Thyroid hormone beta receptor stimulant, crystal form, preparation method and application

Abstract

The invention belongs to the field of medicine, and discloses a thyroid hormone beta receptor agonist, a crystal form, a preparation method and application, the compound is a compound with a structural formula shown in a formula (I) or pharmaceutically acceptable salt thereof, Cu-Ka radiation is used, X-ray powder diffraction of the A crystal form of the compound shown in the formula (I) expressed by a 2 theta angle at 6.10 + / -0.20 degrees, 12.08 + / -0.20 degrees, 12.08 + / -0.20 degrees, 12.08 + / -0.20 degrees, 12.08 + / -0.20 degrees, 12.08 + / -0.20 degrees, 12.08 + / -0.20 degrees, 12.08 + / -0.20 degrees and a characteristic peak exists at 16.49 + / -0.20 DEG C. The invention develops a novel 2-pyridone derivative, and the compound has high agonistic activity and selectivity to a thyroid hormone beta receptor, and can be used for treating metabolic diseases, especially diseases related to the thyroid hormone receptor. The invention also researches a series of crystal forms of the compound, and the crystal form A compound has the advantages of good stability, low hygroscopicity and small heat influence. # imgabs0 #

Description

Thyroid hormone beta receptor agonist, crystal form, preparation method and use

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on December 7, 2022, with application number 202211563493.0 and invention name “A thyroid hormone beta receptor agonist, crystal form, preparation method and use”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a thyroid hormone beta receptor agonist, a crystal form, a preparation method and uses. Background Art

[0003] Thyroid hormones are essential for normal growth and development and for maintaining metabolic balance (Physiological Reviews 2001, 81(3), 1097-1126.). Thyroid hormones are produced by the thyroid gland and secreted into the circulatory system (hypothalamus / pituitary / thyroid system) 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 present in all tissues, but primarily in the liver and kidneys.

[0004] Circulating levels of thyroid hormone are tightly regulated by feedback mechanisms in the hypothalamus / pituitary / thyroid axis. Thyroid dysfunction, leading to hypothyroidism or hyperthyroidism, has profound effects on the heart, body weight, metabolism, metabolic rate, body temperature, cholesterol, bones, muscles, and behavior.

[0005] The biological activity of thyroid hormones is mediated by the thyroid hormone receptor (THR) (Endocrine Reviews (1993) 14 348-399). THRs belong to the nuclear receptor family and are encoded by different genes, α and β, located on human chromosomes 17 and 3. Different protein isoforms are produced by alternative splicing of the primary transcripts, with each gene producing two isoforms: THRα1, THRα2, THRβ1, and THRβ2. THRβ1 and THRβ2 are differentially expressed from their promoters, differing only in their amino termini. THRα1 and THRα2 are derived from differential splicing of pre-mRNA, differing primarily at their carboxyl termini. THRα1, THRβ1, and THRβ2 can bind thyroid hormones. THRβ is mainly distributed in the liver / kidney / pituitary gland and brain tissues, playing an important role in regulating TRH and the behavior of thyroid hormone in the liver. THRα is widely distributed throughout the body and is mainly associated with cardiovascular and skeletal / muscle adverse reactions outside the liver (Drugs (2017) 771613–1621). Therefore, if a thyroid hormone analog can avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormone, it may be used to treat responsive diseases, such as metabolic diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other conditions such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, etc.

[0006] A series of thyroid hormone agonists have been developed in the prior art. These structural agonists are almost all designed and developed based on the structure of T3, the natural ligand of the THR receptor. For example, thyroid hormone analogs with structures different from 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, Example 8 (Compound 31) disclosed in WO2007009913 is MGL-3196, an orally administered small molecule selective agonist of the β subtype of the liver thyroid hormone receptor (THR-β) currently under clinical development. Preclinical toxicology and clinical data indicate that it is a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemia. MGL-3196 significantly reduces LDL cholesterol, triglycerides, and lipoproteins, making it an ideal candidate for reducing cardiovascular risk in patients with NASH and those with dyslipidemia who are on moderate statin doses or are intolerant to statins.

[0007] After that, many documents such as WO2020073974, CN 111320609A, and WO2019240938 disclosed a series of structural modifications in different directions on the pyridazinone ring based on the MGL-3196 structure, but the parent core always has a pyridazinone structure similar to the MGL-3196 structure. The recently disclosed WO2020169069 and WO2021067791 both disclose another pyridinone-like structure, but there are problems with decreased THRβ biological activity and THRβ / THRα selectivity, especially in that most compounds almost lose their pharmacological activity after the nitrogen atom on the pyridinone is replaced, or have extremely poor stability during metabolism in the body and are difficult to develop into drugs.

[0008] The compounds and experimental drugs disclosed in these prior arts still have problems with drugability. Therefore, it is necessary to continue to discover and develop new compounds with high activity and selectivity that have the beneficial effects of thyroid hormones and can avoid adverse effects, as well as new compounds with good in vivo pharmacokinetic effects for the treatment of diseases related to thyroid hormone receptors.

[0009] In view of this, the present invention is proposed.

[0010] Summary of the Invention

[0011] The present invention aims to overcome the shortcomings of the prior art by providing a thyroid hormone beta receptor agonist, crystal form, preparation method, and use. The present invention develops a novel 2-pyridone derivative that exhibits high agonist activity and selectivity for thyroid hormone beta receptors and is useful for treating metabolic diseases, particularly those associated with thyroid hormone receptors. Furthermore, the present invention also investigates a series of crystal forms of the compound, which exhibit excellent stability, low hygroscopicity, and minimal thermal effects.

[0012] In order to solve the above technical problems, the basic concept of the technical solution adopted by the present invention is:

[0013] The first object of the present invention is to provide a compound having the structural formula represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0014] The second object of the present invention is to provide a medicine comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] Preferably, the drug is a thyroid hormone beta receptor agonist. Further, the drug also includes a pharmaceutically acceptable excipient.

[0016] The third object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating metabolic diseases; preferably, the medicament is a thyroid hormone beta receptor agonist; preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic bile duct tumor. Preferably, the thyroid disease includes thyroid cancer and hypothyroidism.

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

[0018] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 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°, 22.49±0.20°.

[0019] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 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°, 22.49±0.20°.

[0020] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 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°, 1 6.49±0.20°, 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°, 24.47±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°, 39.40±0.20°.

[0021] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form A is shown in Figure 1.

[0022] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form A are shown in Table 1:

[0023] Table 1. XRPD pattern analysis data of Form A

[0024] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak at 300.1±3.0°C.

[0025] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is shown in Figure 2.

[0026] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A shows a weight loss of 0.6% at 150.0°C±3.0°C.

[0027] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.

[0028] Furthermore, the present invention provides the use of the crystal form A of compound of formula (I) in the preparation of drugs for treating metabolic diseases.

[0029] Furthermore, the present invention provides the use of the crystal form A of compound of formula (I) in the preparation of drugs for treating thyroid hormone receptor-related diseases.

[0030] Preferably, the drug is a thyroid hormone beta receptor agonist; preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic bile duct tumor.

