Compound with indazole group, THRbeta receptor agonist and application

Abstract

The invention provides a compound with an indazole group, a THRbeta receptor agonist and application, and the compound with the indazole group or pharmaceutically acceptable salt thereof. The invention develops a THRbeta selective agonist with better specificity and druggability, the THRbeta selective agonist can better selectively agonize THRbeta so as to avoid activation of THRalpha, and the harmful effect of excessive thyroid hormone is separated from the potential beneficial effects of lowering cholesterol and blood fat and the like; the invention provides a novel therapeutic drug with a wide prospect for treating a series of serious metabolic diseases to be solved urgently.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical synthesis, more particularly to a compound with indazole group, THR beta receptor agonist and use. BACKGROUND

[0002] The biological activity of thyroid hormone is mediated by thyroid hormone receptors (THR). THR forms heterodimers with retinoid receptors that act as ligand-induced transcription factors. THR regulates gene expression through interactions with DNA response elements and a variety of nuclear co-activators and nuclear co-repressors. The thyroid hormone receptors are derived from two separate genes, alpha and beta. The major thyroid receptor isoforms are alpha 1, alpha 2, beta 1 and beta 2. The thyroid hormone receptor subtypes can differ in their contribution to specific biological responses. The THR beta isoform is mainly expressed in brain and liver tissues and is responsible for the feedback regulation of the HPT axis and the lipid lowering effect. The THR alpha isoform selectively activates effects associated with adverse effects on the heart and bone. Thus, selective activation of the THR beta isoform in liver tissue is beneficial.

[0003] The physiological effects of thyroid hormone affect almost every organ system. Clinically, these effects manifest as changes in metabolic rate, alterations in lipid metabolism and characteristic effects on cardiovascular development. The thyroid receptors that can bind thyroid hormone are divided into three subtypes, alpha 1, beta 1, beta 2, and recent studies have shown that TR beta 1 plays an important role in the regulation of TRH (thyrotropin releasing hormone) and the regulation of thyroid hormone in the liver. TR beta 2 plays a major role in the regulation of TSH (thyroid stimulating hormone) in the liver (J. Clin. invest, 1999, Vol 104, 291-300). MGL-3196 is a thyroid hormone receptor beta (THR beta) selective agonist drug for the treatment of 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 MASH (metabolic associated steatohepatitis) remission, and improvement in the degree of liver tissue inflammation and fibrosis is observed in some patients. However, MGL-3196 still has some limitations in clinical application. Some subjects have adverse events such as diarrhea, nausea, hypertension, and mild thyroid function abnormalities. Therefore, further improvement and development are still needed. SUMMARY

[0004] In view of the deficiencies of the prior art, in order to solve the above problems, a compound with indazole group, THR beta receptor agonist and use are proposed, and the following technical solutions are provided: A compound having an indazole group or a pharmaceutically acceptable salt thereof, characterized in that the structural formula is shown as I: I wherein, 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.

[0005] Further, R1 is selected from isopropyl.

[0006] Further, R3 is selected from hydrogen or cyano.

[0007] Further, the compound or the pharmaceutically acceptable salt thereof is 、 、 、 、 or .

[0008] Further, The preparation process of the compound of formula (I) is as follows: , wherein, The preparation process of the compound of formula (I) is as follows: .

[0009] Further, The preparation process of the compound of formula (I) is as follows: .

[0010] In addition, the present application also provides a thyroid hormone beta receptor agonist comprising the above-mentioned compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0011] The present application also provides the use of the above-mentioned compound or the pharmaceutically acceptable salt thereof or the thyroid hormone beta receptor agonist in the preparation of a medicament for treating a disease or a disorder mediated by the thyroid hormone beta receptor.

[0012] Further, the disease includes 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.

[0013] Due to the adoption of the above technical scheme, the present application has the beneficial technical effects that: 1. The application designs a new compound structure, the target binding ability is enhanced by introducing a urea ring group, and the in vitro activity is improved. 2. The application develops a THR beta selective agonist with better specificity and drugability, the agonist better selectively stimulates THR beta and avoids the activation of THR alpha, separates the harmful effects of thyroid hormone excess from the potential beneficial effects on reducing cholesterol and blood lipids, and provides a new type of promising therapeutic drug for treating a series of major metabolic diseases that need to be solved. DETAILED DESCRIPTION

[0014] In order to make the person skilled in the art better understand the technical solutions of the application, the technical solutions of the application will be described clearly and completely in combination with the embodiments of the application, and other similar embodiments obtained by the person skilled in the art on the basis of the embodiments in the application without creative labor should belong to the protection scope of the application.

