositions of the compounds, are provided. In some embodiments, the compositions containing the compounds or salts thereof, detailed herein, are in a substantially pure form. In some embodiments, “substantially pure” means a composition containing 35% or less impurities, where impurities represent compounds other than the compound or salts thereof that constitute the majority of the composition. For example, a substantially pure composition of a compound means a composition containing 35% or less impurities, where impurities represent compounds other than the compound or salt thereof. In some embodiments, a substantially pure composition of a compound or salt thereof containing 25% or less impurities is provided. In some embodiments, a substantially pure composition of a compound or salt thereof containing 20% ​​or less impurities is provided. In some embodiments, a substantially pure composition of a compound or salt thereof containing 10% or less impurities is provided. In some embodiments, a substantially pure composition of a compound or salt thereof containing 5% or less impurities is provided. In some embodiments, a substantially pure composition of a compound or salt thereof containing 3% or less impurities is provided. In some embodiments, a substantially pure compound composition or salt thereof is provided, the composition containing 1% or less impurities. In some embodiments, a substantially pure compound composition or salt thereof is provided, the composition containing 0.5% or less impurities. In some embodiments, a substantially pure compound composition means that the composition contains 15% or less, in some embodiments 10% or less, in some embodiments 5% or less, in some embodiments 3% or less, and in some embodiments 1% or less impurities, where the impurities may be compounds in different stereochemical forms.

[0223] In some embodiments, the compounds described herein are synthetic compounds prepared for administration to subjects such as humans. In some embodiments, compositions containing substantially pure forms of the compounds are provided. In some embodiments, the present invention encompasses pharmaceutical compositions comprising the compounds detailed herein and pharmaceutically acceptable carriers or excipients. In some embodiments, methods for administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods for administering the compounds are suitable for any of the compounds or forms detailed herein.

[0224] The compound may be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, cheek, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound may be formulated with a suitable carrier to provide a delivery form, including but not limited to tablets, caplets, capsules (such as rigid gelatin capsules or soft elastic gelatin capsules), cachets, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), 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 liquid emulsions), solutions, and elixirs.

[0225] The compounds described herein can be used in the preparation of pharmaceutical formulations, etc., by combining the compound as an active ingredient with a pharmaceutically acceptable carrier, such as those described above. Depending on the therapeutic form of the system (e.g., transdermal patch versus oral tablet), the carrier may be in various forms. Furthermore, the pharmaceutical formulation may contain preservatives, solubilizers, stabilizers, re-wetters, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure. Formulations containing the compounds may also contain other substances having beneficial therapeutic properties. Pharmaceutical formulations can be prepared by known compounding methods. Suitable formulations are, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st This can be found in the ed. (2005), which is incorporated herein by reference.

[0226] Compounds described herein may 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 in the preparation of such compositions include lactose, corn starch or its derivatives, talc, stearic acid or its salts. Acceptable carriers for soft-shell gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure.

[0227] Instructions for use and usage The combinations described herein may be used in some embodiments for the treatment or prevention of liver damage. In some embodiments, a method for treating or preventing liver damage in a patient requiring treatment or prevention of liver damage includes administering to the patient a GLP-1R agonist and a THRβ agonist.

[0228] Liver disorders include, but are not limited to, hepatitis, fibrosis, and steatohepatitis. In some embodiments, the liver disorder is selected from hepatitis, hepatic 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 certain embodiments, the liver disorder is selected from hepatic fibrosis, alcoholic fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the liver disorder is NASH. In another embodiment, the liver disorder is hepatitis. In another embodiment, the liver disorder is hepatic fibrosis. In another embodiment, the liver disorder is alcohol-induced fibrosis. In another embodiment, the liver disorder is steatosis. In another embodiment, the liver disorder is alcoholic steatosis. In another embodiment, the liver disorder is NAFLD. In one embodiment, the therapeutic method provided herein inhibits or slows the progression of NAFLD to NASH. In one embodiment, the therapeutic method provided herein inhibits or slows the progression of NASH. NASH can progress to one or more of the following: cirrhosis, liver cancer, etc. In some embodiments, the liver impairment is NASH. In some embodiments, the patient undergoes a liver biopsy. In some embodiments, the method further includes obtaining the results of the liver biopsy.

[0229] In some embodiments, the method is for treating liver damage in patients requiring treatment for liver damage, the liver damage being selected from the group consisting of inflammation of the liver, hepatic 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).

[0230] In some embodiments, the diseases or conditions to be treated and / or prevented include cardiovascular metabolic disorders, e.g., diabetes mellitus (including prediabetes T1D and / or T2DM), idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile-onset late-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), and non-obese overweight (e.g., BMI 25 kg / m²). 2 ~30kg / m 2 ), eating disorders (including bulimia nervosa, bulimia nervosa, and syndromeal obesity such as Prader-Willi syndrome and Valde-Vidl syndrome), excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL cholesterol, low HDL cholesterol), hyperinsulinemia, liver diseases such as NAFLD, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (for example) These include necrosis and apoptosis, stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, 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, vascular restenosis, impaired glucose metabolism, impaired fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, or hyperapolipoproteinemia.

[0231] In some embodiments, the diseases or conditions treated include sleep apnea, weight gain due to the use of other medications (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 drug abuse), prevention or treatment of polycystic ovary syndrome, or treatment of addiction (e.g., alcohol and / or drug abuse).

[0232] In some embodiments, the Disclosure relates to the co-administration of a GLP-1R agonist and a THRβ agonist to a subject, resulting in a reduction in body fat mass in the subject with little or no reduction in lean body mass in the subject. In some embodiments, the Disclosure Provided herein is a method for treating a cardiovascular metabolic disorder in a subject (e.g., a human patient) requiring treatment of such a disorder, the method comprising administering a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof to the subject.

[0233] In one embodiment, the methods and combinations of the present disclosure relate to a) lowering 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 body weight and / or food intake or inducing satiety in subjects who require it.

[0234] In some embodiments, combinations and methods of the present disclosure relate to treating or preventing obesity, reducing body fat percentage, increasing lean body mass as a percentage of total body weight, or inducing satiety in subjects who require such treatment or prevention.

[0235] In some embodiments, combinations and methods of the present disclosure relate to treating or preventing obesity, reducing body fat percentage, increasing the proportion of lean body mass to total body weight, or inducing satiety in subjects who require such treatment or prevention.

[0236] In some embodiments, combinations and methods of this disclosure relate to the treatment of obesity in subjects requiring treatment for obesity.

[0237] In some embodiments, combinations and methods of this disclosure relate to the treatment or prevention of obesity in subjects requiring treatment or prevention of obesity.

[0238] In some embodiments, combinations and methods of the present disclosure relate to reducing body fat percentage, increasing lean body mass as a percentage of total body weight, or inducing satiety in subjects who require such reductions.

[0239] In some embodiments, the Disclosure provides a method for treating or preventing obesity, reducing body fat, and / or increasing the percentage of lean body mass in total body weight in subjects requiring such treatment, the method comprising the administration of a THR-B agonist (e.g., compound 9) and a GLP-1R agonist, which produce a synergistic effect compared to the administration of a GLP-1R agonist alone.

[0240] In some embodiments, the present disclosure provides a method for treating obesity, reducing body fat, and / or increasing the percentage of lean body mass in total body weight in subjects requiring such treatment, the method comprising the administration of a THR-B agonist (e.g., compound 9) and a GLP-1R agonist, which produce a synergistic effect compared to the administration of a GLP-1R agonist alone.

[0241] In some embodiments, provided herein are methods for treating liver impairment in subjects requiring treatment of liver impairment (e.g., human patients), the methods comprising administering a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof to the subject. Exemplary liver impairments include, but are not limited to, inflammation of the liver, fibrosis, and steatohepatitis. In some embodiments, the liver injury is selected from the list consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis due to pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease, transplanted liver regeneration, congenital hepatic fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher disease, hemochromatosis, and oti-antitrypsin deficiency. In some embodiments, the liver injury is selected from a list consisting of inflammation of the liver, hepatic 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 injury is selected from the group consisting of hepatic fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the liver injury is NASH. In another embodiment, the liver injury is hepatic inflammation. In another embodiment, the liver injury is hepatic fibrosis. In another embodiment, the liver injury is alcohol-induced fibrosis. In another embodiment, the liver injury is steatosis. In another embodiment, the liver injury is alcoholic steatosis. In another embodiment, the liver injury is NAFLD. In one embodiment, the therapeutic method provided herein inhibits or slows the progression of NAFLD to NASH. In one embodiment, the therapeutic method provided herein inhibits or slows the progression of NASH. NASH can progress to one or more of the following conditions, such as cirrhosis and liver cancer.In some embodiments, the liver impairment is NASH. In some embodiments, the patient undergoes a liver biopsy. In some embodiments, the method further includes obtaining the results of the liver biopsy.

[0242] In some embodiments, the Disclosure provides a method for reducing the food intake of a subject requiring a reduction in food intake, the method comprising administering an effective amount of one of the compounds or pharmaceutical compositions disclosed herein to the subject. In some embodiments, administration of the compounds disclosed herein reduces the subject's food intake by at least 10%, 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% compared to the subject's food intake in the absence of the compounds disclosed herein. In some embodiments, the intake of the food in question is reduced by, for example, at least 10%, at least 20%, at least 30%, at least 4, at least 5, at least 6, at least 12 hours, at least 1 day, or at least 2 days after administration, 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%.

[0243] In some embodiments, the Disclosure provides methods for improving glucose tolerance in subjects requiring improved glucose tolerance. In some embodiments, after glucose intake, for example, glucose intake caused by food consumption, and after administration of the compounds disclosed herein, the glucose concentration in the subject's blood is lower than the glucose concentration in the blood if the compounds disclosed herein had not been administered to the subject, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, and 1000% lower.

[0244] According to this application, the compounds described herein or pharmaceutically acceptable salts thereof can be administered by any suitable route in the form of a pharmaceutical composition adapted to such route, in a dose effective for the intended treatment. In some embodiments, the compounds are those of any embodiment of formula (I), or compounds selected from the compounds in Table 1, or pharmaceutically acceptable salts thereof. The compounds and / or compositions described herein can be administered orally, rectally, vaginally, parenterally, or topically.

[0245] In some embodiments, the compound and / or composition may be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or it may involve buccal or sublingual administration so that the compound enters the bloodstream directly from the mouth.

[0246] In some embodiments, the compounds and / or compositions may be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, subarachnoid, intraventricular, urethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous methods. Suitable devices for parenteral administration include needled (including microneedle) syringes, needleless syringes, and injection techniques.

[0247] In some embodiments, the compounds and / or compositions may be administered topically to the skin or mucous membranes, i.e., dermally or transdermally. In some embodiments, the compounds and / or compositions may be administered intranasally or by inhalation. In some embodiments, the compounds and / or compositions may be administered rectally or vaginally. In some embodiments, the compounds and / or compositions may be administered directly to the eyes or ears.

