Crystal form of compound as well as preparation method and application of crystal form

Abstract

The invention relates to the technical field of biological medicine, in particular to a crystal form of a compound as well as a preparation method and application thereof. The invention provides a crystal form B, a crystal form A, a crystal form H, a crystal form N or a crystal form O of a compound shown in a formula (I). The invention has the following advantages: the invention provides a plurality of crystal forms of the compound as shown in the formula I, and the crystal forms have important meanings for the development of pharmaceutical preparations. (I)

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the field of biomedicine, in particular to a crystal form of a compound, a preparation method and application thereof. BACKGROUND

[0002] Site-specific lysine methylation on histones is one of the important epigenetic mechanisms that control and mediate many basic biological processes. Polycomb Repressive Complex 2 (PRC2) inhibits gene transcription by methylating histone H3 lysine 27 (H3K27) in the genomic region of target genes. PRC2 requires at least three core subunits, including SUZ12 (Suppressor of Zeste 12 Homolog), EED (Embryonic Ectoderm Development), and catalytic subunit EZH1 (Enhancer of Zeste Homolog 1) or EZH2 (Enhancer of Zeste Homolog 2). EZH1 and EZH2 are homologous proteins, and both can be integrated into PRC2, although they have different tissue and temporal distributions. In PRC2, EZH2 can directly bind to the cofactor S-adenosyl methionine (SAM) and transfer a methyl group to the H3K27 site to form monomethylated, dimethylated and trimethylated lysine (H3K27me1, H3K27me2 and H3K27me3), thereby inhibiting gene transcription. PRC2-EZH2 has higher activity than PRC2-EZH1, which mainly catalyzes the formation of H3K27me1 and some H3K27me2. EED can bind H3K27me2 / 3 and allosterically activate the enzymatic activity of PRC2 to facilitate the spread of inhibitory marks.

[0003] EZH2 (Enhancer of Zeste Homolog 1 / 2) plays an important role in development and adult tissue homeostasis and is closely associated with a variety of diseases. EZH2 is overexpressed in many cancers, including but not limited to breast cancer, prostate cancer, and hepatocellular carcinoma. EZH2 activating mutations (EZH2 activating mutations lead to increased trimethylation of lysine H3K27me3) have been found in patients with DLBCL (diffuse large B-cell lymphoma), FL (follicular lymphoma), melanoma, and parathyroid carcinoma. In addition, EZH2 inhibitors can release the inhibition of Th1 chemokines in tumor cells and enhance T cell infiltration in ovarian cancer and colorectal cancer. EZH2 provides a pharmacological target for DLBCL and other cancers. In addition, EZH2 also plays an important role in autoimmune diseases and other disorders.

[0004] WO2021057853A1 has disclosed that the compound of formula I is used for treating diseases or disorders mediated by Enhancer of Zeste Homolog 2 (EZH2), Polycomb Repression Complex 2 (PRC2), or a combination of Enhancer of Zeste Homolog 2 (EZH2) and Polycomb Repression Complex 2 (PRC2). Different pharmaceutical crystal forms of the compound of formula I can lead to significant differences in its stability and the like.

[0005] (I) Therefore, it is of great significance to carry out crystal form screening and research of the compound of formula I for drug development. SUMMARY

[0006] The present disclosure aims to provide a crystal form of the compound of formula I and a preparation method and application thereof.

[0007] To achieve the above technical purposes, the technical solution adopted by the present disclosure is: In one aspect, the present disclosure provides a crystal form of a compound of formula (I), which is crystal form A, crystal form B, crystal form H, crystal form N, or crystal form O, (I) In some embodiments of the present disclosure, the XRPD pattern of the crystal form A has characteristic peaks at 2θ values of the following group: 12.6°±0.2°, 18.7°±0.2°, 23.0°±0.2°.

[0008] In some embodiments of the present disclosure, the XRPD pattern of the crystal form A has characteristic peaks at 2θ values of the following group: 12.6°±0.2°, 16.8°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 20.6°±0.2°, 23.0°±0.2°.

[0009] In some embodiments of this disclosure, the XRPD spectrum of crystal form A has characteristic peaks at the 2θ values ​​in the following group: 9.5°±0.2°, 11.3°±0.2°, 12.6°±0.2°, 16.8°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 20.6°±0.2°, 21.2°±0.2°, and 23.0°±0.2°.

[0010] In some embodiments of this disclosure, the XRPD spectrum of crystal form A has a characteristic peak at the 2θ values ​​shown in Table 2.

[0011] In some embodiments of this disclosure, the crystal form A has the same characteristics as... Figure 5 The XRPD patterns are essentially the same.

[0012] In some embodiments of this disclosure, the crystal form A has the same characteristics as... Figure 6 The XRPD patterns are essentially the same.

[0013] In some embodiments of this disclosure, the TGA spectrum of crystal form A shows a weight loss of 1.8 ± 0.5% at 150 ± 2 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0014] In some embodiments of this disclosure, the TGA spectrum of crystal form A shows a weight loss of 1.8 ± 0.3% at 150 ± 1 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0015] In some embodiments of this disclosure, the TGA spectrum of crystal form A shows a weight loss of 1.8 ± 0.2% at 150 ± 0.5 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0016] In some embodiments of this disclosure, the crystal form A has the same characteristics as... Figure 7 The TGA spectra are essentially the same.

[0017] In some embodiments of this disclosure, the DSC spectrum of crystal form A has an endothermic peak at 179±2℃.

[0018] In some embodiments of this disclosure, the DSC spectrum of crystal form A has one endothermic peak, and the peak temperature of the endothermic peak is 179±2 °C.

[0019] In some embodiments of this disclosure, the DSC spectrum of crystal form A has one endothermic peak, and the peak temperature of the endothermic peak is 179±1 °C.

[0020] In some embodiments of this disclosure, the DSC spectrum of crystal form A has one endothermic peak, and the peak temperature of the endothermic peak is 179±0.5 °C.

[0021] In some embodiments of this disclosure, the crystal form A has the same characteristics as... Figure 8 The DSC patterns are essentially the same.

[0022] In some embodiments of this disclosure, crystal form A is a solvent-free crystal form.

[0023] In some embodiments of this disclosure, the XRPD spectrum of crystal form B has characteristic peaks at the 2θ values ​​in the following group: 7.0°±0.2°, 15.0°±0.2°, and 21.4°±0.2°.

[0024] In some embodiments of this disclosure, the XRPD spectrum of crystal form B has characteristic peaks at the 2θ values ​​in the following group: 7.0°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 19.7°±0.2°, 20.5°±0.2°, and 21.4°±0.2°.