[0015] A compound with an indazole group or a pharmaceutically acceptable salt thereof, the structural formula is as shown in I: I Wherein, R1 is selected from hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl; R2 is selected from hydrogen or halogen; R3 is selected from hydrogen, cyano or amino; X1, X2 and X3 are respectively selected from N or CH. The application designs a new compound structure, the target binding ability is enhanced by introducing an indazole group, and the in vitro activity is improved.

[0016] Preparation before synthesis of example 1 Synthesis of compound 1C Synthesis of compound M1 At room temperature, 3-bromo-4-chloro-2-methyl aniline (1.924 g, 8.73 mmol) was weighed and dissolved with dichloromethane (DCM) (20 ml), the system was cooled to 0 oC, trifluoroacetic anhydride (3.22 ml, 23.2 mmol) was added dropwise into the solution, after 1 hour of reaction, potassium nitrate (1.112 g, 11.0 mmol) was added into the system. After the addition, the reaction mixture was stirred at room temperature overnight, LC-MS detection showed that the reaction was complete, then the system was concentrated, 200 ml of dichloromethane was added, washed with 80 ml of water solution*2, washed with brine, then the organic phase was dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound M1 (2.91 g), which was directly used in the next step without further purification. Liquid chromatography-mass spectrometry (LC / MS) was detected in the positive ion mode (ESI) to detect the mass-to-charge ratio (m / z) data LC / MS (ESI) m / z: 359 (M-H).

[0017] Synthesis of compound M2 The crude compound M1 (2.91 g) was dissolved in methanol (MeOH) (70 ml) at room temperature, potassium carbonate (3.614 g, 26.2 mmol) was added, and then the system was heated to 60 o C for 18 hours. Most of the methanol solvent was removed by concentration under reduced pressure, 300 ml of dichloromethane was added, washed with 100 ml of water solution*2, washed with brine, then the organic phase was dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound M2 (1.841 g, yield: 79.8%), which was directly used in the next step without further purification. LC / MS (ESI) m / z: 267 (M+H)+.

[0018] Synthesis of compound 1C The crude compound M2 (1.841 g, 6.97 mmol) was weighed and dissolved in HoAc (60 ml) at room temperature, and the system was cooled to 0 o C, sodium nitrite (0.962 g, 13.94 mmol) was dissolved in 6 ml of water solution and added dropwise into the reaction system. After the addition, the reaction mixture was stirred at room temperature overnight, LC-MS detection showed that the reaction was complete, then the system was poured into 400 ml of ice water, adjusted to pH 7-8 with sodium carbonate, added 300 ml of ethyl acetate for extraction, washed with 100 ml of water solution*2, washed with brine, then the organic phase was dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10-1 / 3, V / V) to obtain the product compound 1C (1.12 g, yield: 58.2%). LC / MS (ESI) m / z: 274 (M-H) - .

[0019] Example 1: 2-(5-chloro-4-{[4-hydroxy-3-(propan-2-yl)phenyl]oxy}-1H-indazol-7-yl)-3,5- dioxo-4H-1,2,4-triazine-6-carbonitrile (Compound 1) Synthetic route: Synthesis of Compound 1A Compound 4-bromo-1-[(methoxymethyl)oxy]-2-(propan-2-yl)benzene (4.72 g, 18.22 mmol) was weighed out and dissolved in tetrahydrofuran (THF) (50 ml) at room temperature, and then cooled to -78 °C under nitrogen protection, and n-BuLi (8.4 ml, 20.96 mmol) was slowly added dropwise while maintaining the temperature at no higher than -65 °C. After the addition was completed, the reaction was maintained at -78 °C for 30 min, and then isopropyl boronic acid pinacol ester (4.07 g, 21.86 mmol) was added dropwise, and then slowly warmed to room temperature overnight. The next day, the system was cooled to -78 °C, and an aqueous ammonium chloride solution (150 ml) was added to quench the reaction, and then extracted twice with EA (100 ml), and the combined organic phases were washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (developing agent: n-heptane:EA = 10:1, V / V) to obtain Compound 1A (4.766 g, yield 100%). o C. After the addition was completed, the reaction was maintained at -78 °C for 30 min, and then isopropyl boronic acid pinacol ester (4.07 g, 21.86 mmol) was added dropwise, and then slowly warmed to room temperature overnight. The next day, the system was cooled to -78 °C, and an aqueous ammonium chloride solution (150 ml) was added to quench the reaction, and then extracted twice with EA (100 ml), and the combined organic phases were washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (developing agent: n-heptane:EA = 10:1, V / V) to obtain Compound 1A (4.766 g, yield 100%). o C. After the addition was completed, the reaction was maintained at -78 °C for 30 min, and then isopropyl boronic acid pinacol ester (4.07 g, 21.86 mmol) was added dropwise, and then slowly warmed to room temperature overnight. The next day, the system was cooled to -78 °C, and an aqueous ammonium chloride solution (150 ml) was added to quench the reaction, and then extracted twice with EA (100 ml), and the combined organic phases were washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (developing agent: n-heptane:EA = 10:1, V / V) to obtain Compound 1A (4.766 g, yield 100%). o C. After the addition was completed, the reaction was maintained at -78 °C for 30 min, and then isopropyl boronic acid pinacol ester (4.07 g, 21.86 mmol) was added dropwise, and then slowly warmed to room temperature overnight. The next day, the system was cooled to -78 °C, and an aqueous ammonium chloride solution (150 ml) was added to quench the reaction, and then extracted twice with EA (100 ml), and the combined organic phases were washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (developing agent: n-heptane:EA = 10:1, V / V) to obtain Compound 1A (4.766 g, yield 100%).

