Compound with heterocyclic structure, THRbeta receptor agonist and application

Abstract

The invention provides a compound with a heterocyclic structure, a THRbeta receptor agonist and application, and the compound with the heterocyclic structure 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] This invention relates to the field of pharmaceutical synthesis agents, and more specifically to a compound having a heterocyclic group, a THRβ receptor agonist, and its uses. Background Technology

[0002] Thyroid hormones are commonly used to treat obesity, dyslipidemia, type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, and hypothyroidism. 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. Thyroid hormone receptors originate from two separate genes, α and β. The physiological effects of thyroid hormones affect almost every organ system. Clinically, these effects manifest as changes in metabolic rate, altered 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 a crucial 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). Currently available drugs have limitations in terms of treatment response in some patients, and some even experience adverse events. Therefore, to address the shortcomings of existing drugs in terms of response rate, safety, and pharmacokinetic behavior, there is an urgent need to develop selective THRβ agonists with better specificity and drug-likeness. Further improvements and development are therefore required. Summary of the Invention

[0003] To address the shortcomings of existing technologies and solve the aforementioned problems, a compound with a heterocyclic structure, a THRβ receptor agonist, and its uses are proposed, along with the following technical solution: A compound having a heterocyclic structural group or a pharmaceutically acceptable salt thereof, with the structural formula shown in I: I in, R1 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl; R2 is selected from hydrogen, deuterium, halogen, cyano or amino; R3 is selected from hydrogen, cyano, or amino; X1 and X2 are selected from N or CR3 respectively; X3 is selected from N or CH; When X2 is selected from CH, X1 is not selected from CH; E1 is selected from -C(=O)- or -C(=S)-.

[0004] Furthermore, R1 is selected from isopropyl.

[0005] Furthermore, R2 is selected from hydrogen, cyano, and amino.

[0006] Furthermore, R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl groups are respectively marked with 1, 2 or 3 R groups X1 Replaced by, R X1 The radical is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 alkyl.

[0007] Furthermore, the compound or a pharmaceutically acceptable salt thereof is , , , , , , , , , , , , , , or .

[0008] Furthermore, The preparation process is as follows: .

[0009] Furthermore, The synthetic route is as follows: .

[0010] 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.

[0011] 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.

[0012] 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.

[0013] Due to the adoption of the above technical solutions, the beneficial technical effects of the present invention are as follows: 1. This invention designs a new compound structure that enhances target binding ability and improves in vitro activity by introducing a urea ring group; 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

[0014] 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.

[0015] A compound having a heterocyclic structural group or a pharmaceutically acceptable salt thereof, with the structural formula shown in I: I in, R1 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl; R2 is selected from hydrogen, deuterium, halogen, cyano or amino; R3 is selected from hydrogen, cyano, or amino; X1 and X2 are selected from N or CR3 respectively; X3 is selected from N or CH; When X2 is selected from CH, X1 is not selected from CH; E1 is selected from -C(=O)- or -C(=S)-.

[0016] Example 1 2-(3,5-dichloro-4-{[8-oxoylide-9-(propyl-2-yl)-7- H -purine-2-yl]oxyphenyl)-2 H ,3 H 4 H 5 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 1) The synthesis route is as follows: Synthesis of Compound 1A At room temperature, 1.031 g (5.31 mmol) of 2,4-dichloro-5-nitropyrimidine was weighed and dissolved in 20 mL of dichloromethane (DCM). The system was cooled to -78 °C with dry ice and ethanol. Isopropylamine hydrochloride (0.533 g, 5.58 mmol) and N,N-diisopropylethylamine (DIPEA) (3 mL, 16.9 mmol) were added to the solution. After reacting for half an hour, the temperature was raised to 0 °C. After stirring for another hour, the reaction was confirmed to be complete by liquid chromatography-mass spectrometry (LC-MS). The reaction was quenched with water, and then 200 mL of dichloromethane was added. The mixture was washed with 80 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 crude product 1A (1.09 g, yield: 94.8%), which was directly used in the next reaction without further purification. The mass-to-nuclear ratio (m / z) detected by liquid chromatography-mass spectrometry (LC / MS) in positive ion mode with electrospray ionization (ESI) is LC / MS (ESI) m / z: 217 (M+H). + .