[0025] In some embodiments of this disclosure, the XRPD spectrum of crystal form B has characteristic peaks at the 2θ values ​​in the following group: 7.0°±0.2°, 12.1°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 15.5°±0.2°, 16.9°±0.2°, 19.7°±0.2°, 20.5°±0.2°, and 21.4°±0.2°.

[0026] In some embodiments of this disclosure, the XRPD spectrum of crystal form B has a characteristic peak at the 2θ value shown in Table 3.

[0027] In some embodiments of this disclosure, the crystal form B has the same characteristics as... Figure 10 The XRPD patterns are essentially the same.

[0028] In some embodiments of this disclosure, the TGA spectrum of crystal form B shows a weight loss of 1.1 ± 0.5% at 150 ± 2 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0029] In some embodiments of this disclosure, the TGA spectrum of crystal form B shows a weight loss of 1.1 ± 0.3% at 150 ± 1 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0030] In some embodiments of this disclosure, the TGA spectrum of crystal form B shows a weight loss of 1.1 ± 0.2% at 150 ± 0.5 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0031] In some embodiments of this disclosure, the crystal form B has the same characteristics as... Figure 11 The TGA spectra are essentially the same.

[0032] In some embodiments of this disclosure, the DSC spectrum of crystal form B has an endothermic peak at 188±2℃.

[0033] In some embodiments of this disclosure, the DSC spectrum of crystal form B has one endothermic peak, and the peak temperature of the endothermic peak is 188±2 °C.

[0034] In some embodiments of this disclosure, the DSC spectrum of crystal form B has one endothermic peak, and the peak temperature of the endothermic peak is 188±1 °C.

[0035] In some embodiments of this disclosure, the DSC spectrum of crystal form B has one endothermic peak, and the peak temperature of the endothermic peak is 188±0.5 °C.

[0036] In some embodiments of this disclosure, the crystal form B has the same characteristics as... Figure 12 The DSC patterns are essentially the same.

[0037] In some embodiments of this disclosure, the crystal form B is a solvent-free crystal form.

[0038] In some embodiments of this disclosure, the XRPD spectrum of the crystal form H has characteristic peaks at the 2θ values ​​in the following group: 5.4°±0.2°, 10.2°±0.2°, and 18.5°±0.2°.

[0039] In some embodiments of this disclosure, the XRPD spectrum of crystal form H has characteristic peaks at the 2θ values ​​of the following group: 5.4°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 18.5°±0.2°, 19.4°±0.2°, and 22.0°±0.2°.

[0040] In some embodiments of this disclosure, the XRPD spectrum of crystal form H has characteristic peaks at the following 2θ values: 5.4°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 12.3°±0.2°, 15.2°±0.2°, 18.5°±0.2°, 19.4°±0.2°, and 22.0°±0.2°.

[0041] In some embodiments of this disclosure, the XRPD spectrum of the crystal form H has a characteristic peak at the 2θ value shown in Table 4.

[0042] In some embodiments of this disclosure, the crystal form H has the same properties as... Figure 15 The XRPD patterns are essentially the same.

[0043] In some embodiments of this disclosure, the crystal form H has the same properties as... Figure 16 The XRPD patterns are essentially the same.

[0044] In some embodiments of this disclosure, the TGA spectrum of crystal form H shows a weight loss of 13.1 ± 0.5% at 130 ± 2 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0045] In some embodiments of this disclosure, the TGA spectrum of crystal form H shows a weight loss of 13.1 ± 0.3% at 130 ± 1 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0046] In some embodiments of this disclosure, the TGA spectrum of crystal form H shows a weight loss of 13.1 ± 0.2% at 130 ± 0.5 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0047] In some embodiments of this disclosure, the crystal form H has the same properties as... Figure 17 The TGA spectra are essentially the same.

[0048] In some embodiments of this disclosure, the DSC spectrum of the crystalline form H has endothermic peaks at 46±2 °C, 86±2 °C, and 152±2 °C.

[0049] In some embodiments of this disclosure, the DSC spectrum of the compound crystal form H shown in formula (I) has three endothermic peaks, the peak temperatures of which are 46±2 ℃, 86±2 ℃ and 152±2 ℃, respectively.

[0050] In some embodiments of this disclosure, the DSC spectrum of the compound crystal form H shown in formula (I) has three endothermic peaks, the peak temperatures of which are 46±1 ℃, 86±1 ℃ and 152±1 ℃, respectively.

[0051] In some embodiments of this disclosure, the DSC spectrum of the compound crystal form H shown in formula (I) has three endothermic peaks, the peak temperatures of which are 46±0.5 ℃, 86±0.5 ℃ and 152±0.5 ℃, respectively.

[0052] In some embodiments of this disclosure, the crystal form H has the same properties as... Figure 18 The DSC patterns are essentially the same.

[0053] In some embodiments of this disclosure, the crystal form H is a hydrate crystal form.

[0054] In some embodiments of this disclosure, the XRPD spectrum of the crystal form N has characteristic peaks at the 2θ values ​​in the following group: 9.9°±0.2°, 11.7°±0.2°, and 14.8°±0.2°.

[0055] In some embodiments of this disclosure, the XRPD spectrum of the crystal form N has characteristic peaks at the 2θ values ​​in the following group: 9.9°±0.2°, 11.7°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 18.1°±0.2°, and 21.3°±0.2°.

[0056] In some embodiments of this disclosure, the XRPD spectrum of the crystal form N has characteristic peaks at the 2θ values ​​in the following group: 9.9°±0.2°, 11.7°±0.2°, 12.7°±0.2°, 13.4°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 18.1°±0.2°, 20.2°±0.2°, and 21.3°±0.2°.

[0057] In some embodiments of this disclosure, the XRPD spectrum of the crystal form N has a characteristic peak at the 2θ value shown in Table 5.

[0058] In some embodiments of this disclosure, the crystal form N has the same properties as... Figure 20 The XRPD patterns are essentially the same.

[0059] In some embodiments of this disclosure, the TGA spectrum of the N crystal form shows a weight loss of 2.6 ± 0.5% at 130 ± 2 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0060] In some embodiments of this disclosure, the TGA spectrum of the N crystal form shows a weight loss of 2.6 ± 0.3% at 130 ± 1 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0061] In some embodiments of this disclosure, the TGA spectrum of the N crystal form shows a weight loss of 2.6 ± 0.2% at 130 ± 0.5 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0062] In some embodiments of this disclosure, the crystal form N has the same properties as...Figure 21 The TGA spectra are essentially the same.

