Compounds having an indazole group, thr beta receptor agonists and uses

Abstract

The present application provides a kind of compound with indazole group, THR beta receptor agonist and use, compound with indazole group or its pharmaceutically acceptable salt.The present application develops a kind of THR beta selective agonist with better specificity and drugability, the present agonist is better selective agonist THR beta and avoids the activation of THR alpha, separates the harmful influence of thyroid hormone excess from potential beneficial effects such as lowering cholesterol and blood lipids, provides a kind of new type of treatment drug with broad prospects for treating a series of major metabolic diseases in urgent need of solution.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis agents, and more specifically to a compound having an indazole group, a THRβ receptor agonist, and its uses. Background Technology

[0002] The biological activity of thyroid hormones is mediated by the thyroid hormone receptor (THR). The THR forms a heterodimer with retinoid receptors, which act as ligand-inducible transcription factors. The THR regulates gene expression through interactions with DNA response elements and various nuclear co-activators and co-repressors. The thyroid hormone receptor originates from two separate genes, α and β. The main thyroid receptor isotypes are α1, α2, β1, and β2. THR isotypes can differ in their contribution to specific biological responses. The THRβ isotype is primarily expressed in brain and liver tissues and is responsible for feedback regulation of the HPT axis and lipid-lowering effects. Selective activation of the THRα isotype is associated with adverse effects on the heart and bone. Therefore, selective activation of the THRβ isotype in liver tissue is beneficial.

[0003] The physiological effects of thyroid hormones influence almost every organ system. Clinically, these effects manifest as changes in metabolic rate, alterations in lipid metabolism, and characteristic effects on cardiovascular development. Thyroid receptors that bind thyroid hormones are classified into three subtypes: α1, β1, and β2. Recent studies have shown that TRβ1 plays an important role in regulating TRH (thyrotropin-releasing hormone) and thyroid hormones in the liver. TRβ2 plays a major role in regulating TSH (thyroid-stimulating hormone) in the liver (J. Clin. Invest, 1999, Vol 104, 291-300). MGL-3196 is a selective thyroid hormone receptor β (THRβ) agonist used to treat non-alcoholic steatohepatitis (NASH). Clinical studies have shown that MGL-3196 has good effects in promoting intrahepatic lipid clearance, improving magnetic resonance proton density fat fraction (MRI-PDFF), and achieving remission of MASH (metabolism-associated steatohepatitis), and improvements in the degree of liver tissue inflammation and fibrosis have been observed in some patients. However, MGL-3196 still has some limitations in clinical application. Some subjects experienced adverse events, such as diarrhea, nausea, hypertension, and mild thyroid dysfunction. Therefore, further improvement and development are needed. Summary of the Invention

[0004] To address the shortcomings of existing technologies and solve the aforementioned problems, a compound with an indazole group, a THRβ receptor agonist, and its uses are proposed, and the following technical solution is provided:

[0005] A compound having an indazole group or a pharmaceutically acceptable salt thereof, characterized in that it has the structural formula shown in I:

[0006]

[0007] I

[0008] in,

[0009] R1 is selected from hydrogen, C1-C6 alkyl, or C 3- C 10 cycloalkyl;

[0010] R2 is selected from hydrogen or halogen;

[0011] R3 is selected from hydrogen, cyano, or amino;

[0012] X1, X2 and X3 are selected from N or CH respectively.

[0013] Furthermore, R1 is selected from isopropyl.

[0014] Furthermore, R3 is selected from hydrogen or cyano.

[0015] Furthermore, the compound or a pharmaceutically acceptable salt thereof is , , , , or .

[0016] Furthermore, The preparation process is as follows:

[0017] ,

[0018] in, The preparation process is as follows: .

[0019] Furthermore, The preparation process is as follows:

[0020] .

[0021] In addition, the present invention provides a thyroid hormone β receptor agonist comprising the above-described compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0022] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof or thyroid hormone β-receptor agonists in the preparation of medicaments for treating diseases or conditions mediated by thyroid hormone β-receptors.

[0023] Furthermore, the diseases mentioned include diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, dementia, Parkinson's disease, or kidney disease.