[0017] Synthesis of compound 1C At room temperature, 1A (0.0502 g, 0.23 mmol) was weighed and dissolved in N,N-dimethylformamide (DMF) (1.5 ml). 1B (WO2020227549) (0.0663 g, 0.24 mmol) and potassium carbonate (K2CO3, 0.0635 g, 0.46 mmol) were added to the solution. After reacting for 4 hours, the reaction was confirmed to be complete by LC-MS. The reaction was quenched by extraction with water, followed by the addition of 60 ml of ethyl acetate. The mixture was washed with 30 ml of aqueous solution three times, then washed with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1C (0.0910 g, yield: 87.3%), which was directly used in the next reaction without further purification. LC / MS (ESI) m / z: 454 (M+H)+.

[0018] Synthesis of Compound 1D At room temperature, 1C (0.0235 g, 0.052 mmol) was weighed and dissolved in ethanol (EtOH) (2 ml) and water (0.4 ml). Then, iron powder (Fe 0.0152 g, 0.26 mmol) and ammonium chloride (NH4Cl, 0.0276 g, 0.52 mmol) were added. After the addition was complete, the system was heated to 50°C and reacted overnight, then heated to 70°C and reacted for another 2.5 hours. LC-MS was used to confirm the completeness of the reaction. The mixture was cooled to room temperature, and 50 ml of ethyl acetate was added. The mixture was washed with 20 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 crude product was purified using a preparative plate. The system was developed (dichloromethane / methanol = 30 / 1, V / V) to give compound 1D (0.0120 g, yield: 55%). LC / MS (ESI) m / z: 424 (M+H)+.

[0019] Synthesis of Compound 1 Compound 1D (0.0120 g, 0.0284 mmol) was weighed at room temperature, dissolved in 1.5 ml of tetrahydrofuran (THF), and then N,N-carbonyldiimidazole (CDI) (0.0056 g, 0.0340 mmol) was added. After reacting for 1 hour, the temperature was raised to 60 °C and the reaction was continued for 3 hours. The reaction was confirmed to be complete by LC-MS. After cooling to room temperature, the mixture was concentrated, 30 ml of ethyl acetate was added, and the mixture was washed with 10 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 the crude product. The crude product was purified by preparative plate analysis. The system was developed (dichloromethane / methanol = 25 / 1, V / V) to give compound 1 (0.0088 g, yield: 69%). LC / MS (ESI) m / z: 450 (M+H) + .

[0020] Example 2 2-(4-{[9-(1,1,1,3,3,3-2H6)propyl-2-yl-8-oxoylide-7H-purine-2-yl]oxy}-3,5-dichlorophenyl)-2H,3H,4H,5H-1,2,4-triazacyclohexane-3,5-dione (Compound 2) The synthesis route is as follows: Synthesis of Compound 2A At room temperature, weigh 1.031 g (5.31 mmol) of 2,4-dichloro-5-nitropyrimidine, dissolve it in 20 ml of dichloromethane (DCM), and cool the system to -78 °C with dry ice and ethanol. Then, dissolve (1,1,1,3,3,3- 2 H6) Isopropylamine hydrochloride (0.533 g, 5.58 mmol) and N,N-diisopropylethylamine (DIPEA) (3 mL, 16.9 mmol) were added to the solution. After reacting for half an hour, the temperature was raised to 0°C. After stirring for another hour, the reaction was detected to be complete by liquid chromatography-mass spectrometry (LC-MS). The reaction was quenched with water, and then 200 mL of dichloromethane was added. The mixture was washed with 80 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 crude product 2A (1.09 g, yield: 94.8%), which was directly used in the next reaction without further purification.

[0021] Synthesis of Compound 2 Following the synthetic method of compound 1, 1A was replaced with 2A. 2A and 1B were synthesized in DMF as solvent under the action of potassium carbonate to form 2B. 2B was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 2C. 2C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give compound 2 (56 mg). LC / MS (ESI) (m / z): 456 (M+H) + .

