Thyroid hormone β receptor agonist, crystalline form, manufacturing method and use thereof

Abstract

The present invention, which belongs to the pharmaceutical field, discloses a thyroid hormone β receptor agonist, a crystalline form, a preparation method, and uses thereof. The compound is a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof. When Cu-Ka radiation is used, crystalline form A of the compound represented by formula (I) exhibits characteristic peaks at angles of 6.10±0.20°, 12.08±0.20°, and 16.49±0.20° in the X-ray powder diffraction pattern at 2θ angles. The present invention has developed a novel 2-pyridone derivative that has high agonistic activity and selectivity for the thyroid hormone β receptor and can be used to treat metabolic diseases, particularly diseases related to the thyroid hormone receptor. Furthermore, the present invention has investigated a series of crystalline forms of this compound, which have advantages such as good stability, low hygroscopicity, and resistance to heat. JPEG2025540242000035.jpg5774

Description

[Technical Field]

[0001] This application claims priority from a Chinese patent application filed with the State Intellectual Property Office of the People's Republic of China on December 7, 2022, bearing application number 202211563493.0 and entitled "Thyroid hormone beta receptor agonists, crystalline forms, preparation methods and uses thereof," the entire contents of which are incorporated herein by reference.

[0002] The present invention belongs to the technical field of pharmaceuticals, and specifically relates to thyroid hormone β receptor agonists, crystalline forms, preparation methods and uses thereof. [Background technology]

[0003] Thyroid hormones play an important role in normal growth and development and maintaining metabolic balance (Physiological Reviews 2001,81(3),1097-1126.). Thyroid hormones are produced by the thyroid gland and secreted into the circulation (hypothalamus / pituitary / thyroid axis) in two different forms: T4 and T3. T4 is the main form secreted by the thyroid gland, while T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, which are found in all tissues but are primarily present in the liver and kidney. [ka]

[0004] Circulating levels of thyroid hormones are precisely regulated by feedback mechanisms in the hypothalamic-pituitary-thyroid axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism can have profound effects on the heart, weight, metabolism, metabolic rate, body temperature, cholesterol, bones, muscles, and behavior.

[0005] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (THRs) (Endocrine Reviews (1993) 14, 348-399). THRs belong to the nuclear receptor family and are encoded by distinct α and β genes located on chromosomes 17 and 3 in humans. Different protein isoforms are produced by selective cleavage of the primary transcript, with each gene producing two subtypes: THRα1, THRα2, THRβ1, and THRβ2. THRβ1 and THRβ2 are derived from differential promoter expression, and these two subtypes differ only in their amino termini. THRα1 and THRα2 are derived from differential splicing of precursor mRNA, and the differences are primarily in their carboxyl termini. THRα1, THRβ1, and THRβ2 can bind to thyroid hormones. THRβ is distributed mainly in the liver, kidney, pituitary gland, and cerebral tissues and plays an important role in regulating the actions of TRH and thyroxine in the liver. However, THRα is widely distributed throughout the body and is primarily associated with extrahepatic adverse cardiovascular and skeletal / muscular effects (Drugs (2017) 77, 1613-1621). Therefore, thyroid hormone analogs that can avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones could be used to treat metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and diabetes, as well as other diseases such as hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, and thyroid diseases.

[0006] In the prior art, a series of thyroid hormone agonists have been developed, most of which were designed based on the structure of T3, the natural ligand of the THR receptor. For example, thyroid hormone analogs having structures different from those of the compounds of the present invention have been disclosed (Agricultural and Biol. Chem. 1974, 38(6), 1169; J. Med. Chem. 1989, 32, 320; J. Med. Chem. 2014, 57(10), 3912; WO2007009913; WO2010122980). Among them, compound 31 in Example 8 of WO2007009913 is MGL-3196, an orally administered small molecule hepatic thyroid hormone receptor β subtype (THR-β) selective agonist that is currently the most widely used in clinical trials. Preclinical toxicology and Phase I clinical data indicate that MGL-3196 can significantly reduce LDL cholesterol, triglycerides, and lipoproteins as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemia, making it an ideal candidate for cardiovascular risk in patients with NASH and dyslipidemia at moderate statin doses or intolerant to statins.

[0007] Subsequently, many publications, such as WO2020073974, CN111320609A, and WO2019240938, have disclosed that a series of structural modifications were made to the pyridazinone ring in different directions based on the MGL-3196 structure, but the parent nucleus all had a pyridazinone structure similar to that of MGL-3196. Recently published WO2020169069 and WO2021067791 have disclosed other pyridinone-like structures, but these had problems such as reduced THRβ biological activity and THRβ / THRα selectivity. In particular, after the nitrogen atom on the pyridone was substituted, most compounds lost their pharmacological activity or were extremely unstable during metabolism in the body, making pharmaceutical development difficult.

[0008] The compounds and experimental drugs disclosed in these prior art technologies have issues with drug discovery potential, etc. Therefore, in order to treat diseases related to the thyroid hormone receptor, it is necessary to continue to discover and develop novel highly active and highly selective compounds that can retain the beneficial effects of thyroid hormone while avoiding its adverse effects, as well as novel compounds with favorable in vivo pharmacokinetic effects.

[0009] It is with this in mind that the present invention has been proposed. Summary of the Invention [Problem to be solved by the invention]

[0010] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a thyroid hormone β receptor agonist, a crystalline form, a preparation method, and uses thereof. The present invention has developed a novel 2-pyridone derivative that has high agonistic activity and selectivity for the thyroid hormone β receptor and can be used to treat metabolic diseases, particularly diseases related to the thyroid hormone receptor. Furthermore, the present invention has also investigated a series of crystalline forms of this compound that have advantages such as good stability, low hygroscopicity, and resistance to heat. [Means for solving the problem]

[0011] In order to solve the above technical problems, the basic concept of the technical solution of the present invention is as follows:

[0012] A first object of the present invention is to provide a compound having a structural formula represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0013] Formula (I) [ka]

[0014] A second object of the present invention is to provide a drug containing, as an active ingredient, a compound having a structural formula represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0015] Preferably, the drug is a thyroid hormone β-receptor agonist. Furthermore, the drug further comprises a pharmaceutically acceptable excipient therefor.

[0016] A third object of the present invention is to provide use of a compound having a structural formula represented by formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for a metabolic disease. Preferably, the therapeutic agent is a thyroid hormone β-receptor agonist. Preferably, the metabolic disease includes obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangiocarcinoma. Preferably, the thyroid disease includes thyroid cancer and hypothyroidism.

[0017] A fourth object of the present invention is to provide a crystalline form A of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 6.10±0.20°, 12.08±0.20°, and 16.49±0.20°.

[0018] In some embodiments of the present invention, the crystals of crystalline form A have an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 6.10±0.20°, 12.08±0.20°, 13.61±0.20°, 15.71±0.20°, 16.49±0.20°, 20.05±0.20°, 21.47±0.20°, and 22.49±0.20°.

[0019] In some embodiments of the present invention, the crystals of crystalline form A have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 6.10±0.20°, 12.08±0.20°, 13.61±0.20°, 15.71±0.20°, 16.49±0.20°, 20.05±0.20°, 20.73±0.20°, 21.47±0.20°, 21.80±0.20°, and 22.49±0.20°.

[0020] In some embodiments of the present invention, the crystals of crystalline form A have an X-ray powder diffraction pattern of 6.10±0.20°, 6.86±0.20°, 8.64±0.20°, 10.14±0.20°, 12.08±0.20°, 12.75±0.20°, 13.64±0.20°, 14.44±0.20°, 15.22±0.20°, 15.45±0.20°, 15.75±0.20°, and 16.49±0.20°. 20°, 17.14±0.20°, 17.89±0.20°, 18.08±0.20°, 18.62±0.20°, 18.82±0.20°, 19.09±0.20°, 19.59±0.20°, 20.07±0.20°, 21.53±0.20°, 21.83±0.20°, 22.51±0.20°, 23.26±0.20°, 23.90±0.20°, 24.16±0.20°, 24.4 7±0.20°, 24.89±0.20°, 25.56±0.20°, 25.77±0.20°, 26.17±0.20°, 26.46±0.20°, 26.65±0.20°, 26.97±0.20°, 27.51±0.20°, 27.79±0.20°, 28.41±0.20°, 28.83±0.20°, 29.05±0.20°, 29.59±0.20°, 30.47±0.20° , 31.03±0.20°, 31.37±0.20°, 31.97±0.20°, 32.30±0.20°, 32.71±0.20°, 33.26±0.20°, 33.37±0.20°, 34.35±0.20°, 35.62±0.20°, 36.09±0.20°, 38.20±0.20°, 38.74±0.20°, and 39.40±0.20°.

[0021] In some embodiments of the present invention, the crystals of crystalline form A have an XRPD pattern as shown in FIG.

[0022] In some embodiments of the present invention, the crystals of crystalline form A have analytical data of their XRPD pattern as shown in Table 1 below.

[0023] Table 1: Analysis data of XRPD pattern of crystals of crystalline form A [Table 1-1] [Table 1-2]

[0024] In some embodiments of the present invention, the crystals of crystalline form A have a single endothermic peak at 300.1±3.0°C in a differential scanning calorimetry curve.

[0025] In some embodiments of the present invention, the crystals of crystalline form A have a DSC curve as shown in FIG.

[0026] In some embodiments of the present invention, the crystalline form A exhibits a weight loss rate of 0.6% at 150.0°C ± 3.0°C in the thermogravimetric analysis curve.

[0027] In some embodiments of the present invention, the crystals of crystalline form A have a TGA curve as shown in FIG.

[0028] The present invention further provides the use of crystalline form A of the compound of formula (I) in the manufacture of a medicament for the treatment of a metabolic disease.

[0029] The present invention further provides use of a crystal of crystalline Form A of compound of formula (I) in the manufacture of a medicament for the treatment of a disease associated with thyroid hormone receptors.

[0030] Preferably, the therapeutic agent is a thyroid hormone β-receptor agonist. Preferably, the metabolic disease includes obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangiocarcinoma.

[0031] As a result of analysis, it was found that the crystalline form A of the compound of formula (I) has good stability and low hygroscopicity under high temperature, high humidity, long-term and accelerated conditions.

[0032] A fifth object of the present invention is to provide a method for preparing crystalline form A of the compound represented by formula (I), which comprises the steps of: Step (1) of dissolving the compound represented by formula (I) in a mixed solvent of tetrahydrofuran and methanol, and heating the mixture to completely dissolve the compound; Step (2) of adding water to the solution under stirring, gradually cooling the solution, continuing to stir, and filtering; and (3) washing the resulting filter cake with methanol, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound represented by formula (I).