[0248] The dosage regimens for the compounds and / or compositions described herein are based on a variety of factors, including the patient's type, age, weight, sex, and medical condition, the severity of the condition, the route of administration, and the activity of the specific compound used. Therefore, dosage regimens can vary considerably. In some embodiments, the total daily dose of the compounds of this application is typically about 0.001 to about 100 mg / kg (i.e., mg of the compound per kg of body weight) for the treatment of the indicated conditions considered herein. In one embodiment, the total daily dose of the compounds of this application is about 0.01 to about 30 mg / kg, in another embodiment about 0.03 to about 10 mg / kg, and in yet another embodiment about 0.1 to about 3 mg / kg. It is not uncommon for the administration of the compounds of this application to be repeated multiple times a day (typically four times or less). Usually, multiple doses per day can be used to increase the total daily dose as needed.

[0249] Appropriate dosages of the THRβ agonists described herein are, for example, described in PCT Publications WO2021231646, WO2023086561, and WO2023083288, which are incorporated herein by reference, respectively.

[0250] In some embodiments, approximately 0.5 mg to approximately 100 mg of THRβ agonist is administered to the subject. In some embodiments, approximately 0.5 mg to approximately 90 mg of the compound is administered to the subject. In some embodiments, approximately 1 mg to approximately 90 mg of the compound is administered to the subject. In some embodiments, approximately 3 mg to approximately 90 mg of the compound is administered to the subject. In some embodiments, approximately 0.5 mg to approximately 30 mg of the compound is administered to the subject. In some embodiments, approximately 1 mg to approximately 30 mg of the compound is administered to the subject. In some embodiments, approximately 3 mg to approximately 90 mg of the compound is administered to the subject. In some embodiments, approximately 1 mg to approximately 5 mg of the compound is administered to the subject. In some embodiments, approximately 1 mg to approximately 3 mg of the compound is administered to the subject. In some embodiments, approximately 5 mg to approximately 10 mg of the compound is administered to the subject. In some embodiments, approximately 10 mg to approximately 15 mg of the compound is administered to the subject. In some embodiments, approximately 15 mg to approximately 20 mg of the compound is administered to the subject. In some embodiments, approximately 20 mg to 25 mg of the compound is administered to the subject. In some embodiments, approximately 25 mg to 30 mg of the compound is administered to the subject. In some embodiments, approximately 1 mg of the compound is administered to the subject. In some embodiments, approximately 2 mg of the compound is administered to the subject. In some embodiments, approximately 3 mg of the compound is administered to the subject. In some embodiments, approximately 4 mg of the compound is administered to the subject. In some embodiments, approximately 5 mg of the compound is administered to the subject. In some embodiments, approximately 6 mg of the compound is administered to the subject. In some embodiments, approximately 7 mg of the compound is administered to the subject. In some embodiments, approximately 8 mg of the compound is administered to the subject. In some embodiments, approximately 9 mg of the compound is administered to the subject. In some embodiments, approximately 10 mg of the compound is administered to the subject. In some embodiments, approximately 15 mg of the compound is administered to the subject. In some embodiments, approximately 20 mg of the compound is administered to the subject. In some embodiments, approximately 25 mg of the compound is administered to the subject. In some embodiments, approximately 30 mg of the compound is administered to the subject. In some embodiments, the compound is compound 9 as described herein.

[0251] combination In further embodiments, the pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that complement the desired effect. In some embodiments, the GLP-1R agonist and the THRβ agonist are administered in close proximity in time (for example, the GLP-1R agonist and the THRβ agonist may be administered simultaneously). Accordingly, this disclosure provides a method for treating or preventing cardiovascular metabolic disorders, comprising administering a GLP-1R agonist and a THRβ agonist in close proximity in time.

[0252] 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 in close temporal proximity to a THRβ agonist of formula (II-1) or (II-1a), or a pharmaceutically acceptable salt thereof.

[0253] 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 in close temporal proximity to a THRβ agonist (e.g., 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).

[0254] In some embodiments, a GLP-1R agonist of formula (II**) or a pharmaceutically acceptable salt thereof is administered in close temporal proximity to a THRβ agonist of formula (II-1) or (II-1a) or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, a GLP-1R agonist of formula (II**) or a pharmaceutically acceptable salt thereof is administered in close temporal proximity to a THRβ agonist (e.g., 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).

[0256] In some embodiments, the THRβ agonist of formula (II-1) or (II-1a), or a pharmaceutically acceptable salt thereof, is a GLP-1R agonist (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) It is administered in temporal proximity to 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-P01), (II**), or (II*), or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, “temporal proximity” means that the administration of one therapeutic agent occurs within a period before or after the administration of another therapeutic agent, and the therapeutic effect of the first therapeutic agent overlaps with the therapeutic effect of the second therapeutic agent. In some embodiments, the therapeutic effect of the first therapeutic agent completely overlaps with the therapeutic effect of the second therapeutic agent. In some embodiments, “temporal proximity” means that the administration of one therapeutic agent occurs within a period before or after the administration of another therapeutic agent, and there is a synergistic effect between the first therapeutic agent and the second therapeutic agent. “Temporal proximity” can vary depending on a variety of factors, including but not limited to the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the person to whom the therapeutic agent is administered, the disease or condition being treated or improved, the therapeutic outcome to be achieved, the dosage, frequency, and duration of administration of the therapeutic agent, the pharmacokinetics and pharmacodynamics of the therapeutic agent, and the route through which the therapeutic agent is administered. In some embodiments, “temporal proximity” means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple doses of one therapeutic agent may occur in temporal proximity to a single dose of another therapeutic agent. In some embodiments, temporal proximity may vary during a treatment cycle or within a dosing plan.

[0258] In some embodiments, the THRβ agonist is administered to the patient before the GLP-1R agonist. In some embodiments, the THRβ agonist is administered to the patient 0-1 hours, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, or 5-6 hours before 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 before the GLP-1R agonist. In some embodiments, the THRβ agonist reaches a steady state in the patient before the administration of the GLP-1R agonist. In some embodiments, the GLP-1R agonist is administered to the patient before the THRβ agonist. In some embodiments, the GLP-1R agonist is administered to the patient 0–1, 1–2, 2–3, 3–4, 4–5, or 5–6 days before the THRβ agonist. In some embodiments, the GLP-1R agonist reaches a steady state in the patient before the administration of the THRβ agonist. In some embodiments, the THRβ agonist is administered to the patient substantially simultaneously with the GLP-1R agonist.

[0259] Products and kits This disclosure further provides articles comprising the compounds or salts thereof described herein, the compositions described herein, or one or more unit doses described herein in suitable packaging. In certain embodiments, the articles are intended for use in any of the methods described herein. Suitable packaging (e.g., containers) are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0260] This disclosure further provides a kit for carrying out the method of this disclosure, which includes at least two compounds described herein, or pharmaceutically acceptable salts thereof, or a composition comprising one of the compounds described herein, or a pharmaceutically acceptable salt thereof. The kit may use any of the compounds disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the kit includes the GLP-1R agonists described herein (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), (IY), (IZ), (IA) A) (IAB), (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 THRβ agonist (e.g., 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). The kit may be used for one or more of the uses described herein and may therefore contain instructions for treatment as described herein.

[0261] The kit generally includes suitable packaging. The kit may include one or more containers containing any compound described herein or a pharmaceutically acceptable salt thereof. Each component may be packaged in a separate container, or several components may be combined in a single container where cross-reactivity and shelf life are acceptable. In some embodiments, the kit includes GLP-1R agonists (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), (IY), (IZ), (IAA), (IA B) A container containing compounds of formula (IAC), (IAD), (IAE), (IAG), (IAH), (IAI), (IAJ), (I**), (I''), (I'''*), (I'''), (I*), (I'), (I), (I-P01), (II**), or (II*), or a pharmaceutically acceptable salt thereof, and a THRβ agonist (e.g., compounds of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6), or a pharmaceutically acceptable salt thereof).In other embodiments, the kit includes GLP-1R agonists (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), (IY), (IZ), (IAA), (IAB), (IAC) The system includes a first container containing compounds of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6), or pharmaceutically acceptable salts thereof, and a second container containing a THRβ agonist (for example, compounds of formula (II-1), (II-1a), (II-2), (II-3), (II-4), (II-5), or (II-6), or pharmaceutically acceptable salts thereof).

[0262] The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages), or subunit doses. For example, a kit may be provided that contains a sufficient dose of a compound as disclosed herein (e.g., compound 9), or a pharmaceutically acceptable salt thereof, and / or additional pharmaceutically active compounds useful for the diseases detailed herein, to provide effective treatment of the target over a long period, for example, 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. The kit may also contain multiple unit doses of the compound and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and compounding pharmacies).

[0263] The kit may also include an electronic storage medium (e.g., a magnetic diskette or optical disc) containing instructions related to the use of the component(s) of the method of this disclosure, but may optionally include a set of instructions, generally in writing. The instructions included in the kit generally include information about the components and their administration to a subject.

[0264] General biological protocols Non-alcoholic steatohepatitis (NASH) mouse model When this mouse model is fed a high-fat diet, it develops non-alcoholic steatohepatitis (NASH) and gains weight.

[0265] Liver biopsy Mice are anesthetized, and a small abdominal incision is made along the midline to expose the left lateral lobe of the liver. A cone-shaped wedge of liver tissue is excised from the distal portion of the lobe and fixed in 10% neutral buffered formalin for histological examination. The cut surface of the liver is immediately electrocoagulated using bipolar coagulation.

[0266] Blood sampling and plasma preparation In vivo blood sample: Collect samples at week 8, 30 minutes after administration, 1 hour after administration, 2 hours after administration, 4 hours after administration, 6 hours after administration, and 24 hours after administration (before the next administration). Collect and mix blood from the tail vein, tongue, or cheek in a Microvette tube of appropriate size containing anticoagulant. Centrifuge the blood. Transfer the plasma supernatant to a new tube and immediately freeze on dry ice. Final blood sample: Open the peritoneal cavity under anesthesia and collect and mix blood from the heart using a syringe containing anticoagulant. Centrifuge the blood, transfer the plasma supernatant to a new tube and immediately freeze on dry ice.

[0267] Tissue sampling Liver (NASH) After the animals are killed, their livers are collected and weighed.

[0268] The liver is divided into the left lateral lobe, middle lobe, right lateral lobe, and caudate lobe.

[0269] The post-biopsy section is excised from the left lateral lobe, 4 mm from the pre-biopsy site with its end intact. The tissue is collected in paraformaldehyde. A liver sponsor tissue sample is cut from the left middle lobe, placed in a tube, and directly submerged in liquid nitrogen.

[0270] A liver RNA sequencing (RNAseq) sample is cut from the center of the left lateral lobe, rapidly frozen (directly placed in liquid nitrogen in a Nunc filter), collected in a pre-cooled tube, and then placed in liquid nitrogen.

