Crystal form of thyroid hormone β receptor modulator

Abstract

The present invention relates to a polymorph of a compound that can be used as a thyroid hormone β receptor modulator, a preparation method therefor and a use thereof, and a pharmaceutical composition containing the polymorph. The use is a use in the preparation of drugs for treating various thyroid-related diseases.

Description

A crystal form of thyroid hormone beta receptor modulator Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to polymorphs of compounds, pharmaceutical compositions and uses thereof. Background Art

[0002] Thyroid hormones are essential for normal human growth and development. Both insufficient and excessive secretion can cause illness. Hypothyroidism can impair both physical and intellectual development, leading to cretinism. Adult hypothyroidism can cause myxedema. Hyperthyroidism can cause nervousness, irritability, tremors, increased heart rate, and increased cardiac output. Thyroid hormones promote oxidation, increase oxygen consumption, and boost basal metabolic rate, leading to increased heat production.

[0003] The biological activity of thyroid hormones is mediated through thyroid hormone receptors (TRs). Thyroid hormone receptors belong to the superfamily of nuclear receptors. TRs have a ligand-binding domain, a DNA-binding domain, and an amino-terminal domain. There are four TR subtypes: TRα1, TRα2, TRβ1, and TRβ2. TRα1 is predominant in the heart, while TRβ1 is predominant in the liver. TRβ2 mRNA expression is primarily restricted to the pituitary gland and hypothalamus. TRα1, TRβ1, and TRβ2 can bind to thyroid hormones and produce corresponding physiological effects. TRα2 does not bind to thyroid hormones.

[0004] Leveraging the advantages of thyroid hormones in increasing metabolic rate, oxygen consumption, and heat release can provide therapeutic benefits, such as treating obesity. Hyperthyroidism is often accompanied by increased food intake, but also an overall increase in basal metabolic rate (BMR), and a weight loss of approximately 15%. Hypothyroidism, on the other hand, is often associated with a 25-30% weight gain. Most patients experiencing weight gain experience weight gain when treated with T3 for hypothyroidism. Furthermore, thyroid hormones can lower serum low-density lipoprotein (LDL) levels (Journal of Molecular and Celluar Cardiology 37(2004):1137-1146). Existing research indicates that hyperthyroidism can significantly lower serum total cholesterol, primarily due to thyroid hormones increasing hepatic LDL receptor expression, thereby promoting the metabolism of cholesterol into bile acids. Hypothyroidism is also associated with hypercholesterolemia. Therefore, thyroid hormones may reduce the incidence of atherosclerosis and other cardiovascular diseases.

[0005] Due to individual differences, the use of thyroid hormones to treat diseases is often accompanied by side effects of supraphysiological doses, including heart problems (primarily tachycardia), muscle weakness, and excessive weight loss. Long-term use is also associated with bone loss. By modifying thyroid hormones, the adverse effects of thyroxine mimetic hormones themselves can be reduced while retaining their beneficial effects, allowing the development of appropriate drugs to treat the following diseases: obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver diseases (fatty liver, NASH, NAFLD, etc.), cardiovascular diseases (atherosclerosis, etc.), thyroid diseases (hypothyroidism, thyroid cancer, etc.), and other related diseases.

[0006] The compound 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione disclosed in WO2021244582A1 is a novel thyroid hormone β receptor modulator having a structure of formula I.

[0007] The compound can be used to treat thyroid hormone-related diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver diseases (fatty liver, NASH, NAFLD, etc.), cardiovascular diseases (atherosclerosis, etc.), and thyroid diseases (hypothyroidism, thyroid cancer, etc.). Summary of the Invention

[0008] One of the objectives of this application is to provide polymorphic forms of the compound of Formula I (2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione). The various crystalline forms prepared herein can be identified and distinguished from other crystalline forms using conventional crystal characterization methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Studies of the properties of the crystalline forms described herein unexpectedly revealed that the various crystalline forms exhibit advantages such as good solubility, low hygroscopicity, and / or excellent stability, making them suitable as pharmaceutical crystalline forms.

[0009] The present application provides a crystalline form M of a compound represented by formula I,

[0010] In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M shows characteristic diffraction peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 12.11±0.2°, 15.59±0.2°, 19.16±0.2°, and 26.98±0.2°.

[0011] In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M shows characteristic diffraction peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 11.38°±0.2°, 12.11±0.2°, 14.04°±0.2°, 14.67°±0.2°, 15.59±0.2°, 19.16±0.2°, and 26.98±0.2°.