[0024] Due to the adoption of the above technical solutions, the beneficial technical effects of the present invention are as follows:

[0025] 1. This invention designs a new compound structure that enhances target binding ability and improves in vitro activity by introducing a urea ring group;

[0026] 2. This invention develops a THRβ selective agonist with better specificity and drug-likeness. This agonist more selectively activates THRβ while avoiding activation of THRα, separating the harmful effects of excessive thyroid hormones from the potential beneficial effects such as lowering cholesterol and blood lipids. This provides a promising new class of therapeutic drugs for the treatment of a series of major metabolic diseases that urgently need to be addressed. Detailed Implementation

[0027] To enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Based on the embodiments in this application, other similar embodiments obtained by those skilled in the art without creative effort should all fall within the scope of protection of this application.

[0028] A compound having an indazole group or a pharmaceutically acceptable salt thereof, with the structural formula shown in I:

[0029]

[0030] I

[0031] R1 is selected from hydrogen, C1-C6 alkyl, or C3-C6 alkyl. 10 Cycloalkyl; R2 is selected from hydrogen or halogen; R3 is selected from hydrogen, cyano, or amino; X1, X2, and X3 are selected from N or CH, respectively. This invention designs a novel compound structure that enhances target binding ability and improves in vitro activity by introducing an indazole group.

[0032] Example 1: Preparation before synthesis

[0033] Synthesis of compound 1C

[0034]

[0035] Synthesis of compound M1

[0036] Weigh 1.924 g (8.73 mmol) of 3-bromo-4-chloro-2-methylaniline at room temperature, dissolve it in dichloromethane (DCM) (20 ml), and cool the system to 0 °C using an ice-water bath. o C. Trifluoroacetic anhydride (3.22 ml, 23.2 mmol) was added dropwise to the solution. After reacting for 1 hour, potassium nitrate (1.112 g, 11.0 mmol) was added to the system. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction was confirmed to be complete by LC-MS. The system was then concentrated, 200 ml of dichloromethane was added, and the mixture was washed with 80 ml of aqueous solution twice. After washing with brine, the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound M1 (2.91 g). This crude compound was directly used in the next reaction without further purification. The mass-to-nucleus ratio (m / z) was detected by liquid chromatography-mass spectrometry (LC / MS) in positive ion mode with electrospray ionization (ESI) and was LC / MS (ESI) m / z: 359 (MH).

[0037] Synthesis of compound M2

[0038] At room temperature, crude compound M1 (2.91 g) was dissolved in methanol (MeOH) (70 ml), potassium carbonate (3.614 g, 26.2 mmol) was added, and the system was then heated to 60°C. o The reaction was carried out at C for 18 hours. Most of the methanol solvent was removed by concentration under reduced pressure. 300 ml of dichloromethane was added, and the mixture was washed twice with 100 ml of aqueous solution and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound M2 (1.841 g, yield: 79.8%). This crude compound was directly proceeded to the next reaction without further purification. LC / MS (ESI) m / z: 267 (M+H)+.

[0039] Synthesis of compound 1C

[0040] At room temperature, 1.841 g (6.97 mmol) of crude compound M2 was weighed, dissolved in HoAc (60 ml), and the system was cooled to 0 °C using an ice-water bath. oC. Sodium nitrite (0.962 g, 13.94 mmol) was dissolved in 6 ml of aqueous solution and added dropwise to the reaction system. After the addition was complete, the reaction mixture was stirred overnight at room temperature. LC-MS was used to confirm the completeness of the reaction. The system was then transferred to 400 ml of ice water, and the pH was adjusted to 7-8 with sodium carbonate. 300 ml of ethyl acetate was added for extraction. The mixture was washed with 100 ml of aqueous solution twice, followed by washing with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 10-1 / 3, V / V) to give product compound 1C (1.12 g, yield: 58.2%). LC / MS (ESI) m / z: 274 (MH) - .