[0020] Synthesis of Compound 1B Compound 1A (4.766 g, 15.58 mmol) was weighed out and dissolved in tetrahydrofuran (THF) (40 ml) and water (40 ml) at room temperature, and then NaBO3.4H2O (7.15 g, 46.72 mmol) was added, and the reaction was maintained at room temperature for 2 h, and then LC-MS was used to detect that the reaction was complete. EA (200 ml) was added, and then washed with water (100 ml) and brine (100 ml), and then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (developing agent: n-heptane:EA = 4:1, V / V) to obtain Compound 1B (2.163 g, two-step yield 50.6%), LC / MS (ESI) m / z: 197 (M+H) + .

[0021] Synthesis of Compound 1D 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) + .

[0022] Synthesis of compound 1E 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)+.

[0023] Synthesis of compound 1F 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) + .

[0024] Synthesis of Compound 1G 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. oC, drop in sodium nitrite (14 mg, 0.2 mmol) in water 0.5 ml. After droping, keep the reaction for 30 minutes, and use this system as system A.

[0025] Take N-cyanoacetyl urethane (32 mg, 0.2 mmol), add pyridine (2 ml) and water (1 ml) to dissolve, and then add 0-5 o C, keep the reaction for 0.5 hour, and use this system as system B. Quickly add system A into system B, and then remove the ice water bath, and keep the reaction for 2 hours at room temperature. After detecting the reaction is complete by LC-MS, add ethyl acetate and water, adjust the pH to 3 by 1 M / L hydrochloric acid, wash the organic phase by water, and then by brine, dry by anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude compound 1G, which is directly used in the next step reaction. LC / MS (ESI) m / z: 485 (M+H) + .

[0026] Synthesis of compound 1 At room temperature, take the crude compound 1G (0.062 g, 0.133 mmol), add acetic acid (8 ml) to dissolve, and then add sodium acetate (0.105 g, 1.33 mmol). Under nitrogen protection, heat to 120 o C, keep the reaction for 2 hours. After cooling to room temperature, add ethyl acetate and water, wash the organic phase by water once, and then by brine, dry by anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify by preparative plate, and use the developing system (DCM:MeOH=10:1) to obtain the title compound 1 (3.4 mg). LC / MS (ESI) m / z: 439 (M+H) + .

[0027] Example 2: 2-(5-chloro-4-{[4-hydroxy-3-(propan-2-yl)phenyl]oxy}-1H-indazol-7-yl)-2H,3H,4H,5H-1,2,4-triazine-3,5-dione (compound 2) Synthetic route: Synthesis of compound 2A At room temperature, take compound 1 (13.1 mg, 0.03 mmol), add isopropanol (1.5 ml) and water (1.0 ml) to dissolve, and then add KOH (17 mg, 0.3 mmol). Under nitrogen protection, heat to 70 oC reaction 6h, LC-MS detection reaction complete, add 1N hydrochloric acid to adjust pH to 4-5, add water 15ml, DCM / MeOH (10:1) 30ml*2 extraction, combined organic phase, salt water (10ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration, get crude compound 2A, direct use in next step reaction, LC / MS (ESI) m / z: 458 (M+H) + .