[0022] Example 3 2-(4-{[9-(1,1,1,2,3,3,3- 2 H7)propyl-2-yl-8-oxo-ylide-7H-purine-2-yl]oxy-3,5-dichlorophenyl)-2H,3H,4H,5H-1,2,4-triazacyclohexane-3,5-dione (compound 3) The synthesis route is as follows: Synthesis of compound 3A Weigh 1.031 g (5.31 mmol) of 2,4-dichloro-5-nitropyrimidine at room temperature, dissolve it in 20 ml of dichloromethane (DCM), and cool the system to -78 °C with dry ice and ethanol. 2H7) Isopropylamine hydrochloride (0.533 g, 5.58 mmol) and N,N-diisopropylethylamine (DIPEA) (3 mL, 16.9 mmol) were added to the solution. After reacting for half an hour, the temperature was raised to 0°C. After stirring for another hour, the reaction was detected to be complete by liquid chromatography-mass spectrometry (LC-MS). The reaction was quenched with water, and then 200 mL of dichloromethane was added. The mixture was washed with 80 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 crude product 3A. This crude product was directly used for the next reaction without further purification.

[0023] Synthesis of Compound 3 Following the synthetic method of compound 1, 1A was replaced with 3A. 3A and 1B were synthesized in DMF as solvent under the action of potassium carbonate to form 3B. 3B was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 3C. 3C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to obtain compound 3. LC / MS (ESI) (m / z): 457 (M+H) + .

[0024] Example 4 2-(3,5-Dichloro-4-{[9-(propyl-2-yl)-8-thionyl-7-yl) H -purine-2-yl]oxyphenyl)-2 H ,3 H 4 H 5 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 4) The synthesis route is as follows: Following the synthetic method of compound 1, 1D was synthesized with thiocarbonyldiimidazole substituted with carbonyldiimidazole (CDI) to obtain compound 4, as detailed below: Synthesis of Compound 4 Compound 1D (0.0120 g, 0.0284 mmol) was weighed at room temperature, dissolved in 1.5 ml of tetrahydrofuran (THF), and then 0.0061 g, 0.0340 mmol of thiocarbonyl diimidazole (ThICD) was added. After reacting for 1 hour, the temperature was raised to 60 °C and the reaction was continued for 3 hours. The reaction was confirmed to be complete by LC-MS. After cooling to room temperature, the mixture was concentrated, 30 ml of ethyl acetate was added, and the mixture was washed with 10 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 the crude product. The crude product was purified by preparative plate analysis. The system was developed (dichloromethane / methanol = 25 / 1, V / V) to obtain compound 4 (126 mg). LC / MS (ESI) m / z: 466 (M+H) + .

[0025] Example 5 2-(3,5-dichloro-4-{[2-oxoylide-1-(propyl-2-yl)-3-} H -imidazo[4,5- c ]pyridin-6-yl]oxyphenyl)-2 H ,3 H 4 H 5 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 5) The synthesis route is as follows: Synthesis of compound 5A At room temperature, 1.031 g (5.31 mmol) of 2,4-dichloro-5-nitropyridine was weighed and dissolved in 20 mL of dichloromethane (DCM). The system was cooled to -78 °C with dry ice and ethanol. Isopropylamine hydrochloride (0.533 g, 5.58 mmol) and N,N-diisopropylethylamine (DIPEA) (3 mL, 16.9 mmol) were added to the solution. After reacting for half an hour, the temperature was raised to 0 °C. After stirring for another hour, the reaction was confirmed to be complete by liquid chromatography-mass spectrometry (LC-MS). The reaction was quenched with water, and then 200 mL of dichloromethane was added. The mixture was washed with 80 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 crude product 5A (1.09 g, yield: 94.8%), which was directly used in the next reaction without further purification.

[0026] Synthesis of Compound 5 Following the synthetic method of compound 1, compound 1A was substituted with 5A. 5A and 1B were synthesized in DMF as solvent under the action of potassium carbonate to form 5B. 5B was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 5C. 5C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 5 (19.4 mg). LC / MS (ESI) m / z: 449 (M+H) + .