[0271] A liver triglyceride (TG) TC portion is excised from the right middle lobe, opposite the sponsor portion, excluding the end. The sample is weighed individually, collected in a tube, and then placed in liquid nitrogen.

[0272] Additional liver sections can be taken from the right lateral lobe, collected in a tube, and placed in liquid nitrogen to serve as preliminary tissue for testing, which can then be used for further analysis if necessary.

[0273] Biopsy treatment Microtome sectioning of formalin-fixed paraffin-embedded (FFPE) biopsies The FFPE biopsy specimen is placed in 10% neutral buffered formalin, then transferred to 70% EtOH. Next, before embedding in a block, the FFPE biopsy specimen is infiltrated in a histoquinet. The biopsy tissue is cut to 3 μm on a microtome, and the sections are mounted on Superfrost Plus slides.

[0274] NAFLD Activity Score (NAS) and Fibrosis Stage Liver samples stained with hematoxylin and eosin (H&E) or picrosilius red (PSR) are used to calculate NAS and fibrosis stage scores using the clinical criteria outlined by Kleiner et al. 2005. Total NAS represents the sum of the scores for fatty liver, inflammation, and ballooning, ranging from 0 to 8. Adapted from Design and validation of a histological scoring system for nonalcoholic fatty liver disease, Kleiner et al., Hepatology 41; 2005.

[0275] Histological staining procedure Slides containing paraffin-embedded sections are deparaffinized in xylene and then rehydrated in a series of stepwise ethanol treatments.

[0276] Hematoxylin and eosin (H&E) staining: Incubate the slides in Meyer hematoxylin (Dako), wash with tap water, stain with eosin Y solution (Sigma-Aldrich), dehydrate, and cover with a coverslip.

[0277] Sirius Red (PSR) staining: Incubate the slide in Weigert iron hematoxylin (Sigma-Aldrich), wash with tap water, stain with picro-Sirius Red (Sigma-Aldrich), and wash twice with acidic water. Remove excess water by shaking the slide, then dehydrate the slide by changing the water three times in 100% ethanol, clear in xylene, and cover with a coverslip.

[0278] Immunohistochemistry (IHC) using a single chromogen is performed using standard procedures. Briefly, after antigen recovery and blockade of endogenous peroxidase activity, the slides are incubated with the primary antibody. The primary antibody is detected using a polymeric HRP-linker antibody conjugate. The primary antibody is then visualized using DAB as the chromogen. Finally, the sections are counterstained with hematoxylin and covered with coverslips. The slides are scanned under a 20x objective lens using a ScanScope AT slide scanner (Aperio).

[0279] Gene expression analysis using RNA sequencing RNA isolation: Collect tissue and rapidly freeze it in liquid nitrogen. Store the sample at -70°C until processing. Isolate the RNA using the NucleoSpin® kit (MACHEREY-NAGEL).

[0280] Library preparation and sequencing: Using a total of 10 ng to 1 μg of purified RNA from each sample, a cDNA library is generated using the NEBNext® Ultra® II Directional RNA Library Prep Kit for Illumina (New England Biolabs). The cDNA library is then sequenced on a NextSeq500 using the NextSeq500 / 550 High Output Kit V2 (Illumina).

[0281] Data Analysis: Sequencing data will be aligned to animal species genomes obtained from the Ensembl database using Spliced ​​Transcripts Alignment to a Reference (STAR) software. In bioinformatics analysis, data quality will be assessed using standard RNA sequencing quality control parameters, between-group and within-group variability will be assessed using principal component analysis and hierarchical clustering, and differentially expressed genes will be identified using R-package DESeq2. Downstream analyses, such as pathway analysis or target identification, will be performed as agreed upon with the sponsor.

[0282] Blood and plasma assays Alanine transaminase (ALT), aspartate transaminase (AST), triglycerides (TG), and total cholesterol (TC): Blood samples are collected in heparinized tubes, plasma is separated, and stored at -70°C until analysis. Samples are measured using commercially available kits.

[0283] Cytokeratin 18 (CK18-M30): Blood samples are collected in EDTA tubes, plasma is separated, and stored at -70°C until analysis. CK18 is measured using a commercially available ELISA kit.

[0284] Insulin: Blood samples are collected in heparinized tubes, plasma is separated, and stored at -70°C until analysis. Insulin is measured using a commercially available MSD platform.

[0285] TIMP-1: Blood samples are collected in EDTA tubes, plasma is separated, and stored at -70°C until analysis. TIMP-1 is measured using a commercially available ELISA kit.

[0286] PIIINP: Blood samples are collected in EDTA tubes, plasma is separated, and stored at -70°C until analysis. PIIINP is measured using a commercially available ELISA kit.

[0287] Tissue assay Triglycerides (TG) and total cholesterol (TC): Liver samples are homogenized, and TG and TC are extracted. The samples are centrifuged, and the TG and TC content in the supernatant is measured using a commercially available kit.

[0288] Oral glucose tolerance test (OGTT) On the day of the OGTT, random blood glucose levels and body weight of mice are measured. In the morning, before fasting, the mice are administered the corresponding compound or vehicle, then fasted for 6 hours, and basal fasting glucose is measured by tail vein incision. Glucose is administered orally at a dose volume of 5 mL / kg at 2 g / kg. Blood glucose levels are measured at 0 minutes (before administration), 15 minutes, 30 minutes, 60 minutes, and 120 minutes after glucose administration. A second dose is administered after the OGTT treatment.

[0289] Final plasma and tissue collection The body weight and food intake of all mice were measured, followed by a 6-hour fasting period. All mice were then euthanized with CO2, and blood was collected by cardiac puncture. The blood samples were processed by centrifugation to obtain serum and stored for TC / TG / LDL / HDL / AST / ALT analysis. The blood samples were mixed with the K2EDTA anticoagulant, processed by centrifugation to obtain plasma, and stored for insulin and other possible analyses.

[0290] Weigh and record the entire liver and epididymal fat. Fix the left lobule of the liver with formalin. Rapidly freeze and store the remaining liver. Collect the pancreas and fix it with formalin. Freeze the brown fat, subcutaneous white fat, epididymal white adipose tissue, and hypothalamic region of the brain with liquid nitrogen and store for any qPCR analysis.

[0291] Procedure for collecting hypothalamus The brain tissue is placed in a mold, with the olfactory bulb positioned in the center of the groove. The brain tissue is sliced ​​into eight coronal sections spaced 2 mm apart. The third section (6-8 mm) of coronal brain tissue is removed, and the section is cut along the boundary of the purple area with a scalpel to separate the cerebral cortex. The remaining tissue becomes the hypothalamus.

[0292] weight loss analysis Body weight, food intake, and water intake will be measured daily. Body composition will be measured using EchoMRI. Subcutaneous fat will be collected and weighed at the end of the study. UCP-1 expression in the subcutaneous adipose tissue sample will be evaluated by qPCR and Western blot analysis.

[0293] Numbering implementation Embodiments 1-169

[0294] 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 patients requiring treatment for hepatic impairment or cardiovascular metabolic disease.

[0295] 2. A combination of a THRβ agonist or a pharmaceutically acceptable salt thereof and a GLP-1R agonist or a pharmaceutically acceptable salt thereof to achieve weight loss in patients requiring it.

[0296] 3. A combination according to Embodiment 1 or 2, wherein the THRβ agonist is a compound of formula (II-1), [ka] (In the formula, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyls, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10Aliphatic rings, or substituted or unsubstituted C 5~10 It is an aromatic ring, and the substituents are hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, and -NHC. 1~4 Alkyl, -N(C 1~4 Alkyl)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 One or more substances selected from the group consisting of cycloalkyls, and if they contain two substituents, the two substituents may form a ring structure together with the carbons linked to them. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination thereof, or a pharmaceutically acceptable salt thereof.

[0297] 4. A combination described in any one of the prior embodiments, wherein the THRβ agonist is a compound of formula (II-1a), [ka] (In the formula, R1 to R3 are defined as described in detail herein with respect to formula (II-1), R4 is hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)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 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination thereof, or a pharmaceutically acceptable salt thereof.

[0298] 5. A combination according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0299] 6. The combination according to any one of the prior embodiments, wherein the THRβ agonist is the potassium salt of compound 9.

[0300] 7. A combination according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 -C1~C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl groups. R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group which may be substituted with a halo or a C1-C3 alkyl group. R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5At least one heteroatom of is S, and further R 5 Hello, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 membered heterocyclene or a 5-12 membered heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1~C6 alkylene-**, then the C1~C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or a C1-C6 alkyl group. Ring B is C3~C 10 Cycloalkyl, C6~C 14The combination is an aryl, a 4-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which may be independently substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0301] 8. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] The aforementioned combination.

[0302] 9. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, halogen, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. X 4 is hydrogen, C1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -(C 1-6 Alkylene)-(C 3-10 Cycloalkyl), or -(C 1-6 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 Cycloalkyl, or C 6-10 The alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally composed of one or more deuterium atoms, C11. 1-6 Substituted with alkoxy, hydroxyl, -CN, or oxo, the cycloalkyl, heterocyclyl, or aryl group optionally contains one or more halogens, C 1-6 Substituted with alkoxy or -CN, R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C is optionally substituted with deuterium. 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, -CN, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is a halogen, hydrogen, -C(O)OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 12 These are hydrogen, -C(O)OH, and -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ ,-(C 2-6 Alkynylene)-C(O)OH, -(C 1-6 Alkylene)-C(O)OH, -NR N12 -(C 1-6 Alkylene)-C(O)OH, 5-10 member heteroaryl, or one or more oxo compounds of any choice. 1-6 Alkyl, or C 1-6It is a 5-10 member heterocycline substituted with a haloalkyl group. R N12 and R N12’ H or C 1-6 It is alkyl, X 1 teeth, [ka] And, In the formula, R 3 and R 3’ These are independently H, D, or C 1-6 Alkyl, and the C 1-6 The alkyl group is optionally substituted with deuterium. Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 5-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterosicurenes may be optionally selected from one or more oxo and C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-(C 1-6 Alkylene)-, *-NR L -(C 1-6 Alkylene)-, *-O-(C 1-6Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. In the formula, R L is H or C 1-6 It is alkyl, Ring C is, Choose one or more C's at your discretion. 3-10 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-10 membered heterocyclyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, C 3-10 A cycloalkyl or a 6-membered aryl substituted with -C(O)NR'2, In the formula, R' is H or C 1-6 The six-membered aryl, which is alkyl Optionally, one or more halogens, -CN, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 The combination is a bicyclic 9 or 10-membered heteroaryl or heterocyclyl substituted with alkyl, halogen, -CN, or oxo.

[0303] 10. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-5), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, Branched C 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 6-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 The combination is a bicyclic 9 or 10-membered heteroaryl compound containing two nitrogen atoms, which is substituted with alkyl or oxo atoms.