[0041] Example 1:

[0042] 2-(5-chloro-4-{[4-hydroxy-3-(prop-2-yl)phenyl]oxy}-1H-indazol-7-yl)-3,5-dioxanediol-4H-1,2,4-triazacyclohexane-6-carboxynitrile (Compound 1)

[0043]

[0044] Synthesis route:

[0045]

[0046] Synthesis of Compound 1A

[0047] At room temperature, 4.72 g (18.22 mmol) of compound 4-bromo-1-[(methoxymethyl)oxy]-2-(prop-2-yl)benzene was weighed, dissolved in 50 ml of tetrahydrofuran (THF), and then cooled to -78°C with dry ice under nitrogen protection. o Under conditions C, n-BuLi (8.4 ml, 20.96 mmol) was slowly added dropwise, with the temperature maintained below -65°C during the addition process. o C. After the addition was complete, the reaction was maintained at this temperature for 30 minutes. Then, isopropanol pinacol borate (4.07 g, 21.86 mmol) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature overnight. The next day, the system was cooled to -78°C. o C. Quench the reaction by adding 150 ml of ammonium chloride aqueous solution, extract by adding EA (100 ml) * 2, combine the organic phases, wash with water (100 ml) and brine (100 ml), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (developing solvent: n-heptane: EA = 10:1, V / V) to give compound 1A (4.766 g, yield 100%).

[0048] Synthesis of Compound 1B

[0049] Compound 1A (4.766 g, 15.58 mmol) was weighed at room temperature, dissolved and dispersed in tetrahydrofuran (THF) (40 mL) and water (40 mL), and then NaBO3·4H2O (7.15 g, 46.72 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was confirmed to be complete by LC-MS. EA (200 mL) was added, and the mixture was washed with 100 mL of water and 100 mL of brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (evolving solvent: n-heptane:EA = 4:1, V / V) to give compound 1B (2.163 g, two-step yield 50.6%). LC / MS (ESI) m / z: 197 (M+H) + .

[0050] Synthesis of Compound 1D

[0051] Compound 1B (883 mg, 4.5 mmol) and compound 1C (826 mg, 3 mmol) were weighed at room temperature, dissolved in dimethyl sulfoxide (DMSO) (40 ml), and then sodium carbonate (477 mg, 4.5 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until complete. Water (200 ml) was added, and the mixture was extracted with EA (100 ml * 2). The organic phases were combined, washed with 100 ml of water and 100 ml of brine, and dried over anhydrous sodium sulfate. The mixtures were filtered, concentrated under reduced pressure, and purified by column chromatography (evolving solvent: n-heptane:EA = 4:1, V / V) to give compound 1D (995 mg, yield 84.7%). LC / MS (ESI) m / z: 392 (M+H) + .

[0052] Synthesis of compound 1E

[0053] At room temperature, compound 1D (0.354 g, 0.9 mmol) was weighed, dissolved in 15 ml of DMF, and then cooled to 0°C using an ice-water bath. o C. Add 60% NaH (45 mg, 1.08 mmol). After stirring and maintaining the temperature for 1 hour, add 0.5 ml of N,N-dimethylformamide (DMF) solution containing acetyl chloride (93 mg, 1.17 mmol) dropwise, and slowly raise the temperature to room temperature overnight. Add 75 ml of ammonium chloride aqueous solution, extract with 100 ml of ethyl acetate, wash with 80 ml of aqueous solution, wash with brine, dry the organic phase with sodium sulfate, filter, concentrate under reduced pressure to obtain crude product, and purify the residue by silica gel column chromatography (eluent: n-heptane: EA = 3:1, V / V) to obtain product compound 1E (57.6 mg, yield: 15%). LC / MS (ESI) m / z: 434(M+H)+.

[0054] Synthesis of compound 1F

[0055] At room temperature, compound 1E (58 mg, 0.1334 mmol), ZnCl2 (73 mg, 0.535 mmol), and 10% Pd / C (67 mg) were weighed and dissolved in ethyl acetate (8 ml) and acetic acid (0.8 ml). A hydrogen balloon was inserted, and the mixture was purged three times. After stirring at room temperature for 6 hours, the mixture was filtered and concentrated under reduced pressure to obtain crude compound 1F, which was directly used in the next reaction. LC / MS (ESI) m / z: 404 (M+H) + .

[0056] Synthesis of Compound 1G

[0057] At room temperature, weigh 54 mg (0.133 mmol) of compound 1F, add 1 ml of acetic acid, 1 ml of 3 M / L hydrochloric acid, and 1 ml of water. After dissolving and dispersing, cool to 0-5 °C. o C. Add 0.5 ml of an aqueous solution of sodium nitrite (14 mg, 0.2 mmol). After the addition is complete, keep the mixture warm for 30 minutes. This system is referred to as reaction system A.