[0063] In some embodiments of this disclosure, the DSC spectrum of the N crystal form has an endothermic peak at 152±2 °C.

[0064] In some embodiments of this disclosure, the DSC spectrum of the N crystal form has one endothermic peak, and the peak temperature of the endothermic peak is 152±2 °C.

[0065] In some embodiments of this disclosure, the DSC spectrum of the N crystal form has one endothermic peak, and the peak temperature of the endothermic peak is 152±1 °C.

[0066] In some embodiments of this disclosure, the DSC spectrum of the N crystal form has one endothermic peak, and the peak temperature of the endothermic peak is 152 ± 0.5 °C.

[0067] In some embodiments of this disclosure, the crystal form N has the same properties as... Figure 22 The DSC patterns are essentially the same.

[0068] In some embodiments of this disclosure, the crystal form N is a solvent-free crystal form.

[0069] In some embodiments of this disclosure, the XRPD spectrum of the crystal form O has characteristic peaks at the 2θ values ​​in the lower group: 10.8°±0.2°, 12.3°±0.2°, and 17.3°±0.2°.

[0070] In some embodiments of this disclosure, the XRPD spectrum of the crystal form O has characteristic peaks at the 2θ values ​​in the following group: 10.8°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 16.1°±0.2°, 17.3°±0.2°, and 25.5°±0.2°.

[0071] In some embodiments of this disclosure, the XRPD spectrum of the crystal form O has characteristic peaks at the 2θ values ​​in the following group: 10.8°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 16.1°±0.2°, 17.3°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 24.2°±0.2°, and 25.5°±0.2°.

[0072] In some embodiments of this disclosure, the XRPD spectrum of the crystal form O has a characteristic peak at the 2θ value shown in Table 6.

[0073] In some embodiments of this disclosure, the crystal form O has the same characteristics as... Figure 24 The XRPD patterns are essentially the same.

[0074] In some embodiments of this disclosure, the TGA spectrum of the crystal form O shows a weight loss of 5.0 ± 0.5% at 110 ± 2 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0075] In some embodiments of this disclosure, the TGA spectrum of the crystal form O shows a weight loss of 5.0 ± 0.3% at 110 ± 1 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0076] In some embodiments of this disclosure, the TGA spectrum of the crystal form O shows a weight loss of 5.0 ± 0.2% at 110 ± 0.5 °C (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss).

[0077] In some embodiments of this disclosure, the crystal form O has the same characteristics as... Figure 25 The TGA spectra are essentially the same.

[0078] In some embodiments of this disclosure, the DSC spectrum of the crystalline form O has endothermic peaks at 93±2 °C and 126±2 °C.

[0079] In some embodiments of this disclosure, the DSC spectrum of the crystalline O has two endothermic peaks, the peak temperatures of which are 93±2 ℃ and 126±2 ℃, respectively.

[0080] In some embodiments of this disclosure, the DSC spectrum of the crystalline O has two endothermic peaks, the peak temperatures of which are 93±1 ℃ and 126±1 ℃, respectively.

[0081] In some embodiments of this disclosure, the DSC spectrum of the crystalline O has two endothermic peaks, with peak temperatures of 93±0.5 ℃ and 126±0.5 ℃, respectively.

[0082] In some embodiments of this disclosure, the crystal form O has the same characteristics as... Figure 26 The DSC patterns are essentially the same.

[0083] In some embodiments of this disclosure, the crystal form O is a hydrate crystal form.

[0084] On the other hand, this disclosure provides a method for preparing the compound of the crystal form A, crystal form B, crystal form H, crystal form N or crystal form O as shown in formula (I) above.

[0085] In some embodiments of this disclosure, the method for preparing crystal form A is method A-1 or method A-2; The A-1 method includes the following steps: (A-1-1) An organic solvent is added to the amorphous solid of the compound shown in Formula I to obtain a suspension; (A-1-2) The suspension is stirred at -40 to 0°C for 10 to 30 days, and the solid is separated to obtain a wet sample; (A-1-3) The wet sample was placed at 5-35°C and vacuum dried for 1-6 days to obtain the compound crystal form A shown in Formula I.

[0086] In some embodiments of this disclosure, in step (A-1-2), the temperature of the suspension stirring is -30 to -10°C.

[0087] In some embodiments of this disclosure, in step (A-1-2), the temperature of the suspension stirring is -25 to -15°C.

[0088] In some embodiments of this disclosure, in step (A-1-2), the suspension is stirred for 15 to 25 days.

[0089] In some embodiments of this disclosure, in step (A-1-2), the suspension is stirred for 16 to 20 days.

[0090] In some embodiments of this disclosure, in step (A-1-3), the temperature of the vacuum drying is 10 to 30°C.

[0091] In some embodiments of this disclosure, in step (A-1-3), the temperature of the vacuum drying is 15-25°C.

[0092] In some embodiments of this disclosure, in step (A-1-3), the vacuum drying time is 1 to 5 days.

[0093] In some embodiments of this disclosure, in step (A-1-3), the vacuum drying time is 2 to 4 days.

[0094] In some embodiments of this disclosure, in step (A-1-1), the organic solvent is any one solvent of the ether class or a mixture of two or more solvents in any proportion.

[0095] In some embodiments of this disclosure, in step (A-1-1), the organic solvent is diethyl ether, diisopropyl ether, or methyl tert-butyl ether.

[0096] In some embodiments of this disclosure, in step (A-1-1), the organic solvent is methyl tert-butyl ether.

[0097] In some embodiments of this disclosure, the A-2 method includes the following steps: (A-2-1) Add a first organic solvent to the solid of crystal form B of the compound shown in Formula I, filter, add a second organic solvent to the filtrate, add crystal form A of the compound shown in Formula I as a seed crystal; continue to add the second organic solvent, place at -15 to 25°C and stir for 1 to 6 hours to precipitate a solid; separate the solid to obtain a wet sample; (A-2-2) The wet sample was placed in a vacuum at -15 to 25°C and dried overnight to obtain the compound crystal form A shown in Formula I.

[0098] In some embodiments of this disclosure, in step (A-2-1), the first organic solvent is any one of the furan solvents or a mixture of two or more solvents in any proportion.

[0099] In some embodiments of this disclosure, in step (A-2-1), the first organic solvent is methyltetrahydrofuran.

[0100] In some embodiments of this disclosure, in step (A-2-1), the first organic solvent is 2-methyltetrahydrofuran.