[0033] Preferably, in step (1), the volume ratio of tetrahydrofuran to methanol in the mixed solvent is in the range of 2:1 to 1:2.

[0034] Preferably, in step (1), the concentration of the compound represented by formula (I) in the mixed solvent is in the range of 0.02 to 0.2 g / ml.

[0035] Preferably, in step (1), the mixture is heated to 45 to 65°C.

[0036] Preferably, in step (2), the ratio of the volume of water added to the volume of the mixed solvent in step (1) is in the range of 1:2 to 3:1.

[0037] Preferably, in step (2), water is added to the solution at 15 to 35°C, the solution is slowly cooled to 15 to 30°C, and the solution is continuously stirred for 0.5 to 1 hour.

[0038] Alternatively, the manufacturing method includes: Step (1) of dissolving the compound represented by formula (I) in N,N-dimethylformamide, dissolving it to a clear solution, and then filtering it; Step (2) adding water to the solution under stirring to precipitate a solid, followed by stirring overnight and centrifuging; and (3) washing the resulting filter cake with water, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound represented by formula (I).

[0039] Preferably, in step (1), the concentration of the compound represented by formula (I) in N,N-dimethylformamide is in the range of 0.1 to 0.3 g / ml.

[0040] Preferably, the ratio of the volume of water added in step (2) to the volume of N,N-dimethylformamide in step (1) is 1:2 to 3:1.

[0041] Preferably, in step (2), water is added to the solution at 15 to 35°C.

[0042] Alternatively, the manufacturing method includes: Step (1) of dissolving the compound represented by formula (I) in dimethyl sulfoxide, dissolving it to a clear solution, and then filtering it; Step (2) adding water to the solution under stirring to precipitate a solid, followed by stirring overnight and centrifuging; and (3) washing the resulting filter cake with water, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound represented by formula (I).

[0043] Preferably, in step (1), the concentration of the compound represented by formula (I) in dimethyl sulfoxide is in the range of 0.3 to 0.8 g / ml.

[0044] Preferably, in step (2), the ratio of the volume of water added to the volume of dimethyl sulfoxide added in step (1) is in the range of 3:1 to 7:1.

[0045] Preferably, in step (2), water is added to the solution at 15 to 35°C.

[0046] Alternatively, the manufacturing method includes: Step (1) of dissolving the compound of formula (I) in methanol, heating to complete dissolution, and filtering; (2) concentrating and removing a portion of the methanol until a solid is precipitated, followed by cooling and centrifuging; and (3) washing the resulting filter cake with methanol, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound represented by formula (I).

[0047] Preferably, in step (1), the concentration of the compound represented by formula (I) in methanol is in the range of 0.01 to 0.1 g / ml.

[0048] Preferably, in step (1), the mixture is heated to a temperature in the range of 45 to 65°C.

[0049] Preferably, in step (2), a portion of the methanol is removed by concentration at a temperature of 30 to 50°C.

[0050] Preferably, in step (2), the mixture is cooled to room temperature of 20 to 30°C.

[0051] A sixth object of the present invention is to provide a crystalline form B of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.35±0.20°, 10.36±0.20°, and 18.32±0.20°.

[0052] In some embodiments of the present invention, the crystals of crystalline form B have an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 9.35±0.20°, 10.36±0.20°, 11.77±0.20°, 12.65±0.20°, 15.21±0.20°, 18.32±0.20°, 19.60±0.20°, and 22.74±0.20°.

[0053] In some embodiments of the present invention, the crystals of crystalline form B have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.35±0.20°, 10.36±0.20°, 11.77±0.20°, 12.65±0.20°, 15.21±0.20°, 18.32±0.20°, 19.60±0.20°, 20.03±0.20°, 21.30±0.20°, and 22.74±0.20°.

[0054] In some embodiments of the present invention, the crystals of crystalline form B have an X-ray powder diffraction pattern of 4.99°, 7.54°, 9.34°, 10.35°, 11.02°, 11.36°, 11.76°, 12.64°, 13.97°, 15.21°, 16.24°, 17.46°, 18.32°, 18.69°, 19.33°, 19.59°, 20.03°, 20.42°, 20.72° , 21.29°, 22.13°, 22.74°, 23.59°, 24.13°, 24.37°, 24.95°, 25.39°, 25.83°, 26.24°, 26.49°, 26.97°, 28.04°, 28.18°, 28.81°, 29.83°, 30.87°, 33.56°, 35.64°, 37.66°, and 39.26° 2θ angles.

[0055] In some embodiments of the present invention, the crystals of crystalline form B have an XRPD pattern as shown in FIG.

[0056] In some embodiments of the present invention, the crystals of crystalline form B have analytical data of their XRPD pattern as shown in Table 2 below.

[0057] Table 2: Analysis data of XRPD pattern of crystals of crystalline form B [Table 2]

[0058] In some embodiments of the present invention, the crystals of crystalline form B have a differential scanning calorimetry curve with two endothermic peaks at 139.5°C ± 3.0°C and 315.6°C ± 3.0°C.

[0059] In some embodiments of the present invention, the crystals of crystalline form B have a DSC curve as shown in FIG.

[0060] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystals of crystalline form B shows a weight loss rate of 16.0% at 150.0°C ± 3.0°C.

[0061] In some embodiments of the present invention, the crystals of crystalline form B have a TGA curve as shown in FIG.

[0062] A seventh object of the present invention is to provide a crystalline form C of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 5.96±0.20°, 10.96±0.20°, and 22.84±0.20°.

[0063] In some embodiments of the present invention, the crystals of crystalline form C have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 5.96±0.20°, 9.25±0.20°, 10.96±0.20°, 11.94±0.20°, 21.92±0.20°, 22.84±0.20°, 23.69±0.20°, and 28.12±0.20°.

[0064] In some embodiments of the present invention, the crystals of crystalline form C have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 5.96±0.20°, 9.25±0.20°, 10.96±0.20°, 11.94±0.20°, 15.52±0.20°, 19.50±0.20°, 21.92±0.20°, 22.84±0.20°, 23.69±0.20°, and 28.12±0.20°.

[0065] In some embodiments of the present invention, the crystals of crystalline form C have an X-ray powder diffraction pattern of 5.96°, 9.25°, 9.91°, 10.96°, 11.51°, 11.93°, 12.29°, 12.55°, 13.56°, 14.41°, 15.04°, 15.52°, 16.41°, 16.68°, 17.30°, 17.51°, 17.92°, 18.45°, 18.79°, 19.50°, 20.01°, 20.33°, 20.70°, 21.42°, 21.92°, 22.24°, 22.83°, 23.68°, 24.11° , 24.48°, 24.78°, 25.23°, 25.69°, 25.96°, 26.20°, 26.41°, 26.70°, 26.95°, 27.86°, 28.12°, 28.54°, 28.99°, 29.60°, 30.49°, 30.96°, 31.50°, 32.02°, 32.59°, 33.16°, 33.3°, 33.64°, 34.18°, 34.94°, 35.28°, 35.85°, 36.83°, 37.46°, 38.02°, 39.11°, and 39.347°.

[0066] In some embodiments of the present invention, the crystals of crystalline form C have an XRPD pattern as shown in FIG.

[0067] In some embodiments of the present invention, the crystals of crystalline form C have analytical data of their XRPD pattern shown in Table 3 below.

[0068] Table 3: Analysis data of XRPD pattern of crystals of crystalline form C [Table 3-1] [Table 3-2]

[0069] In some embodiments of the present invention, the crystals of crystalline form C have a differential scanning calorimetry curve with two endothermic peaks at 123.7°C±3.0°C and 315.7°C±3.0°C.

[0070] In some embodiments of the present invention, the crystals of crystalline form C have a DSC curve as shown in FIG.

[0071] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystals of crystalline form C shows a weight loss rate of 10.9% at 150.0°C ± 3.0°C.

[0072] In some embodiments of the present invention, the crystals of crystalline form C have a TGA curve as shown in FIG.

[0073] An eighth object of the present invention is to provide a crystalline form D of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.97±0.20°, 11.66±0.20°, and 15.83±0.20°.

[0074] In some embodiments of the present invention, the crystals of crystalline form D have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.97±0.20°, 9.08±0.20°, 11.66±0.20°, 12.47±0.20°, 15.83±0.20°, 17.98±0.20°, 20.47±0.20°, and 20.74±0.20°.

[0075] In some embodiments of the present invention, the crystals of crystalline form D have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.97°, 9.08°, 11.66°, 12.47°, 15.83°, 17.98°, 20.47°, 20.74°, 23.37°, and 25.04°.

[0076] In some embodiments of the present invention, the crystals of crystalline form D have an X-ray powder diffraction pattern of 4.91°, 6.96°, 7.97°, 9.07°, 9.30°, 10.16°, 11.65°, 12.46°, 13.19°, 13.82°, 14.35°, 14.88°, 15.82°, 17.15°, 17.43°, 17.97°, 18.22°, 18.75°, 19.50°, 20. It has characteristic diffraction peaks at angles 2θ of 47°, 20.74°, 21.69°, 23.12°, 23.36°, 23.86°, 24.45°, 25.04°, 25.33°, 26.32°, 26.57°, 26.95°, 27.37°, 28.07°, 28.91°, 30.61°, 31.96°, 32.45°, 32.75°, 34.36°, 35.25°, and 37.64°.

[0077] In some embodiments of the present invention, the crystals of crystalline form D have an XRPD pattern as shown in FIG.

[0078] In some embodiments of the present invention, the crystals of crystalline form D have analytical data of their XRPD pattern as shown in Table 4 below.

[0079] Table 4: Analytical data of XRPD pattern of crystalline form D [Table 4]

[0080] A ninth object of the present invention is to provide a crystalline form E of the compound represented by formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 12.43±0.20°, 12.70±0.20°, and 17.94±0.20°.

[0081] In some embodiments of the present invention, the crystalline form E has an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 9.02±0.20°, 10.15±0.20°, 12.43±0.20°, 12.70±0.20°, 17.94±0.20°, 19.08±0.20°, 20.66±0.20°, and 24.96±0.20°.

[0082] In some embodiments of the present invention, the crystals of crystalline form E have an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 9.02±0.20°, 10.14±0.20°, 12.43±0.20°, 12.70±0.20°, 17.94±0.20°, 19.08±0.20°, 20.66±0.20°, 22.28±0.20°, 24.95±0.20°, and 26.55±0.20°.