[0058] Weigh out N-cyanoaceturane (32 mg, 0.2 mmol), dissolve it in pyridine (2 ml) and water (1 ml), and heat at 0-5°C. o The reaction mixture was stirred for 0.5 hours, and this system was designated as system B. System A was rapidly added to system B, and the ice-water bath was removed. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was confirmed to be complete by LC-MS, ethyl acetate and water were added, and the pH was adjusted to 3 with 1 M / L hydrochloric acid. The organic phase was washed with water and then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1 G of crude compound, which was used directly in the next reaction. LC / MS (ESI) m / z: 485 (M+H) + .

[0059] Synthesis of Compound 1

[0060] At room temperature, 1g of the crude compound (0.062g, 0.133 mmol) was weighed, dissolved in acetic acid (8ml), and then sodium acetate (0.105g, 1.33mmol) was added. Under nitrogen protection, the mixture was heated to 120°C. o React at C for 2 hours. Cool to room temperature, add ethyl acetate and water, wash the organic phase once with water and once with brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by preparative plate, develop the system (DCM:MeOH = 10:1), and give title compound 1 (3.4 mg). LC / MS (ESI) m / z: 439 (M+H) +.

[0061] Example 2:

[0062] 2-(5-chloro-4-{[4-hydroxy-3-(prop-2-yl)phenyl]oxy}-1H-indazol-7-yl)-2H,3H,4H,5H-1,2,4-triazacyclohexane-3,5-dione (Compound 2)

[0063]

[0064] Synthesis route:

[0065]

[0066] Synthesis of Compound 2A

[0067] At room temperature, compound 1 (13.1 mg, 0.03 mmol) was weighed, dissolved in isopropanol (1.5 ml) and water (1.0 ml), and then KOH (17 mg, 0.3 mmol) was added. The mixture was then heated to 70°C under nitrogen protection. o The reaction proceeded for 6 hours at C. LC-MS analysis confirmed the reaction was complete. The pH was adjusted to 4-5 with 1N hydrochloric acid, followed by the addition of 15ml of water. Extraction was performed using two 30ml DCM / MeOH (10:1) solutions. The organic phases were combined, washed with 10ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 2A, which was directly used in the next reaction. LC / MS (ESI) m / z: 458 (M+H) + .

[0068] Synthesis of Compound 2

[0069] At room temperature, 10 mg of compound 2A was weighed and dissolved in 1 ml of HOAc and 0.05 ml of mercaptoacetic acid. The mixture was then heated to 120°C under nitrogen protection. o The reaction was carried out at C for 6 hours. LC-MS analysis showed the reaction was complete. EA (45 ml) was added, followed by washing with 35 ml of water (2 times), then with brine. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (developing solvent: DCM:MeOH = 10:1:1, V / V) to give compound 2 (3.4 mg). LC / MS (ESI) m / z: 414 (M+H) + .

[0070] Example 3:

[0071] 3-(5-chloro-4-{[4-hydroxy-3-(propyl-2-yl)phenyl]oxy}-1H-indazol-7-yl)-2,6-dioxane-1H-pyrimidin-5-carboxynitrile (Compound 3)

[0072]

[0073] Synthesis route:

[0074]

[0075] Synthesis of compound 3A:

[0076] Weigh at room temperature N 2 g of cyanoacetylurane (12.82 mmol), triethyl orthoformate (7.6 g, 51.28 mmol), and acetic anhydride (3.92 g, 38.46 mmol) were dissolved in acetonitrile (30 ml) and reacted at 80°C for 3 hours under nitrogen protection. The solvent was removed by vacuum concentration, and MTBE (30 ml) was added and the mixture was slurried to give compound 3A (0.9 g). LC / MS (ESI) m / z: 213 (M+H)+.

[0077] Synthesis of compound 3:

[0078] Following the synthetic method of compound 1, replace compound 3A with compound 1. N -Cyanoacetylurane, yielding title compound 3 (7 mg, 75% yield). LC / MS (ESI) m / z: 438(M+H)+.