[0012] In certain embodiments, in the X-ray powder diffraction pattern obtained using CuKα radiation, the crystalline form M shows characteristic diffraction peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 11.38°±0.2°, 12.11±0.2°, 14.04°±0.2°, 14.67°±0.2°, 15.59±0.2°, 19.16±0.2°, 20.67°±0.2°, 22.94°±0.2°, 24.37°±0.2°, 26.98°±0.2°, and 27.37°±0.2°.

[0013] In certain embodiments, the X-ray powder diffraction pattern of the crystalline Form M is substantially the same as that of FIG1 .

[0014] In certain embodiments, the crystalline Form M shows substantially no weight loss when heated to about 30° C.-180° C. in a thermogravimetric analysis test ( FIG. 2 ).

[0015] In certain embodiments, the crystalline Form M shows an endothermic peak at about 205-210° C. in a differential scanning calorimetry test.

[0016] In certain embodiments, the DSC spectrum of the crystalline form M is substantially the same as that in FIG3 .

[0017] The present application provides a crystalline form N of a compound represented by formula I.

[0018] In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in a diffraction angle 2θ, the crystalline form N shows characteristic diffraction peaks at 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2°.

[0019] In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in a diffraction angle 2θ, the crystalline form N shows characteristic diffraction peaks at 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 14.16±0.2°, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2°.

[0020] In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in a diffraction angle 2θ, the crystalline form N shows characteristic diffraction peaks at 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 14.16±0.2°, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, 19.85°±0.2°, 20.63°±0.2°, 23.01°±0.2°, 26.42°±0.2°, and 28.54°±0.2°.

[0021] In certain embodiments, the X-ray powder diffraction pattern of Form N is substantially the same as that of FIG. 4 .

[0022] In certain embodiments, the Form N shows substantially no weight loss when heated to about 30° C.-180° C. in thermogravimetric analysis testing ( FIG. 5 ).

[0023] In certain embodiments, the crystalline Form N shows an endothermic peak at about 204-207° C. in a differential scanning calorimetry test.

[0024] In certain specific embodiments, the DSC spectrum of the crystalline form N is substantially the same as that in FIG6 .

[0025] The present application provides a hydrate crystal form O of a compound represented by formula I, wherein the water content of the hydrate crystal form O is that of a hemihydrate.

[0026] Single crystals of Form O were prepared and the crystal structure information was measured by single crystal X-ray diffraction. The crystallographic parameters of Form O (M = 838.44 g / mol) are: triclinic system, P-1 space group, α=95.276(3)°,β=106.113(4)°,γ=109.816(4)°. Unit cell volume The number of molecules in the unit cell Z = 2, the unit cell density ρ calc =1.513g / cm 3 .

[0027] In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in a diffraction angle 2θ, the crystalline form O shows characteristic diffraction peaks at 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 14.01±0.2°, 24.11±0.2°, and 26.57±0.2°.

[0028] In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in a diffraction angle 2θ, the crystalline form O shows characteristic diffraction peaks at 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 11.82±0.2°, 12.21±0.2°, 13.34±0.2°, 14.01±0.2°, 24.11±0.2°, and 26.57±0.2°.

[0029] In certain embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in a diffraction angle 2θ, the crystalline form O shows characteristic diffraction peaks at 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 11.82±0.2°, 12.21±0.2°, 13.34±0.2°, 14.01±0.2°, 16.20°±0.2°, 20.30°±0.2°, 20.75°±0.2°, 21.12°±0.2°, 24.11°±0.2°, and 26.57±0.2°.

[0030] In certain embodiments, the X-ray powder diffraction pattern of Form O is substantially the same as that of FIG. 7 .

[0031] In certain embodiments, the thermogravimetric analysis test of Form O shows ( FIG. 8 ) that the weight loss in the range of 40-140° C. is 2.14%. Based on the weight loss temperature and weight loss, Form O is presumed to be a hemihydrate (theoretical weight loss is 2.19%), which is consistent with the single crystal results and DSC results.

[0032] In certain embodiments, the Form O shows a broad endothermic peak in the range of 60-140°C in a differential scanning calorimetry test, which is a desolvation peak, and a sharp endothermic peak at 174-177°C, which is a melting peak, indicating that Form O is a solvate, which is confirmed to be a hemihydrate based on the single crystal results.