[0031] Analysis revealed that the crystalline form A of the compound of formula (I) has good stability under high temperature, high humidity, long-term and accelerated conditions, and has low hygroscopicity.

[0032] A fifth object of the present invention is to provide a method for preparing Form A of the compound represented by formula (I), comprising:

[0033] (1) dissolving the compound of formula (I) in a mixed solvent of tetrahydrofuran and methanol, and heating to completely dissolve it;

[0034] (2) Add water to the solution while stirring, slowly cool the solution, continue stirring, and filter;

[0035] (3) The obtained filter cake was washed with methanol, collected, and vacuum dried to constant weight to obtain Form A of the compound of formula (I).

[0036] Preferably, in step (1), the volume ratio of tetrahydrofuran to methanol in the mixed solvent is 2:1 to 1:2.

[0037] Preferably, in step (1), the concentration of the compound of formula (I) in the mixed solvent is 0.02 to 0.2 g / ml.

[0038] Preferably, in step (1), the temperature is heated to 45-65°C.

[0039] Preferably, in step (2), the volume ratio of the added water to the mixed solvent in step (1) is 1:2 to 3:1.

[0040] Preferably, in step (2), water is added to the solution at 15-35° C.; the solution is slowly cooled to 15-30° C. and stirred for 0.5-1 h.

[0041] Or the preparation method comprises:

[0042] (1) dissolving the compound of formula (I) in N,N-dimethylformamide, filtering after clearing the solution;

[0043] (2) Add water to the solution under stirring, precipitate the solid, stir overnight, and centrifuge;

[0044] (3) The obtained filter cake is washed with water, collected, and vacuum-dried to constant weight to obtain Form A of the compound of formula (I).

[0045] Preferably, in step (1), the concentration of the compound of formula (I) in N,N-dimethylformamide is 0.1 to 0.3 g / ml.

[0046] Preferably, in step (2), the volume ratio of the added water to the volume of N,N-dimethylformamide in step (1) is 1:2 to 3:1.

[0047] Preferably, in step (2), water is added to the solution at 15-35°C.

[0048] Or the preparation method comprises:

[0049] (1) dissolving the compound of formula (I) in dimethyl sulfoxide, filtering after the solution becomes clear;

[0050] (2) Add water to the solution under stirring, precipitate the solid, stir overnight, and centrifuge;

[0051] (3) The obtained filter cake is washed with water, collected, and vacuum-dried to constant weight to obtain Form A of the compound of formula (I).

[0052] Preferably, in step (1), the concentration of the compound of formula (I) in dimethyl sulfoxide is 0.3-0.8 g / ml.

[0053] Preferably, in step (2), the volume ratio of the added water to the volume of the dimethyl sulfoxide in step (1) is 3:1 to 7:1.

[0054] Preferably, in step (2), water is added to the solution at 15-35°C.

[0055] Or the preparation method comprises:

[0056] (1) Dissolve the compound of formula (I) in methanol, heat until completely dissolved, and filter;

[0057] (2) Concentrate to remove part of the methanol until solid precipitates, cool, and centrifuge;

[0058] (3) The obtained filter cake was washed with methanol, collected, and vacuum dried to constant weight to obtain Form A of the compound of formula (I).

[0059] Preferably, in step (1), the concentration of the compound of formula (I) in methanol is 0.01 to 0.1 g / ml.

[0060] Preferably, in step (1), the temperature is heated to 45-65°C.

[0061] Preferably, in step (2), the temperature for concentrating and removing part of the methanol is 30-50°C.

[0062] Preferably, in step (2), the mixture is cooled to room temperature (20-30°C).

[0063] The sixth object of the present invention is to provide a crystalline form B of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.35±0.20°, 10.36±0.20°, and 18.32±0.20°.

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 22.74±0.20°.

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2θ angles: 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°.

[0066] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction at the following 2θ angles: 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°, 39.26°.

[0067] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form B is shown in Figure 4.

[0068] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form B are shown in Table 2:

[0069] Table 2. XRPD pattern analysis data of Form B

[0070] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned B crystal form has an endothermic peak at 139.5°C±3.0°C and 315.6±3.0°C.

[0071] In some embodiments of the present invention, the DSC spectrum of the above-mentioned Form B is shown in Figure 5.

[0072] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form B shows a weight loss of 16.0% at 150.0°C±3.0°C.

[0073] In some embodiments of the present invention, the TGA spectrum of the above-mentioned Form B is shown in Figure 6.

[0074] The seventh object of the present invention is to provide a crystalline form C of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.96±0.20°, 10.96±0.20°, and 22.84±0.20°.

[0075] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 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°, 28.12±0.20°.

[0076] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 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°, 28.12±0.20°.

[0077] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction at the following 2θ angles:

[0078] 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°, 2 4.78°, 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°, 39.347°.

[0079] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form C is shown in Figure 7.

[0080] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form C are shown in Table 3:

[0081] Table 3. XRPD pattern analysis data of Form C

[0082] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned C crystal form has an endothermic peak at 123.7°C±3.0°C and 315.7±3.0°C.

[0083] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form C is shown in Figure 8.

[0084] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form C shows a weight loss of 10.9% at 150.0°C±3.0°C.

[0085] In some embodiments of the present invention, the TGA spectrum of the above-mentioned C crystal form is shown in Figure 9.

[0086] The eighth object of the present invention is to provide a crystal form D of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.97±0.20°, 11.66±0.20°, and 15.83±0.20°.

[0087] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 20.74±0.20°.

[0088] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 7.97°, 9.08°, 11.66°, 12.47°, 15.83°, 17.98°, 20.47°, 20.74°, 23.37°, and 25.04°.

[0089] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction at the following 2θ angles: 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°, 20.47°, 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°, 37.64°.

[0090] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form is shown in Figure 10.

[0091] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned D crystal form are shown in Table 4:

[0092] Table 4. XRPD pattern analysis data of Form D

[0093] The ninth object of the present invention is to provide a crystalline form E of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.43±0.20°, 12.70±0.20°, and 17.94±0.20°.

[0094] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 24.96±0.20°.

[0095] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 26.55±0.20°.

[0096] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form has characteristic diffraction at the following 2θ angles: 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°, 20.6 6°, 21.99°, 22.28°, 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°, 39.66°.

[0097] In some embodiments of the present invention, the XRPD pattern of the above-mentioned E crystal form is shown in Figure 11.

[0098] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned E crystal form are shown in Table 5:

[0099] Table 5. XRPD pattern analysis data of Form E

[0100] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned E crystal form has an endothermic peak at 151.1°C±3.0°C and 315.2±3.0°C.

[0101] In some embodiments of the present invention, the DSC spectrum of the above-mentioned E crystal form is shown in Figure 12.

[0102] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned E crystal form shows a weight loss of 6.6% at 150.0°C±3.0°C.

[0103] In some embodiments of the present invention, the TGA spectrum of the above-mentioned E crystal form is shown in Figure 13.

[0104] The tenth object of the present invention is to provide a crystalline form F of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.13±0.20°, 12.18±0.20°, and 18.25±0.20°.