[0079] Example 4:

[0080] 1-(5-chloro-4-{[4-hydroxy-3-(propyl-2-yl)phenyl]oxy}-1H-indazol-7-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (compound 4)

[0081]

[0082] Synthesis route:

[0083] Following the synthetic method of compound 2, compound 1 was replaced with compound 3 to obtain title compound 4 (3 mg), LC / MS (ESI) m / z: 413 (M+H). + The details are as follows.

[0084] Synthesis of Compound 4

[0085] Compound 3 (10 mg) was weighed at room temperature, dissolved in 1 ml of HOAc and 0.05 ml of thioglycolic acid, and then heated to 120°C under nitrogen protection. oThe reaction was carried out at C for 6 hours. LC-MS analysis showed the reaction was complete. EA (45 ml) was added, followed by washing with 35 ml of water (2 times), then with brine. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (developing solvent: DCM:MeOH = 10:1:1, V / V) to give compound 4 (3.4 mg). LC / MS (ESI) m / z: 414 (M+H) + .

[0086] Example 5:

[0087] 2-(5-chloro-4-{[5-hydroxy-4-(propyl-2-yl)pyrimidin-2-yl]oxy}-1H-indazol-7-yl)-3,5-dioxanedi-4H-1,2,4-triazacyclohexane-6-carboxynitrile (Compound 5)

[0088]

[0089] Synthesis route:

[0090]

[0091] The specific route is as follows:

[0092] Synthesis of compound 5C

[0093] Compounds 5A (197.3 mg, 0.91 mmol) and 5B (361.1 mg, 0.91 mmol) were weighed and dissolved in DMF (10 mL). Potassium carbonate (251.3 mg, 1.82 mmol) was added, and the mixture was stirred at room temperature for 12 h. After confirming the completeness of the reaction by TLC, the mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated and purified by silica gel column chromatography to obtain product 5C (487.2 mg).

[0094] Synthesis of compound 5D

[0095] Compound 5C (487.2 mg, 0.92 mmol) was weighed and dissolved in ethanol and water (5 / 1, 36 mL). Fe powder (257.4 mg, 4.58 mmol) and ammonium chloride (486.2 mg, 9.17 mmol) were added, and the mixture was stirred at 75 °C for 4 h. After confirming the reaction was complete by TLC, the mixture was filtered and washed with ethanol. The organic phase was concentrated and purified by silica gel column chromatography to obtain product 5D (239 mg).

[0096] Synthesis of compound 5E

[0097] Compound 5D (70.3 mg, 0.13 mmol), B2(Pin)2 (68.1 mg, 0.26 mmol), Pd(dppf)Cl2 (9.7 mg, 0.013 mmol), and KOAc (39.2 mg, 0.39 mmol) were weighed and dissolved in dioxane (3 mL). The mixture was stirred overnight at 95 °C. After confirming the complete reaction by TLC, the mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated and dissolved in THF / H2O (2 / 1, 9 mL). NaBO3·4H2O (100.5 mg, 0.65 mmol) was added under ice bath, and the reaction was carried out at room temperature. After confirming the complete reaction by TLC, the mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated and purified by silica gel column chromatography to obtain product 5E.

[0098] Synthesis of Compound 5

[0099] Following the synthetic method of compound 1, compound 1F was replaced with compound 5E to obtain title compound 5 (3 mg), LC / MS (ESI) m / z: 439 (M+H)+.

[0100] Example 6:

[0101] 2-(5-chloro-4-{[5-hydroxy-4-(propyl-2-yl)pyrimidin-2-yl]oxy}-1H-indazol-7-yl)-2H,3H,4H,5H-1,2,4-triazacyclohexane-3,5-dione (compound 6)

[0102]

[0103] Synthesis route:

[0104]

[0105] Following the synthetic method of compound 5, compound 5C was substituted with compound 6A to obtain the title compound 6G. LC / MS (ESI) m / z: 441 (M+H) + The specific process is as follows:

[0106] Synthesis of compound 6H

[0107] At room temperature, 6g of compound (13.1mg, 0.03mmol) was weighed, dissolved in isopropanol (1.5ml) and water (1.0ml), then KOH (17mg, 0.3mmol) was added, and the mixture was heated to 70°C under nitrogen protection. oThe reaction proceeded for 6 hours at C. LC-MS analysis confirmed the reaction was complete. The pH was adjusted to 4-5 with 1N hydrochloric acid, followed by the addition of 15ml of water. Extraction was performed using two 30ml DCM / MeOH (10:1) solutions. The organic phases were combined, washed with 10ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 6H. This crude compound was used directly in the next reaction. LC / MS (ESI) m / z: 458 (MH) + .