[0033] In certain embodiments, the DSC spectrum of the crystalline Form O is substantially the same as that in FIG9 .

[0034] Another object of the present application is to provide a pharmaceutical composition comprising the above-mentioned polymorph.

[0035] Another object of the present application is to provide the use of the above-mentioned polymorph or pharmaceutical composition in the preparation of a drug for preventing or treating diseases related to the action of thyroid hormone beta receptor agonists.

[0036] Another object of the present application is to provide the use of the above-mentioned polymorphs or pharmaceutical compositions in the preparation of drugs for preventing or treating thyroid hormone-related diseases, such as obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, thyroid cancer, metabolic syndrome, cardiovascular disease, coronary artery disease, myocardial infarction, ventricular dysfunction, heart failure, fatty liver, cirrhosis, diabetes, steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, atherosclerosis, or hypothyroidism.

[0037] Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of this application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application relates. Accordingly, the descriptions in the drawings and specification of this application are merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 X-ray powder diffraction pattern of Form M

[0039] Figure 2 Thermogravimetric analysis of Form M

[0040] Figure 3 Differential scanning calorimetry analysis of Form M

[0041] Figure 4 X-ray powder diffraction pattern of Form N

[0042] Figure 5 Thermogravimetric analysis of Form N

[0043] Figure 6 Differential scanning calorimetry analysis of Form N

[0044] Figure 7 X-ray powder diffraction pattern of Form O

[0045] Figure 8 Thermogravimetric analysis of Form O

[0046] Figure 9 Differential scanning calorimetry analysis of Form O

[0047] Figure 10 Schematic diagram of the asymmetric unit of the single crystal sample of Form O

[0048] Figure 11 X-ray powder diffraction pattern of Form A

[0049] Figure 12 Differential scanning calorimetry analysis of Form A

[0050] Figure 13 X-ray powder diffraction pattern of amorphous Example

[0051] The present invention will be further illustrated by specific examples below, but these examples are not intended to limit the scope of protection of the present invention. Those skilled in the art may make improvements to the preparation methods and apparatus within the scope of the claims, and such improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the appended claims.

[0052] The abbreviations used in the present invention are explained as follows: XRPD: X-ray powder diffraction DSC: Differential scanning calorimetry TGA: Thermogravimetric analysis DVS: Dynamic vapor sorption HPLC: High performance liquid chromatography RH: Relative humidity Instruments and methods 1. X-ray powder diffraction (XRPD) 1.1 Detection conditions XRPD was measured on an Empyrean X-ray diffractometer at room temperature using a copper target Cu Kα radiation (I Kα1 : I Kα2 =0.5, λ1=1.540598, λ2=1.544426). Specific instrument parameters are shown in Table 1.

[0053] Table 1 Instrument parameters

[0054] 2. Differential Scanning Calorimetry (DSC)

[0055] 2.1 Test conditions

[0056] DSC was performed using a Netzsch DSC 214Nevio differential scanning calorimeter. The specific test conditions were as follows: temperature range: 40°C-250°C, heating rate: 10°C / min, aluminum crucible, gas atmosphere: N2, gas flow rate: 50 mL / min.

[0057] 3. Thermogravimetric analysis (TGA)

[0058] 3.1 Test conditions

[0059] TGA was determined by Mettler TGA 2 thermogravimetric analysis. The specific test conditions were as follows: temperature range: 30°C–800°C, heating rate: 10°C / min, alumina crucible, gas atmosphere: N2, gas flow rate: 50 mL / min.

[0060] Unless otherwise specified in the examples, the room temperature is 20°C to 30°C.

[0061] Example 1

[0062] 500 mg of the compound of formula I was weighed into a reaction vessel, 5 mL of n-heptane was added, and the mixture was slurried at 80°C for 2 hours. The mixture was transferred to room temperature and allowed to stand for 0.5 hours. The mixture was filtered, and the filter cake was washed with 2.5 mL of n-heptane. The resulting solid was dried at 80°C for 10 hours, with a yield of 92%.

[0063] X-ray powder diffraction (XRPD) analysis confirmed that the crystalline form was Form M. The X-ray powder diffraction data are shown in Table 2, and the diffraction pattern is shown in FIG1.

[0064] The thermogravimetric analysis (TGA) of the Form M is shown in Figure 2. Figure 2 shows that the Form M has essentially no weight loss when heated to about 30°C-180°C.