[0105] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 22.70±0.20°.

[0106] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 24.63±0.20°.

[0107] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form has characteristic diffraction at the following 2θ angles: 6.0876.34°, 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°, 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°, 39.54°.

[0108] In some embodiments of the present invention, the XRPD pattern of the above-mentioned F crystal form is shown in Figure 14.

[0109] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form F are shown in Table 6:

[0110] Table 6. XRPD pattern analysis data of Form F

[0111] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned F crystal form has an endothermic peak at 158.9°C±3.0°C and 315.6±3.0°C.

[0112] In some embodiments of the present invention, the DSC spectrum of the above-mentioned F crystal form is shown in Figure 15.

[0113] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned F crystal form shows a weight loss of 13.5% at 150.0°C±3.0°C.

[0114] In some embodiments of the present invention, the TGA spectrum of the above-mentioned F crystal form is shown in Figure 16.

[0115] The eleventh object of the present invention is to provide a crystalline form G of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.15±0.20°, 12.74±0.20°, and 15.37±0.20°.

[0116] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 22.76±0.20°.

[0117] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 23.64±0.20°.

[0118] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form has characteristic diffraction at the following 2θ angles: 6.0126.33°, 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°, 20.32°, 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°, 38.69°.

[0119] In some embodiments of the present invention, the XRPD pattern of the above-mentioned G crystal form is shown in Figure 17.

[0120] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form G are shown in Table 7:

[0121] Table 7. XRPD pattern analysis data of Form G

[0122] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned G crystal form has an endothermic peak at 157.5℃±3.0℃ and 316.6±3.0℃.

[0123] In some embodiments of the present invention, the DSC spectrum of the above-mentioned G crystal form is shown in Figure 18.

[0124] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned G crystal form shows a weight loss of 11.9% at 175.0°C±3.0°C.

[0125] In some embodiments of the present invention, the TGA spectrum of the above-mentioned G crystal form is shown in Figure 19.

[0126] The twelfth object of the present invention is to provide a H crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.59±0.20°, 10.18±0.20°, and 18.66±0.20°.

[0127] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 22.80±0.20°.

[0128] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 25.12±0.20°.

[0129] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form has characteristic diffraction at the following 2θ angles: 9.59410.18°, 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°, 20.12°, 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°, 35.94°.

[0130] In some embodiments of the present invention, the XRPD pattern of the above-mentioned H crystal form is shown in Figure 20.

[0131] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned H crystal form are shown in Table 8:

[0132] Table 8. XRPD pattern analysis data of Form H

[0133] The thirteenth object of the present invention is to provide Form I of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.06±0.20°, 12.45±0.20°, and 17.99±0.20°.

[0134] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form I has characteristic diffraction peaks at the following 2θ angles: 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°, 26.57±0.20°.

[0135] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form I has characteristic diffraction peaks at the following 2θ angles: 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°, 26.57±0.20°.

[0136] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form I has characteristic diffraction at the following 2θ angles: 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°, 36.24°.

[0137] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form I is shown in Figure 21.

[0138] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form I are shown in Table 9:

[0139] Table 9. XRPD pattern analysis data of Form I

[0140] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned Form I has an endothermic peak at 316.0°C±3.0°C.

[0141] In some embodiments of the present invention, the DSC spectrum of the above-mentioned Form I is shown in Figure 22.

[0142] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form I shows a weight loss of 1.1% at 150°C±3.0°C.

[0143] In some embodiments of the present invention, the TGA spectrum of the above-mentioned Form I is shown in Figure 23.

[0144] The fourteenth object of the present invention is to provide a J crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.15±0.20°, 18.08±0.20°, and 19.23±0.20°.

[0145] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 28.19±0.20°.

[0146] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 28.19±0.20°.

[0147] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form has characteristic diffraction at the following 2θ angles: 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°, 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°, 38.28°.

[0148] In some embodiments of the present invention, the XRPD pattern of the above-mentioned J crystal form is shown in Figure 24.

[0149] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned J crystal form are shown in Table 10:

[0150] Table 10. XRPD pattern analysis data of Form J

[0151] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned J crystal form has an endothermic peak at 135.3℃±3.0℃ and 315.2℃±3.0℃.

[0152] In some embodiments of the present invention, the DSC spectrum of the above-mentioned J crystal form is shown in Figure 25.

[0153] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned J crystal form shows a weight loss of 15.3% at 170.0°C±3.0°C.

[0154] In some embodiments of the present invention, the TGA spectrum of the above-mentioned J crystal form is shown in Figure 26.

[0155] The fifteenth object of the present invention is to provide a K crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.11±0.20°, 16.30±0.20°, and 18.19±0.20°.

[0156] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 27.39±0.20°.

[0157] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 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°, 36.75±0.20°.

[0158] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction at the following 2θ angles: 8.6119.11°, 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°, 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°, 38.09°.

[0159] In some embodiments of the present invention, the XRPD pattern of the above-mentioned K crystal form is shown in Figure 27.

[0160] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned K crystal form are shown in Table 11:

[0161] Table 11. XRPD pattern analysis data of Form K

[0162] The present invention also provides use of the above-mentioned compound in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J or crystal form K in the preparation of drugs for treating metabolic diseases.

[0163] Preferably, the drug acts as a thyroid hormone beta receptor agonist.

[0164] Preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic bile duct tumor. Preferably, the thyroid diseases include thyroid cancer and hypothyroidism.

[0165] The present invention also provides a drug comprising the above-mentioned compound in crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J or crystal form K as an active ingredient.

[0166] Preferably, the drug is a thyroid hormone beta receptor agonist. Further, the drug also includes a pharmaceutically acceptable excipient.

[0167] After adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art:

[0168] 1. The present invention has developed a new 2-pyridone derivative, which has high activity and selectivity for thyroid hormone β receptor and can be used to treat metabolic diseases, especially diseases related to thyroid hormone receptor.

[0169] In the in vitro enzyme activity test of thyroid receptor β (THRβ), the EC of the compound of formula (I) was 50 The value is 0.04596μM, indicating that the compound can promote the binding of THRβ to its coactivator peptide and has potential agonist activity on THRβ. In the thyroid receptor β (THRβ) cytological activity test, it was found that at the cellular level, the EC value of the compound of formula (I) is 50 The pharmacokinetic evaluation of the compound in rats revealed that the blood concentration of the compound of formula (I) was low, while the liver concentration was relatively high. Therefore, the compound of formula (I) has good liver targeting activity.

[0170] 2. The present invention also studied a series of crystalline forms of the compound, including Forms AK, which have the advantages of good stability, low hygroscopicity, and minimal thermal effects. Among them, Form A of the compound of formula (I) has good stability and low hygroscopicity under high temperature, high humidity, long-term and accelerated conditions.