[0083] In some embodiments of the present invention, the crystals of crystalline form E have an X-ray powder diffraction pattern of 3.17°, 6.10°, 6.37°, 6.88°, 7.11°, 7.89°, 9.02°, 10.14°, 11.60°, 12.01°, 12.18°, 12.43°, 12.69°, 13.19°, 13.73°, 14.77°, 15.59°, 15.91°, 16.75°, 17.10°, 17.94°, 18.70°, 19.07°, 19.54°, 19.86°, 20.66°, 21.99°, 22.01°, 23.01°, 24.01°, 25.01°, 26.01°, 27.01°, 28.01°, 29.01°, 30.01°, 31.01°, 32.01°, 33.01°, 34.01°, 35.01°, 36.01°, 37.01°, 38.01°, 39.01°, 40.01°, 41.01°, 42.01°, 43.01°, 44.01°, 45.01°, 46.01°, 47.01°, 48.01°, 49.01°, 50.01°, 51.01°, 52.01°, 53.01°, 54.01°, 55.01°, 56.0 It has characteristic diffraction peaks at angles 2θ of 2.28°, 22.68°, 23.34°, 23.60°, 23.80°, 24.07°, 24.39°, 24.95°, 26.55°, 27.20°, 27.46°, 27.96°, 28.25°, 28.87°, 29.33°, 29.77°, 30.02°, 30.35°, 30.51°, 31.66°, 32.07°, 32.74°, 33.94°, 34.49°, 34.70°, 35.71°, 36.27°, 38.61°, and 39.66°.

[0084] In some embodiments of the present invention, the crystals of crystalline form E have an XRPD pattern as shown in FIG.

[0085] In some embodiments of the present invention, the crystals of crystalline form E have analytical data of their XRPD pattern as shown in Table 5 below.

[0086] Table 5: Analytical data of XRPD pattern of crystalline form E [Table 5-1] [Table 5-2]

[0087] In some embodiments of the present invention, the crystalline form E has a differential scanning calorimetry curve with two endothermic peaks at 151.1°C ± 3.0°C and 315.2°C ± 3.0°C.

[0088] In some embodiments of the present invention, the crystals of crystalline form E have a DSC curve as shown in FIG.

[0089] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystalline form E shows a weight loss rate of 6.6% at 150.0°C ± 3.0°C.

[0090] In some embodiments of the present invention, the crystals of crystalline form E have a TGA curve as shown in FIG.

[0091] A tenth object of the present invention is to provide a crystalline form F of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.13±0.20°, 12.18±0.20°, and 18.25±0.20°.

[0092] In some embodiments of the present invention, the crystals of crystalline form F have an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 7.13±0.20°, 12.18±0.20°, 12.68±0.20°, 15.59±0.20°, 18.25±0.20°, 19.05±0.20°, 22.34±0.20°, and 22.70±0.20°.

[0093] In some embodiments of the present invention, the crystals of crystalline form F have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.13±0.20°, 12.18±0.20°, 12.68±0.20°, 15.59±0.20°, 17.73±0.20°, 18.25±0.20°, 19.05±0.20°, 22.34±0.20°, 22.70±0.20°, and 24.63±0.20°.

[0094] In some embodiments of the present invention, the crystalline form E has an X-ray powder diffraction pattern of 6.087°, 6.34°, 7.13°, 9.72°, 10.10°, 12.18°, 12.68°, 12.86°, 14.18°, 14.77°, 15.15°, 15.59°, 15.89°, 16.70°, 17.10°, 17.48°, 17.72°, 18.24°, 18.68°, 19.04°, 19.48°, 19.84°, 20.22°, 20.62°, 21.10°, 21.31°, 21.96°, 22.34°, 22.70°, 23.36°, 23.61°, It has characteristic diffraction peaks at angles 2θ of 23.84°, 24.10°, 24.62°, 25.15°, 25.31°, 25.71°, 26.32°, 26.49°, 26.68°, 27.03°, 27.20°, 27.84°, 28.07°, 28.28°, 29.37°, 29.77°, 29.99°, 30.32°, 30.50°, 31.92°, 32.58°, 32.99°, 32.99°, 34.52°, 35.08°, 35.77°, 36.14°, 36.48°, 37.75°, 38.22°, 38.61°, 39.44°, and 39.54°.

[0095] In some embodiments of the present invention, the crystals of crystalline form F have an XRPD pattern as shown in FIG.

[0096] In some embodiments of the present invention, the crystals of crystalline form F have analytical data of their XRPD pattern as shown in Table 6 below.

[0097] Table 6: Analysis data of XRPD pattern of crystals of crystalline form F [Table 6-1] [Table 6-2]

[0098] In some embodiments of the present invention, the crystals of crystalline form F have a differential scanning calorimetry curve with two endothermic peaks at 158.9°C±3.0°C and 315.6°C±3.0°C.

[0099] In some embodiments of the present invention, the crystals of crystalline form F have a DSC curve as shown in FIG.

[0100] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystals of crystalline form F shows a weight loss rate of 13.5% at 150.0°C ± 3.0°C.

[0101] In some embodiments of the present invention, the crystals of crystalline form F have a TGA curve as shown in FIG.

[0102] An eleventh object of the present invention is to provide a crystalline form G of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 12.15±0.20°, 12.74±0.20°, and 15.37±0.20°.

[0103] In some embodiments of the present invention, the crystals of crystalline form G have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.09±0.20°, 12.15±0.20°, 12.74±0.20°, 15.37±0.20°, 17.63±0.20°, 18.15±0.20°, 22.57±0.20°, and 22.76±0.20°.

[0104] In some embodiments of the present invention, the crystals of crystalline form G have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 7.09±0.20°, 12.15±0.20°, 12.74±0.20°, 15.37±0.20°, 17.63±0.20°, 18.15±0.20°, 22.21±0.20°, 22.57±0.20°, 22.76±0.20°, and 23.64±0.20°.

[0105] In some embodiments of the present invention, the crystals of crystalline form E have an X-ray powder diffraction pattern of 6.012°, 6.33°, 7.09°, 9.66°, 10.03°, 10.96°, 11.49°, 12.14°, 12.73°, 14.11°, 14.31°, 14.68°, 15.04°, 15.37°, 15.78°, 16.56°, 16.92°, 17.33°, 17.63°, 18.14°, 18.54°, 18.98°, 19.31°, 19.74°, 20. It has characteristic diffraction peaks at angles 2θ of 0.32°, 20.60°, 21.06°, 21.93°, 22.20°, 22.56°, 22.76°, 23.25°, 23.63°, 23.82°, 24.44°, 24.64°, 26.66°, 26.95°, 27.90°, 28.28°, 29.69°, 29.98°, 30.35°, 31.31°, 31.62°, 32.93°, 34.22°, 34.84°, 36.85°, 38.09°, and 38.69°.

[0106] In some embodiments of the present invention, the crystals of crystalline form G have an XRPD pattern as shown in FIG.

[0107] In some embodiments of the present invention, the crystals of crystalline form G have analytical data of their XRPD pattern as shown in Table 7 below.

[0108] Table 7: Analysis data of XRPD pattern of crystals of crystalline form G [Table 7-1] [Table 7-2]

[0109] In some embodiments of the present invention, the crystals of crystalline form G have two endothermic peaks in their differential scanning calorimetry curves at 157.5°C±3.0°C and 316.6°C±3.0°C.

[0110] In some embodiments of the present invention, the crystals of crystalline form G have a DSC curve as shown in FIG.

[0111] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystals of crystalline form G shows a weight loss rate of 11.9% at 175.0°C ± 3.0°C.

[0112] In some embodiments of the present invention, the crystals of crystalline form G have a TGA curve as shown in FIG.

[0113] A twelfth object of the present invention is to provide a crystal of crystalline form H of compound represented by formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.59±0.20°, 10.18±0.20°, and 18.66±0.20°.

[0114] In some embodiments of the present invention, the crystals of crystalline form H have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.59±0.20°, 10.18±0.20°, 11.29±0.20°, 11.83±0.20°, 15.57±0.20°, 18.66±0.20°, 20.13±0.20°, and 22.80±0.20°.

[0115] In some embodiments of the present invention, the crystals of crystalline form H have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.59±0.20°, 10.18±0.20°, 11.29±0.20°, 11.83±0.20°, 12.77±0.20°, 15.57±0.20°, 18.66±0.20°, 20.13±0.20°, 22.80±0.20°, and 25.12±0.20°.

[0116] In some embodiments of the present invention, the crystals of crystalline form H have an X-ray powder diffraction pattern of 9.594°, 10.18°, 11.29°, 11.82°, 12.37°, 12.77°, 13.93°, 14.16°, 15.23°, 15.57°, 16.22°, 16.44°, 17.65°, 17.96°, 18.66°, 19.22°, 19.67°, 20.1°. It has characteristic diffraction peaks at angles 2θ of 2°, 20.93°, 21.21°, 22.79°, 23.74°, 24.28°, 25.12°, 26.26°, 26.87°, 27.37°, 27.64°, 28.18°, 28.38°, 29.01°, 29.59°, 30.15°, 30.30°, 31.29°, 34.41°, 35.59°, and 35.94°.

[0117] In some embodiments of the present invention, the crystals of crystalline form H have an XRPD pattern as shown in FIG.

[0118] In some embodiments of the present invention, the crystals of crystalline form H have analytical data of their XRPD pattern as shown in Table 8 below.

[0119] Table 8: Analysis data of XRPD pattern of crystals of crystalline form H [Table 8]

[0120] A thirteenth object of the present invention is to provide a crystal of crystalline form I of compound represented by formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.06±0.20°, 12.45±0.20°, and 17.99±0.20°.

[0121] In some embodiments of the present invention, the crystals of Form I have an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 9.06±0.20°, 10.18±0.20°, 12.45±0.20°, 13.18±0.20°, 17.99±0.20°, 20.79±0.20°, 24.42±0.20°, 25.05±0.20°, and 26.57±0.20°.

[0122] In some embodiments of the present invention, the crystals of Form I have an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 9.06±0.20°, 10.18±0.20°, 12.45±0.20°, 17.99±0.20°, 18.74±0.20°, 20.53±0.20°, 20.79±0.20°, 24.42±0.20°, 25.05±0.20°, and 26.57±0.20°.

[0123] In some embodiments of the present invention, the crystals of crystalline Form I have an X-ray powder diffraction pattern of 6.041°, 6.90°, 9.06°, 9.32°, 10.18°, 12.45°, 13.17°, 13.72°, 15.55°, 15.99°, 16.70°, 17.17°, 17.99°, 18.74°, 19.55°, 20.52° , 20.79°, 22.01°, 22.41°, 22.68°, 24.41°, 25.04°, 26.34°, 26.57°, 27.48°, 28.01°, 28.89°, 29.79°, 30.64°, 31.63°, 32.86°, 34.55°, 34.67°, and 36.24° 2θ angles.

[0124] In some embodiments of the present invention, the crystals of crystalline Form I have an XRPD pattern as shown in FIG.