[0304] 11. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (II**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, R 3 and R 3’ These are independently H or D, X 1 * is N or CR f1 And, X 2* and X 3* They are independently CH or CF, Each R f3 These are, independently, halogen, -CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, R 1** is either H, or C which is optionally substituted with one or more deuterium or halogens. 1-2 The aforementioned combination is alkyl.

[0305] 12. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is compound 1-2, [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0306] 13. The combination according to any one of the prior embodiments, wherein the GLP-1R agonist is the meglumine salt of compound 1-2.

[0307] 14. The combination described in any one of the prior embodiments, wherein the THRβ agonist is selected from those listed in Tables 6 to 11.

[0308] 15. The combination described in any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1 to 5.

[0309] 16. The combination described in any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0310] 17. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof, in the aforementioned combination.

[0311] 17a. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0312] 17b. A combination according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0313] 17c. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination wherein the GLP-1R agonist is danuglypron or a pharmaceutically acceptable salt thereof.

[0314] 18. A combination according to any one of the prior embodiments, wherein the THRβ agonist is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2, [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0315] 19. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2, [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0316] 20. A method for treating a patient who requires treatment for hepatic impairment or cardiovascular metabolic disease, comprising administering to the patient a combination according to any one of the embodiments described above.

[0317] 21. A method for treating a patient who requires treatment for hepatic impairment or cardiovascular metabolic disease, comprising administering to the patient a therapeutically effective amount of a combination according to any one of the above embodiments.

[0318] 22. A method for increasing the ratio of lean body mass to total body mass in a patient who requires such an increase, the method comprising administering to the patient a combination according to any one of the embodiments described above.

[0319] 23. A method for reducing the ratio of body fat to total body weight in a patient who requires such reduction, the method comprising administering to the patient a combination according to any one of the embodiments described above.

[0320] 24. A method for achieving weight loss in a patient requiring weight loss, comprising administering to the patient a combination according to any one of the embodiments described above.

[0321] 25. The aforementioned patient weighs 20 kg / m². 2 ~25kg / m 2 The method according to any one of the above embodiments, having a body mass index (BMI) of

[0322] 26. The aforementioned patient weighs 25 kg / m². 2 ~30kg / m 2 The method according to any one of the above embodiments, having a BMI.

[0323] 27. The aforementioned patient weighs 30 kg / m². 2 The method according to any one of the above embodiments, having the above BMI.

[0324] 28. The method according to any one of the prior embodiments, wherein the cardiovascular metabolic disease is obesity.

[0325] 29. The method according to any one of the prior embodiments, wherein the liver disorder is NASH.

[0326] 30. The method according to any one of the prior embodiments, wherein the liver disorder is hepatic fibrosis.

[0327] 31. The method according to any one of the prior embodiments, wherein the GLP-1R agonist component of the above combination is administered to the subject multiple times.

[0328] 32. The method according to any one of the prior embodiments, wherein the THR-β agonist component of the combination is administered to the subject multiple times.

[0329] 33. The method according to any one of the prior embodiments, wherein both the GLP-1R agonist component and the THRβ agonist component of the combination described above are administered to the subject multiple times.

[0330] 34. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0331] 35. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0332] 36. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0333] 37. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0334] 38. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0335] 39. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0336] 40. The method according to any one of the prior embodiments, wherein the initial administration of the THRβ agonist is substantially simultaneous with that of the GLP-1R agonist.

[0337] 41. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered before the first dose of the GLP-1R agonist.

[0338] 42. The method according to Embodiment 40, wherein the subsequent administration of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0339] 43. The method according to Embodiment 41 or 42, wherein the subsequent administration of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0340] 44. The method according to any one of embodiments 41 to 43, wherein the subsequent administration of the THRβ agonist is substantially concurrent with the administration of the GLP-1R agonist.

[0341] 45. A method for improving the response to GLP-1R agonist administration in patients who require improvement in this response, (i) To the patient, compound 9 [ka] or administering a pharmaceutically acceptable salt thereof, (ii) The method comprising administering a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0342] 46. ​​The method according to embodiment 45, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases the fat reduction associated with the administration of the GLP-1R agonist.

[0343] 47. The method according to Embodiment 45, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases the fat loss associated with the administration of the GLP-1R agonist while maintaining lean body mass.

[0344] 48. The method according to Embodiment 45, wherein the administration of compound 9 or a pharmaceutically acceptable salt thereof is performed before or concurrently with the administration of the GLP-1R agonist.

[0345] 49. The method according to 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.

[0346] 50. The method according to any one of the prior embodiments, wherein the GLP-1R agonist is administered to the subject multiple times.

[0347] 51. The method according to any one of the prior embodiments, wherein the THRβ agonist component is administered to the subject multiple times.

[0348] 52. The method according to any one of the prior embodiments, wherein both the GLP-1R agonist and the THR-β agonist are administered to the subject multiple times.

[0349] 53. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0350] 54. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0351] 55. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0352] 56. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0353] 57. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0354] 58. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0355] 59. The method according to any one of the prior embodiments, wherein the initial administration of the THRβ agonist is substantially simultaneous with that of the GLP-1R agonist.

[0356] 60. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered before the first dose of the GLP-1R agonist.

[0357] 61. The method according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0358] 62. The method according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0359] 63. The method according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is substantially concurrent with the administration of the GLP-1R agonist.

[0360] 64. Combination therapy for the treatment of obesity in patients requiring treatment of obesity, comprising a THRβ agonist or a pharmaceutically acceptable salt thereof and a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0361] 65. The combination therapy described in Embodiment 64, wherein the THRβ agonist is a compound of formula (II-1). [ka] (In the formula, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyls, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10 Aliphatic rings, or substituted or unsubstituted C 5~10 It is an aromatic ring, and the substituents are hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, and -NHC. 1~4 Alkyl, -N(C 1~4 Alkyl)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 3~6One or more substances selected from the group consisting of cycloalkyls, and if they contain two substituents, the two substituents may form a ring structure together with the carbons linked to them. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination therapy, or a pharmaceutically acceptable salt thereof.

[0362] 66. The combination therapy according to Embodiment 64 or 65, wherein the THRβ agonist is a compound of formula (II-1a). [ka] (In the formula, R1 to R3 are defined as described in detail herein with respect to formula (II-1), R4 is hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)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 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination therapy, or a pharmaceutically acceptable salt thereof.

[0363] 67. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

[0364] 67a. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0365] 67b. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0366] 67c. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is danuglipron or a pharmaceutically acceptable salt thereof.

[0367] 68. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is the potassium salt of compound 9.

[0368] 69. A combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 is -C1-C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl groups. R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group which may be substituted with a halo or a C1-C3 alkyl group. R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom of is S, and further R 5 Hello, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 membered heterocyclene or a 5-12 membered heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1~C6 alkylene-**, then the C1~C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or a C1-C6 alkyl group. Ring B is C3~C 10 Cycloalkyl, C6~C 14 The combination therapy, wherein the aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl is independently substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0369] 70. A combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] The aforementioned combination therapy.

[0370] 71. A combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, halogen, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 Cycloalkyl, or C 6-10 The alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally composed of one or more deuterium atoms, C11. 1-6 Substituted with alkoxy, hydroxyl, -CN, or oxo, the cycloalkyl, heterocyclyl, or aryl group optionally contains one or more halogens, C 1-6 Substituted with alkoxy or -CN, R 6is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C is optionally substituted with deuterium. 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, -CN, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is a halogen, hydrogen, -C(O)OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 12 These are hydrogen, -C(O)OH, and -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ ,-(C 2-6 Alkynylene)-C(O)OH, -(C 1-6 Alkylene)-C(O)OH, -NR N12 -(C 1-6 Alkylene)-C(O)OH, 5-10 member heteroaryl, or one or more oxo compounds of any choice. 1-6 Alkyl, or C 1-6 It is a 5-10 member heterocycline substituted with a haloalkyl group. R N12 and R N12’ H or C 1-6 It is alkyl, X 1 teeth, [ka] And, In the formula, R 3 and R 3’ These are independently H, D, or C 1-6 Alkyl, and the C 1-6 The alkyl group is optionally substituted with deuterium. Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice.1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 5-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterosicurenes may be optionally selected from one or more oxo and C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-(C 1-6 Alkylene)-, *-NR L -(C 1-6 Alkylene)-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. In the formula, R L is H or C 1-6 It is alkyl, Ring C is, Choose one or more C's at your discretion. 3-10 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-10 membered heterocyclyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, C 3-10 A cycloalkyl or a 6-membered aryl substituted with -C(O)NR'2, In the formula, R' is H or C 1-6 The six-membered aryl, which is alkyl Optionally, one or more halogens, -CN, C 1-6 Haloalkyl, -OC1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 The combination therapy is a bicyclic 9 or 10-membered heteroaryl or heterocyclil substituted with alkyl, halogen, -CN, or oxo.

[0371] 72. A combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-5). [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5-CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, Branched C 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 6-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 The combination therapy is a bicyclic 9 or 10-membered heteroaryl compound containing two nitrogen atoms, which is alkyl or oxo-substituted.

[0372] 73. A combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (II**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, R 3 and R 3’ These are independently H or D, X 1 * is N or CR f1 And, X 2* and X 3* They are independently CH or CF, Each R f3 These are, independently, halogen, -CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, R 1** is either H, or C which is optionally substituted with one or more deuterium or halogens. 1-2 The aforementioned combination therapy, which is alkyl.

[0373] 74. A combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is compound 1-2, [ka] The combination therapy, or a pharmaceutically acceptable salt thereof.

[0374] 75. The combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is the meglumine salt of compound 1-2.

[0375] 76. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is selected from those listed in Tables 6 to 11.

[0376] 77. The combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1 to 5.

[0377] 78. The combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0378] 79. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

[0379] 79a. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0380] 79b. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0381] 79c. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is danuglipron or a pharmaceutically acceptable salt thereof.

[0382] 80. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 [ka] The combination therapy, or a pharmaceutically acceptable salt thereof.

[0383] 81. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9 [ka] or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2 [ka] The combination therapy, or a pharmaceutically acceptable salt thereof.

[0384] 82. The aforementioned patient weighed 25 kg / m². 2 ~30kg / m 2 A combination therapy according to any one of the prior embodiments, having a body mass index (BMI).

[0385] 83. The aforementioned patient weighed 30 kg / m². 2 The combination therapy described in any one of the prior embodiments, having the above BMI.

[0386] 84. The combination therapy according to any one of the prior embodiments, wherein the GLP-1R agonist component of the combination therapy is administered to the subject multiple times.

[0387] 85. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist component of the combination therapy is administered to the subject multiple times.

[0388] 86. The combination therapy according to any one of the prior embodiments, wherein both the GLP-1R agonist component and the THR-β agonist component of the combination therapy are administered to the subject multiple times.

[0389] 87. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is administered before or concurrently with the GLP-1R agonist.