[0101] In some embodiments of this disclosure, in step (A-2-1), the second organic solvent is any one solvent of the ether class or a mixture of two or more solvents in any proportion.

[0102] In some embodiments of this disclosure, in step (A-2-1), the second organic solvent is diisopropyl ether, diethyl ether, or methyl tert-butyl ether.

[0103] In some embodiments of this disclosure, in step (A-2-1), the second organic solvent is diisopropyl ether.

[0104] In some embodiments of this disclosure, in step (A-2-2), the temperature of the vacuum drying is 10–30°C.

[0105] In some embodiments of this disclosure, in step (A-2-2), the temperature of the vacuum drying is 15-25°C.

[0106] In some embodiments of this disclosure, the method for preparing crystal form B includes the following steps: (B-1-1) Add a mixed solvent to crystal form C of the compound shown in Formula I and heat to 35–65°C to dissolve; after filtration, first cool to 25–55°C and maintain the temperature with stirring for 0.5–4 hours; second cool to 5–35°C and maintain the temperature with stirring for 8–16 hours to precipitate a solid; third cool to -10–20°C and maintain the temperature with stirring for 1–8 hours; separate the solid to obtain a wet sample; (B-1-2) The wet sample was placed in a vacuum at 25-55°C and dried overnight to obtain the compound B shown in Formula I.

[0107] In some embodiments of this disclosure, in step (B-1-1), the mixed solvent is any one of methanol / water, ethanol / water, propanol / water, or butanol / water.

[0108] In some embodiments of this disclosure, in step (B-1-1), the mixed solvent is any one of methanol / water, ethanol / water, or propanol / water.

[0109] In some embodiments of this disclosure, in step (B-1-1), the mixed solvent is ethanol / water.

[0110] In some embodiments of this disclosure, in step (B-1-1), the volume ratio of ethanol to water in the mixed solvent is (1-5):(1-5).

[0111] In some embodiments of this disclosure, in step (B-1-1), the volume ratio of ethanol to water in the mixed solvent is (1-3):(1-3).

[0112] In some embodiments of this disclosure, in step (B-1-1), the volume ratio of ethanol to water in the mixed solvent is (1-1.5):(1-1.5).

[0113] In some embodiments of this disclosure, in step (B-1-1), the volume ratio of ethanol to water in the mixed solvent is 1:(1 to 1.5).

[0114] In some embodiments of this disclosure, in step (B-1-1), the heating temperature is 40–60°C.

[0115] In some embodiments of this disclosure, in step (B-1-1), the heating temperature is 45-55°C.

[0116] In some embodiments of this disclosure, in step (B-1-1), the temperature of the first cooling is 30–50°C.

[0117] In some embodiments of this disclosure, in step (B-1-1), the temperature of the first cooling is 35-45°C.

[0118] In some embodiments of this disclosure, in step (B-1-1), the first stirring time is 1 to 3 hours.

[0119] In some embodiments of this disclosure, in step (B-1-1), the temperature of the second cooling is 10–30°C.

[0120] In some embodiments of this disclosure, in step (B-1-1), the temperature of the second cooling is 15-25°C.

[0121] In some embodiments of this disclosure, in step (B-1-1), the second stirring time is 11 to 13 hours.

[0122] In some embodiments of this disclosure, in step (B-1-1), the temperature of the third cooling step is 1 to 15°C.

[0123] In some embodiments of this disclosure, in step (B-1-1), the temperature of the third cooling step is 1 to 10°C.

[0124] In some embodiments of this disclosure, in step (B-1-1), the third stirring time is 2 to 6 hours.

[0125] In some embodiments of this disclosure, in step (B-1-1), the third stirring time is 3 to 5 hours.

[0126] In some embodiments of this disclosure, in step (B-1-2), the temperature of the vacuum drying is 30 to 50°C.

[0127] In some embodiments of this disclosure, in step (B-1-2), the temperature of the vacuum drying is 35-45°C.

[0128] In some embodiments of this disclosure, the method for preparing crystal form H is either the H-1 method or the H-2 method; The H-1 method includes the following steps: (H-1-1) Water is added to the amorphous solid of the compound shown in Formula I to obtain a suspension; (H-1-2) The suspension is stirred at -15 to 25°C for 1 to 10 days, and the solid is separated to obtain a wet sample; (H-1-3) The wet sample was dried overnight at 5-40°C by forced air drying to obtain the compound H shown in Formula I.

[0129] In some embodiments of this disclosure, in step (H-1-2), the temperature of the suspension stirring is -10 to 20°C.

[0130] In some embodiments of this disclosure, in step (H-1-2), the temperature of the suspension stirring is 0 to 10°C.

[0131] In some embodiments of this disclosure, in step (H-1-2), the suspension is stirred for 5 to 9 days.

[0132] In some embodiments of this disclosure, in step (H-1-2), the suspension is stirred for 6 to 8 days.

[0133] In some embodiments of this disclosure, in step (H-1-3), the temperature of the blower drying is 10-35°C.

[0134] In some embodiments of this disclosure, in step (H-1-3), the temperature of the blower drying is 20-30°C.

[0135] In some embodiments of this disclosure, the water is pure water.

[0136] In some embodiments of this disclosure, the H-2 method includes the following steps: (H-2-1) Water is added to the amorphous solid of the compound shown in Formula I, and solid of crystal form H of the compound shown in Formula I is added as a seed crystal to obtain a suspension. (H-2-2) The suspension was stirred overnight at -15 to 25°C, water was added, and the suspension was stirred overnight at -15 to 25°C. Water was added, and the suspension was stirred for 1 to 10 days at -15 to 25°C. The solid was separated to obtain a wet sample. (H-2-3) The wet sample was dried overnight at 5-40°C by forced air drying to obtain the compound H shown in Formula I.

[0137] In some embodiments of this disclosure, in step (H-2-2), the temperature of the suspension stirring is -10 to 20°C.

[0138] In some embodiments of this disclosure, in step (H-2-2), the temperature of the suspension stirring is 0 to 10°C.

[0139] In some embodiments of this disclosure, in step (H-2-2), the suspension is stirred for 3 to 8 days.

[0140] In some embodiments of this disclosure, in step (H-2-2), the suspension is stirred for 5 to 7 days.

[0141] In some embodiments of this disclosure, in step (H-2-3), the temperature of the blower drying is 10–35°C.

[0142] In some embodiments of this disclosure, in step (H-2-3), the temperature of the blower drying is 20-30°C.

[0143] In some embodiments of this disclosure, the water is pure water.