[0125] In some embodiments of the present invention, the crystals of crystalline form I have an XRPD pattern analytical data shown in Table 9 below.

[0126] Table 9: Analysis data of XRPD pattern of crystals of crystalline form I [Table 9]

[0127] In some embodiments of the present invention, the crystals of crystalline form I have a differential scanning calorimetry curve that has one endothermic peak at 316.0±3.0°C.

[0128] In some embodiments of the present invention, the crystals of crystalline form I have a DSC curve as shown in FIG.

[0129] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystals of crystalline form I shows a weight loss rate of 1.1% at 150°C ± 3.0°C.

[0130] In some embodiments of the present invention, the crystals of crystalline form I have a TGA curve as shown in FIG.

[0131] A fourteenth object of the present invention is to provide a crystalline form J of the compound represented by formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.15±0.20°, 18.08±0.20°, and 19.23±0.20°.

[0132] In some embodiments of the present invention, the crystals of crystalline form J have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.15±0.20°, 10.66±0.20°, 14.91±0.20°, 15.75±0.20°, 18.08±0.20°, 18.28±0.20°, 19.23±0.20°, and 28.19±0.20°.

[0133] In some embodiments of the present invention, the crystals of crystalline form J have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.15±0.20°, 10.66±0.20°, 14.91±0.20°, 15.75±0.20°, 18.08±0.20°, 18.28±0.20°, 19.23±0.20°, 23.27±0.20°, 23.66±0.20°, and 28.19±0.20°.

[0134] In some embodiments of the present invention, the crystals of crystalline form J have an X-ray powder diffraction pattern of 7.47°, 9.15°, 10.66°, 10.86°, 11.22°, 11.77°, 12.62°, 12.85°, 13.72°, 14.91°, 15.75°, 18.07°, 18.28°, 19.23°, 19.90°, 20.60°, 21.00°, 21.38°, 21.86°, 22.11°, 22.46°. It has characteristic diffraction peaks at angles 2θ of 23.01°, 23.27°, 23.65°, 24.05°, 24.35°, 25.13°, 25.29°, 25.79°, 26.43°, 27.29°, 27.54°, 28.19°, 29.21°, 30.57°, 32.36°, 32.68°, 32.82°, 34.82°, 35.83°, 36.64°, 36.99°, 37.41°, and 38.28°.

[0135] In some embodiments of the present invention, the crystals of crystalline form J have an XRPD pattern as shown in FIG.

[0136] In some embodiments of the present invention, the crystals of crystalline form J have analytical data of their XRPD pattern as shown in Table 10 below.

[0137] Table 10: Analysis data of XRPD pattern of crystals of crystalline form J [Table 10]

[0138] In some embodiments of the present invention, the crystals of crystalline form J have a differential scanning calorimetry curve with two endothermic peaks at 135.3°C ± 3.0°C and 315.2°C ± 3.0°C.

[0139] In some embodiments of the present invention, the crystals of crystalline form J have a DSC curve as shown in FIG.

[0140] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystals of crystalline form J shows a weight loss rate of 15.3% at 170°C ± 3.0°C.

[0141] In some embodiments of the present invention, the crystals of crystalline form J have a TGA curve as shown in FIG.

[0142] A fifteenth object of the present invention is to provide a crystal of crystalline form K of the compound represented by formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.11±0.20°, 16.30±0.20°, and 18.19±0.20°.

[0143] In some embodiments of the present invention, the crystals of crystalline form K have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.11±0.20°, 16.30±0.20°, 17.15±0.20°, 18.19±0.20°, 19.60±0.20°, 24.45±0.20°, 25.01±0.20°, and 27.39±0.20°.

[0144] In some embodiments of the present invention, the crystals of crystalline form K have an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 9.11±0.20°, 10.41±0.20°, 16.30±0.20°, 17.15±0.20°, 18.19±0.20°, 19.60±0.20°, 24.45±0.20°, 25.01±0.20°, 27.39±0.20°, and 36.75±0.20°.

[0145] In some embodiments of the present invention, the crystals of crystalline form K have an X-ray powder diffraction pattern of 8.611°, 9.11°, 10.15°, 10.41°, 10.88°, 12.58°, 13.64°, 14.96°, 15.13°, 16.29°, 17.15°, 17.32°, 18.18°, 18.72°, 19.59°, 19.92°, 20.17°, 20.45° It has characteristic diffraction peaks at angles 2θ of 20.83°, 22.28°, 22.47°, 22.89°, 23.78°, 24.07°, 24.45°, 25.01°, 26.59°, 27.38°, 28.22°, 28.82°, 29.81°, 30.40°, 31.12°, 34.11°, 34.66°, 35.96°, 36.74°, and 38.09°.

[0146] In some embodiments of the present invention, the crystals of crystalline form K have an XRPD pattern as shown in FIG.

[0147] In some embodiments of the present invention, the crystals of crystalline form K have analytical data of their XRPD pattern as shown in Table 11 below.

[0148] Table 11: Analysis data of XRPD pattern of crystals of crystalline form K [Table 11-1]

[0149] The present invention further provides use of a crystal of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I, crystalline form J, or crystalline form K of the compound in the manufacture of a therapeutic agent for a metabolic disease.

[0150] Preferably, the therapeutic agent is a thyroid hormone beta receptor agonist.

[0151] Preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangiocarcinoma. Preferably, the thyroid disease includes thyroid cancer and hypothyroidism.

[0152] The present invention further provides a drug containing, as an active ingredient, a crystal of the compound of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I, crystalline form J, or crystalline form K.

[0153] Preferably, the drug is a thyroid hormone β-receptor agonist. Furthermore, the drug further comprises a pharmaceutically acceptable excipient therefor.

[0154] By employing the above-described technical techniques, the present invention provides the following advantageous effects compared to conventional techniques.

[0155] 1. In the present invention, novel 2-pyridone derivatives have been developed which have high agonistic activity and selectivity for the thyroid hormone β receptor and can be used to treat metabolic diseases, particularly diseases associated with the thyroid hormone receptor.

[0156] In vitro enzyme activity test of thyroid receptor β (THRβ) was carried out, and the EC 50 The EC value of the compound represented by formula (I) was 0.04596 μM, indicating that this compound can promote the binding of THRβ and its coactivator peptide, and has potential agonist activity against THRβ. Furthermore, a cellular activity test of thyroid receptor β (THRβ) was performed, and the EC value of the compound represented by formula (I) was 0.04596 μM. 50 The agonist activity of this compound against thyroid receptor β (THRβ) was 0.214 μM. Pharmacokinetic evaluation in rats revealed that the blood concentration of the compound represented by formula (I) was low and the liver concentration was relatively high, demonstrating that the compound represented by formula (I) has excellent liver targeting ability.

[0157] 2. In addition, in the present invention, a series of crystalline forms of the compound, such as crystalline forms A to K, which have advantages such as good stability, low hygroscopicity, and resistance to heat, have been studied. Among them, crystalline form A of the compound represented by formula (I) has good stability and low hygroscopicity under high temperature, high humidity, long-term and accelerated conditions.

[0158] Specific embodiments of the present invention will be described in more detail below with reference to the drawings. [Brief explanation of the drawings]

[0159] [Figure 1] 1 is an XRPD pattern of the crystals of crystalline form A of the compound of formula (I) using Cu-Kα radiation. [Figure 2] 1 is a DSC curve of crystals of crystalline form A of compound represented by formula (I). [Figure 3] 1 is a TGA curve of crystals of crystalline form A of compound represented by formula (I). [Figure 4] 1 is an XRPD pattern of crystals of crystalline form B of compound of formula (I) using Cu-Kα radiation. [Figure 5] 1 is a DSC curve of crystals of crystalline form B of compound represented by formula (I). [Figure 6] 1 is a TGA curve of crystals of crystalline form B of compound represented by formula (I). [Figure 7] 1 is an XRPD pattern of crystals of crystalline form C of compound of formula (I) using Cu-Kα radiation. [Figure 8] 1 is a DSC curve of crystals of crystalline form C of compound represented by formula (I). [Figure 9] 1 is a TGA curve of crystals of crystalline form C of compound represented by formula (I). [Figure 10] 1 is an XRPD pattern of crystals of crystalline form D of compound of formula (I) using Cu-Kα radiation. [Figure 11] 1 is an XRPD pattern of crystals of crystalline form E of compound of formula (I) using Cu-Kα radiation. [Figure 12] 1 is a DSC curve of crystals of crystalline form E of compound represented by formula (I). [Figure 13] 1 is a TGA curve of crystals of crystalline form E of compound represented by formula (I). [Figure 14] 1 is an XRPD pattern of crystals of crystalline form F of compound of formula (I) using Cu-Kα radiation. [Figure 15] 1 is a DSC curve of crystals of crystalline form F of compound represented by formula (I). [Figure 16] 1 is a TGA curve of crystals of crystalline form F of compound represented by formula (I). [Figure 17] 1 is an XRPD pattern of the crystals of crystalline form G of compound of formula (I) using Cu-Kα radiation. [Figure 18] 1 is a DSC curve of crystals of crystalline form G of compound represented by formula (I). [Figure 19] 1 is a TGA curve of crystals of crystalline form G of compound represented by formula (I). [Figure 20] 1 is an XRPD pattern of crystals of crystalline form H of compound of formula (I) using Cu-Kα radiation. [Figure 21] 1 is an XRPD pattern of crystals of crystalline form I of compound of formula (I) using Cu-Kα radiation. [Figure 22] 1 is a DSC curve of crystals of crystalline form I of the compound represented by formula (I). [Figure 23] 1 is a TGA curve of crystals of crystalline form I of compound represented by formula (I). [Figure 24] 1 is an XRPD pattern of the crystal of crystalline form J of the compound represented by formula (I) using Cu-Kα radiation. [Figure 25] 1 is a DSC curve of crystals of crystalline form J of the compound represented by formula (I). [Figure 26] 1 is a TGA curve of crystals of crystalline form J of compound represented by formula (I). [Figure 27] 1 is an XRPD pattern of the crystals of crystalline form K of the compound of formula (I) using Cu-Kα radiation. [Figure 28]1 is a DVS pattern of crystals of crystalline form A of compound of formula (I).

[0160] It should be noted that these drawings and written descriptions are not intended to limit the scope of the invention in any way, but rather to explain the concept of the invention to those skilled in the art by reference to specific embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0161] In order to make the purpose, technical means and advantages of the embodiments of the present invention clearer, the technical means in the embodiments will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. The following embodiments are used to explain the present invention, but do not limit the scope of the present invention.

[0162] [Definition and Explanation] Unless otherwise specified, the following terms and phrases used herein shall have the following meanings: Certain phrases or terms, unless specifically defined, should not be considered uncertain or unclear and should be understood according to their ordinary meaning. Product names mentioned herein shall refer to the corresponding product or its active ingredients.