[0390] 88. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0391] 89. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0392] 90. The combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0393] 91. The combination therapy according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0394] 92. The combination therapy according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0395] 93. The combination therapy according to any one of the prior embodiments, wherein the initial administration of the THRβ agonist is substantially simultaneous with that of the GLP-1R agonist.

[0396] 94. The combination therapy according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered before the first dose of the GLP-1R agonist.

[0397] 95. The combination therapy according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered in close proximity in time to the administration of the GLP-1R agonist.

[0398] 96. The combination therapy according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0399] 97. The combination therapy according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is substantially concurrent with the administration of the GLP-1R agonist.

[0400] 98. THR-β agonists or pharmaceutically acceptable salts thereof, and GLP-1R agonists or pharmaceutically acceptable salts thereof, for use in combination therapy for the treatment of obesity in patients requiring treatment of obesity.

[0401] 99. The THRβ agonist is a compound of formula (II-1). [ka] (In the formula, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyls, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10Aliphatic rings, or substituted or unsubstituted C 5~10 It is an aromatic ring, and the substituents are hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, and -NHC. 1~4 Alkyl, -N(C 1~4 Alkyl)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 One or more substances selected from the group consisting of cycloalkyls, and if they contain two substituents, the two substituents may form a ring structure together with the carbons linked to them. The halogen atom is selected from the group consisting of F, Cl, and Br. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to Embodiment 98.

[0402] 100. The THRβ agonist is a compound of formula (II-1a). [ka] (In the formula, R1 to R3 are defined as described in detail herein with respect to formula (II-1), R4 is hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)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 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to Embodiment 98 or 99.

[0403] 101. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tylzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

[0404] 101a. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0405] 101b. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0406] 101c. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is danuglypron or a pharmaceutically acceptable salt thereof.

[0407] 102. THR-β agonists or pharmaceutically acceptable salts thereof, and GLP-1R agonists or pharmaceutically acceptable salts thereof, for use according to any one of the prior embodiments, wherein the THRβ agonist is the potassium salt of compound 9.

[0408] 103. The GLP-1R agonist is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 -C1~C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl groups. R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group which may be substituted with a halo or a C1-C3 alkyl group. R 5is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom of is S, and further R 5 Hello, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 membered heterocyclene or a 5-12 membered heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1~C6 alkylene-**, then the C1~C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or a C1-C6 alkyl group. Ring B is C3~C 10Cycloalkyl, C6~C 14 THR-β agonists or pharmaceutically acceptable salts thereof, and GLP-1R agonists or pharmaceutically acceptable salts thereof, for use according to any one of the prior embodiments, each being an aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, which may each be independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0409] 104. The GLP-1R agonist is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments.

[0410] 105. The GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, halogen, -OX 4 , or -NR 8 R 9is or R 1 and R 4 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 Cycloalkyl, or C 6-10 The alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally composed of one or more deuterium atoms, C11. 1-6 Substituted with alkoxy, hydroxyl, -CN, or oxo, the cycloalkyl, heterocyclyl, or aryl group optionally contains one or more halogens, C 1-6 Substituted with alkoxy or -CN, R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R2 teeth, hydrogen, C is optionally substituted with deuterium. 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, -CN, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is a halogen, hydrogen, -C(O)OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 12 These are hydrogen, -C(O)OH, and -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ ,-(C 2-6 Alkynylene)-C(O)OH, -(C 1-6Alkylene)-C(O)OH, -NR N12 -(C 1-6 Alkylene)-C(O)OH, 5-10 member heteroaryl, or one or more oxo compounds of any choice. 1-6 Alkyl, or C 1-6 It is a 5-10 member heterocycline substituted with a haloalkyl group. R N12 and R N12’ H or C 1-6 It is alkyl, X 1 teeth, [ka] And, In the formula, R 3 and R 3’ These are independently H, D, or C 1-6 Alkyl, and the C 1-6 The alkyl group is optionally substituted with deuterium. Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 5-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterosicurenes may be optionally selected from one or more oxo and C 1-6 Alkyl, C 1-6Substituted with alkoxy or halogen, L is a bond, *-(C 1-6 Alkylene)-, *-NR L -(C 1-6 Alkylene)-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. In the formula, R L is H or C 1-6 It is alkyl, Ring C is, Choose one or more C's at your discretion. 3-10 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-10 membered heterocyclyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, C 3-10 A cycloalkyl or a 6-membered aryl substituted with -C(O)NR'2, In the formula, R' is H or C 1-6 The six-membered aryl, which is alkyl Optionally, one or more halogens, -CN, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 THR-β agonists or pharmaceutically acceptable salts thereof, for use according to any one of the prior embodiments, which are bicyclic 9 or 10-membered heteroaryl or heterocyclils substituted with alkyl, halogen, -CN, or oxo.

[0411] 106. The GLP-1R agonist is a compound of formula (I-5). [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, Branched C 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C 1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 6-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 THR-β agonists or pharmaceutically acceptable salts thereof, for use according to any one of the prior embodiments, which are bicyclic 9 or 10-membered heteroaryls containing two nitrogen atoms, substituted with alkyl or oxo.

[0412] 107. The GLP-1R agonist is a compound of formula (II**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, R 3 and R 3’ These are independently H or D, X 1 * is N or CR f1 And, X 2* and X 3* They are independently CH or CF, Each R f3 These are, independently, halogen, -CN, and C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, R 1** is either H, or C which is optionally substituted with one or more deuterium or halogens. 1-2 A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, which are alkyl, for use according to any one of the prior embodiments.

[0413] 108. The GLP-1R agonist is compound 1-2, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments.

[0414] 109. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is a meglumine salt of compound 1-2.

[0415] 110. THR-β agonists or pharmaceutically acceptable salts thereof, and GLP-1R agonists or pharmaceutically acceptable salts thereof, for use according to any one of the prior embodiments, wherein the THRβ agonist is selected from those listed in Tables 6 to 11.

[0416] 111. The GLP-1R agonist is selected from those listed in Tables 1 to 5, and the THR-β agonist or a pharmaceutically acceptable salt thereof is selected for use according to any one of the prior embodiments.

[0417] 112. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0418] 113. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tylzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

[0419] 113a. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0420] 113b. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0421] 113c. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is danuglypron or a pharmaceutically acceptable salt thereof.

[0422] 114. The THRβ agonist is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments.

[0423] 115. The THRβ agonist is compound 9 [ka] or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2 [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments.

[0424] 116. The aforementioned patient weighs 25 kg / m². 2 ~30kg / m 2A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, having a body mass index (BMI) of .

[0425] 117a. The patient was 27 kg / m² 2 A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, having the above BMI, for use according to any one of the prior embodiments.

[0426] 117b. The aforementioned patient weighs 30 kg / m². 2 A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, having the above BMI, for use according to any one of the prior embodiments.

[0427] 118. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is administered multiple times to the subject.

[0428] 119. THR-β agonists or pharmaceutically acceptable salts thereof, and GLP-1R agonists or pharmaceutically acceptable salts thereof, for use according to any one of the prior embodiments, wherein the THRβ agonist is administered multiple times to the subject.

[0429] 120. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein both the GLP-1R agonist and the THR-β agonist are administered multiple times to the subject.

[0430] 121. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the THR-β agonist is administered before or simultaneously with the GLP-1R agonist.

[0431] 122. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the THR-β agonist is administered in temporal proximity to the GLP-1R agonist.

[0432] 123. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0433] 124. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the THR-β agonist is administered substantially concurrently with the GLP-1R agonist.

[0434] 125. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the initial dose of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0435] 126. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0436] 127. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the initial administration of the THRβ agonist is substantially simultaneous with that of the GLP-1R agonist.

[0437] 128. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered before the first dose of the GLP-1R agonist.

[0438] 129. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0439] 130. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0440] 131. A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered substantially concurrently with the GLP-1R agonist.

[0441] 132. A method for treating obesity in a patient requiring treatment, comprising administering to the patient a THRβ agonist or a pharmaceutically acceptable salt thereof and a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0442] 133. The THRβ agonist is a compound of formula (II-1). [ka] (In the formula, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyls, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10 Aliphatic rings, or substituted or unsubstituted C 5~10 It is an aromatic ring, and the substituents are hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, and -NHC. 1~4 Alkyl, -N(C 1~4 Alkyl)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 One or more substances selected from the group consisting of cycloalkyls, and if they contain two substituents, the two substituents may form a ring structure together with the carbons linked to them. The halogen atom is selected from the group consisting of F, Cl, and Br. The method according to Embodiment 132, or a pharmaceutically acceptable salt thereof.

[0443] 134. The THRβ agonist is a compound of formula (II-1a). [ka] (In the formula, R1 to R3 are defined as described in detail herein with respect to formula (II-1), R4 is hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)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 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. The method according to embodiment 132 or 133, or a pharmaceutically acceptable salt thereof.

[0444] 135. The THRβ agonist is compound 9, [ka] The method according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

[0445] 135a. The THRβ agonist is compound 9, [ka] The method according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0446] 135b. The THRβ agonist is compound 9, [ka] The method according to any one of the prior embodiments, wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0447] 135c. The THRβ agonist is compound 9, [ka] The method according to any one of the prior embodiments, wherein the GLP-1R agonist is danuglypron or a pharmaceutically acceptable salt thereof.

[0448] 136. The method according to any one of the prior embodiments, wherein the THRβ agonist is the potassium salt of compound 9.

[0449] 137. A method according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 -C1~C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl groups. R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4 These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group which may be substituted with a halo or a C1-C3 alkyl group. R 5is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom of is S, and further R 5 Hello, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 membered heterocyclene or a 5-12 membered heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1~C6 alkylene-**, then the C1~C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1 However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or a C1-C6 alkyl group. Ring B is C3~C 10Cycloalkyl, C6~C 14 The method, wherein the substituents are aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which may be independently substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0450] 138. A method according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] The method described above.

[0451] 139. A method according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, halogen, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. X4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, C 3-10 Cycloalkyl, or C 6-10 The alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally composed of one or more deuterium atoms, C11. 1-6 Substituted with alkoxy, hydroxyl, -CN, or oxo, the cycloalkyl, heterocyclyl, or aryl group optionally contains one or more halogens, C 1-6 Substituted with alkoxy or -CN, R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6 The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, C is optionally substituted with deuterium. 1-6 Alkyl, C 1-6Haloalkyl, -(O)-C 1-6 Alkyl, -CN, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is a halogen, hydrogen, -C(O)OH, or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 12 These are hydrogen, -C(O)OH, and -C(O)NR N12 R N12’ -C(O)NR 12 S(O)2R 12’ ,-(C 2-6 Alkynylene)-C(O)OH, -(C 1-6 Alkylene)-C(O)OH, -NR N12 -(C 1-6 Alkylene)-C(O)OH, 5-10 member heteroaryl, or one or more oxo compounds of any choice. 1-6 Alkyl, or C1-6 It is a 5-10 member heterocycline substituted with a haloalkyl group. R N12 and R N12’ H or C 1-6 It is alkyl, X 1 teeth, [ka] And, In the formula, R 3 and R 3’ These are independently H, D, or C 1-6 Alkyl, and the C 1-6 The alkyl group is optionally substituted with deuterium. Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 5-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 5-10 membered heteroarirenes, or 3-10 membered heterosicurenes may be optionally selected from one or more oxo and C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-(C 1-6 Alkylene)-, *-NR L -(C 1-6 Alkylene)-, *-O-(C 1-6Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. In the formula, R L is H or C 1-6 It is alkyl, Ring C is, Choose one or more C's at your discretion. 3-10 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-10 membered heterocyclyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -CN, C 3-10 A cycloalkyl or a 6-membered aryl substituted with -C(O)NR'2, In the formula, R' is H or C 1-6 The six-membered aryl, which is alkyl Optionally, one or more halogens, -CN, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 The method, wherein the bicyclic 9 or 10-membered heteroaryl or heterocyclyl is substituted with an alkyl, halogen, -CN, or oxo.