[0171] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0172] FIG1 is a Cu-Kα radiation XRPD spectrum of the crystalline form A of the compound of formula (I);

[0173] FIG2 is a DSC spectrum of the crystalline form A of compound of formula (I);

[0174] FIG3 is a TGA spectrum of the crystalline form A of compound of formula (I);

[0175] FIG4 is an XRPD spectrum of the crystal form B of the compound of formula (I) using Cu-Kα radiation;

[0176] FIG5 is a DSC spectrum of the crystalline form B of compound of formula (I);

[0177] FIG6 is a TGA spectrum of the crystalline form B of compound of formula (I);

[0178] FIG7 is a Cu-Kα radiation XRPD spectrum of the crystalline form C of the compound of formula (I);

[0179] FIG8 is a DSC spectrum of the crystalline form C of compound of formula (I);

[0180] FIG9 is a TGA spectrum of the crystalline form C of compound of formula (I);

[0181] FIG10 is an XRPD spectrum of the crystal form D of the compound of formula (I) using Cu-Kα radiation;

[0182] FIG11 is an XRPD spectrum of the crystal form E of the compound of formula (I) using Cu-Kα radiation;

[0183] FIG12 is a DSC spectrum of the crystalline form E of the compound of formula (I);

[0184] FIG13 is a TGA spectrum of the crystalline form E of the compound of formula (I);

[0185] FIG14 is an XRPD spectrum of the crystalline form F of the compound of formula (I) using Cu-Kα radiation;

[0186] FIG15 is a DSC spectrum of the crystalline form F of compound of formula (I);

[0187] Figure 16 is a TGA spectrum of the crystalline form F of compound of formula (I);

[0188] FIG17 is an XRPD spectrum of the crystalline form G of the compound of formula (I) using Cu-Kα radiation;

[0189] FIG18 is a DSC spectrum of the crystalline form G of compound of formula (I);

[0190] Figure 19 is a TGA spectrum of the crystalline form G of compound of formula (I);

[0191] FIG20 is an XRPD spectrum of Form H of the compound of formula (I) using Cu-Kα radiation;

[0192] FIG21 is an XRPD spectrum of the crystalline form of compound (I) of formula (I) using Cu-Kα radiation;

[0193] FIG22 is a DSC spectrum of the crystalline form 1 of compound of formula (I);

[0194] Figure 23 is a TGA spectrum of the crystalline form of compound I of formula (I);

[0195] FIG24 is an XRPD spectrum of Form J of the compound of formula (I) using Cu-Kα radiation;

[0196] Figure 25 is a DSC spectrum of Form J of the compound of formula (I);

[0197] Figure 26 is a TGA spectrum of Form J of the compound of formula (I);

[0198] FIG27 is an XRPD spectrum of the crystal form K of the compound of formula (I) using Cu-Kα radiation;

[0199] Figure 28 is a DVS spectrum of the crystalline form A of compound of formula (I).

[0200] It should be noted that these drawings and textual descriptions are not intended to limit the conceptual scope of the present invention in any way, but rather to illustrate the concept of the present invention for those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0201] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions 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 illustrate the present invention but are not used to limit the scope of the present invention.

[0202] Definition and Description

[0203] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0204] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0205] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0206] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0207] All solvents used in the present invention were commercially available and used without further purification.

[0208] The solvents used in the present invention are commercially available. The present invention uses the following abbreviations: EtOH represents ethanol; MeOH represents methanol; EtOAc represents ethyl acetate; DCM represents dichloromethane; mp represents melting point; THF represents tetrahydrofuran; K2CO3 represents potassium carbonate; and DMF represents N,N-dimethylformamide.

[0209] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0210] 1. X-ray powder diffractometer (XRPD) method of the present invention

[0211] Instrument model: Bruker D8 Advance Diffractometer, Test method: >2 mg of sample is used for XRPD detection.

[0212] The detailed XRPD parameters are as follows: X-ray source: Cu, kα radiation, light tube voltage: 40 kV, light tube current: 40 mA,

[0213] Divergence slit: 0.6mm, Soller slit: 2.5mm, receiving slit: 8mm, filter: nickel sheet, measurement time: 6min,

[0214] Scan angle range: 3°-40°2θ / 3°-30°2θ, step width angle: 0.02°2θ, step length: 18.3 sec / 36.6 sec, sample plate rotation speed: none.

[0215] 2. Differential Scanning Calorimeter (DSC) method of the present invention

[0216] Instrument model: TA Instruments Q200 DSC differential scanning calorimeter.

[0217] Test method: Take a sample (0.5mg-5mg) and place it in a covered aluminum crucible (lid without perforation / lid with perforation). At a heating rate of 10℃ / min, under the protection of 50mL / min dry N2, the sample is heated from 0℃ to 320℃ / 350℃. At the same time, the TA software records the heat change of the sample during the heating process.

[0218] 3. Thermogravimetric analysis (TGA) method of the present invention

[0219] Instrument model: TA Instruments Q500 TGA thermogravimetric analyzer

[0220] Test method: Take a sample (1mg-10mg) and place it in a platinum crucible. Using segmented high-resolution detection, heat the sample from room temperature to 350℃ at a heating rate of 10℃ / min under the protection of 40mL / min dry N2. At the same time, the TA software records the weight change of the sample during the heating process.

[0221] 4. Dynamic Vapor Sorption (DVS) Method of the Present Invention

[0222] Instrument model: TA Instruments Q5000 SA dynamic moisture adsorption instrument

[0223] Test conditions: Weigh 1mg-10mg of sample and place it in the DVS sample pan for testing.

[0224] Detailed DVS parameters are as follows: Temperature: 25°C, Equilibrium: dm / dt = 0.01% / min for 15.00 min, Drying: Drying at 0% RH for 90 min, RH (%) test step: 10% RH (%) test step range: 0%-80%-0%

[0225] The moisture absorption evaluation is classified as follows: Note: ΔW% indicates the weight gain of the test product at 25±1℃ and 80±2%RH (European Pharmacopoeia 6.0).

[0226] Example 1: Preparation of compound of formula (I)

[0227] Step 1: Compound 1 (5.0 g, 24.75 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) under nitrogen protection. Lithium diisopropylamide (27.23 mL, 54.45 mmol) was added dropwise at -78°C. The mixture was reacted at -50°C for 40 minutes, after which (S)-(-)-propylene oxide (6.587 g) was added. The mixture was reacted at -50°C for 30 minutes, then naturally warmed to room temperature and reacted for 4 hours. The reaction was quenched with 3 mL of saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 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),3.8 1(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).

[0228] Step 2: Dissolve compound 2 (2.38 g) in toluene (25.0 mL), add 2,6-lutidine (2 g), then trifluoromethanesulfonic anhydride (2.5 g), and react for 1 hour. Add potassium carbonate (3.2 g), react at 75°C for 2 hours, add 100 mL of water, extract with ethyl acetate (100 mL x 3), wash once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. Add THF and hydrobromic acid to the flask. React at approximately 60°C for 3 days. Cool the reaction mixture to room temperature, adjust the pH to 7-8 with sodium bicarbonate, extract three times with EA, combine the organic phases, wash with 1N HCl, and then with brine. Dry over sodium sulfate and concentrate to obtain 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).