[0065] The differential scanning calorimetry (DSC) test of the crystal form M is shown in Figure 3. Figure 3 shows an endothermic peak at about 205-210°C.

[0066] Table 2 X-ray powder diffraction data of Form M

[0067] Example 2

[0068] 326 mg of the drug substance was weighed into a reaction vessel, 1 mL of ethyl acetate was added, and the mixture was dissolved at 80°C. 10 mL of n-hexane was added dropwise. The mixture was kept warm for 10 min and then transferred to room temperature with stirring. After 30 min, the mixture was filtered and dried. The obtained solid was confirmed to be Form N by X-ray powder diffraction (XRPD) analysis.

[0069] The XRPD analysis showed that the X-ray powder diffraction data of Form N are shown in Table 3, and its diffraction pattern is shown in FIG4 .

[0070] Thermogravimetric analysis (TGA) of Form N is shown in Figure 5. Figure 5 shows that Form M exhibits virtually no weight loss when heated to approximately 30°C-180°C, indicating that Form N is a non-solvated isomorph, consistent with the DSC results. A small amount of weight loss (approximately 1.21%) occurs around 200°C, indicating a decomposition temperature of Form N of 322.72°C (extrapolated onset).

[0071] The differential scanning calorimetry (DSC) test of Form N is shown in Figure 6. Figure 6 shows an endothermic peak at about 204-207°C.

[0072] Table 3 X-ray powder diffraction data of Form N

[0073] Example 3

[0074] 1.000 g of the drug substance was weighed into a reaction vessel, 5 mL of ethyl acetate was added and stirred to dissolve, 50 mL of n-heptane was slowly added, and the mixture was stirred for 4 hours to crystallize, then filtered and dried. The resulting solid was confirmed to be Form O by X-ray powder diffraction (XRPD) analysis, with a yield of 73.0%.

[0075] The XRPD analysis showed that the X-ray powder diffraction data of Form O are shown in Table 4, and its diffraction pattern is shown in FIG7 .

[0076] Table 4 X-ray powder diffraction data of Form O

[0077] The thermogravimetric analysis (TGA) results of Form O are shown in Figure 8. Figure 8 shows a weight loss of 2.14% in the 40-140°C range. Based on the weight loss temperature and weight loss, Form O is presumed to be a hemihydrate (theoretical weight loss is 2.19%), which is consistent with the single crystal results and DSC results.

[0078] The differential scanning calorimetry (DSC) test of Form O is shown in Figure 9. Figure 9 shows a broad endothermic peak in the range of 60-140°C, which is a desolvation peak, and a sharp endothermic peak at 174-177°C, which is a melting peak, indicating that Form O is a solvate, which is confirmed to be a hemihydrate based on the single crystal results.

[0079] Single crystals of Form O were obtained, and the crystal structure was determined by single-crystal X-ray diffraction. Single-crystal data were acquired at room temperature (293.15K) using a CCD Xcalibur Nova X-ray spectrometer, using multi-slice scanning with a graphite monochromator using Mo Kα radiation (λ = 0.71073). Olex2 software was used for unit cell refinement and data processing, and ShelXT was used for crystal structure analysis and refinement.

[0080] The crystallographic parameters of Form O (M = 838.44 g / mol) are: triclinic system, P-1 space group, α=95.276(3)°,β=106.113(4)°,γ=109.816(4)°,unit cell volume The number of molecules in the unit cell Z = 2, the unit cell density ρ calc =1.513g / cm 3 The main crystallographic parameters are shown in Table 5.

[0081] Table 5 Main crystallographic parameters of Form O

[0082] The schematic diagram of the asymmetric unit of the single crystal sample molecule is shown in Figure 10. One asymmetric unit structure contains two structural molecules of the compound of formula I and one water molecule, that is, the stoichiometric ratio of the structural molecules of the compound of formula I to the water molecules in crystal form O is 2:1, confirming that it is a hemihydrate.

[0083] Example 4

[0084] 50 mg of the compound of formula I was weighed into a weighing bottle, 2 mL of isopropyl acetate was added at room temperature and shaken to dissolve, the bottle was sealed with a film and allowed to stand at room temperature for slow evaporation and crystallization to obtain a yellow solid, which was characterized as Form A.

[0085] The XRPD analysis showed that the X-ray powder diffraction data of Form A are shown in Table 6, and its diffraction pattern is shown in FIG11 .