[0452] 140. A method according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-5). [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 6 or N, X 6 CR 4 or N, R 1 is -C 1-6 Haloalkyl, -OX 4 , or -NR 8 R 9 is or R 1 and R 4 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 4 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 Alkilen)-(3-8 member heterocyclyl), 3-8 member heterocyclyl,-(CH2CH2-O) 1-5 -CH3, or -(CH2-CH(-OCH3)-CH2-O) 1-5 -CH3, where the alkyl, heteroalkyl, alkylene, or haloalkyl group is optionally substituted with one or more deuterium, hydroxyl, -CN, or oxo, and the cycloalkyl or heterocyclyl group is optionally substituted with one or more halogens or -CN. R 6 is hydrogen, halogen, or -OR 7 And, R 7 and R 2 These combine with the atoms they are bonded to to form a 6-membered heterocycline. R 8 and R 9 These are, independently, hydrogen and C 1-6 Alkyl, or -S(O)2-C 1-6 Selected from alkyl groups, or R 8 and R 9 These combine with the atoms to which they are bonded to form a 6-membered heterocycline, and the C 1-6The alkyl group is optionally substituted with one or more oxos. n is 0, 1, 2, 3, 4, 5, or 6. R 2 teeth, hydrogen, Branched C 1-6 Alkyl, C 1-6 Haloalkyl, -(O)-C 1-6 Alkyl, One or more -CN, C 1-6 C is a haloalkyl group, or optionally substituted with one or more -CN groups. 1-6 C is optionally substituted with alkyl. 3-10 Cycloalkyl, A 4 or 5-membered heterocycline containing at least one oxygen or at least one sulfur atom, optionally comprising one or more oxo, [ka] or C 1-6 The 4 or 5-membered heterocycline, which is substituted with an alkyl group, A five-membered heteroaryl comprising one or two heteroatoms independently selected from N and S, where R 5 The five-membered heteroaryl is one in which at least one heteroatom is S, or R 2 and R 7 These combine with the atoms they are bonded to to form a 5- or 6-membered heterocycline. R 4 is hydrogen or -OR 8 And, R 8 and R 1 These combine with the atoms they are bonded to to form a 6-membered heterocycline. X 1 teeth, [ka] And, In the formula, R 3 is H or C1-6 It is alkyl, Ring A is, [ka] Optionally, choose one or more Halo or C 1-6 Alkyl-substituted phenylene, or one or more halos or C(C) of any choice. 1-6 It is an alkyl-substituted 6-membered heteroarylene, In the formula, * represents X 1 This shows a connection to, X 5 CR 3 or N, X 2 CR 3 or N, L' is a bond or -O-, Ring B is C 6-10 Arylene, 6-10 membered heteroarylene, or 3-10 membered heterocyclene, where C 6-10 Arirenes, 6-10 membered heteroarirenes, or 3-10 membered heterosiclenes are optionally selected as one or more C 1-6 Alkyl, C 1-6 Substituted with alkoxy or halogen, L is a bond, *-CH2-, *-O-(C 1-6 Alkylene)-, or *-(C) 1-6 It is alkylene)-O-, where * indicates a bond to ring B, and the C 1-6 Alkylenes are optionally substituted with deuterium. Ring C is, Choose one or more C's at your discretion. 1-6 Alkyl, 3-10 membered heterocyclyl, halogen, -OCH3, -CN, or C 3-10 Six-membered aryl substituted with cycloalkyl, Optionally, one or more halogens, -CN, and -OC. 1-6 Alkyl, C 3-10 Cycloalkyl, -C(=O)-(C 3-10 Cycloalkyl), [ka] A six-membered heteroaryl containing a nitrogen atom, which is substituted with, or Choose one or more C's at your discretion. 1-6 The method, wherein the compound is a bicyclic 9 or 10-membered heteroaryl compound containing two nitrogen atoms, substituted with alkyl or oxo atoms.

[0453] 141. A method according to any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (II**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, R 3 and R 3’ These are independently H or D, X 1 * is N or CR f1 And, X 2* and X 3* They are independently CH or CF, Each R f3 These are, independently, halogen, -CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, R 1** is either H, or C which is optionally substituted with one or more deuterium or halogens. 1-2 The method, wherein the alkyl group is used.

[0454] 142. A method according to any one of the prior embodiments, wherein the GLP-1R agonist is compound 1-2, [ka] The method, or a pharmaceutically acceptable salt thereof.

[0455] 143. The method according to any one of the prior embodiments, wherein the GLP-1R agonist is the meglumine salt of compound 1-2.

[0456] 144. The method according to any one of the prior embodiments, wherein the THRβ agonist is selected from those listed in Tables 6 to 11.

[0457] 145. The method according to any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1 to 5.

[0458] 146. The method according to any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A.

[0459] 147. A method according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The method wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

[0460] 147a. A method according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The method wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0461] 147b. A method according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The method wherein the GLP-1R agonist is semaglutide or a pharmaceutically acceptable salt thereof.

[0462] 147c. A method according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The method wherein the GLP-1R agonist is danuglypron or a pharmaceutically acceptable salt thereof.

[0463] 148. The method according to any one of the prior embodiments, wherein the THRβ agonist is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 [ka] The method, or a pharmaceutically acceptable salt thereof.

[0464] 149. A method according to any one of the prior embodiments, wherein the THRβ agonist is compound 9 [ka] or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2 [ka] The method, or a pharmaceutically acceptable salt thereof.

[0465] 150. The aforementioned patient weighed 25 kg / m². 2 ~30kg / m 2 A method according to any one of the prior embodiments, having a body mass index (BMI) of .

[0466] 151. The aforementioned patient weighed 30 kg / m². 2 A method according to any one of the prior embodiments, having the above BMI.

[0467] 152. The method according to any one of the prior embodiments, wherein the GLP-1R agonist is administered to the subject multiple times.

[0468] 153. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered to the subject multiple times.

[0469] 154. The method according to any one of the prior embodiments, wherein both the GLP-1R agonist and the THR-β agonist are administered to the subject multiple times.

[0470] 155. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered before or simultaneously with the GLP-1R agonist.

[0471] 156. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0472] 157. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0473] 158. The method according to any one of the prior embodiments, wherein the THRβ agonist is administered substantially simultaneously with the GLP-1R agonist.

[0474] 159. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0475] 160. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0476] 161. The method according to any one of the prior embodiments, wherein the initial administration of the THRβ agonist is substantially simultaneous with that of the GLP-1R agonist.

[0477] 162. The method according to any one of the prior embodiments, wherein the first dose of the THRβ agonist is administered before the first dose of the GLP-1R agonist.

[0478] 163. The method according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered in close proximity in time to the GLP-1R agonist.

[0479] 164. The method according to any one of the prior embodiments, wherein the subsequent administration of the THRβ agonist is administered on the same day as the GLP-1R agonist.

[0480] 165. The method according to any one of the prior embodiments, wherein the subsequent administration of a THRβ agonist is substantially concurrent with the administration of the GLP-1R agonist.

[0481] 166. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0482] 167. A combination therapy according to any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination therapy wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0483] 168. The THRβ agonist is compound 9, [ka] A THR-β agonist or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist or a pharmaceutically acceptable salt thereof, for use according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0484] 169. The method according to any one of the prior embodiments, wherein the GLP-1R agonist is orfolglipron or a pharmaceutically acceptable salt thereof.

[0485] Embodiments A1-A48 A1. A combination comprising a THRβ agonist or a pharmaceutically acceptable salt thereof and a GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0486] A2. The combination described in Embodiment A1, wherein the THRβ agonist is a compound of formula (II-1), [ka] (In the formula, R1 is hydrogen, cyano, substituted or unsubstituted C 1~6 Alkyl, and substituted or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C 1~6 Selected from the group consisting of alkoxys, R2 and R3 are halogen atoms and substituted or unsubstituted C atoms. 1~6 Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyls, and C 1~6 Selected from the group consisting of alkoxys, Ring A is a substituted or unsubstituted saturated or unsaturated C 5~10 Aliphatic rings, or substituted or unsubstituted C 5~10 It is an aromatic ring, and the substituents are hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, and -NHC. 1~4 Alkyl, -N(C 1~4 Alkyl)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 One or more substances selected from the group consisting of cycloalkyls, and if they contain two substituents, the two substituents may form a ring structure together with the carbons linked to them. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination thereof, or a pharmaceutically acceptable salt thereof.

[0487] A3. The combination described in Embodiment A1 or A2, wherein the THRβ agonist is a compound of formula (II-1a), [ka] (In the formula, R1 to R3 are defined as described in detail herein with respect to formula (II-1), R4 is hydrogen, halogen atom, hydroxyl, -OCF3, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2,-CONH2,-CONHC 1~4 Alkyl, -CON(C 1~4 Alkyl)2,-NHCOC 1~4 Alkyl, C 1~6 Alkyl, C 1~6Alkoxy and C 3~6 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination thereof, or a pharmaceutically acceptable salt thereof.

[0488] A4. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0489] A5. The combination according to any one of the prior embodiments, wherein the THRβ agonist is the potassium salt of compound 9.

[0490] A6. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR 4 And, n is either 0 or 1. R is hydrogen, R 1 -C1~C6 alkylene-R 5 And, R 2 These are hydrogen, oxo, or C1-C6 alkyl groups. R 3 R is hydrogen, oxo, or C1-C6 alkyl, 4 is hydrogen, OH, or C1-C6 alkyl, Alternatively, R 3 and R 4These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group which may be substituted with a halo or a C1-C3 alkyl group. R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom of is S, and further R 5 Hello, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 They may be substituted with alkenyls or C1-C6 haloalkyl groups. Ring A is a 5-12 membered heterocyclene or a 5-12 membered heteroarylene, each independently substituted with a halo, CN, C3-C6 cycloalkyl, or a C1-C6 alkyl which may be substituted with a halo 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 a bond point to ring A, and ** represents a bond point to ring B. If L is *-O-C1~C6 alkylene-**, then the C1~C6 alkylene of L is R L It may also be substituted by, where each R L These are independently C1-C6 alkyl or halo, or two R L However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. If L is a C1-C6 alkylene, then the C1-C6 alkylene is R L1 It may also be substituted by, where each R L1 These are independently a halo, OH, oxo, or C1-C6 alkyl, or two R L1However, together with the carbon atoms or multiple carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl or a 3-6 membered heterocycline. R 6 is hydrogen or a C1-C6 alkyl group. Ring B is C3~C 10 Cycloalkyl, C6~C 14 The combination is an aryl, a 4-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which may be independently substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl.