[0027] Example 6 2-(3,5-dichloro-4-{[2-oxoylide-3-(propyl-2-yl)-1-yl) H -imidazo[5,4- b ]pyridin-5-yl]oxyphenyl)-2 H ,3 H 4 H 5 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 6) The synthesis route is as follows: Synthesis of Compound 6A At room temperature, 1.00 g (5.10 mmol) of 2,6-dichloro-3-nitropyridine was weighed and dissolved in 30 ml of ethanol. Isopropylamine (0.643 g, 10.0 mmol) was added to the solution, and the reaction was carried out at room temperature for 12 hours. The reaction was confirmed to be complete by LC-MS. The reaction was quenched with water, and then 200 ml of dichloromethane was added. The mixture was washed with 80 ml of aqueous solution twice and then with brine. The organic phase was dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was obtained by column chromatography (n-heptane / ethyl acetate = 5 / 1, V / V) to give compound 6A (0.971 g).

[0028] Synthesis of Compound 6 Following the synthetic method of compound 1, compound 1A was substituted with compound 6A. 6A and 1B were synthesized in DMF as solvent under the action of potassium carbonate to form 6B. 6B was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 6C. 6C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give title compound 6 (16 mg). LC / MS (ESI) m / z: 449 (M+H) + .

[0029] Example 7 2-(3,5-Dichloro-4-{[7-fluoro-2-oxoylidene-1-(propyl-2-yl)-3- H -imidazo[4,5-c ]pyridin-6-yl]oxyphenyl)-5 H ,2 H ,3 H 4 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 7) Synthesis route: Synthesis of Compound 7A At room temperature, 2,3-difluoro-4-iodopyridine (1.446 g, 6 mmol), Pd2(dba)3 (0.5496 g, 0.6 mmol), Xantphos (0.6936 g, 1.2 mmol), and cesium carbonate (3.910 g, 12 mmol) were weighed and dissolved in 60 ml of 1,4-dioxane. After purging with nitrogen three times, propyl 2-amine (1.416 g, 24 mmol) was added. The mixture was heated to 80 degrees Celsius under nitrogen protection and the reaction tube was sealed for 3 hours. The reaction was confirmed to be complete by LC-MS. EA (200 ml) was added, followed by washing with water (150 ml x 2), then with brine (80 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (evolving solvent: n-heptane:EA = 10:1-4:1, V / V) to give compound 7A (0.86 g, yield 83.8%). LC / MS (ESI) m / z: 173 (M+H) + .

[0030] Synthesis of compound 7B Compound 7A (397 mg, 2.3 mmol) was weighed at room temperature and added to concentrated sulfuric acid (12 ml). After cooling in an ice-water bath, potassium nitrate (465 mg, 4.6 mmol) was added. The mixture was reacted at room temperature for 1 hour, and the system was slowly poured into 200 g of ice. Ethyl acetate (100 ml * 2) was added for extraction. The organic phases were combined, washed with 100 ml of water and 100 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 7B (274 mg). LC / MS (ESI) m / z: 218 (M+H) + .

[0031] Synthesis of Compound 7 Following the synthetic method of compound 1, 1A was replaced with compound 7B. 7B and 1B were synthesized with potassium carbonate in DMSO as solvent to form 7C. 7C was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 7D. 7D was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 7. LC / MS (ESI) (m / z): 467 (M+H) + .

[0032] Example 8 2-(3,5-Dichloro-4-{[7-chloro-2-oxoylide-1-(propyl-2-yl)-3- H -imidazo[4,5- c ]pyridin-6-yl]oxyphenyl)-5 H ,2 H ,3 H 4 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 8) The synthesis route is as follows: Following the synthetic method of compound 7, 2,3-difluoro-4-iodopyridine was substituted with 3-chloro-2-fluoro-4-iodopyridine to give title compound 8 (5.7 mg), LC / MS (ESI) (m / z): 483 (M+H)+.

[0033] Synthesis of Compound 8A At room temperature, 3-chloro-2-fluoro-4-iodopyridine (6 mmol), Pd2(dba)3 (0.5496 g, 0.6 mmol), Xantphos (0.6936 g, 1.2 mmol), and cesium carbonate (3.910 g, 12 mmol) were weighed and dissolved in 60 ml of 1,4-dioxane. After purging with nitrogen three times, propyl 2-amine (1.416 g, 24 mmol) was added. The mixture was heated to 80 degrees Celsius under nitrogen protection and the reaction tube was sealed for 3 hours. The reaction was confirmed to be complete by LC-MS. EA (200 ml) was added, followed by washing with water (150 ml x 2), then with brine (80 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (evolving solvent: n-heptane:EA = 10:1-4:1, V / V) to give compound 8A (0.86 g, yield 83.8%). LC / MS (ESI) m / z: 173 (M+H) + .