[0163] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention.

[0164] The chemical reactions in specific embodiments of the present invention are carried out in suitable solvents appropriate for the chemical transformations of the present invention and the reagents and raw materials required. To obtain the compounds of the present invention, one skilled in the art may need to modify or select synthetic steps or reaction processes based on existing practice.

[0165] The present invention will be described in more detail below with reference to examples, but these examples do not limit the present invention in any way.

[0166] All solvents used in the present invention are commercially available and can be used without further purification.

[0167] The solvents used in the present invention are commercially available products. The following abbreviations are used in the present invention: EtOH: ethanol; MeOH: methanol; EtOAc: ethyl acetate; DCM: dichloromethane; mp: melting point; THF: tetrahydrofuran; K2CO3: Potassium carbonate; DMF: N,N-dimethylformamide.

[0168] Compounds were named according to conventional naming conventions in the art or using ChemDraw® software, except for commercially available compounds, which used the supplier's catalogue name.

[0169] 1. X-ray powder diffractometer (XRPD method) in the present invention Instrument model: Bruker D8 Advance Diffractometer. Test method: Samples (>2 mg) were used for XRPD detection.

[0170] The detailed XRPD parameters are as follows: Radiation source: Cu, kα radiation; Tube voltage: 40 kV; Tube current: 40mA; Divergence slit: 0.6mm; Solar slit: 2.5mm; Receiving slit: 8mm; Filter: Nickel sheet; Measurement time: 6 min; Scan angle range: 3°~40°2θ / 3°~30°2θ; Step width angle: 0.02°2θ; Step length: 18.3 s / 36.6 s; Sample tray speed: None.

[0171] 2. Differential Scanning Calorimetry (DSC) in the Present Invention Instrument model: TA Instruments Q200 DSC differential scanning calorimeter. Test method: The sample (0.5 mg to 5 mg) was placed in an aluminum crucible with a lid (lid without a hole / lid with a hole), and heated from 0°C to 320°C / 350°C at a heating rate of 10°C / min under the protection of dry N2 at 50 mL / min. The thermal changes of the sample during the heating process were recorded using TA software.

[0172] 3. Thermogravimetric Analysis (TGA) in the Present Invention Instrument model: TA Instruments Q500 TGA Thermogravimetric Analyzer. Test method: A sample (1 mg to 10 mg) was taken and placed in a platinum crucible. Using a stepwise high-resolution detection method, the sample was heated from room temperature to 350°C at a heating rate of 10°C / min under the protection of 40 mL / min of dry N2. The weight change of the sample during the heating process was recorded using TA software.

[0173] 4. Dynamic Vapor Sorption Analysis (DVS) in the Present Invention Instrument model: TA Instruments Q5000 SA Dynamic Moisture Sorption Meter Test conditions: A sample (1 mg to 10 mg) was collected and placed in a DVS sample tray for measurement.

[0174] The detailed DVS parameters are as follows: Temperature: 25℃; Balance: dm / dt=0.01% / min for 15.00 min; Drying: Dry at 0% RH for 90 minutes; RH(%) gradient: 10% RH(%); RH(%) gradient range: 0%-80%-0%.

[0175] The degree of moisture absorption is classified as follows: [Table 11-2] Note: ΔW% represents the moisture weight gain of the test article at 25±1°C and 80±2% RH (European Pharmacopoeia 6.0). [Example]

[0176] Example 1: Preparation of compounds of formula (I) [ka]

[0177] Step 1: Compound 1 (5.0 g, 24.75 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen gas protection, lithium diisopropylamide (27.23 mL, 54.45 mmol) was added dropwise at -78 °C. The mixture was then reacted at -50 °C for 40 minutes, followed by the addition of (S)-(-)-epoxypropylene (6.587 g). The mixture was then reacted at -50 °C for 30 minutes, then allowed to warm to room temperature and react for 4 hours. The reaction was then quenched with 3 mL of saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 2 (yellow liquid). MS m / z (ESI): 260.02 [M+1] + , 1 H NMR(500MHz,DMSO-d6)δ:7.77-7.75(d,1H), 6.57-6.55(d,1H),4.49-4.48(d,1H),3.81(s,3H),3.68-3.63(m,1H),2.83-2.75(m, 2H), 1.71-1.66(m, 2H), 1.09-1.08(d, 3H).

[0178] Step 2: Compound 2 (2.38 g) was dissolved in toluene (25.0 mL), 2,6-dimethylpyridine (2 g) was added, and trifluoromethanesulfonic anhydride (2.5 g) was added. The mixture was allowed to react for 1 hour. Potassium carbonate (3.2 g) was added, and the mixture was allowed to react at 75 °C for 2 hours. Next, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. THF and hydrobromic acid were added to the flask. After reacting at approximately 60 °C for 3 days, the reaction mixture was cooled to room temperature, adjusted to pH 7-8 with sodium bicarbonate, and extracted three times with EA. The organic phases were combined, washed with 1N HCl, and then washed with brine. The mixture was then dried over sodium sulfate and concentrated to give compound 3 (white solid). MS m / z (ESI): 227.99 [M+1] + , 1 HNMR(500MHz,DMSO-d6)δ:7.47-7.45(d,1H),6.16-6.14(d,1H),4.73-4.70(d,1H),3.20-3.13(m,1H),2.97-2.93(m,1H), 2.31-2.23(m,1H), 1.82-1.77(m,1H), 1.28-1.26(d,3H).

[0179] Step 3: Compound 3, dioxane (10V), bisborane (1.5 eq), AcOK (2.0 eq), and Pd(dppf)Cl (0.1 eq) were added to a flask, purged with nitrogen gas three times, and reacted at 80-90 °C for 16 hours. The reaction was then cooled to room temperature and quenched. The crude product was purified using a column to obtain compound 4 (white solid). 1 HNMR(500MHz,DMSO-d6)δ:7.63-7.61(d,1H),6.38-6.35(d,1H),4.90-4.83( m,1H),3.43-3.18(m,2H),2.29-2.18(m,2H),1.43-1.37(m,3H),1.30-1.24(m ,12H).

[0180] Step 4: Compound 4 was dissolved in a mixture of 30 mL of tetrahydrofuran and 4.0 mL of water, and 30% hydrogen peroxide (4.0 mL) was added. The mixture was reacted at 25° C. for 16 hours, and then aqueous sodium sulfite solution was added to quench the reaction. Ethyl acetate (30 mL) was then added, and the mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 5 (a pale yellow solid). 1 H NMR(500MHz,DMSO-d6)δ:8.56 (s,1H), 7.13-7.11(d,1H),6.06-6.04(d,1H),4.60-4.57(m,1H),2.99-2.93(m,2H),2.20-2.16(m,1H),1.79-1.75(m,1H),1.24-1.23(md, 3H).

[0181] Step 5: Compound 5 (92.5 mg) was dissolved in 2.0 mL of N,N-dimethylformamide, and 1,3-dichloro-2-fluoro-5-nitrobenzene (117.6 mg) and potassium carbonate (232.2 mg) were added. The mixture was allowed to react at 25°C for 2 hours. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography to give compound 6 (30.1 g, yellow-green solid). MS m / z (ESI): 355.02 [M+1] + .

[0182] Step 6: Compound 6 (10 g) was dissolved in 200 mL of dichloromethane, palladium on carbon (0.5 g) was added, and the mixture was reacted under a hydrogen atmosphere for 6 hours. The mixture was then filtered and the filtrate was concentrated to give compound 7 (0.85 g, yellow solid). MS m / z (ESI): 325.04 [M+1] + . 1 H NMR(500MHz,DMSO-d6)δ:6.87-6.85(d,1H), 6.65(s,2H), 6.10-6.08(d,1H), 5.61(s,2H),4.66-4.64(m,1H),3.16-3.05(m,2H),2.31-2.26(m,1H),1.86-1.82(m,1H),1.29-1.27(d,3H).

[0183] Step 7: Compound 7 (150 mg) was dissolved in a mixture of 3.2 mL of acetic acid, 0.8 mL of water, and 0.4 mL of concentrated hydrochloric acid. Sodium nitrite (33.3 mg) was added at 0°C and the mixture was allowed to react for 10 minutes. Sodium acetate (113.2 mg) was then added and the mixture was allowed to react for another 10 minutes. N-cyanoacetylurethane (143.6 mg) was then added and the mixture was heated to room temperature and allowed to react for 72 hours. Next, 5 mL of water was added, and the mixture was filtered and dried to give compound 8 (1.8 g, yellow solid). MS m / z (ESI): 492.08 [M+1] + . 1 H NMR(500MHz ,DMSO-d6)δ12.15(s,1H),10.92(s,1H),8.00(s,2H),6.97-6.95(d,1H),6.15-6.14(d,1H),4.73-4.68 (m,1H),4.23-4.19(m,2H),3.24-3.09(m,2H),2.37-2.30(m,1H),1.92-1.87(m,1H),1.32-1.26(m,6H).

[0184] Step 8: Compound 8 (180 mg) was dissolved in 3.0 mL of N,N-dimethylacetamide, and sodium acetate (108.9 mg) was added. The mixture was reacted at 120 °C for 2 hours. The solvent was then removed by concentration under reduced pressure, and the resulting mixture was purified to give compound I (1.8 g, pale yellow solid). MS m / z (ESI): 446.03 [M+1] + . 1 H NMR(500MHz,DMSO-d6)δ 13.26(s,1H),7.75(s,2H),7.01-6.99(d,1H),6.12-6.10(d,1H),4.69-4.68(m,1H), 3.23-3.08(m,2H),2.35-2.32(m,1H),1.89-1.85(m,1H),1.31-1.29(m,3H).

[0185] The prepared compounds were further treated according to the methods of Examples 2 to 12 below to obtain different crystalline forms of Compound I.

[0186] Example 2: Preparation of Crystals of Crystalline Form A of Compound of Formula (I) Preparation method 1: 100 g of the compound of formula (I) was dissolved in 1100 ml of a mixed solvent of tetrahydrofuran and methanol (THF / MeOH = 3 / 2) and heated to 60 °C to completely dissolve. Water (1000 mL) was added to the solution at 20-30 °C under stirring. The solution was slowly cooled to 20 °C, stirred for 0.5 hours, and then filtered. The resulting filter cake was washed with methanol. The filter cake was collected and vacuum dried to a constant weight to obtain crystals of crystalline form A of the compound of formula (I).

[0187] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystals of crystalline form A of the compound are shown in Figures 1 to 3, respectively.