[0491] A7. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (I-1a), [ka] In the formula, R 7 These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R 8 teeth, [ka] The aforementioned combination.

[0492] A8. A combination described in any one of the prior embodiments, wherein the GLP-1R agonist is a compound of formula (II**), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R f4 and R f5 Each of them is independent of C 1-6 Selected from 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 a halogen, R 3 and R 3’ These are independently H or D, X 1 * is N or CR f1 And, X 2* and X 3* They are independently CH or CF, Each R f3 These are, independently, halogen, -CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or -C(O)N(R) f3’ ) Selected from 2, Each R f3’ H or C 1-6 Selected from alkyl groups, R 1** is either H, or C which is optionally substituted with one or more deuterium or halogens. 1-2 The aforementioned combination is alkyl.

[0493] A9. A combination according to any one of the prior embodiments, wherein the GLP-1R agonist is compound 1-2, [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0494] A10. The combination according to any one of the prior embodiments, wherein the GLP-1R agonist is the meglumine salt of compound 1-2.

[0495] A11. The combination described in any one of the prior embodiments, wherein the THRβ agonist is selected from those listed in Tables 6-11 or from pharmaceutically acceptable salts thereof.

[0496] A12. The combination described in any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Tables 1 to 5 or from pharmaceutically acceptable salts thereof.

[0497] A13. The combination according to any one of the prior embodiments, wherein the GLP-1R agonist is selected from those listed in Table 5A or from pharmaceutically acceptable salts thereof.

[0498] A14. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tilzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof, in the aforementioned combination.

[0499] A15. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] The GLP-1R agonist is orfolglipron, danuglipron, or semaglutide, or a pharmaceutically acceptable salt thereof, in the aforementioned combination.

[0500] A16. A combination according to any one of the prior embodiments, wherein the THRβ agonist is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0501] A17. A combination described in any one of the prior embodiments, wherein the THRβ agonist is compound 9, [ka] or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2 [ka] The combination thereof, or a pharmaceutically acceptable salt thereof.

[0502] A18. The combination described in any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 0.5 mg to approximately 25 mg.

[0503] A19. The combination according to any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 1 mg to approximately 15 mg.

[0504] A20. The combination described in any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 2 mg to approximately 10 mg.

[0505] A21. The combination according to any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 1 mg.

[0506] A22. The combination according to any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 3 mg.

[0507] A23. The combination according to any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 6 mg.

[0508] A24. The combination according to any one of the prior embodiments, wherein the amount of the THRβ agonist is approximately 10 mg.

[0509] A25. A combination according to any one of the prior embodiments for use in the treatment of patients requiring treatment for liver dysfunction or cardiovascular metabolic disease.

[0510] A26. A combination of any one of the prior embodiments for use in patients requiring weight loss.

[0511] A27. A combination according to any one of the prior embodiments for use in combination therapy for the treatment of obesity in patients requiring treatment for obesity.

[0512] A28. A method for treating a patient who requires treatment for liver dysfunction or cardiovascular metabolic disease, comprising administering to the patient a combination according to any one of the prior embodiments.

[0513] A29. A method for treating a patient who requires treatment for hepatic impairment or cardiovascular metabolic disease, comprising administering to the patient a therapeutically effective dose of a combination of any one of the prior embodiments.

[0514] A30. A method for increasing the ratio of lean body mass to total body mass in a patient who requires such an increase, the method comprising administering to the patient a combination according to any one of the prior embodiments.

[0515] A31. A method for reducing the ratio of body fat to total body weight in a patient, comprising administering to the patient a combination according to any one of the prior embodiments.

[0516] A32. A method for achieving weight loss in a patient requiring weight loss, comprising administering to the patient a combination according to any one of the prior embodiments.

[0517] A33. The aforementioned patient weighed 27 kg / m². 2A method according to any one of the prior embodiments, having the above body mass index (BMI).

[0518] A34. The aforementioned patient weighs 30 kg / m². 2 A method according to any one of the prior embodiments, having the above BMI.

[0519] A35. The method according to any one of the prior embodiments, wherein the administration of the THRβ agonist allows for a reduction in the dose of the GLP-1R agonist while maintaining equivalent weight loss.

[0520] A36. The method according to any one of the prior embodiments, wherein the administration of the THRβ agonist increases weight loss compared to the administration of an equivalent dose of a GLP-1R agonist.

[0521] A37. The method according to any one of the prior embodiments, wherein the cardiovascular metabolic disease is obesity or an obesity-related condition.

[0522] A38. The method according to any one of the prior embodiments, wherein the cardiovascular metabolic disease is diabetes mellitus.

[0523] A39. The method according to any one of the prior embodiments, wherein the combination or method improves blood glucose control in an adult with type 2 diabetes.

[0524] A40. A method for treating obesity or achieving weight loss in patients in need thereof, (i) To the patient, compound 9 [ka] or administering a pharmaceutically acceptable salt thereof, (ii) administering to the patient a GLP-1R agonist or a pharmaceutically acceptable salt thereof, The method comprising administering compound 9 or a pharmaceutically acceptable salt thereof to the patient, thereby improving the patient's response to the GLP-1R agonist or a pharmaceutically acceptable salt thereof.

[0525] A41. The combination or method according to any one of the prior embodiments, wherein the THRβ agonist is administered once or twice daily.

[0526] A42. The combination or method according to any one of the prior embodiments, wherein the THRβ agonist is administered orally.

[0527] A43. The combination or method according to any one of the prior embodiments, wherein the GLP-1R agonist is administered orally.

[0528] A44. The method according to Embodiment A40, wherein the GLP-1R agonist comprises compound 1-2, orphorglipron, semaglutide, tilzepatide, or danuglipron.

[0529] A45. The method according to any one of the prior embodiments, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases the fat reduction associated with the administration of the GLP-1R agonist.

[0530] A46. The method according to any one of the prior embodiments, wherein administration of compound 9 or a pharmaceutically acceptable salt thereof increases the fat loss associated with the administration of the GLP-1R agonist while maintaining lean body mass.

[0531] A47. A combination according to any one of Embodiments A1 to A27 for the preparation of a drug for use in any one of Embodiments A28 to A46.

[0532] A48. Use of the combination described in any one of Embodiments A1 to A27 in the method according to any one of Embodiments A28 to A46. [Examples]

[0533] The combination therapies provided herein can be tested by administering the drug combination to known mouse models and evaluating the results. Such testing methods can be adapted from known ones.

[0534] Example 1. Evaluation of THR-B agonist compound 9 in combination with a GLP-1R agonist (e.g., semaglutide). To evaluate the effects of 12 weeks of treatment with compound 9 alone and in combination with semaglutide on metabolic parameters, NAFLD activity scores, including liver pathology and fibrosis stage, will be determined in male GAN DIO-NASH mice confirmed by biopsy. Sample preparation [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

[0535] Non-alcoholic steatohepatitis (NASH) mouse model Feeding this mouse model a high-fat diet induces non-alcoholic steatohepatitis (NASH). The NASH mice are based on male C57BL / 6JRj mice that 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] Liver biopsy Mice are anesthetized by inhalation anesthesia using isoflurane (2-3%). A small abdominal incision is made along the midline to expose the left lateral lobe of the liver. A cone-shaped wedge (approximately 50 mg) of liver tissue is excised from the distal part of the lobe and fixed in 10% neutral buffered formalin (10% NBF) for histological examination. The cut surface of the liver is immediately electrocoagulated using bipolar coagulation (ERBE VIO 100 electrosurgical unit). The liver is returned to the abdominal cavity, the abdominal wall is sutured, and the skin is closed with staples. For postoperative recovery, mice are subcutaneously administered carprofen (5 mg / kg) on ​​the day of surgery and on the first and second days post-surgery.

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

[0538] Final blood sample: While anesthetized with isoflurane, open the peritoneum and collect cardiac blood using a syringe into an appropriately sized Microvette / Vacuette containing anticoagulant, mixing it five times by inverting it. Allow the blood to stand at 4°C until centrifuged at 3000g for 10 minutes. Transfer the plasma supernatant to a new tube and immediately freeze it on dry ice. Store the sample at -70°C.

[0539] Tissue sampling Liver (NASH) After the animals are killed by cardiac puncture, the livers are recovered and weighed. Specific liver samples and biopsies are designated in Table "Final Samples" and dissected and processed as further described below.

[0540] The liver is divided into the left lateral lobe, middle lobe, right lateral lobe, and caudate lobe. The remaining lobes are not used unless specified in the procedure.

[0541] The post-biopsy tissue (approximately 200 mg, less than 0.7 x 0.5 cm) is excised from the left lateral lobe, 4 mm from the pre-biopsy site with its end intact. The tissue is collected in paraformaldehyde.

[0542] A liver sponsor fragment (approximately 150 mg) is excised from the left middle lobe, placed in a tube, and directly immersed in liquid nitrogen. The sample is stored at -70°C. Note that the size of the sponsor fragment will vary depending on the size of the left middle lobe.

[0543] A liver RNA sequencing (RNAseq) sample (20±10 mg) is excised from the center of the left lateral lobe, rapidly frozen (directly placed in liquid nitrogen in a Nunc filter), collected in a pre-cooled tube, and then placed in liquid nitrogen. The sample is stored at -70°C.

[0544] Take a liver TG TC piece (25±5 mg) from the right middle lobe, opposite the sponsor piece, excluding the end. Weigh each sample individually, collect them in a tube, and place them in liquid nitrogen. Store the samples at -70°C.

[0545] An additional liver section (approximately 100-300 mg) can be taken from the right lateral lobe, collected in a tube, and placed in liquid nitrogen to serve as preliminary tissue for testing. It can be used for further analysis if necessary. Store the sample at -70°C.

[0546] Biopsy treatment Microtome sectioning of formalin-fixed paraffin-embedded (FFPE) biopsies FFPE biopsy material is placed in 10% neutral buffered formalin (10% NBF) for approximately 24 hours, then transferred to 70% EtOH and stored at 4°C. Next, the FFPE biopsy material is impregnated in Histokinette and then embedded in a block. The biopsy tissue is cut to 3 μm on a microtome, the sections are mounted on Superfrost Plus slides and stored at 4°C.