[0034] Synthesis of compound 8B Compound 8A (397 mg, 2.3 mmol) was weighed at room temperature and added to concentrated sulfuric acid (12 ml). After cooling in an ice-water bath, potassium nitrate (465 mg, 4.6 mmol) was added. The mixture was reacted at room temperature for 1 hour, and the system was slowly poured into 200 g of ice. Ethyl acetate (100 ml * 2) was added for extraction. The organic phases were combined, washed with 100 ml of water and 100 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 8B (274 mg). LC / MS (ESI) m / z: 218 (M+H) + .

[0035] Synthesis of Compound 8 Following the synthetic method of compound 1, 1A was replaced by compound 8B. 8B and 1B were synthesized into 8C in the presence of potassium carbonate using DMSO as a solvent. 8C was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 8D. 8D was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to obtain the title compound 8. LC / MS (ESI) (m / z): 467 (M+H) + .

[0036] Example 9 2-(3,5-Dichloro-4-{[7-chloro-2-oxoylide-1-(propyl-2-yl)-3- H -imidazo[4,5- c ]pyridin-6-yl]oxyphenyl)-3,5-dioxane-4 H -1,2,4-Triazacyclohexane-6-carboxynitrile (Compound 9) The synthesis route is as follows: Following the synthetic method of compound 8, compound 1B was replaced with 9A (a common intermediate that can be purchased). 8B and 9A were synthesized into 9B in the presence of potassium carbonate using DMSO as a solvent. 9B was then reacted with ethanol and water, and Fe and NH4Cl were added to generate 9C. 9C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to obtain the title compound 9. LC / MS (ESI) (m / z): 508(M+H)+.

[0037] Example 10: 2-(4-{[7-bromo-2-oxoylide-1-(propyl-2-yl)-3- H -imidazo[4,5- c ]pyridin-6-yl]oxy}-3,5-dichlorophenyl)-5 H ,2 H ,3H 4 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 10) The synthesis route is as follows: Following the synthetic method of compound 1, compound 2,4-dichloro-5-nitropyrimidine was substituted with compound 10A to obtain the title compound 10, as follows: Following the synthetic method of compound 1, compound 2,4-dichloro-5-nitropyrimidine was substituted with compound 10A. 10A reacted with isopropylamine in THF solvent under the action of triethylamine to generate 10B. 10B and 1B were then reacted with potassium carbonate in DMF solvent to synthesize 10C. 10C was then reacted with ethanol and water solvents, and Fe and NH4Cl were added to generate 10D. 10D was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to obtain compound 10 (3.5 mg). LC / MS (ESI) m / z: 529 (M+H) + .

[0038] Example 11: 2-(4-{[4-bromo-2-oxoylidene-3-(propyl-2-yl)-1-yl] H -benzo[ d [Imidazol-5-yl]oxy-3,5-dichlorophenyl)-5 H ,2 H ,3 H 4 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 11) The synthesis route is as follows: Following the synthetic method of compound 1, 2,4-dichloro-5-nitropyrimidine was replaced with compound 11A (3-bromo-2,4-difluoro-1-nitrobenzene). 11A reacted with isopropylamine in THF solvent under the action of triethylamine to generate 11B. 11B and 1B were reacted with potassium carbonate in DMF solvent to synthesize 11C. 11C was reacted with ethanol and water solvents, and Fe and NH4Cl were added to generate 11D. 11D was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 11. LC / MS (ESI) (m / z): 527 (M+H) + .

[0039] Example 12: 2-(3,5-dichloro-4-{[7-methyl-2-oxoylide-1-(propyl-2-yl)-3-yl) H -imidazo[4,5- c ]pyridin-6-yl]oxyphenyl)-5 H ,2 H ,3 H 4 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 12) The synthesis route is as follows: Following the synthetic method of compound 1, 2,4-dichloro-5-nitropyridine was substituted with 12A (3-methyl-2-fluoro-4-iodo-5-nitropyridine). 12A reacted with isopropylamine in THF solvent under the action of triethylamine to generate 12B. 11B reacted with 1B in DMF solvent under the action of potassium carbonate to synthesize 11C. 11C was then reacted with ethanol and water solvents, and Fe and NH4Cl were added to generate 11D. 11D was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 12. LC / MS (ESI) m / z: 463 (M+H) + .