[0028] Synthesis of compound 2 At room temperature, weighed compound 2A (10mg), add HOAc (1ml), dissolved after adding mercaptoacetic acid (0.05ml), nitrogen protection condition, heated to 120 o C reaction 6h, LC-MS detection reaction complete, add EA (45ml), washed with water 35ml*2, salt water washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration, column purification (developing agent: DCM:MeOH =10:1:1, V / V) to get compound 2 (3.4mg), LC / MS (ESI) m / z: 414 (M+H) + .

[0029] Example 3: 3-(5-chloro-4-{[4-hydroxy-3-(propan-2-yl)phenyl]oxy}-1H-indazol-7-yl)-2,6-dioxo-1H- pyrimidine-5-carbonitrile (compound 3) Synthesis route: Synthesis of compound 3A: At room temperature, weighed N -cyanacetylurethane (2g, 12.82mmol), triethyl orthoformate (7.6g, 51.28mmol), acetic anhydride (3.92g, 38.46mmol), add acetonitrile (30ml) dissolution, nitrogen protection condition, heated to 80 degrees reaction 3 hours. Reduced pressure concentration to remove most of the solvent, add MTBE (30ml) to get compound 3A (0.9g). LC / MS (ESI) m / z: 213 (M+H)+.

[0030] Synthesis of compound 3: Reference compound 1 synthesis method, compound 3A instead of compound N -cyanacetylurethane, get the title compound 3 (7mg, yield 75%). LC / MS (ESI) m / z: 438 (M+H)+.

[0031] Example 4: 1-(5-chloro-4-{[4-hydroxy-3-(propan-2-yl)phenyl]oxy}-1H-indazol-7-yl)-1,2,3,4- tetrahydropyrimidine-2,4-dione (Compound 4) Synthetic route: The compound 4 (3 mg) was obtained by the method for synthesizing the reference compound 2, substituting the compound 1 with the compound 3, and LC / MS (ESI) m / z: 413 (M+H) was detected. + The details are as follows.

[0032] Synthesis of compound 4 Compound 3 (10 mg) was weighed, HOAc (1 ml) and mercaptoacetic acid (0.05 ml) were added, and after dissolution, the temperature was increased to 120 o C under nitrogen protection at room temperature, and the reaction was allowed to proceed for 6 h. After LC-MS detection, EA (45 ml) was added, and the mixture was washed with water (35 ml*2) and brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM:MeOH = 10:1:1, V / V) to obtain compound 4 (3.4 mg), and LC / MS (ESI) m / z: 414 (M+H) was detected. + .

[0033] Example 5: 2-(5-chloro-4-{[5-hydroxy-4-(propan-2-yl)pyrimidin-2-yl]oxy}-1H-indazol-7-yl)-3,5- dioxo-4H-1,2,4-triazine-6-carbonitrile (Compound 5) Synthetic route: The details are as follows: Synthesis of compound 5C Compound 5A (197.3 mg, 0.91 mmol) and 5B (361.1 mg, 0.91 mmol) were 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 TLC confirmed that the reaction was complete, the mixture was extracted with ethyl acetate and water three times, and the organic phase was concentrated and purified by silica gel column chromatography to obtain the product 5C (487.2 mg).

[0034] Synthesis of compound 5D Compound 5C (487.2 mg, 0.92 mmol) was dissolved in ethanol and water (5 / 1, 36 mL), Fe powder (257.4 mg, 4.58 mmol), ammonium chloride (486.2 mg, 9.17 mmol) were added, stirred at 75 °C for 4 h. TLC confirmed the reaction was complete, filtered and washed with ethanol, the organic phase was concentrated and purified by silica gel column chromatography to give product 5D (239 mg).

[0035] Synthesis of compound 5E 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), KOAc (39.2 mg, 0.39 mmol) were dissolved in dioxane (3 mL), stirred at 95 °C overnight. TLC confirmed the reaction was complete, extracted with ethyl acetate and water for 3 times, 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, reacted at room temperature. TLC confirmed the reaction was complete, extracted with ethyl acetate and water for 3 times, the organic phase was concentrated and purified by silica gel column chromatography to give product 5E.

[0036] Synthesis of compound 5 The synthesis method of reference compound 1 was used, compound 5E was used to replace compound 1F to obtain title compound 5 (3 mg), LC / MS (ESI) m / z: 439 (M+H)+.