[0229] Step 3: Add compound 3, dioxane (10V), bisborane (1.5eq), AcOK (2.0eq), and Pd(dppf)Cl2 (0.1eq) to a flask. Replace the atmosphere with nitrogen three times and react at 80-90°C for 16 hours. Cool to room temperature to quench and post-process. The crude product is purified by column chromatography to yield compound 4 as a 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,1 H),3.43-3.18(m,2H),2.29-2.18(m,2H),1.43-1.37(m,3H),1.30-1.24(m,12H).

[0230] Step 4:

[0231] Compound 4 was dissolved in a mixed solvent of 30 mL of tetrahydrofuran and 4.0 mL of water, and 30% hydrogen peroxide (4.0 mL) was added and reacted at 25°C for 16 hours. The mixture was quenched by adding aqueous sodium sulfite solution, and ethyl acetate (30 mL) was added. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 5 (pale yellow solid). 1H NMR (500MHz, DMSO-d6) δ: 8.56 (s, 1H), 7.13-7.11 (d, 1H), 6.06-6.04 (d, 1H), 4.60-4.5 7(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).

[0232] Step 5:

[0233] 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

[0234] mg), potassium carbonate (232.2 mg), reacted at 25°C for 2 hours, concentrated under reduced pressure to remove the solvent, and purified by column chromatography to obtain compound 6 (30.1 g, yellow-green solid). MS m / z (ESI): 355.02 [M+1] + .

[0235] Step 6:

[0236] 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 filtered and the filtrate was concentrated to obtain 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).

[0237] Step 7:

[0238] Compound 7 (150 mg) was dissolved in a mixed solvent consisting 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. After reacting for 10 minutes, sodium acetate (113.2.0 mg) was added. After reacting for another 10 minutes, N-cyanoacetylurea (143.6 mg) was added. The mixture was allowed to warm to room temperature and react for 72 hours. 5 mL of water was added, the mixture was filtered, and dried to obtain compound 8 (1.8 g, yellow solid). MS m / z (ESI): 492.08 [M+1] + . 1H 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).

[0239] Step 8:

[0240] 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, and the solvent was removed by concentration under reduced pressure to obtain compound I (1.8 g, light yellow solid). MS m / z (ESI): 446.03 [M+1] + . 1 H NMR(500MHz,DMSO-d6)δ13.26(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).

[0241] The prepared compound was further processed according to the method of the following Examples 2-12 to obtain Compound I in different crystalline forms.

[0242] Example 2: Preparation of Crystalline Form A of Compound (I)

[0243] Preparation method 1:

[0244] The compound of formula (I) (100 g) was dissolved in 1100 ml of a mixed solvent of tetrahydrofuran and methanol (THF / MeOH = 3 / 2) and heated to 60°C until completely dissolved. Water (1000 mL) was added to the solution at 20-30°C while 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 constant weight to obtain Form A of the compound of formula (I).

[0245] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared compound A crystal form are shown in Figures 1-3, respectively.

[0246] Preparation method 2:

[0247] Approximately 100 mg of the compound of formula (I) was added to N,N-dimethylformamide (0.4 mL) to dissolve the solution, which was then filtered. Water (1 mL) was added to the solution at 20-30°C with stirring. After solids precipitated, the solution was stirred overnight and centrifuged. The resulting filter cake was washed with water. The filter cake was collected and vacuum dried to constant weight to obtain Form A of the compound of formula (I).

[0248] Preparation method 3:

[0249] Approximately 100 mg of the compound of formula (I) was added to dimethyl sulfoxide (0.2 mL) to dissolve the solution, which was then filtered. Water (1 mL) was added to the solution at 20-30°C with stirring. After solids precipitated, the solution was stirred overnight and centrifuged. The resulting filter cake was washed with water. The filter cake was collected and vacuum dried to constant weight to obtain Form A of the compound of formula (I).

[0250] Preparation method 4:

[0251] Approximately 1 g of the compound of formula (I) was added to 75 mL of methanol, heated to 60°C until completely dissolved, and then filtered. The methanol was partially concentrated at 40-45°C to precipitate the solid. The mixture was 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 constant weight to obtain Form A of the compound of formula (I).

[0252] Example 3: Preparation of Crystalline Form B of Compound (I)

[0253] Weigh 100 mg of the compound of formula (I), add 4.0 mL of tetrahydrofuran and ultrasonically dissolve it, add 1.0 mL of toluene to keep it clear, and place the solution at 40° C. to evaporate to dryness to obtain Form B of the compound of formula (I).

[0254] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared compound B crystal form are shown in Figures 4-6, respectively.

[0255] Example 4: Preparation of Crystalline Form C of Compound (I)

[0256] 100 mg of the compound of formula (I) was weighed, 40.0 mL of acetone was added and ultrasonically dissolved, 10.0 mL of isopropyl acetate was added to keep the solution clear, and the solution was left to evaporate to dryness at room temperature to obtain Form C of the compound of formula (I).

[0257] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared compound C crystal form are shown in Figures 7-9, respectively.

[0258] Example 5: Preparation of Crystalline Form D of Compound of Formula (I)

[0259] Weigh 100 mg of the compound of formula (I), add 0.4 mL of tetrahydrofuran and ultrasonically dissolve it, add 0.1 mL of water to keep it clear, and leave the solution to evaporate to dryness at room temperature to obtain the crystal form D of the compound of formula (I).

[0260] The Cu-Kα radiation XRPD spectrum of the prepared compound D crystalline form is shown in FIG10 .

[0261] Example 6: Preparation of Crystalline Form E of Compound of Formula (I)

[0262] 100 mg of the compound of formula (I) was weighed, 4.0 mL of tetrahydrofuran was added and ultrasonically dissolved, 1.0 mL of water was added to keep the solution clear, and the solution was left to evaporate to dryness at room temperature to obtain Form E of the compound of formula (I).

[0263] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared Compound E crystal form are shown in Figures 11-13, respectively.

[0264] Example 7: Preparation of Crystalline Form F of Compound of Formula (I)

[0265] 100 mg of the compound of formula (I) was weighed and placed in a centrifuge tube, which was placed in a tetrahydrofuran atmosphere at room temperature for 8 days, and then vacuum-dried at room temperature for about 27.5 h to obtain Form F of the compound of formula (I).

[0266] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared Compound F crystalline form are shown in Figures 14-16, respectively.

[0267] Example 8: Preparation of Crystalline Form G of Compound (IV)

[0268] Weigh 100 mg of the compound of formula (I), add 3.5 mL of tetrahydrofuran to dissolve the solution at room temperature, filter, and add the filtrate dropwise to 20.0 mL of methyl tert-butyl ether solvent. Stir at room temperature for about 2 h until no precipitation occurs. Heat to 4 ° C. and stir for about 21.5 h until a solid precipitates. Centrifuge and dry in vacuo at room temperature for about 4.5 h to obtain Form G of the compound of formula (I).

[0269] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared compound G crystal form are shown in Figures 17-19, respectively.

[0270] Example 9: Preparation of Crystalline Form H of Compound of Formula (I)

[0271] 100 mg of the compound of formula (I) was weighed, 4.0 mL of tetrahydrofuran was added, and the mixture was dissolved by ultrasonication. The mixture was concentrated to dryness under reduced pressure at 60° C. to obtain the H crystal form of the compound of formula (I).