[0188] Preparation method 2: Approximately 100 mg of the compound of formula (I) was collected and dissolved in N,N-dimethylformamide (0.4 mL) to obtain a clear solution, which was then filtered. Water (1 mL) was added to the solution at 20-30°C under stirring conditions to precipitate a solid, followed by stirring overnight and centrifugation. The resulting filter cake was washed with water. The filter cake was collected and vacuum dried to a constant weight to obtain crystals of crystalline form A of the compound of formula (I).

[0189] Preparation method 3: Approximately 100 mg of the compound of formula (I) was collected and dissolved in dimethyl sulfoxide (0.2 mL) to obtain a clear solution, which was then filtered. Water (1 mL) was added to the solution at 20-30°C under stirring conditions to precipitate a solid, followed by stirring overnight and centrifugation. The resulting filter cake was washed with water. The filter cake was collected and vacuum dried to a constant weight to obtain crystals of crystalline form A of the compound of formula (I).

[0190] Preparation method 4: Approximately 1 g of the compound represented by formula (I) was collected, mixed with methanol solvent (75 mL), heated to 60°C, and completely dissolved, followed by filtration. A portion of the methanol solvent was removed by concentration at 40-45°C to precipitate the solid, which was then cooled to room temperature (20-30°C) and centrifuged. The resulting filter cake was washed with methanol. The filter cake was collected and vacuum dried to a constant weight to obtain crystals of crystalline form A of the compound represented by formula (I).

[0191] Example 3: Preparation of Crystals of Crystalline Form B of Compound of Formula (I) 100 mg of the compound of formula (I) was weighed, 4.0 mL of tetrahydrofuran was added, and the mixture was sonicated to dissolve the solution, and then 1.0 mL of toluene was added while maintaining the clear solution. The solution was evaporated to dryness at 40°C without a cap to obtain crystals of crystalline form B of the compound of formula (I).

[0192] The XRPD pattern using Cu-Kα radiation, DSC curve and TGA curve of the prepared crystals of crystalline form B of the compound are shown in Figures 4 to 6, respectively.

[0193] Example 4: Preparation of Crystals of Form C of Compound of Formula (I) 100 mg of the compound of formula (I) was weighed, 40.0 mL of acetone was added, and the mixture was sonicated to dissolve the solution, and then 10.0 mL of isopropyl acetate was added while maintaining the clear solution. The solution was then evaporated to dryness at room temperature without a cap to obtain crystalline form C of the compound of formula (I).

[0194] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystalline form C of the compound are shown in Figures 7 to 9, respectively.

[0195] Example 5: Preparation of Crystals of Crystalline Form D of Compound of Formula (I) 100 mg of the compound of formula (I) was weighed, 0.4 mL of tetrahydrofuran was added, and the solution was dissolved by ultrasonication until it became clear. 0.1 mL of water was then added while maintaining the clear solution. The solution was then evaporated to dryness at room temperature without a lid to obtain crystals of crystalline form D of the compound of formula (I).

[0196] The XRPD pattern of the prepared compound having crystalline form D using Cu-Kα radiation is shown in FIG.

[0197] Example 6: Preparation of Crystals of Form E of Compound of Formula (I) 100 mg of the compound of formula (I) was weighed, 4.0 mL of tetrahydrofuran was added, and the solution was dissolved by ultrasonication until it became clear. 0.1 mL of water was then added while maintaining the clear solution. The solution was then evaporated to dryness at room temperature without a lid to obtain crystals of crystalline form E of the compound of formula (I).

[0198] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystals of crystalline form E of the compound are shown in Figures 11 to 13, respectively.

[0199] Example 7: Preparation of crystals of crystalline form F of compound of formula (I) 100 mg of the compound of formula (I) was weighed out, placed in a centrifuge tube, and left at room temperature for 8 days under a tetrahydrofuran atmosphere, followed by vacuum drying at room temperature for approximately 27.5 hours to obtain crystals of crystalline form F of the compound of formula (I).

[0200] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystals of crystalline form F of the compound are shown in Figures 14 to 16, respectively.

[0201] Example 8: Preparation of crystals of crystalline form G of compound of formula (I) 100 mg of the compound of formula (I) was weighed, and 3.5 mL of tetrahydrofuran was added at room temperature. The solution was dissolved to a clear solution, and then filtered. The filtrate was then added dropwise to 20.0 mL of methyl tert-butyl ether solvent and stirred at room temperature for approximately 2 hours, during which a solid precipitated. The mixture was stirred at 4°C for approximately 21.5 hours, during which a solid precipitated, and then centrifuged. The mixture was then vacuum dried at room temperature for approximately 4.5 hours to obtain crystals of crystalline form G of the compound of formula (I).

[0202] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystalline form G of the compound are shown in Figures 17 to 19, respectively.

[0203] Example 9: Preparation of crystals of crystalline form H of compound of formula (I) 100 mg of the compound represented by formula (I) was weighed, and 4.0 mL of tetrahydrofuran was added. The mixture was dissolved by ultrasonic waves until it became clear, and then concentrated under reduced pressure at 60°C to obtain crystals of crystalline form H of the compound represented by formula (I).

[0204] The XRPD pattern of the prepared compound in crystalline form H using Cu-Kα radiation is shown in FIG.

[0205] Example 10: Preparation of Crystals of Crystalline Form I of Compound of Formula (I) 100 mg of the compound of formula (I) was weighed, 3.0 mL of tetrahydrofuran was added, and the mixture was sonicated to dissolve the solution, and then 0.5 mL of acetonitrile was added while maintaining the clear solution. The solution was then evaporated to dryness at 40°C without a cap to obtain crystals of Form I of the compound of formula (I).

[0206] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystals of crystalline form I of the compound are shown in Figures 21 to 23, respectively.

[0207] Example 11: Preparation of Crystals of Crystal Form J of Compound of Formula (I) 120 mg of the compound of formula (I) was weighed, 8.0 mL of toluene was added, and the suspension was stirred at room temperature for 8 days and centrifuged. The resulting solid was then vacuum dried at room temperature for about 27.5 hours to obtain crystals of crystalline form J of the compound of formula (I).

[0208] The XRPD pattern using Cu-Kα radiation, the DSC curve and the TGA curve of the prepared crystals of crystalline form J of the compound are shown in Figures 24 to 26, respectively.

[0209] Example 12: Preparation of crystals of crystalline form K of compound of formula (I) 20 mg of the compound of formula (I) was weighed, and 8.0 mL of ethanol was added at room temperature to dissolve the solution until it became clear. The solution was then filtered, and 12.0 mL of isopropyl acetate was added dropwise to the filtrate. The solution was stirred at room temperature to confirm that no solids were precipitated. The solution was then transferred to 4°C and stirred for 2 days, and no solids were precipitated. The solution was then evaporated to dryness at 40°C without a lid to obtain crystals of crystalline form K of the compound of formula (I).

[0210] The XRPD pattern of the prepared compound in crystalline form K using Cu-Kα radiation is shown in FIG.

[0211] Test Example 1: Study on the hygroscopicity of crystals of crystalline form A of the compound of formula (I) Test material: TA Instruments Q5000 SA Dynamic Moisture Sorption Meter Test method: 1 mg to 10 mg of sample was weighed out and placed in a DVS sample tray for measurement. Test results: The DVS pattern of the crystals of crystalline form A of compound of formula (I) is shown in FIG. 28, and ΔW was 0.6%. Test conclusion: The crystals of crystalline form A of the compound of formula (I) exhibited a hygroscopic weight gain of 0.6% at 25°C and 80% RH, and were slightly hygroscopic.

[0212] Test Example 2: Solid-state stability test of crystals of crystalline form A of the compound of formula (I) In accordance with the "Guideline for Stability Testing of Drug Substances and Drug Products" (Chinese Pharmacopoeia, 2015 Edition, Part 4, General Provisions 9001), the stability of the crystals of Form A of compound of formula (I) under high temperature (50°C, uncapped), accelerated (40°C / 75% relative humidity, uncapped), high humidity (25°C / 85% relative humidity, uncapped) and prolonged (25°C / 65% relative humidity, uncapped) conditions was investigated.

[0213] Approximately 10 mg of the compound of formula (I) was accurately weighed and placed in a dry and clean glass flask in a thin layer. The flask was covered with aluminum foil with small holes in it, and influence factor tests were performed under high temperature (60°C), accelerated conditions (40°C / 75%RH), high humidity conditions (25°C / 85%RH), and long-term conditions (25°C / 65%RH). Two samples were placed under each condition. However, samples for XRPD detection were placed separately. For samples placed under different conditions, XRPD and melting point were detected at the planned end of the test, and the detection results were compared with the initial test results on day 0. The test results are shown in Table 12 below.

[0214] Table 12: Solid state stability test results for crystalline form A of compound of formula (I) [Table 12]

[0215] Conclusion: It was found that the crystalline form A of compound of formula (I) exhibited good stability under high temperature, high humidity, long-term and accelerated conditions.

[0216] Test Example 3: In vitro enzyme activity test of thyroid receptor β (THRβ) A time-resolved fluorometry-fluorescence resonance energy transfer (TR-FRET) assay was used to assess the agonist activity of test compounds by binding to thyroid hormone receptor β (THRβ) and its coactivator peptide SRC2-2.

[0217] The THRβ ligand-binding domain (THRβ LBD) was fused with a GST tag and its coactivator peptide, SRC2-2, was biotinylated. The binding ability of THRβ LBD to SRC2-2 was measured by detecting tightly bound europium-labeled anti-GST antibody and D2-labeled streptavidin using TR-FRET.

[0218] Testing Procedure: (1) Test compounds were dissolved in DMSO to prepare a 30 mM stock solution. This stock solution can be stored in a desiccator at room temperature for 3 months, but for long-term storage, it should be stored in a -20°C freezer. A 1x reaction buffer was prepared with 50 mM HEPES (pH 7.0), 50 mM KF, 1 mM DTT, 0.05% NP-40, and 0.2% BSA.

[0219] (a) 10 μM of the positive compound T3 (100×) and 1 mM of the test compound (100×) (the compound of crystalline form A prepared in Example 2) were prepared using DMSO.

[0220] (b) 10 μM T3 and 1 mM test compound were serially diluted 3-fold on a 96-well plate to give 10 concentration points.

[0221] (c) The above 100x positive compounds and test compounds were diluted 4x with 1x reaction buffer.

[0222] (d) 5 μL of 4× positive or test compounds (see step c) were added to a 384-well assay plate.

[0223] (e) 4x THRβ-LBD (0.8 nM) and 4x RXRα (0.8 nM) solutions were prepared using 1x reaction buffer.

[0224] (f) 5 μL of the solution prepared in step e was taken and added to the assay plate (prepared in step d), and the reaction was allowed to proceed at room temperature for 15 minutes.