[0108] Synthesis of Compound 6

[0109] At room temperature, 10 mg of compound 6H was weighed, dissolved in 1 ml of HOAc and 0.05 ml of mercaptoacetic acid, and then heated to 120°C under nitrogen protection. o The reaction was carried out at C for 6 hours. LC-MS analysis showed the reaction was complete. EA (45 ml) was added, followed by washing with 35 ml of water (2 times), then with brine. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (developing solvent: DCM:MeOH = 10:1:1, V / V) to give compound 6 (3.4 mg). LC / MS (ESI) m / z: 414 (MH) + .

[0110] Biological evaluations were performed on Examples 1-6 above.

[0111] Tests of the cellular-level agonistic activity of compounds on thyroid hormone receptors

[0112] I. Cell Plating (96-well plate)

[0113] 1) Digest logarithmically growing hTHRβ DR4-Luc HEK293 and hTHRα DR4-Luc HEK293 cells. Terminate the digestion reaction with 90% DMEM + 10% Charcoal Stripped FBS medium, centrifuge, discard the supernatant, and resuspend in 90% DMEM + 10% Charcoal Stripped FBS medium.

[0114] 2) Seed the resuspended cells into 96-well cell culture plates, resuspending the cells at a rate of 30,000 cells per well, 90 μL / well of cell suspension, and incubate overnight at 37°C.

[0115] II. Compound Incubation

[0116] 1. First, dilute with DMSO to prepare a 1000* DMSO sample solution. Then, further dilute the DMSO sample solution 100 times (1ul DMSO sample + 99ul culture medium) using 90% DMEM + 10% Charcoal Stripped FBS medium to obtain a 10* sample gradient dilution solution. Subsequent concentrations are diluted 3-fold, for a total of 9 concentration gradients.

[0117] 2. Add serially diluted 10* concentration samples (10 μL / well) to a 96-well plate and set up a blank control group, and continue to incubate overnight in a 37°C cell culture incubator.

[0118] 3. Remove the 96-well plate from the incubator and allow it to return to room temperature. Add 100 μL / well of One-Lite Luciferase assay reagent and let it stand for approximately 3 minutes. Then, place the plate in a microplate reader to read the values. Based on the readings for each concentration gradient well, use Prism Graphpad software to fit the gradient curve of cell activation by the sample and calculate the EC50 of the sample.

[0119] 4. The positive control drug is Resmetirom (MGL-3196), which is a highly selective THRβ agonist.

[0120] 5. Experimental Results

[0121] Table 1 EC50 of Examples 1-6

[0122]

[0123] The above experimental results show that the compounds with the disclosed structure have higher activity or selectivity than the positive compounds.

[0124] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A compound having an indazole group or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula is shown in I: I in, R1 is selected from hydrogen, C1-C6 alkyl, or C 3- C 10 cycloalkyl; R2 is selected from hydrogen or halogen; R3 is selected from hydrogen, cyano, or amino; X1, X2 and X3 are selected from N or CH respectively.

2. A compound having an indazole group or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from isopropyl.

3. A compound having an indazole group or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R3 is selected from hydrogen or cyano.

4. A compound having an indazole group or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound or its pharmaceutically acceptable salt is , , , , or .

5. A method for preparing a compound having an indazole group according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, The preparation process is as follows: ， in, The preparation process is as follows: 。 6. A method for preparing a compound having an indazole group according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, The preparation process is as follows: ， in, The preparation process is as follows: 。 7. A thyroid hormone β-receptor agonist, characterized in that, It comprises a compound containing an indazole group according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

8. Use of the indazole group compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, or the thyroid hormone β-receptor agonist of claim 7, in the preparation of a medicament for treating diseases or conditions mediated by thyroid hormone β-receptors.

9. The use according to claim 8, characterized in that, The diseases mentioned include diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, dementia, Parkinson's disease, or kidney disease.

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