[0547] NAFLD Activity Score (NAS) and Fibrosis Stage Liver samples stained with hematoxylin and eosin (H&E) or picrosilius red (PSR) are used to calculate NAS and fibrosis stage scores using the clinical criteria outlined by Kleiner et al. 2005. Total NAS represents the sum of the scores for fatty liver, inflammation, and ballooning, ranging from 0 to 8. Adapted from Design and validation of a histological scoring system for nonalcoholic fatty liver disease, Kleiner et al., Hepatology 41; 2005.

[0548] Histological staining procedure In short, slides containing paraffin-embedded sections are deparaffinized in xylene and then rehydrated in a series of stepwise ethanol treatments.

[0549] Hematoxylin and eosin (H&E) stain...

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 according to claim 1, wherein the THRβ agonist is a compound of formula (II-1). 【Chemistry 1】 (In the formula, R １ However, hydrogen, cyano, substituted or unsubstituted C １～６ Alkyl, and substituted or unsubstituted C ３～６ Selected from the group consisting of cycloalkyls, the substituents are halogen atoms, hydroxyl atoms, and C １～６ Selected from the group consisting of alkoxys, R ２ and R ３ However, halogen atoms and substituted or unsubstituted C １～６ Each atom is independently selected from the group consisting of alkyls, and the substituents are halogen atoms, hydroxyl atoms, and C １～６ Selected from the group consisting of alkoxys, 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, and the substituents are hydrogen, a halogen atom, hydroxy, -OCF ３ , -NH ２ , -NHC １～４ alkyl, -N(C １～４ alkyl) ２ , -CONH ２ , -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 are one or more substances selected from the group consisting of, and when two substituents are contained, the two substituents may together with the carbon to which they are attached form a ring structure The halogen atom is selected from the group consisting of F, Cl, and Br. The combination thereof, or a pharmaceutically acceptable salt thereof.

3. The combination according to claim 1 or 2, wherein the THRβ agonist is a compound of formula (II-1a). 【Chemistry 2】 (In the formula, R １ ~R ３ However, formula (II-1) is defined as described in detail herein, R ４ However, hydrogen, halogen atom, hydroxyl, -OCF ３ , -NH ２ , - NHC １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -CONH ２ , -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 Selected from the group consisting of cycloalkyl groups, m is an integer in the range of 1 to 4. The halogen atom is selected from the group consisting of F, Cl, and Br. The combination thereof, or a pharmaceutically acceptable salt thereof.

4. The combination according to any one of the prior claims, wherein the THRβ agonist is compound 9, 【Transformation 3】 The combination thereof, or a pharmaceutically acceptable salt thereof.

5. The combination according to any one of the prior claims, wherein the THRβ agonist is the potassium salt of compound 9.

6. A combination according to any one of the prior claims, wherein the GLP-1R agonist is a compound of formula (I-1), 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, in the formula, X is N or CH, Y is N or CR ４ And, n is either 0 or 1, R is hydrogen, R １ is, -C １ ~C ６ Alkilen-R ５ And, R ２ is hydrogen, oxo, or C １ ~C ６ It is alkyl, R ３ is hydrogen, oxo, or C １ ~C ６ It is alkyl, R ４ is hydrogen, OH, or C １ ~C ６ It is alkyl, Alternatively, R ３ and R ４ These, together with the carbon atoms to which they are bonded, form a halo or C １ ~C ３ C may be substituted with alkyl. ３ ~C ６ Forming a cycloalkyl group, R ５ is a five-membered heterocyclyl or five-membered heteroaryl, each containing one, two, or three heteroatoms independently selected from O, N, and S, where R ５ At least one heteroatom of is S, and further R ５ Ha, -O-C １－６ Alkyl, C １－６ Alkyl, C １－６ Alkenyl, or C １ ~C ６ It may be substituted with a haloalkyl group. Ring A is a 5-12 member heterocyclene or a 5-12 member heteroarylene, each independently comprising a halo, CN, and C. ３ -C ６ C which may be substituted with a cycloalkyl group, or a halo or OH group. １ -C ６ It may also be substituted with alkyl groups. L represents a bond, -O-, C １ ~C ６ Alkylene, *-O-C １ ~C ６ Alkylene-**, *-C １ ~C ６ Alkylene-O-** or *-NR ６ -C １ ~C ６ Alkylene-**, and here, * represents a bond point to ring A, and ** represents a bond point to ring B. L is *-O-C １ ~C ６ When it is alkylene-**, the C of L １ ~C ６ The alkylene may be substituted by R Ｌ where each R Ｌ is independently C １ ~C ６ alkyl or halo, or two Rs Ｌ together with the carbon atom or carbon atoms to which they are attached form C ３ ~C ６ cycloalkyl or 3-6 membered heterocyclyl, L is C １ ~C ６ When it is alkylene, the C １ ~C ６ alkylene may be substituted by R Ｌ１ and each R Ｌ１ is independently halo, OH, oxo, or C １ ~C ６ alkyl, or two Rs Ｌ１ together with the carbon atom or carbon atoms to which they are attached form C ３ ~C ６ cycloalkyl or 3- to 6-membered heterocyclyl, R ６ is hydrogen or C １ ~C ６ It is alkyl, Ring B is C ３ ~C １０ Cycloalkyl, C ６ ~C １４ These are aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl compounds, each independently of halo, CN, oxo, and C. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ The combination may be substituted with one to three substituents independently selected from the group consisting of , and phenyl.

7. A combination according to any one of the prior claims, wherein the GLP-1R agonist is a compound of formula (I-1a), 【Transformation 5】 or a pharmaceutically acceptable salt thereof, In the formula, R ７ These are hydrogen, chloro, bromo, fluoro, methyl, or vinyl. R ８ teeth, 【Transformation 6】 The aforementioned combination.

8. A combination according to any one of the prior claims, wherein the GLP-1R agonist is a compound of formula (II**), 【Transformation 7】 or a pharmaceutically acceptable salt thereof, in the formula, R ｆ４ and R ｆ５ Each of them is independent of C １－６ Selected from 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 a halogen, R ３ and R ３’ These are independently H or D, X １ * indicates N or CR ｆ１ And, X ２＊ and X ３＊ These are independently CH or CF, Each R ｆ３ These are, independently, halogen, -CN, and C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or -C(O)N(R) ｆ３’ ) ２ Selected from, Each R ｆ３’ H or C １－６ Selected from alkyl groups, R １＊＊ is either H, or C which is optionally substituted with one or more deuterium or halogens. １－２ The aforementioned combination is alkyl.

9. A combination according to any one of the prior claims, wherein the GLP-1R agonist is compound 1-2, 【Transformation 8】 The combination thereof, or a pharmaceutically acceptable salt thereof.

10. The combination according to any one of the prior claims, wherein the GLP-1R agonist is the meglumine salt of compound 1-2.

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

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

13. The combination according to any one of the prior claims, wherein the GLP-1R agonist is selected from those listed in Table 5A or from pharmaceutically acceptable salts thereof.

14. A combination according to any one of the prior claims, wherein the THRβ agonist is compound 9 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, The combination wherein the GLP-1R agonist is orfolglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tylzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

15. A combination according to any one of the prior claims, wherein the THRβ agonist is compound 9 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, The combination wherein the GLP-1R agonist is orfolglipron, danuglipron, or semaglutide, or a pharmaceutically acceptable salt thereof.

16. A combination according to any one of the prior claims, wherein the THRβ agonist is resmethylome, VK2809, sovethyrom, eprothyrom, ALG-055009, CNPT-101101, CNPT-101207, ASC41, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is compound 1-2 【Chemistry 11】 The combination thereof, or a pharmaceutically acceptable salt thereof.

17. A combination according to any one of the prior claims, wherein the THRβ agonist is compound 9 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, wherein the GLP-1R agonist is compound 1-2 【Chemistry 13】 The combination thereof, or a pharmaceutically acceptable salt thereof.

18. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 0.5 mg to approximately 25 mg.

19. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 1 mg to approximately 15 mg.

20. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 2 mg to approximately 10 mg.

21. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 1 mg.

22. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 3 mg.

23. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 6 mg.

24. The combination according to any one of the prior claims, wherein the amount of the THRβ agonist is approximately 10 mg.

25. A combination according to any one of the prior claims for use in the treatment of patients requiring treatment for liver dysfunction or cardiovascular metabolic disease.

26. A combination according to any one of the prior claims for use in patients who require weight loss to achieve it.

27. A combination according to any one of the prior claims, for use in combination therapy for the treatment of obesity in patients requiring treatment for obesity.

28. A method for treating a patient who requires treatment for liver dysfunction or cardiovascular metabolic disease, comprising administering to the patient a combination according to any one of the prior claims.

29. A method for treating a patient who requires treatment for liver dysfunction or cardiovascular metabolic disease, comprising administering to the patient a therapeutically effective amount of the combination according to any one of the prior claims.

30. A method for increasing the ratio of lean body mass to total body mass in a patient who requires such an increase, the method comprising administering to the patient a combination according to any one of the prior claims.

31. A method for reducing the ratio of body fat mass to total body weight in a patient who requires such reduction, the method comprising administering to the patient a combination according to any one of the prior claims.

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

33. The patient weighs 27 kg / m ２ The method according to any one of the prior claims, having the above body mass index (BMI).

34. The aforementioned patient weighed 30 kg / m². ２ The method according to any one of the prior claims, having the above BMI.

35. The method according to any one of the prior claims, wherein the administration of the THRβ agonist allows for a reduction in the dose of the GLP-1R agonist while maintaining equivalent weight loss.

36. The method according to any one of the prior claims, wherein the administration of the THRβ agonist increases weight loss compared to the administration of an equivalent dose of a GLP-1R agonist.

37. The method according to any one of the prior claims, wherein the cardiovascular metabolic disease is obesity or an obesity-related condition.

38. The method according to any one of the prior claims, wherein the cardiovascular metabolic disease is diabetes mellitus.

39. The method according to any one of the prior claims, wherein the combination or method improves blood glucose control in an adult having type 2 diabetes.

40. A method for treating obesity or achieving weight loss in patients who require it, (i) The patient is given compound 9 【Chemistry 14】 or administering a pharmaceutically acceptable salt thereof, (ii) administering to the patient a GLP-1R agonist or a pharmaceutically acceptable salt thereof, The method comprising administering compound 9 or a pharmaceutically acceptable salt thereof to the patient, thereby improving the patient's response to the GLP-1R agonist or a pharmaceutically acceptable salt thereof.

41. The combination or method according to any one of the prior claims, wherein the THRβ agonist is administered once or twice daily.

42. The combination or method according to any one of the prior claims, wherein the THRβ agonist is administered orally.

43. The combination or method according to any one of the prior claims, wherein the GLP-1R agonist is administered orally.

44. The method according to claim 40, wherein the GLP-1R agonist comprises compound 1-2, orfolglipron, semaglutide, tilzepatide, or danuglipron.

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

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

47. A combination according to any one of claims 1 to 27 for preparing a drug for use in the method according to any one of claims 28 to 46.

48. The use of the combination described in any one of claims 1 to 27 in the method according to any one of claims 28 to 46.

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