[0040] Example 13: 6-{[2,6-dichloro-4-(3,5-dioxane-4-)} H -1,2,4-Triazacyclohexane-2-yl)phenyl]oxy}-2-oxo-1-(propyl-2-yl)-3 H -imidazo[4,5- c Pyridine-7-carboxynitrile (compound 13) The synthesis route is as follows: Following the synthetic method of compound 7, 2,4-dichloro-5-nitropyridine was substituted with 13A (2,4-dichloro-5-nitropyrimidine). 13A reacted with isopropylamine in THF solvent under the action of triethylamine to generate 13B. 11B reacted with 1B in DMF solvent under the action of potassium carbonate to synthesize 11C. 11C was then reacted with ethanol and water solvents, and Fe and NH4Cl were added to generate 11D. 11D was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 13. LC / MS (ESI) m / z: 474 (M+H) + .

[0041] Example 14: 2-(3,5-dichloro-4-{[8-oxoylidene-9-(1,1,1-trifluoroprop-2-yl)-7-) H -purine-2-yl]oxyphenyl)-4 H 5 H ,2 H ,3 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 14) The synthesis route is as follows: Following the synthetic method of compound 1, 1,1,1-trifluoroisopropylamine hydrochloride was substituted for isopropylamine hydrochloride. 2,4-Dichloro-5-nitropyrimidine was reacted with 1,1,1-trifluoroisopropylamine hydrochloride and DIPEA in DCM solvent to generate 14A. 14A and 1B were reacted with potassium carbonate in DMF solvent to synthesize 14B. 14B was reacted with ethanol and water solvents, and Fe and NH4Cl were added to generate 14C. 14C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 14. LC / MS (ESI) m / z: 504 (M+H) + .

[0042] Example 15: 2-[3,5-dichloro-4-({8-oxo-9-[(2 S )-1,1,1-trifluoropropyl-2-yl]-7 H [-purine-2-yl]oxyphenyl]-4 H 5 H ,2 H ,3 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 15) The synthesis route is as follows: Following the synthetic method of compound 14, 1,1,1-trifluoroisopropylamine hydrochloride was replaced with (R)-1,1,1-trifluoroisopropylamine hydrochloride. 2,4-Dichloro-5-nitropyrimidine was reacted with (R)-1,1,1-trifluoroisopropylamine hydrochloride and DIPEA in DCM to generate 15A. 15A and 1B were reacted with potassium carbonate in DMF to synthesize 15B. 15B was reacted with ethanol and water, and Fe and NH4Cl were added to generate 15C. 15C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 15. LC / MS (ESI) m / z: 504 (M+H) + .

[0043] Example 16: 2-[3,5-dichloro-4-({8-oxo-9-[(2 R )-1,1,1-trifluoropropyl-2-yl]-7 H [-purine-2-yl]oxyphenyl]-4 H 5 H ,2 H ,3 H -1,2,4-Triazacyclohexane-3,5-dione (Compound 16) The synthesis route is as follows: Following the synthetic method of compound 14, 1,1,1-trifluoroisopropylamine hydrochloride was replaced with (S)-1,1,1-trifluoroisopropylamine hydrochloride. 2,4-Dichloro-5-nitropyrimidine was reacted with (S)-1,1,1-trifluoroisopropylamine salt and DIPEA in DCM to generate 15A. 15A and 1B were reacted with potassium carbonate in DMF to synthesize 15B. 15B was reacted with ethanol and water, and Fe and NH4Cl were added to generate 15C. 15C was then reacted with tetrahydrofuran (THF) and N,N-carbonyldiimidazole (CDI) to give the title compound 16. LC / MS (ESI) m / z: 504 (M+H) + .

[0044] Biological evaluations were performed on Examples 1-16 above. Biological Assessment 1: Assay of the cellular-level agonistic activity of the compound on thyroid hormone receptors I. Cell Plating (96-well plate) 1) Digest logarithmically growing hTHRβ DR4-LucHEK293 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.