[0144] In some embodiments of this disclosure, the method for preparing the N crystal form includes the following steps: (N-1-1) The wet sample of the crystal form H of the compound shown in Formula I was placed in a vacuum and dried overnight at 35-65°C to obtain the crystal form N of the compound shown in Formula I.

[0145] In some embodiments of this disclosure, in step (N-1-1), the temperature of the vacuum drying is 40-60°C.

[0146] In some embodiments of this disclosure, in step (N-1-1), the temperature of the vacuum drying is 45-55°C.

[0147] On the other hand, this disclosure provides a method for preparing the compound of the crystal form A, crystal form B, crystal form H, crystal form N or crystal form O as described above, wherein the method for preparing the compound of the crystal form O as described in formula (I) includes the following steps: (O-1-1) Add water to the solid C of the compound shown in Formula I, mix by rotation at 5-35°C, remove the aqueous phase, and obtain a wet sample; (O-1-2) The wet sample was placed at 5-35°C and vacuum dried for 10-20 hours to obtain the compound O shown in Formula I.

[0148] In some embodiments of this disclosure, in step (O-1-1), the rotational mixing time is 1 to 5 hours.

[0149] In some embodiments of this disclosure, in step (O-1-1), the rotational mixing time is 1 to 3 hours.

[0150] In some embodiments of this disclosure, in step (O-1-1), the temperature of the rotary mixing is 10 to 30°C.

[0151] In some embodiments of this disclosure, in step (O-1-1), the temperature of the rotary mixing is 15-25°C.

[0152] In some embodiments of this disclosure, in step (O-1-2), the vacuum drying time is 12 to 18 hours.

[0153] In some embodiments of this disclosure, in step (O-1-2), the vacuum drying time is 14 to 18 hours.

[0154] In some embodiments of this disclosure, in step (O-1-2), the temperature of the vacuum drying is 10-30°C.

[0155] In some embodiments of this disclosure, in step (O-1-2), the temperature of the vacuum drying is 15-25°C.

[0156] On the other hand, this disclosure provides a pharmaceutical composition comprising any one or more of the following crystal forms: crystal form A, crystal form B, crystal form H, crystal form N or crystal form O, as described above, or any one or more of the following crystal forms: crystal form A, crystal form B, crystal form H, crystal form N or crystal form O, prepared by the method described above, and optionally a pharmaceutically acceptable carrier.

[0157] In some embodiments of this disclosure, the pharmaceutical composition comprises a compound of formula (I) crystal form B as described above, or a compound of formula (I) crystal form B prepared by the preparation method described above, and optionally a pharmaceutically acceptable carrier.

[0158] In some embodiments of this disclosure, the pharmaceutical composition further includes one or more other therapeutically active agents.

[0159] The therapeutic active agent is selected from anticancer agents, immunomodulators, anti-allergic agents, antiemetics, analgesics, and cell protectants.

[0160] On the other hand, this disclosure provides a pharmaceutical formulation comprising any one or more of the following crystal forms: crystal form A, crystal form B, crystal form H, crystal form N, or crystal form O, as described above, or any one or more of the following crystal forms: crystal form A, crystal form B, crystal form H, crystal form N, or crystal form O, prepared by the preparation method described above.

[0161] In some embodiments of this disclosure, the pharmaceutical formulation comprises the pharmaceutical composition as described above.

[0162] In some embodiments of this disclosure, the pharmaceutical preparation is a powder, tablet, lozenge, capsule, granule, pill, dispersible powder, suspension, solution, emulsion, syrup, aerosol, cream, ointment, gel, injection, lyophilized powder for injection, or suppository dosage form.

[0163] In some embodiments of this disclosure, the pharmaceutical preparation is used to treat diseases or conditions mediated by Zeste homolog enhancer 2 (EZH2), polycomb inhibitory complex 2 (PRC2), or a combination of Zeste homolog enhancer 2 (EZH2) and polycomb inhibitory complex 2 (PRC2).

[0164] In some embodiments of this disclosure, the disease or condition is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

[0165] On the other hand, this disclosure provides the use of any one or more of the following crystal forms A, B, H, N or O of the compound represented by formula (I) as described above, or any one or more of the following crystal forms A, B, H, N or O of the compound represented by formula (I) prepared by the preparation method described above, in the preparation of a pharmaceutical composition or pharmaceutical formulation as described above.

[0166] In some embodiments of this disclosure, the drug is used to treat diseases or conditions mediated by Zeste homolog enhancer 2 (EZH2), polycomb inhibitory complex 2 (PRC2), or a combination of Zeste homolog enhancer 2 (EZH2) and polycomb inhibitory complex 2 (PRC2).

[0167] On the other hand, this disclosure provides a method for treating diseases or conditions mediated by a combination of Zeste homolog enhancer 2 (EZH2), polycomb inhibitory complex 2 (PRC2), or Zeste homolog enhancer 2 (EZH2) and polycomb inhibitory complex 2 (PRC2), comprising administering to a patient in need any one or more of the following crystal forms: crystal form A, crystal form B, crystal form H, crystal form N, or crystal form O, as described above; or any one or more of the following crystal forms: crystal form A, crystal form B, crystal form H, crystal form N, or crystal form O, as described above, prepared by the aforementioned preparation method; a pharmaceutical composition as described above; or a pharmaceutical preparation as described above.

[0168] On the other hand, this disclosure provides any one or more of the following crystal forms A, B, H, N or O of the compound represented by formula (I) as described above, or any one or more of the following crystal forms A, B, H, N or O of the compound represented by formula (I) prepared by the preparation method described above, as described above, pharmaceutical compositions, or pharmaceutical preparations, for prevention and / or treatment.

[0169] On the other hand, this disclosure provides any one or more of the following crystal forms A, B, H, N, or O of the compound represented by formula (I) as described above, or any one or more of the following crystal forms A, B, H, N, or O of the compound represented by formula (I) prepared by the preparation method described above, as described above, pharmaceutical compositions, or pharmaceutical preparations as described above, for treating diseases or conditions mediated by a combination of Zeste homolog enhancer 2 (EZH2), polycomb inhibitory complex 2 (PRC2), or Zeste homolog enhancer 2 (EZH2) and polycomb inhibitory complex 2 (PRC2).

[0170] On the other hand, this disclosure provides a method for treating a disease or condition mediated by a combination of Zeste homolog enhancer 2 (EZH2), polycomb inhibitory complex 2 (PRC2), or Zeste homolog enhancer 2 (EZH2) and polycomb inhibitory complex 2 (PRC2), the method comprising administering to a patient an effective amount of any one or more of the following crystal forms A, B, H, N, or O of the compound of formula (I) as described above, or any one or more of the following crystal forms A, B, H, N, or O of the compound of formula (I) prepared by the preparation method described above, a pharmaceutical composition as described above, or a pharmaceutical preparation as described above.