[0272] The XRPD spectrum of the prepared Compound H crystalline form under Cu-Kα radiation is shown in FIG20 .

[0273] Example 10: Preparation of Crystalline Form I of Compound (I)

[0274] Weigh 100 mg of the compound of formula (I), add 3.0 mL of tetrahydrofuran and ultrasonically dissolve it, add 0.5 mL of acetonitrile to keep it clear, and place the solution at 40° C. to evaporate to dryness to obtain Form I of the compound of formula (I).

[0275] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared Compound I crystalline form are shown in Figures 21-23, respectively.

[0276] Example 11: Preparation of Crystalline Form J of Compound of Formula (I)

[0277] 120 mg of the compound of formula (I) was weighed, 8.0 mL of toluene was added, the suspension was stirred at room temperature for 8 days, centrifuged, and the resulting solid was dried under vacuum at room temperature for about 27.5 h to obtain Form J of the compound of formula (I).

[0278] The Cu-Kα radiation XRPD spectrum, DSC spectrum and TGA spectrum of the prepared Compound J crystal form are shown in Figures 24-26, respectively.

[0279] Example 12: Preparation of Crystalline Form K of Compound of Formula (I)

[0280] Weigh 20 mg of the compound of formula (I), add 8.0 mL of ethanol to dissolve it at room temperature, filter, add 12.0 mL of isopropyl acetate dropwise to the filtrate, and stir at room temperature. No solid is precipitated. Transfer to 4°C and stir for two days. No solid is precipitated. Transfer to 40°C and evaporate to dryness in an open air to obtain Form K of the compound of formula (I).

[0281] The XRPD spectrum of the prepared compound K crystal form under Cu-Kα radiation is shown in Figure 27.

[0282] Test Example 1: Hygroscopicity Study of Crystalline Form A of Compound (I)

[0283] Experimental materials: TA Instruments Q5000 SA dynamic moisture adsorption instrument

[0284] Experimental method: Weigh 1mg-10mg of sample and place it in the DVS sample tray for testing.

[0285] Experimental results: The DVS spectrum of the crystal form A of compound of formula (I) is shown in Figure 28, ΔW = 0.6%.

[0286] Experimental conclusion: The weight gain of the crystal form A of the compound of formula (I) at 25°C and 80% RH is 0.6%, which is slightly hygroscopic.

[0287] Test Example 2: Solid Stability Test of Crystalline Form A of Compound (I)

[0288] In accordance with the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2015 Edition, Part IV, General Rules 9001), the stability of the crystalline form A of compound of formula (I) was investigated under high temperature (50°C, open), accelerated (40°C / relative humidity 75%, open), high humidity (25°C / relative humidity 85%, open) and long-term (25°C / relative humidity 65%, open) conditions.

[0289] Accurately weigh approximately 10 mg of the compound of formula (I) and place it in a dry, clean glass bottle. Spread it into a thin layer, cover with aluminum foil, poke a small hole in it, and place it under the influencing factor test conditions of 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). Place two samples under each condition, and place the sample for XRPD analysis separately. Samples placed under different conditions were sampled at the planned test endpoint for XRPD and melting point analysis. The test results were compared with the initial test results on day 0. The test results are shown in Table 12 below:

[0290] Table 12 Solid stability test results of the crystal form of compound A of formula (I)

[0291] Conclusion: The crystalline form A of compound of formula (I) has good stability under high temperature, high humidity, long-term and accelerated conditions.

[0292] Experimental Example 3: Thyroid receptor β (THRβ) in vitro enzyme activity test

[0293] Time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used to evaluate the agonist activity of the test compounds by binding to thyroid hormone receptor β (THRβ) and its coactivator peptide SRC2-2.

[0294] The THRβ ligand-binding domain (THRβLBD) was fused to a GST tag, and its coactivator peptide SRC2-2 was biotinylated. The binding of THRβLBD to SRC2-2 was determined by TR-FRET detection using a tightly bound europium-labeled anti-GST antibody and D2-labeled streptavidin.

[0295] Experimental procedures

[0296] 1) Dissolve the test compound in DMSO to prepare a 30 mM stock solution. Store in a desiccator at room temperature for three months. For long-term storage, store in a -20°C freezer. 1x reaction buffer consists of 50 mM HEPES (pH 7.0), 50 mM KF, 1 mM DTT, 0.05% NP-40, and 0.2% BSA.

[0297] a) 10 μM positive compound T3 (100×) and 1 mM test compound (100×) (crystal form A compound prepared in Example 2) were prepared using DMSO.

[0298] b) In a 96-well plate, 10 μM T3 and 1 mM test compound were serially diluted three-fold to measure 10 concentration points.

[0299] c) Dilute the above 100× positive compound and test compound to 4× with 1× reaction buffer.

[0300] d) Add 5 μL of 4× positive compound or test chemical (see step c) to a 384-well assay plate.

[0301] e) Prepare 4×THRβ-LBD (0.8 nM) and 4×RXRα (0.8 nM) solutions using 1× reaction buffer.

[0302] f) Add 5 μL of the solution from step e to the experimental plate (prepared in step d) and react at room temperature for 15 min.

[0303] g) Prepare a mixture containing 400 nM 2×Biotin-SRC2-2 coactivator peptide, 25 nM 2×Streptavidin-d2 and 2×Europium anti-GST (1:200) in 1× reaction buffer.

[0304] h) Add 10 μL of the mixture prepared in step g to each well of the experimental plate to initiate the reaction.

[0305] i) Centrifuge the test plate at 1000 rpm for 1 min.

[0306] j) Incubate at room temperature in the dark for 1 h.

[0307] k) Use BMG to read the values ​​at wavelengths of 665 nm and 615 nm.

[0308] 2) Data Analysis

[0309] The activity rate is calculated as follows:

[0310] ratio 阳性对照 : The average value of the ratio of all positive control wells in the whole plate.

[0311] ratio 阴性对照 : The average value of the ratio of all negative control wells in the whole plate.

[0312] 3) Calculate EC 50 :

[0313] The EC of the compound was obtained using the following nonlinear fitting formula: 50 (half agonist concentration).

[0314] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -x)*HillSlope))

[0315] X: log value of compound concentration; Y: compound activity rate.

[0316] Table 13 Thyroid receptor β (THRβ) in vitro enzyme activity EC 50 Test results

[0317] Conclusion: The EC of the compound of formula (I) 50 The value was 0.04596 μM, indicating that this compound promoted the binding of THRβ to its coactivator peptide and had potential agonist activity on THRβ.

[0318] Experimental Example 4: Thyroid Receptor β (THRβ) Cytological Activity Test

[0319] This study used a fluorescent reporter gene assay to evaluate the agonistic effects of two test compounds on the THRβ target.