[0045] 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.

[0046] II. Compound Incubation 1. First, dilute with DMSO to prepare a 1000* dimethyl sulfoxide (DMSO) sample solution. Then, further dilute the DMSO sample solution 100-fold with 90% DMEM + 10% Charcoal Stripped FBS medium (1 μL DMSO sample + 99 μL medium) to obtain a 10* sample gradient solution. Subsequent concentrations are then diluted 3-fold, for a total of 9 concentration gradients.

[0047] 2. Add serially diluted 10* concentration samples (10 uL / 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.

[0048] 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.

[0049] 4. The positive control drug is Resmetirom (MGL-3196), which is a highly selective THRβ agonist.

[0050] 5. Experimental Results Table 1 EC50 of Examples 1-16 The above experimental results show that the compounds with the disclosed structure have higher activity or selectivity than the positive compounds.

[0051] Biological assessment 2: Therapeutic effects of compounds in a high-fat diet-induced mouse model The effects of the compounds on NASH were assessed using a mouse model induced by a high-fat diet combined with CCl4. Eight-week-old C57 / BL6J mice were fed a high-fat diet (XTHF60, Jiangsu Xietong Biotechnology) for 12 weeks to induce obesity, with mouse weights ranging from 40 to 40 g. Obese mice were divided into six groups according to average body weight. Mice were intraperitoneally injected with carbon tetrachloride (CCl4) every three days and continued on the high-fat diet. During this period, the solvent and the test compound were administered orally via gavage daily. The dosage of the compound was 3 mg / kg.

[0052] Twenty-eight days after administration, mice were sacrificed and serum lipids, serum liver injury, hematoxylin-eosin (H&E) staining of liver tissue, and Sirius red histological staining of liver tissue were analyzed.

[0053] As shown in Table 2, compared with the solvent control group of NASH mice, the serum lipids and serum liver injury indicators of NASH mice treated with compound 1 were improved to a certain extent.

[0054] Table 2 Serum biochemistry of NASH mice *: P ≤ 0.05 Steroid degeneration scores were calculated using H&E staining as follows: 0 points, <5%; 1 point, 5-33%; 2 points, >33-66%; 3 points, >66%. Fibrosis was evaluated using the Ishak score based on Sirius red histological staining of liver tissue. Specifically, Ishak 0: normal liver; Ishak 1: minor dilatation of the hepatic hilum; Ishak 2: major dilatation of the hepatic hilum; Ishak 3: major dilatation of the hepatic hilum with mild bridging fibrosis; Ishak 4: dilatation of the hepatic hilum with significant bridging fibrosis; Ishak 5: bridging fibrosis with nodules; Ishak 6: possible or confirmed cirrhosis.

[0055] As shown in Table 3, compared with the solvent control group of NASH mice, NASH mice treated with compound 1 showed better improvement in steatosis score and fibrosis than the control drug MGL3196.

[0056] Table 3. NAS scores and fibrosis in NASH mice *: P ≤ 0.05.

[0057] 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 a heterocyclic structure or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula is shown in I: I in, R1 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl; R2 is selected from hydrogen, deuterium, halogen, cyano or amino; R3 is selected from hydrogen, cyano, or amino; X1 and X2 are selected from N or CR3 respectively; X3 is selected from N or CH; When X2 is selected from CH, X1 is not selected from CH; E1 is selected from -C(=O)- or -C(=S)-.

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

3. A compound having a heterocyclic structure or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R2 is selected from hydrogen, cyano, or amino.

4. A compound having a heterocyclic structure or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl groups are respectively marked with 1, 2 or 3 R groups X1 Replaced by, R X1 The radical is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 alkyl.

5. A compound having a heterocyclic structure or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound or its pharmaceutically acceptable salt is , , , , , , , , , , , , , , , or .

6. A compound having a heterocyclic structure or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, The preparation process is as follows: 。 7. A compound having a heterocyclic structure or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, The synthetic route is as follows: 。 8. A thyroid hormone β-receptor agonist, characterized in that, It comprises a compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

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

10. The use according to claim 9, 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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