[0225] (g) A mixture containing 400 nM of 2 x biotin-SRC2-2 coactivator peptide, 25 nM of 2 x streptavidin-d2, and 2 x europium anti-GST (1:200) was prepared using 1 x reaction buffer.

[0226] (h) 10 μL of the mixture prepared in step g was added to each well of the assay plate to initiate the reaction.

[0227] (i) The assay plate was centrifuged at 1000 rpm for 1 minute.

[0228] (j) Incubated at room temperature in the dark for 1 hour.

[0229] (k) The values ​​were read at wavelengths of 665 nm and 615 nm using a BMG.

[0230] (2) Data analysis The activity rate was calculated using the following formula:

[0231]

number

number

number

[0232] (3)EC 50 Calculation of The EC of the compound from the following nonlinear fit equation 50 (50% agonist concentration) was calculated.

[0233]

number

[0234] Table 13: EC for in vitro enzymatic activity of Thyroid Receptor β (THRβ) 50 Test results [Table 13]

[0235] Conclusion: EC of the compound of formula (I) 50 The agonistic activity of this compound was 0.04596 μM, demonstrating that this compound can promote the binding of THRβ to its coactivating peptide and has potential agonistic activity against THRβ.

[0236] Test Example 4: Cytological activity test of thyroid receptor β (THRβ) In this study, we evaluated the agonistic effects of two test compounds on the THRβ target using a fluorescent reporter gene assay.

[0237] pGL4.35[luc2P / 9XGAL4UAS / Hygro] contains nine GAL4-UAS repeats (upstream activation sequences), which drive transcription of the luciferase reporter gene luc2P, which responds to binding of a fusion protein containing a Gal4 DNA binding domain to the thyroid receptor beta (THRβ) ligand-binding domain within the pBIND THRβ carrier. Stimulation of THRβ by a test compound results in an increased luminescence signal.

[0238] Testing Procedure: (1) The test compound (the compound of crystalline form A prepared in Example 2) was dissolved in DMSO to prepare a 30 mM stock solution. The positive compound was dissolved in DMSO to prepare a 5 mM stock solution, which was then diluted to a 0.5 mM stock solution. All compounds were dissolved in DMSO and stored in a refrigerator at -20°C. The compounds were serially diluted 3-fold with DMSO on a 384-well plate (10-point concentration gradient, starting concentration 30 mM).

[0239] A positive compound (T3) was serially diluted 3-fold in DMSO (10-point gradient, starting concentration 0.25 mM) in a 384-well plate. A 500X positive control (0.25 mM, T3) and a 500X negative control (100% DMSO) were prepared.

[0240] (2) HEK293T cells were cultured according to ATCC standards, and the test was performed on exponentially growing cells. The culture supernatant was discarded, and the cells were washed twice with PBS. The cells were digested with trypsin digestion solution, and the digestion was terminated with complete medium. The cells were collected and counted. Cells with a viability of over 90% were used for the test. 2.5 x 10 6 HEK293T cells were seeded onto a 60 mm cell culture dish. The culture dish containing the seeded cells was placed in a 37°C, 5% CO2 incubator and cultured overnight (18 hours).

[0241] (3) LipoLTX&PLUS transfection reagent was placed at room temperature, and two 1.5 mL EP tubes were prepared. While being careful not to touch the inner walls of the tubes, 12 μL of LipoLTX reagent and 250 μL of Opti-MEM™ medium were added to one EP tube, and 6 μg of plasmid and 250 μL of Opti-MEM™ medium were added to the other EP tube. Then, 6 μL of Lipo PLUS reagent was added, mixed well with a pipette, and left at room temperature for 5 minutes. The two EP tubes were then mixed and left at room temperature for 15 minutes. The transfection reagent containing the well-mixed plasmid was added to a 60 mm cell culture dish. The culture dish was placed in a 37°C, 5% CO2 incubator and incubated for 5 hours.

[0242] (4) 50 nL of diluted compound was transferred to a 384-well cell culture plate using an Echo 655. Cells were seeded at 17,000 cells per well in 25 μL of FBS medium containing 5% activated charcoal. The cell culture plate was incubated overnight (16–20 hours) in a 37°C, 5% CO2 incubator.

[0243] (5) The Britelite plus assay reagent was left at room temperature. The 384-well cell plate was left at room temperature. 25 μL of Britelite plus detection reagent was added to each well of the cell culture plate. Luminescence values ​​were detected using Envision.

[0244] (6) The percentage of agonist was calculated using the following formula:

[0245]

number

number

number

[0246] (7)EC 50 was calculated. EC values ​​of compounds from the following nonlinear curve fits using Graphpad 8.0 50 was calculated.

[0247]

number

[0248] The test results are shown in Table 14 below.

[0249] Table 14: In vitro cellular activity of THRβ EC 50 Test results [Table 14]

[0250] Conclusion: At the cellular level, the EC 50 The agonistic activity of the compound represented by formula (I) was 0.214 μM, which indicates that the compound represented by formula (I) has excellent agonistic activity against thyroid receptor β (THRβ).

[0251] Test Example 5: Pharmacokinetic evaluation in rats <Test Purpose> The pharmacokinetic parameters of the compound of formula (I) in rats are detected.

[0252] <Experimental scheme> (1) Test drug: Compound represented by formula (I) (compound of crystalline form A prepared in Example 2).

[0253] (2) Experimental animals: 6 male CD rats aged 6 to 8 weeks

[0254] (3) Experimental Procedure: The compound was administered at a concentration of 0.5 mg / mL at a dose of 5 mg / kg. Samples were collected from the animals by crossover sampling at 2, 6, and 10 hours after administration. Drug concentrations in plasma samples were measured using LC-MS / MS, and the kinetic parameters of the test drugs are shown in Table 15 below.

[0255] Table 15: Rat L / P concentration ratio test results [Table 15]

[0256] Conclusion: The compound of formula (I) showed low blood drug concentrations and relatively high liver drug concentrations in rats, demonstrating that the compound of formula (I) has excellent liver targeting ability.

[0257] The above is merely a preferred embodiment of the present invention and does not limit the present invention in any way. The present invention has been disclosed above in the form of a preferred embodiment, but it is not intended to limit the present invention. A person skilled in the art can make some changes and modifications to the equivalent embodiments using the technical content described above without departing from the scope of the technical technique of the present invention. However, any simple amendment, equivalent change, and improvement made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical technique of the present invention still falls within the scope of the technical technique of the present invention.

Claims

1. A compound having a structural formula represented by the following formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) 【Chemistry 1】 Preferably, the compound having the structural formula represented by formula (I) or a pharmaceutically acceptable salt thereof is used to manufacture a therapeutic agent for a metabolic disease, Preferably, the therapeutic agent is a thyroid hormone beta receptor agonist, and preferably, the metabolic disease includes obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangiocarcinoma.

2. A crystal of crystalline form A of the compound according to claim 1, wherein the X-ray powder diffraction pattern shown at an angle 2θ using Cu-Kα radiation has characteristic peaks at angles of 6.10±0.20°, 12.08±0.20°, and 16.49±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 6.10±0.20°, 12.08±0.20°, 13.61±0.20°, 15.71±0.20°, 16.49±0.20°, 20.05±0.20°, 21.47±0.20°, and 22.49±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 6.10±0.20°, 12.08±0.20°, 13.61±0.20°, 15.71±0.20°, 16.49±0.20°, 20.05±0.20°, 20.73±0.20°, 21.47±0.20°, 21.80±0.20°, and 22.49±0.20°; Preferably, the XRPD pattern of the crystals of crystalline form A is as shown in Figure 1; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form A has one endothermic peak at 300.1±3.0°C, Preferably, the DSC curve of the crystals of crystalline form A is as shown in Figure 2; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form A shows a weight loss rate of 0.6% at a position of 150.0°C ± 3.0°C, Preferably, the crystal of crystalline form A is characterized in that the TGA curve of the crystal of crystalline form A is as shown in Figure 3.

3. A method for producing the crystal of crystalline form A according to claim 2, comprising the steps of: Step (1) of dissolving the compound represented by formula (I) in a mixed solvent of tetrahydrofuran and methanol, and heating the mixture to completely dissolve the compound; Step (2) of adding water to the solution under stirring, gradually cooling the solution, continuing to stir, and filtering; and (3) washing the obtained filter cake with methanol, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound of formula (I), Preferably, in step (1), the volume ratio of tetrahydrofuran to methanol in the mixed solvent is in the range of 2:1 to 1:2; Preferably, in step (1), the concentration of the compound represented by formula (I) in the mixed solvent is in the range of 0.02 to 0.2 g / ml; Preferably, in step (1), the mixture is heated to 45 to 65°C, Preferably, in step (2), the ratio of the volume of water added to the volume of the mixed solvent in step (1) is in the range of 1:2 to 3:1; Preferably, in step (2), water is added to the solution at 15 to 35°C, the solution is slowly cooled to 15 to 30°C, and stirring is continued for 0.5 to 1 hour; Alternatively, the manufacturing method comprises: Step (1) of dissolving the compound represented by formula (I) in N,N-dimethylformamide to obtain a clear solution, and then filtering the solution; Step (2) of adding water to the solution under stirring to precipitate a solid, followed by stirring overnight and centrifuging; and (3) washing the obtained filter cake with water, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound of formula (I), Preferably, in step (1), the concentration of the compound represented by formula (I) in N,N-dimethylformamide is in the range of 0.1 to 0.3 g / ml; Preferably, in step (2), the ratio of the volume of water added to the volume of N,N-dimethylformamide added in step (1) is in the range of 1:2 to 3:1; Preferably, in step (2), water is added to the solution at 15 to 35°C; Alternatively, the manufacturing method comprises: Step (1) of dissolving the compound represented by formula (I) in dimethyl sulfoxide, dissolving it to a clear solution, and then filtering it; Step (2) of adding water to the solution under stirring to precipitate a solid, followed by stirring overnight and centrifuging; and (3) washing the obtained filter cake with water, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound of formula (I), Preferably, in step (1), the concentration of the compound represented by formula (I) in dimethyl sulfoxide is in the range of 0.3 to 0.8 g / ml; Preferably, in step (2), the ratio of the volume of water added to the volume of dimethyl sulfoxide added in step (1) is in the range of 3:1 to 7:1; Preferably, in step (2), water is added to the solution at 15 to 35°C; Alternatively, the manufacturing method comprises: Step (1) of dissolving the compound of formula (I) in methanol, heating to completely dissolve the compound, and filtering the resulting solution; (2) concentrating and removing a portion of the methanol until a solid is precipitated, followed by cooling and centrifuging; and (3) washing the obtained filter cake with methanol, recovering the filter cake, and drying it under vacuum until it reaches a constant weight to obtain crystals of crystalline form A of the compound of formula (I), Preferably, in step (1), the concentration of the compound represented by formula (I) in methanol is in the range of 0.01 to 0.1 g / ml; Preferably, in step (1), the mixture is heated to 45 to 65°C, Preferably, in step (2), a portion of the methanol is removed by concentration at a temperature of 30 to 50°C; Preferably, the method is characterized in that in step (2), the mixture is cooled to room temperature of 20 to 30°C.