[0171] In some embodiments of this disclosure, the disease or condition is selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

[0172] This disclosure has the following advantages: (1) This disclosure provides multiple crystal forms of the compound shown in Formula I, which is of great significance for drug development.

[0173] (2) This disclosure provides multiple crystal forms of the compound shown in Formula I, wherein crystal form B has better stability than crystal form A and is suitable for drug development.

[0174] (3) This disclosure provides various crystal forms of the compound shown in Formula I, which can be used in medicaments for treating diseases or conditions mediated by a combination of Zeste homolog enhancer 2 (EZH2), polycomb inhibitory complex 2 (PRC2) or Zeste homolog enhancer 2 (EZH2) and polycomb inhibitory complex 2 (PRC2). Attached Figure Description

[0175] To more clearly illustrate the technical solutions in the specific embodiments of this disclosure or the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this disclosure. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. The accompanying drawings are incorporated in and constitute a part of this specification, illustrating embodiments consistent with this specification, and are used together with the specification to explain the principles of this specification.

[0176] Figure 1 The XRPD diagram of crystal form C of the compound shown in Formula I is shown.

[0177] Figure 2 The TGA diagram of crystal form C of the compound shown in Formula I is shown.

[0178] Figure 3 The DSC diagram of crystal form C of the compound shown in Formula I is shown.

[0179] Figure 4 The crystal form C of the compound shown in Formula I is shown. 1 H NMR spectrum.

[0180] Figure 5 The XRPD diagram of crystal form A of the compound shown in Formula I is shown.

[0181] Figure 6 The XRPD diagram of crystal form A of the compound shown in Formula I is shown.

[0182] Figure 7 The TGA diagram of crystal form A of the compound shown in Formula I is shown.

[0183] Figure 8 The DSC diagram of crystal form A of the compound shown in Formula I is shown.

[0184] Figure 9 The crystal form A of the compound shown in Formula I is shown. 1 H NMR spectrum.

[0185] Figure 10 The XRPD diagram of crystal form B of compound shown in Formula I is shown.

[0186] Figure 11The TGA diagram of crystal form B of compound I is shown.

[0187] Figure 12 The DSC diagram of crystal form B of compound I is shown.

[0188] Figure 13 The crystal form B of the compound shown in Formula I is shown. 1 H NMR spectrum.

[0189] Figure 14 The XRPD diagram of the amorphous compound shown in Formula I is displayed.

[0190] Figure 15 The XRPD diagram of the crystal form H of the compound shown in Formula I is shown.

[0191] Figure 16 The XRPD diagram of the crystal form H of the compound shown in Formula I is shown.

[0192] Figure 17 The TGA diagram of crystal form H of the compound shown in Formula I is shown.

[0193] Figure 18 The DSC diagram of crystal form H of the compound shown in Formula I is shown.

[0194] Figure 19 The crystal form H of the compound shown in Formula I is shown. 1 H NMR spectrum.

[0195] Figure 20 The XRPD diagram of the crystal form N of the compound shown in Formula I is shown.

[0196] Figure 21 The TGA diagram of crystal form N of compound I is shown.

[0197] Figure 22 The DSC diagram of crystal form N of compound I is shown.

[0198] Figure 23 The crystal form N of the compound shown in Formula I is shown. 1 H NMR spectrum.

[0199] Figure 24 The XRPD diagram of the crystal form O of the compound shown in Formula I is shown.

[0200] Figure 25 The TGA diagram of crystal form O of compound I is shown.

[0201] Figure 26 The DSC diagram of the crystal form O of the compound represented by Formula I is shown.

[0202] Figure 27 The crystal form O of the compound shown in Formula I is shown.1 H NMR spectrum.

[0203] Figure 28 The XRPD overlay images of compound A, as shown in Formula I, before and after DVS testing are shown (from top to bottom: before testing, after testing).

[0204] Figure 29 The XRPD overlay images of compound B, as shown in Formula I, before and after DVS testing are shown (from top to bottom: before testing, after testing).

[0205] Figure 30 The XRPD overlay images of the compound C crystal form shown in Formula I before and after DVS testing are shown (from top to bottom: before test, after test).

[0206] Figure 31 The XRPD overlay images of the compound N crystal form shown in Formula I before and after DVS testing are shown (from top to bottom: before testing, after testing).

[0207] Figure 32 The XRPD overlay images of the compound O shown in Formula I before and after DVS testing are shown (from top to bottom: before test, after test).

[0208] Figure 33 The XRPD overlay of the remaining solids of the compound A (as shown in Formula I) in pure water is displayed (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0209] Figure 34 The XRPD overlay of the remaining solid in FaSSIF for crystal form A of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0210] Figure 35 The XRPD overlay of the remaining solid in FeSSIF for crystal form A of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0211] Figure 36 The XRPD overlay of the remaining solids of compound B (formula I) in pure water is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0212] Figure 37 The XRPD overlay of the remaining solid in FaSSIF for crystal form B of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0213] Figure 38The XRPD overlay of the remaining solid of compound B (formula I) in FeSSIF is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0214] Figure 39 The XRPD overlay of the remaining solids of the compound C (as shown in Formula I) in pure water is displayed (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0215] Figure 40 The XRPD overlay of the remaining solid in FaSSIF for the crystal form C of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0216] Figure 41 The XRPD overlay of the remaining solid of the compound C of Formula I in FeSSIF is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0217] Figure 42 The XRPD overlay of the remaining solids of the compound H (as shown in Formula I) in pure water is displayed (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0218] Figure 43 The XRPD overlay of the remaining solid in FaSSIF for the crystal form H of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0219] Figure 44 The XRPD overlay of the remaining solid in FeSSIF for the crystal form H of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0220] Figure 45 The XRPD overlay of the remaining solids of the compound O (as shown in Formula I) in pure water is displayed (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0221] Figure 46 The XRPD overlay of the remaining solid in FaSSIF for the crystal form O of compound I is shown (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0222] Figure 47 The XRPD overlay of the remaining solid of the compound O in FeSSIF, as shown in Formula I, is displayed (from top to bottom: initial state, 1 hour of equilibrium, 2 hours of equilibrium, 4 hours of equilibrium).