[0320] pGL4.35[luc2P / 9XGAL4UAS / Hygro] contains nine repeats of the GAL4-UAS sequence (upstream activating sequence). This sequence drives transcription of the luciferase reporter gene luc2P in response to binding of a fusion protein containing the Gal4 DNA binding domain to the thyroid receptor β (THRβ) ligand binding domain contained in the pBIND THRβ vector. Stimulation of THRβ by the test article results in an increase in luminescent signal.

[0321] The experimental process is as follows:

[0322] 1) The test compound (Crystal Form A compound prepared in Example 2) was dissolved in DMSO to prepare a 30 mM stock solution. Positive compounds were dissolved in DMSO to prepare a 5 mM stock solution, which was further diluted to a 0.5 mM stock solution. All compounds were dissolved in DMSO and stored in a -20°C refrigerator. In a 384-well plate, the compounds were diluted three-fold in DMSO over a 10-step concentration gradient, starting at 30 mM.

[0323] In a 384-well plate, the positive compound (T3) was serially diluted 3-fold with DMSO, with a 10-point concentration gradient starting at 0.25 mM. A 500× positive control (0.25 mM, T3) and a 500× negative control (100% DMSO) were prepared.

[0324] 2) HEK293T cells were cultured according to ATCC standards. Experiments were performed during the exponential growth phase. The supernatant was gently discarded and the cells were washed twice with PBS. The cells were digested with trypsin solution and digested with complete culture medium. The cells were harvested and counted. Cell viability was greater than 90% for use in experiments. 2.5 × 10 6 HEK293T cells were plated into a 60 mm cell culture dish and placed in a 37°C 5% CO2 incubator for 18 hours.

[0325] 3) Place LipoLTX & PLUS transfection reagent at room temperature and prepare two 1.5mL EP tubes. Add 12μL LipoLTX reagent and 250μL Opti-MEM into one EP tube. TM In another EP tube, add 6 μg of plasmid and 250 μL of Opti-MEM TM Add 6 μL of Lipo PLUS reagent to the culture medium, mix thoroughly with a pipette, and let stand at room temperature for 5 minutes. Combine the two EP tubes and let stand at room temperature for 15 minutes. Add the mixed plasmid and transfection reagent to a 60 mm cell culture dish. Incubate the dish at 37°C in a 5% CO2 incubator for 5 hours.

[0326] 4) Transfer 50 nL of the diluted compound to a 384-well cell culture plate using an Echo655. Seed cells at 17,000 cells per well in 25 μL of 5% charcoal-stripped FBS medium. Incubate the plate overnight at 37°C in a 5% CO2 incubator for 16-20 hours.

[0327] 5) Allow Britelite Plus Detection Reagent to stand at room temperature. Place a 384-well cell culture plate at room temperature. Add 25 μL of Britelite Plus Detection Reagent to each well of the plate. Measure luminescence using Envision.

[0328] 6) The percentage of excitement is calculated as follows:

[0329] RLU: Resulting Luminescence

[0330] The average luminescence value of all positive control wells on the entire plate.

[0331] The average luminescence value of all negative control wells in the whole plate.

[0332] 7) Calculate EC 50 :

[0333] Using Graphpad8.0, the following nonlinear fitting formula was used to obtain the EC of the compound. 50 .

[0334] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0335] X: log value of compound concentration; Y: percentage of compound stimulation

[0336] The experimental results are shown in Table 14:

[0337] Table 14 THRβ in vitro cell activity EC 50 Test results

[0338] Conclusion: At the cellular level, the EC of the compound of formula (I) 50 The agonist activity of the compound of formula (I) on thyroid receptor β (THRβ) was 0.214 μM.

[0339] Experimental Example 5 Pharmacokinetic Evaluation in Rats

[0340] Purpose of the experiment:

[0341] The pharmacokinetic parameters of the compound of formula (I) in rats were detected.

[0342] Experimental plan:

[0343] 1) Experimental drug: compound of formula (I); (crystal form A compound prepared in Example 2).

[0344] 2) Experimental animals: 6 male CD rats aged 6-8 weeks;

[0345] 3) Experimental procedures:

[0346] The compound was administered at a dose of 5 mg / kg and a concentration of 0.5 mg / mL. Samples were collected from the animals at 2, 6, and 10 hours post-dose. Drug concentrations in plasma samples were determined using LC-MS / MS. The kinetic parameters for the test drug are shown in Table 15:

[0347] Table 15 Rat liver-blood ratio test results

[0348] Conclusion: The blood concentration of the compound of formula (I) in rats is low, while the liver concentration is relatively high, which indicates that the compound of formula (I) has good liver targeting.

[0349] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as above in terms of a preferred embodiment, it is not intended to limit the present invention. Any technician familiar with the present invention can make slight changes or modifications to equivalent embodiments using the above-mentioned technical contents without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the solution of the present invention.

Claims

1. A compound, characterized in that A compound having the structural formula represented by formula (I) or a pharmaceutically acceptable salt thereof: Preferably, the compound having the structural formula represented by formula (I) or a pharmaceutically acceptable salt thereof is used to prepare a drug for treating metabolic diseases; Preferably, the drug is a thyroid hormone beta receptor agonist; preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic bile duct tumor.

2. A crystal form A of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 6.10 ± 0.20°, 12.08 ± 0.20°, and 16.49 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form A is shown in Figure 1; Preferably, the differential scanning calorimetry curve of Form A has an endothermic peak at 300.1±3.0°C; Preferably, the DSC spectrum of Form A is shown in FIG2 ; Preferably, the thermogravimetric analysis curve of Form A shows a weight loss of 0.6% at 150.0°C ± 3.0°C; Preferably, the TGA spectrum of crystal form A is shown in FIG3 .

3. A method for preparing the crystal form A according to claim 2, characterized in that: include: (1) dissolving the compound of formula (I) in a mixed solvent of tetrahydrofuran and methanol, and heating to completely dissolve it; (2) Add water to the solution while stirring, slowly cool the solution, continue stirring, and filter; (3) washing the obtained filter cake with methanol, collecting the filter cake, and vacuum drying to constant weight to obtain Form A of the compound of formula (I); Preferably, in step (1), the volume ratio of tetrahydrofuran to methanol in the mixed solvent is 2:1 to 1:2; Preferably, in step (1), the concentration of the compound of formula (I) in the mixed solvent is 0.02 to 0.2 g / ml; Preferably, in step (1), heating to 45-65°C; Preferably, in step (2), the volume of the water added is in a ratio of 1:2 to 3:1 to the volume of the mixed solvent in step (1); Preferably, in step (2), water is added to the solution at 15-35° C.; the solution is slowly cooled to 15-30° C. and stirred for 0.5-1 h; Or the preparation method comprises: (1) dissolving the compound of formula (I) in N,N-dimethylformamide, filtering after clearing the solution; (2) Add water to the solution under stirring conditions, precipitate solids, stir overnight, and centrifuge; (3) washing the obtained filter cake with water, collecting the filter cake, and vacuum drying to constant weight to obtain Form A of the compound of formula (I); Preferably, in step (1), the concentration of the compound of formula (I) in N,N-dimethylformamide is 0.1 to 0.3 g / ml; Preferably, in step (2), the volume ratio of the water added to the volume of N,N-dimethylformamide in step (1) is 1:2 to 3:1; Preferably, in step (2), water is added to the solution at 15-35°C; Or the preparation method comprises: (1) dissolving the compound of formula (I) in dimethyl sulfoxide, filtering after the solution becomes clear; (2) Add water to the solution under stirring conditions, precipitate solids, stir overnight, and centrifuge; (3) washing the obtained filter cake with water, collecting the filter cake, and vacuum drying to constant weight to obtain Form A of the compound of formula (I); Preferably, in step (1), the concentration of the compound of formula (I) in dimethyl sulfoxide is 0.3 to 0.8 g / ml; Preferably, in step (2), the volume ratio of the added water to the volume of the dimethyl sulfoxide in step (1) is 3:1 to 7:1; Preferably, in step (2), water is added to the solution at 15-35°C; Or the preparation method comprises: (1) Dissolve the compound of formula (I) in methanol, heat until completely dissolved, and filter; (2) Concentrate to remove part of the methanol until solid precipitates, cool, and centrifuge; (3) washing the obtained filter cake with methanol, collecting the filter cake, and vacuum drying to constant weight to obtain Form A of the compound of formula (I); Preferably, in step (1), the concentration of the compound of formula (I) in methanol is 0.01 to 0.1 g / ml; Preferably, in step (1), heating to 45-65°C; Preferably, in step (2), the temperature for concentrating and removing part of the methanol is 30-50°C; Preferably, in step (2), the mixture is cooled to room temperature (20-30°C).