4. A crystal of crystalline form B of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 9.35±0.20°, 10.36±0.20°, and 18.32±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.35±0.20°, 10.36±0.20°, 11.77±0.20°, 12.65±0.20°, 15.21±0.20°, 18.32±0.20°, 19.60±0.20°, and 22.74±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.35±0.20°, 10.36±0.20°, 11.77±0.20°, 12.65±0.20°, 15.21±0.20°, 18.32±0.20°, 19.60±0.20°, 20.03±0.20°, 21.30±0.20°, and 22.74±0.20°; Preferably, the XRPD pattern of the crystals of crystalline form B is as shown in Figure 4; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form B has one endothermic peak at 139.5°C ± 3.0°C and one endothermic peak at 315.6°C ± 3.0°C, respectively; Preferably, the DSC curve of the crystals of crystalline form B is as shown in Figure 5; Preferably, the thermogravimetric analysis curve of crystalline form B shows a weight loss rate of 16.0% at 150.0°C ± 3.0°C; Preferably, the crystals of crystalline form B are characterized in that the TGA curve of the crystals of crystalline form B is as shown in Figure 6.

5. A crystal of crystalline form C of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 5.96±0.20°, 10.96±0.20°, and 22.84±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 5.96±0.20°, 9.25±0.20°, 10.96±0.20°, 11.94±0.20°, 21.92±0.20°, 22.84±0.20°, 23.69±0.20°, and 28.12±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 5.96±0.20°, 9.25±0.20°, 10.96±0.20°, 11.94±0.20°, 15.52±0.20°, 19.50±0.20°, 21.92±0.20°, 22.84±0.20°, 23.69±0.20°, and 28.12±0.20°; Preferably, the XRPD pattern of crystals of crystalline form C is as shown in Figure 7; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form C has one endothermic peak at 123.7±3.0°C and one endothermic peak at 315.7±3.0°C, respectively; Preferably, the DSC curve of the crystals of crystalline form C is as shown in Figure 8; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form C shows a weight loss rate of 10.9% at 150.0°C ± 3.0°C; Preferably, the TGA curve of the crystals of crystalline form C is as shown in Figure 9.

6. A crystal of crystalline form D of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 7.97±0.20°, 11.66±0.20°, and 15.83±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 7.97±0.20°, 9.08±0.20°, 11.66±0.20°, 12.47±0.20°, 15.83±0.20°, 17.98±0.20°, 20.47±0.20°, and 20.74±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 7.97°, 9.08°, 11.66°, 12.47°, 15.83°, 17.98°, 20.47°, 20.74°, 23.37°, and 25.04°; Preferably, the crystal of crystalline form D is characterized in that the XRPD pattern of crystalline form D is as shown in Figure 10.

7. A crystal of crystalline form E of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 12.43±0.20°, 12.70±0.20°, and 17.94±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.02±0.20°, 10.15±0.20°, 12.43±0.20°, 12.70±0.20°, 17.94±0.20°, 19.08±0.20°, 20.66±0.20°, and 24.96±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.02±0.20°, 10.14±0.20°, 12.43±0.20°, 12.70±0.20°, 17.94±0.20°, 19.08±0.20°, 20.66±0.20°, 22.28±0.20°, 24.95±0.20°, and 26.55±0.20°; Preferably, the XRPD pattern of crystalline form E is as shown in Figure 11; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form E has one endothermic peak at 151.1±3.0°C and one endothermic peak at 315.2±3.0°C, respectively; Preferably, the DSC curve of the crystals of crystalline form E is as shown in Figure 12; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form E shows a weight loss rate of 6.6% at 150.0°C ± 3.0°C, Preferably, the crystal of crystalline form E is characterized in that the TGA curve of the crystal of crystalline form E is as shown in Figure 13.

8. A crystal of crystalline form F of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 7.13±0.20°, 12.18±0.20°, and 18.25±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 7.13±0.20°, 12.18±0.20°, 12.68±0.20°, 15.59±0.20°, 18.25±0.20°, 19.05±0.20°, 22.34±0.20°, and 22.70±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 7.13±0.20°, 12.18±0.20°, 12.68±0.20°, 15.59±0.20°, 17.73±0.20°, 18.25±0.20°, 19.05±0.20°, 22.34±0.20°, 22.70±0.20°, and 24.63±0.20°; Preferably, the XRPD pattern of crystals of crystalline form F is as shown in Figure 14; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form F has one endothermic peak at 158.9±3.0°C and one endothermic peak at 315.6±3.0°C, respectively; Preferably, the DSC curve of the crystals of crystalline form F is as shown in Figure 15; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form F shows a weight loss rate of 13.5% at a temperature of 150.0°C ± 3.0°C; Preferably, the TGA curve of the crystals of crystalline form F is as shown in Figure 16.

9. A crystal of crystalline form G of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 12.15±0.20°, 12.74±0.20°, and 15.37±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 7.09±0.20°, 12.15±0.20°, 12.74±0.20°, 15.37±0.20°, 17.63±0.20°, 18.15±0.20°, 22.57±0.20°, and 22.76±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 7.09±0.20°, 12.15±0.20°, 12.74±0.20°, 15.37±0.20°, 17.63±0.20°, 18.15±0.20°, 22.21±0.20°, 22.57±0.20°, 22.76±0.20°, and 23.64±0.20°; Preferably, the XRPD pattern of the crystals of crystalline form G is as shown in Figure 17; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form G has one endothermic peak at 157.5°C ± 3.0°C and one endothermic peak at 316.6°C ± 3.0°C, respectively; Preferably, the DSC curve of the crystals of crystalline form G is as shown in Figure 18; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form G shows a weight loss rate of 11.9% at 175.0°C ± 3.0°C, Preferably, the TGA curve of the crystal of crystalline form G is as shown in Figure 19.

10. A crystal of crystalline form H of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 9.59±0.20°, 10.18±0.20°, and 18.66±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.59±0.20°, 10.18±0.20°, 11.29±0.20°, 11.83±0.20°, 15.57±0.20°, 18.66±0.20°, 20.13±0.20°, and 22.80±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.59±0.20°, 10.18±0.20°, 11.29±0.20°, 11.83±0.20°, 12.77±0.20°, 15.57±0.20°, 18.66±0.20°, 20.13±0.20°, 22.80±0.20°, and 25.12±0.20°; Preferably, the crystal of crystalline form H has an XRPD pattern as shown in Figure 20.

11. A crystal of crystalline form I of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 9.06±0.20°, 12.45±0.20°, and 17.99±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.06±0.20°, 10.18±0.20°, 12.45±0.20°, 13.18±0.20°, 17.99±0.20°, 20.79±0.20°, 24.42±0.20°, 25.05±0.20°, and 26.57±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.06±0.20°, 10.18±0.20°, 12.45±0.20°, 17.99±0.20°, 18.74±0.20°, 20.53±0.20°, 20.79±0.20°, 24.42±0.20°, 25.05±0.20°, and 26.57±0.20°; Preferably, the XRPD pattern of the crystals of crystalline form I is as shown in Figure 21; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form I has one endothermic peak at 316.0±3.0°C; Preferably, the DSC curve of the crystals of crystalline form I is as shown in Figure 22; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form I shows a weight loss rate of 1.1% at 150.0°C ± 3.0°C, Preferably, the crystal of crystalline form I is characterized in that the TGA curve of crystalline form I is as shown in Figure 23.

12. A crystal of crystalline form J of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 9.15±0.20°, 18.08±0.20°, and 19.23±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.15±0.20°, 10.66±0.20°, 14.91±0.20°, 15.75±0.20°, 18.08±0.20°, 18.28±0.20°, 19.23±0.20°, and 28.19±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.15±0.20°, 10.66±0.20°, 14.91±0.20°, 15.75±0.20°, 18.08±0.20°, 18.28±0.20°, 19.23±0.20°, 23.27±0.20°, 23.66±0.20°, and 28.19±0.20°; Preferably, the XRPD pattern of crystals of crystalline form J is as shown in Figure 24; Preferably, the differential scanning calorimetry curve of the crystals of crystalline form J has one endothermic peak at 135.3±3.0°C and one endothermic peak at 315.2±3.0°C, respectively; Preferably, the DSC curve of the crystals of crystalline form J is as shown in Figure 25; Preferably, the thermogravimetric analysis curve of the crystals of crystalline form J shows a weight loss rate of 15.3% at a position of 170.0°C ± 3.0°C, Preferably, the TGA curve of the crystal of crystalline form J is as shown in Figure 26.

13. A crystal of crystalline form K of the compound of claim 1, When Cu-Kα radiation is used, the X-ray powder diffraction pattern shown at an angle 2θ has characteristic peaks at angles of 9.11±0.20°, 16.30±0.20°, and 18.19±0.20°, Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.11±0.20°, 16.30±0.20°, 17.15±0.20°, 18.19±0.20°, 19.60±0.20°, 24.45±0.20°, 25.01±0.20°, and 27.39±0.20°; Preferably, the X-ray powder diffraction pattern, measured at angles 2θ, has characteristic peaks at angles of 9.11±0.20°, 10.41±0.20°, 16.30±0.20°, 17.15±0.20°, 18.19±0.20°, 19.60±0.20°, 24.45±0.20°, 25.01±0.20°, 27.39±0.20°, and 36.75±0.20°; Preferably, the crystal of crystalline form K is characterized in that the XRPD pattern of the crystal of crystalline form K is as shown in Figure 27.

14. 13. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, a crystal of crystalline form A of the compound of claim 2, a crystal of crystalline form A of the compound produced by the production method of claim 3, a crystal of crystalline form B of the compound of claim 4, a crystal of crystalline form C of the compound of claim 5, a crystal of crystalline form D of the compound of claim 6, a crystal of crystalline form E of the compound of claim 7, a crystal of crystalline form F of the compound of claim 8, a crystal of crystalline form G of the compound of claim 9, a crystal of crystalline form H of the compound of claim 10, a crystal of crystalline form I of the compound of claim 11, a crystal of crystalline form J of the compound of claim 12, or a crystal of crystalline form K of the compound of claim 13 in the production of a therapeutic agent for a metabolic disease, Preferably, the therapeutic agent is a thyroid hormone β-receptor agonist, Preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic cholangiocarcinoma.

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