[0037] Example 6: 2-(5-chloro-4-{[5-hydroxy-4-(propan-2-yl)pyrimidin-2-yl]oxy}-1H-indazol-7-yl)- 2H,3H,4H,5H-1,2,4-triazepine-3,5-dione (compound 6) Synthesis route: The synthesis method of reference compound 5 was used, compound 6A was used to replace compound 5C to obtain title compound 6G, LC / MS (ESI) m / z: 441 (M+H) + , as follows: Synthesis of compound 6H Compound 6G (13.1 mg, 0.03 mmol) was dissolved in isopropanol (1.5 ml) and water (1.0 ml) at room temperature, KOH (17 mg, 0.3 mmol) was added, and the temperature was increased to 70 oC reaction 6h, LC-MS detection reaction complete, add 1N hydrochloric acid to adjust pH to 4-5, add water 15ml, DCM / MeOH (10:1) 30ml*2 extraction, combined organic phase, salt water (10ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration, get crude compound 6H, direct use in next step reaction, LC / MS (ESI) m / z: 458 (M-H) + .

[0038] Synthesis of compound 6 At room temperature, weighed compound 6H (10mg), added HOAc (1ml), dissolved after adding mercaptoacetic acid (0.05ml), nitrogen protection condition, heated to 120 o C reaction 6h, LC-MS detection reaction complete, add 1N hydrochloric acid to adjust pH to 4-5, add water 15ml, DCM / MeOH (10:1) 30ml*2 extraction, combined organic phase, salt water (10ml) washing, anhydrous sodium sulfate drying, filtration, reduced pressure concentration, get crude compound 6H, direct use in next step reaction, LC / MS (ESI) m / z: 458 (M-H) + .

[0039] Biological evaluation of the above examples 1-6 Compound agonist activity test on thyroid hormone receptor at cell level I. Cell plating (96-well plate) 1) Digest the logarithmically growing hTHRβ DR4-Luc HEK293 and hTHRα DR4-Luc HEK293 cells, and terminate the digestion reaction with 90% DMEM+10% Charcoal Stripped FBS medium. Centrifuge and discard the supernatant, and resuspend in 90% DMEM+10% Charcoal Stripped FBS medium.

[0040] 2) Resuspend the cells in a 96-well cell culture plate, resuspend the cells at a concentration of 30000 cells per well, 90uL / well cell suspension, and incubate in a 37 incubator overnight.

[0041] II. Compound incubation 1. First dilute the DMSO sample solution to 1000* with DMSO, then continue to dilute the DMSO sample solution 100 times (1ul DMSO) with 90% DMEM+10% Charcoal Stripped FBS medium (99ul medium) to obtain a 10* sample gradient dilution solution. The subsequent concentration is diluted according to a 3-fold gradient, a total of 9 concentration gradients.

[0042] 2. Add gradient dilution of 10* concentration sample (10uL / well) in 96-well plate and set up blank control, continue to incubate overnight in 37 degree cell incubator.

[0043] 3. Take out the 96-well plate from the incubator, after recovering to room temperature, add 100uL / well One-Lite Luciferase detection reagent and place for about 3 minutes, then put into the microplate reader to read the values. According to the read values of each gradient concentration well, use Prism Graphpad software to fit the gradient curve of sample activating cells, and calculate the EC50 of the sample.

[0044] 4. The positive control drug is Resmetirom (MGL-3196), which is a highly selective THRβ agonist.

[0045] 5. Experimental results Table 1 EC50 of Examples 1-6 The above experimental results show that the activity or selectivity of the compound of the structure of the present disclosure is higher than that of the positive compound.

[0046] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description of the specification is only for the sake of clarity, and those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can be combined appropriately to form other embodiments that those skilled in the art can understand.

Claims

1. A compound having an indazole group or a pharmaceutically acceptable salt thereof, characterized in that, of the formula I: I wherein, R1is selected from hydrogen, C1-C6alkyl or C3-C10cycloalkyl; R2is selected from hydrogen or halogen; R3is selected from hydrogen, cyano or amino; X1, X2and X3are independently selected from N or CH.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is selected from isopropyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3is selected from hydrogen or cyano.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The compound or pharmaceutically acceptable salt thereof is , , , , or .

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein The preparation scheme for is as follows: ， wherein The preparation scheme of is as follows: 。 6. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein The preparation scheme for is as follows: wherein, The preparation scheme of is as follows: 。 7. A thyroid hormone β receptor agonist, characterized in that, pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

8. Use of a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a thyroid hormone beta receptor agonist according to claim 7, for the manufacture of a medicament for the treatment of a disease or disorder mediated by the thyroid hormone beta receptor.

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

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