4. A crystal form B of the compound according to claim 1, characterized in that Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.35 ± 0.20°, 10.36 ± 0.20°, and 18.32 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angle is 9.35±0.20°, 10.36±0.20°, 11.77±0.20°, There are characteristic peaks at 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 Form B is shown in FIG4 ; Preferably, the differential scanning calorimetry curve of Form B has an endothermic peak at 139.5°C ± 3.0°C and 315.6 ± 3.0°C; Preferably, the DSC spectrum of Form B is shown in FIG5 ; Preferably, the thermogravimetric analysis curve of Form B shows a weight loss of 16.0% at 150.0°C ± 3.0°C; Preferably, the TGA spectrum of Form B is shown in FIG6 .

5. A crystal form C of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 5.96 ± 0.20°, 10.96 ± 0.20°, and 22.84 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form C is shown in FIG7 ; Preferably, the differential scanning calorimetry curve of Form C has an endothermic peak at 123.7±3.0°C and 315.7±3.0°C; Preferably, the DSC spectrum of Form C is shown in FIG8 ; Preferably, the thermogravimetric analysis curve of Form C shows a weight loss of 10.9% at 150.0°C ± 3.0°C; Preferably, the TGA spectrum of Form C is shown in FIG9 .

6. A crystal form D of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.97 ± 0.20°, 11.66 ± 0.20°, and 15.83 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 7.97°, 9.08°, 11.66°, 12.47°, 15.83°, 17.98°, 20.47°, 20.74°, 23.37°, and 25.04°; Preferably, the XRPD pattern of Form D is shown in FIG10 .

7. A crystalline form E of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 12.43 ± 0.20°, 12.70 ± 0.20°, and 17.94 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form E is shown in FIG11 ; Preferably, the differential scanning calorimetry curve of the E crystal form has an endothermic peak at 151.1°C ± 3.0°C and 315.2 ± 3.0°C; Preferably, the DSC spectrum of Form E is shown in FIG12 ; Preferably, the thermogravimetric analysis curve of Form E shows a weight loss of 6.6% at 150.0°C ± 3.0°C; Preferably, the TGA spectrum of Form E is shown in FIG13 .

8. A crystal form F of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 7.13 ± 0.20°, 12.18 ± 0.20°, and 18.25 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form F is shown in FIG14 ; Preferably, the differential scanning calorimetry curve of the F crystal form has an endothermic peak at 158.9°C ± 3.0°C and 315.6 ± 3.0°C; Preferably, the DSC spectrum of Form F is shown in FIG15 ; Preferably, the thermogravimetric analysis curve of Form F shows a weight loss of 13.5% at 150.0°C ± 3.0°C; Preferably, the TGA spectrum of Form F is shown in FIG16 .

9. A G crystal form of the compound according to claim 1, characterized in that Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 12.15 ± 0.20°, 12.74 ± 0.20°, and 15.37 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form G is shown in FIG17 ; Preferably, the differential scanning calorimetry curve of Form G has an endothermic peak at 157.5°C ± 3.0°C and 316.6 ± 3.0°C; Preferably, the DSC spectrum of Form G is shown in FIG18 ; Preferably, the thermogravimetric analysis curve of Form G shows a weight loss of 11.9% at 175.0°C ± 3.0°C; Preferably, the TGA spectrum of Form G is shown in FIG19 .

10. A H crystal form of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.59 ± 0.20°, 10.18 ± 0.20°, and 18.66 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 XRPD pattern of Form H is shown in FIG20 .

11. A crystalline form I of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.06 ± 0.20°, 12.45 ± 0.20°, and 17.99 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form I is shown in Figure 21; Preferably, the differential scanning calorimetry curve of Form I has an endothermic peak at 316.0°C ± 3.0°C; Preferably, the DSC spectrum of Form I is shown in FIG22 ; Preferably, the thermogravimetric analysis curve of Form I shows a weight loss of 1.1% at 150°C ± 3.0°C; Preferably, the TGA spectrum of Form I is shown in Figure 23.

12. A J crystal form of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.15 ± 0.20°, 18.08 ± 0.20°, and 19.23 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 Form J is shown in FIG24 ; Preferably, the differential scanning calorimetry curve of Form J has an endothermic peak at 135.3°C ± 3.0°C and 315.2°C ± 3.0°C; Preferably, the DSC spectrum of Form J is shown in FIG25 ; Preferably, the thermogravimetric analysis curve of Form J shows a weight loss of 15.3% at 170.0°C ± 3.0°C; Preferably, the TGA spectrum of Form J is shown in FIG26 .

13. A K crystal form of the compound according to claim 1, characterized in that: Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 9.11 ± 0.20°, 16.30 ± 0.20°, and 18.19 ± 0.20°; Preferably, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 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 expressed in 2θ angles has characteristic peaks at 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 XRPD pattern of Form K is shown in FIG27 .

14. Use of any one of the compound of claim 1 or a pharmaceutically acceptable salt thereof, the crystal form A of the compound of claim 2, the crystal form A of the compound prepared by the preparation method of claim 3, the crystal form B of the compound of claim 4, the crystal form C of the compound of claim 5, the crystal form D of the compound of claim 6, the crystal form E of the compound of claim 7, the crystal form F of the compound of claim 8, the crystal form G of the compound of claim 9, the crystal form H of the compound of claim 10, the crystal form I of the compound of claim 11, the crystal form J of the compound of claim 12, and the crystal form K of the compound of claim 13 in the preparation of a medicament for treating metabolic diseases; Preferably, the drug acts as a thyroid hormone beta receptor agonist; Preferably, the metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, thyroid disease, and intrahepatic bile duct tumor.

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