[0223] Figure 48 The XRPD comparison diagrams of the stability of the compound A crystal form shown in Formula I before and after placement are shown (from top to bottom: before placement, after 4 weeks of open placement at 25 ℃ / 60%RH, and after 4 weeks of sealed placement at 40 ℃ / 75%RH).

[0224] Figure 49 The XRPD comparison diagrams of the stability of the compound B crystal form shown in Formula I before and after placement are shown (from top to bottom: before placement, after 4 weeks of open placement at 25 ℃ / 60%RH, and after 4 weeks of sealed placement at 40 ℃ / 75%RH).

[0225] Figure 50 The XRPD comparison diagrams of the stability of the crystal form C of the compound shown in Formula I before and after placement are shown (from top to bottom: before placement, after 4 weeks of open placement at 25 ºC / 60%RH, and after 4 weeks of sealed placement at 40 ºC / 75%RH).

[0226] Figure 51 The XRPD comparison diagrams of the stability of the compound H crystal form shown in Formula I before and after placement are shown (from top to bottom: before placement, after 4 weeks of open placement at 25 ºC / 60%RH, and after 4 weeks of sealed placement at 40 ºC / 75%RH).

[0227] Figure 52 The XRPD comparison diagrams of the stability of the N crystal form of the compound shown in Formula I before and after placement are shown (from top to bottom: before placement, after 4 weeks of open placement at 25 ºC / 60%RH, and after 4 weeks of sealed placement at 40 ºC / 75%RH).

[0228] Figure 53 The XRPD comparison diagrams of the stability of the compound O crystal form shown in Formula I before and after placement are shown (from top to bottom: before placement, after 4 weeks of open placement at 25 ºC / 60%RH, and after 4 weeks of sealed placement at 40 ºC / 75%RH).

[0229] Figure 54 The XRPD overlay images of compound A, as shown in Formula I, before and after grinding are shown (from top to bottom: before grinding, after grinding).

[0230] Figure 55 The XRPD overlay images of compound B, as shown in Formula I, before and after grinding are shown (from top to bottom: before grinding, after grinding).

[0231] Figure 56 The XRPD overlay images of the compound C crystal form shown in Formula I before and after grinding are shown (from top to bottom: before grinding, after grinding).

[0232] Figure 57The XRPD overlay images of the compound H, represented by Formula I, before and after grinding are shown (from top to bottom: before grinding, after grinding).

[0233] Figure 58 The XRPD overlay images of the compound O shown in Formula I before and after grinding are shown (from top to bottom: before grinding, after grinding).

[0234] Figure 59 The XRPD overlay images of compound A, as shown in Formula I, before and after tableting are shown (from top to bottom: before tableting, after 5 kN tableting, and after 10 kN tableting).

[0235] Figure 60 The XRPD overlay images of compound B (formula I) before and after tableting are shown (from top to bottom: before tableting, after 5 kN tableting, and after 10 kN tableting).

[0236] Figure 61 The XRPD overlay images of the compound H crystal form shown in Formula I before and after tableting are shown (from top to bottom: before tableting, after 5 kN tableting, and after 10 kN tableting).

[0237] Figure 62 The XRPD overlay images of the N crystal form of the compound shown in Formula I before and after tableting are shown (from top to bottom: before tableting, after 5 kN tableting, and after 10 kN tableting).

[0238] Figure 63 The XRPD overlay images of the compound O crystal form shown in Formula I before and after tableting are shown (from top to bottom: before tableting, after 5 kN tableting, and after 10 kN tableting).

[0239] Figure 64 A PSD diagram of crystal form A of the compound represented by Formula I is shown.

[0240] Figure 65 The PSD diagram of crystal form B of compound I is shown.

[0241] Figure 1 A PSD diagram of the crystal form C of the compound shown in Formula I is displayed. Detailed Implementation

[0242] Definitions and Explanations To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the cell and tissue culture, microbiology-related terms, and laboratory procedures used herein are all widely used terms and routine procedures in their respective fields. Meanwhile, to better understand this disclosure, definitions and explanations of relevant terms are provided below. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. It should also be understood that the terminology used in this application is for describing specific embodiments only and is not intended to be limiting.

[0243] Unless otherwise expressly stated, the terms “a,” “an,” and “the” as used in this specification and the appended claims cover one or more types.

[0244] As used herein, the terms “comprising” and “having”, and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0245] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0246] The term "crystal form" refers to a crystal form that has the same chemical composition but different spatial arrangements of molecules and / or ions that form crystals.

[0247] The term "amorphous" refers to a solid form of molecules and / or ions that are not crystalline. Amorphous solids do not exhibit definite X-ray powder diffraction patterns with clear maximum values.

[0248] The term "X-ray powder diffraction pattern substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the major peaks shown in the X-ray powder diffraction pattern appear in the X-ray powder diffraction pattern; the major peaks refer to the peaks with a relative intensity greater than 10%, preferably greater than 30%, with the highest peak as a reference (the relative intensity of the highest peak is specified as 100%).

[0249] In this disclosure, "patient," "subject," and "subject" have the same meaning, referring to humans or other warm-blooded mammals. Humans, as the "subject" of this invention, include adults, infants, and children. Other warm-blooded mammals include, but are not limited to, non-human primates such as chimpanzees, other apes or monkeys, as well as other zoo animals, domesticated mammals, or laboratory animals such as cats, pigs, dogs, cattle, sheep, mice, rats, and guinea pigs. Preferably, the "subject" of this invention is a human.

[0250] The crystal forms of the compounds represented by Formula I in this disclosure include both the nonsolvent (anhydrous) and solvate (solvent-containing) crystal forms of the compounds represented by Formula I.

[0251] The term "effective amount" or "therapeutic effective amount" refers to the amount of any mixture, pharmaceutical composition, or formulation of any two of the crystal forms A, B, C, N, O, and H described in this disclosure in any proportion, sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined above), according to methods mastered by a clinically qualified physician in the art. Determining the therapeutically effective dose is within the capabilities of a clinician or researcher in the art and may vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, including the subject's weight and age, general health status, severity of the disease, route of administration, and other factors affecting efficacy, such as a history of drug allergies. The specific dosage will vary depending on factors such as the specific compound or crystal form selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0252] In this document, the term "about" is used to mean approximately, roughly, about, or in a range. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the indicated value. Generally, the term "about" is used here to modify the value as varying within a reasonable range of fluctuation as understood by those skilled in the art. Specifically, when "about" is used in conjunction with a temperature range, it refers to a temperature fluctuating within, for example, ±5°C, ±4°C, ±3°C, ±2°C, ±1°C. When "about" is used in conjunction with a range representing weight loss, it refers, as appropriate, to a weight fluctuating within, for example, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.4%.