[0086] Table 6 X-ray powder diffraction data of Form A

[0087] Thermogravimetric analysis (TGA) of the crystalline form A showed that the crystalline form A lost about 2.48% of its weight when heated to about 30° C.-180° C.

[0088] The crystal form A in the differential scanning calorimetry (DSC) test is shown in Figure 12. Figure 12 shows that the crystal form A has endothermic peaks at about 175.1°C and 205.6°C in the differential scanning calorimetry test.

[0089] Example 5:

[0090] The compound of formula I was obtained according to the method described in Example 6 of WO2021244582A1, and was characterized as an amorphous form by PXRD, and its diffraction pattern is shown in Figure 13. The amorphous form lost about 7% of its weight when heated to about 30°C-180°C in a thermogravimetric analysis test (TGA), and had endothermic peaks at about 120.7°C and 206.1°C in a differential scanning calorimetry test (DSC).

[0091] Example 6: Moisture absorption test

[0092] Hygroscopicity was investigated using a dynamic vapor sorption instrument (DVS). 20-50 mg of the sample to be tested was weighed and placed into the instrument's sample tray. The relative humidity was then programmed to increase in steps of 10% from 10% to 98% RH, and then to decrease in steps of 10% from 98% to 10% RH. Balance was achieved by a mass change rate of less than 0.002. Hygroscopicity results for Forms M, N, O, A, and the amorphous form are shown in Table 7.

[0093] Table 7 Hygroscopicity study results

[0094] Example 7: Solubility Test

[0095] Test method: Weigh an excess of the sample to be tested into a centrifuge tube, add 1-5 mL of a pH 1.0-pH 8.0 medium, shake in a 37°C water bath for 24 hours, filter, and measure the solubility of the filtrate by HPLC. The results are shown in Table 8.

[0096] Table 8 Equilibrium solubility data

[0097] Example 8:

[0098] According to the method described in Examples 2-11 of CN117209480A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, and Form L of the compound of Formula I were obtained, and the obtained compounds were subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and the type of crystal form was determined. The results are shown in Table 9.

[0099] Table 9 TGA and DSC test results of Form B-Form L

[0100] Crystalline Form B, Crystalline Form C, Crystalline Form D, Crystalline Form E, Crystalline Form F, Crystalline Form G, Crystalline Form H, Crystalline Form J, Crystalline Form K, and Crystalline Form L are all solvates of the compound of Formula I, which have problems such as residual solvents, complex quality control, and poor operability, and do not have advantages in drug development.

[0101] Example 9: Stability Test

[0102] Test method: Compounds of Formula I in different crystalline forms were placed in clean containers and placed under high humidity, high temperature, and light conditions for 30 days. Samples were taken on days 0, 5, 10, and 30 to detect their crystalline forms. The compounds were placed under accelerated conditions for 30 days, and samples were taken on days 0 and 30 to detect their crystalline forms. The results are detailed in Table 10.

[0103] Table 10 Crystal stability study

Claims

1. Polymorph M of 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, characterized in that, In the X-ray powder diffraction pattern obtained using CuKα radiation, characteristic peaks are shown at diffraction angles 2θ of 6.58 ± 0.2°, 10.15° ± 0.2°, 12.11 ± 0.2°, 15.59 ± 0.2°, 19.16 ± 0.2°, 26.98 ± 0.2°; preferably, in the X-ray powder diffraction pattern obtained using CuKα radiation for the crystal form M, characteristic peaks are shown at diffraction angles 2θ of 6.58 ± 0.2°, 10.15° ± 0.2°, 11.38° ± 0.2°, 12.11 ± 0.2°, 14.04° ± 0.2°, 14.67° ± 0.2°, 15.59 ± 0.2°, 19.16 ± 0.2°, 26.98 ± 0.2°; more preferably, in the X-ray powder diffraction pattern obtained using CuKα radiation for the crystal form M, characteristic peaks are shown at diffraction angles 2θ of 6.58 ± 0.2°, 10.15° ± 0.2°, 11.38° ± 0.2°, 12.11 ± 0.2°, 14.04° ± 0.2°, 14.67° ± 0.2°, 15.59 ± 0.2°, 19.16 ± 0.2°, 20.67° ± 0.2°, 22.94° ± 0.2°, 24.37° ± 0.2°, 26.98° ± 0.2°, 27.37° ± 0.2°.

2. The crystalline form M according to claim 1, wherein The X-ray powder diffraction pattern of the crystal form M is substantially the same as that of Figure 1.

3. The crystalline form M according to claim 1, wherein The crystal form M shows an endothermic peak at 205 - 210 °C in differential scanning calorimetry test; preferably, the DSC pattern of the crystal form M is substantially the same as that of Figure 3.

4. Polymorph N of 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, characterized in that, In the X-ray powder diffraction pattern obtained using CuKα radiation, characteristic peaks are shown at diffraction angles 2θ of 6.28 ± 0.2°, 10.21° ± 0.2°, 12.29 ± 0.2°, 15.81 ± 0.2°, 18.96 ± 0.2°, 26.42 ± 0.2°; preferably, in the X-ray powder diffraction pattern obtained using CuKα radiation for the crystal form N, characteristic peaks are shown at diffraction angles 2θ of 6.28 ± 0.2°, 10.21° ± 0.2°, 12.29 ± 0.2°, 14.16 ± 0.2°, 14.67 ± 0.2°, 15.20 ± 0.2°, 15.81 ± 0.2°, 18.96 ± 0.2°, 26.42 ± 0.2°; more preferably, in the X-ray powder diffraction pattern obtained using CuKα radiation for the crystal form N, characteristic peaks are shown at diffraction angles 2θ of 6.28 ± 0.2°, 10.21° ± 0.2°, 12.29 ± 0.2°, 14.16 ± 0.2°, 14.67 ± 0.2°, 15.20 ± 0.2°, 15.81 ± 0.2°, 18.96 ± 0.2°, 19.85° ± 0.2°, 20.63° ± 0.2°, 23.01° ± 0.2°, 26.42° ± 0.2°, 28.54° ± 0.2°.

5. The crystalline form N according to claim 4, wherein The X-ray powder diffraction pattern of the crystal form N is substantially the same as that of Figure 4.

6. The crystalline form N according to claim 4, wherein The crystalline form N shows an endothermic peak at 204-207 °C in differential scanning calorimetry test; preferably, the DSC pattern of the crystalline form N is substantially the same as that of Figure 6.

7. Polymorph O of 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, characterized in that, In the X-ray powder diffraction pattern obtained using CuKα radiation, characteristic peaks are shown at diffraction angles 2θ of 8.14 ± 0.2°, 8.68° ± 0.2°, 9.11 ± 0.2°, 14.01 ± 0.2°, 24.11 ± 0.2°, and 26.57 ± 0.2°; preferably, in the X-ray powder diffraction pattern obtained using CuKα radiation for the crystalline form O, characteristic peaks are shown at diffraction angles 2θ of 8.14 ± 0.2°, 8.68° ± 0.2°, 9.11 ± 0.2°, 11.82 ± 0.2°, 12.21 ± 0.2°, 13.34 ± 0.2°, 14.01 ± 0.2°, 24.11 ± 0.2°, and 26.57 ± 0.2°; more preferably, in the X-ray powder diffraction pattern obtained using CuKα radiation for the crystalline form O, characteristic peaks are shown at diffraction angles 2θ of 8.14 ± 0.2°, 8.68° ± 0.2°, 9.11 ± 0.2°, 11.82 ± 0.2°, 12.21 ± 0.2°, 13.34 ± 0.2°, 14.01 ± 0.2°, 16.20° ± 0.2°, 20.30° ± 0.2°, 20.75° ± 0.2°, 21.12° ± 0.2°, 24.11° ± 0.2°, and 26.57 ± 0.2°; more preferably, the crystallographic parameters of the crystalline form O are: triclinic system, P-1 space group, α = 95.276(3)°, β = 106.113(4)°, γ = 109.816(4)°.

8. The crystalline form O according to claim 7, wherein The X-ray powder diffraction pattern of the crystalline form O is substantially the same as that of Figure 7.

9. A pharmaceutical composition, characterized in that Containing the crystalline form as described in any one of claims 1-8.

10. Use of the crystalline form as described in any one of claims 1-8 and the pharmaceutical composition as described in claim 9 in the preparation of a medicament for preventing or treating a disease related to the action of a thyroid hormone β receptor agonist; preferably, the disease related to the action of a thyroid hormone β receptor agonist is obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, thyroid cancer, metabolic syndrome, cardiovascular disease, coronary artery disease, myocardial infarction, ventricular dysfunction, heart failure, fatty liver, liver cirrhosis, diabetes, steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, atherosclerosis, or hypothyroid disease or disorder.

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