[0253] In this document, "no further significant weight loss" means that the percentage of weight loss is less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1%.

[0254] The term "multiple" means two or more, and "two or more" includes two, as well as more than two.

[0255] Example To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. The following is merely a further description of this disclosure, and the scope of protection of this disclosure is not limited thereto. Unless otherwise stated, the methods and materials of the embodiments, experimental examples, and other examples described below are all conventional products that can be purchased from the market.

[0256] The experimental conditions for embodiments 1-17 of this disclosure are as follows: The instruments and methods used for data collection are as follows: (1) X-ray powder diffractometer (XRPD) The XRPD patterns described in this disclosure are acquired using a PANalytical or Bruker X-ray powder diffractometer. The XRPD method parameters described in this disclosure are as follows: (2) Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic moisture adsorption-desorption analysis (DVS), and proton nuclear magnetic resonance spectroscopy (NMR) analysis. 1 H NMR) The TGA images described in this disclosure were acquired using a Discovery TGA 5500 / TGA 550 thermogravimetric analyzer. The TGA method parameters described in this disclosure are as follows: Scan rate: 10 °C / min; Protective gas: N2.

[0257] The DSC plots described in this disclosure were acquired using a TA Instruments Discovery DSC 2500 / DSC 250 differential scanning calorimeter. The DSC method parameters described in this disclosure are as follows: Scan rate: 10 °C / min; Protective gas: N2.

[0258] The DVS graph described in this disclosure is acquired on SMS DVS Intrinsic. The parameters of the DVS method are as follows: Temperature: 25 °C; Carrier gas, flow rate: N2, 200 mL / min; dm / dt: 0.002% / min; Minimum dm / dt equilibration time: 10 min; Maximum balancing time: 180 min; Relative humidity range: 0%RH-95%RH.

[0259] The contents described in this disclosure 1 1H NMR data were acquired using a Bruker 400 MHz nuclear magnetic resonance spectrometer. Deuterated dimethyl sulfoxide was used as the solvent.

[0260] (3) Particle size distribution of crystal form (PSD) The PSD results described in this disclosure were acquired using a Microtrac S3500 laser particle size analyzer. The test employed a wet method, and the dispersion medium was Isopar G. The method parameters for the laser particle size analyzer are as follows: *Flow rate 60% is 60% of 65 ml / sec.

[0261] (4) Tableting machine The pressure stability described in this disclosure was achieved using a SYP-5BS tablet press from Shanghai Xinnuo Instrument Equipment Co., Ltd. The adhesion was achieved using an A258RC5P14X001 tablet press from ENERPAC.

[0262] (5) Vibrating ball mill The ball milling described in this disclosure was performed using a Gridmann GT300 vibratory ball mill. (6) Vibration tester The flowability test was performed using a ZS-2E vibratory compactor from Tianjin Tianda Tianfa Technology Co., Ltd., with a vibration speed of 250±1 times / min and a vibration stroke of 3±0.2 mm.

[0263] Example 1: Preparation of crystal form C of the compound shown in Formula I The compound crystal form C shown in Formula I was prepared by recrystallization according to the method disclosed in Example 7 of patent application CN118598873A.

[0264] The preparation process of crystal form C of the compound shown in Formula I is as follows: Weigh 2091.1 mg of the solid compound of Formula I into a 20 mL glass vial, add 12 mL of methanol, and equilibrate at 60 °C for about 1 hour to obtain a clear solution. Then transfer to 5 °C and let stand overnight to precipitate the solid. Separate the solid by vacuum filtration, and allow the wet sample to air dry at room temperature for about 4 hours to obtain crystal form C of the compound of Formula I.

[0265] The X-ray powder diffraction pattern of crystal form C of the compound shown in Formula I is as follows: Figure 2 As shown, its X-ray powder diffraction data are shown in Table 1.

[0266] The TGA image of crystal form C of the compound shown in Formula I is as follows: Figure 3As shown, when heated to 150 °C, there is a mass loss of approximately 5.6%.

[0267] The DSC diagram of crystal form C of the compound shown in Formula I is as follows: Figure 4 As shown, an endothermic peak begins to appear when it is heated to around 136 °C.

[0268] The compound with crystal form C shown in Formula I 1 H NMR such as Figure 5 As shown, the molar ratio of methanol to AXT-1003 is 0.76, corresponding to a residual solubility of 4.7% (using deuterated dimethyl sulfoxide as solvent).

[0269] The compound C shown in Formula I is a methanol solvate.

[0270] Table 1: X-ray powder diffraction data of crystal form C of the compound shown in Formula I Example 2: Preparation of crystal form A of the compound shown in Formula I 1 Weigh 29.8 mg of the amorphous solid of the compound of formula I obtained by the preparation method in Example 5 into a 1.5 mL glass vial, and add 0.5 mL of methyl tert-butyl ether to obtain a suspension. Place the suspension at -20 °C and stir magnetically for approximately 18 days. Centrifuge to separate the solid, and vacuum dry the wet sample at room temperature for approximately 3 days to obtain crystal form A of the compound of formula I. The X-ray powder diffraction pattern of crystal form A of the compound of formula I is shown below. Figure 6 As shown.

[0271] Example 3: Preparation of crystal form A of the compound shown in Formula I 2 Weigh 1516.4 mg of the solid form B of the compound of formula I obtained by the preparation method of Example 4 into a 20 mL glass vial, and add 20 mL of 2-methyltetrahydrofuran. After filtration, slowly add 10 mL of diisopropyl ether to the filtrate, followed by 75.2 mg of the solid form A of the compound of formula I obtained by the preparation method of Example 2 as a seed crystal. Continue to add 30 mL of diisopropyl ether, stir at room temperature for about 3 hours, and a solid precipitates. Separate the solid by vacuum filtration, and place the wet sample in a vacuum dryer at room temperature overnight to obtain the solid form A of the compound of formula I.

[0272] The X-ray powder diffraction pattern of crystal form A of the compound shown in Formula I is as follows: Figure 7 As shown in Table 2, its X-ray powder diffraction data are as follows.

[0273] The TGA image of crystal form A of the compound shown in Formula I is as follows: Figure 8 As shown, when heated to 150 °C, there is a mass loss of approximately 1.8%.

[0274] The DSC diagram of crystal form A of the compound shown in Formula I is as follows:Figure 9 As shown, an endothermic peak begins to appear when it is heated to around 179 °C.

[0275] The crystal form A of the compound shown in Formula I 1 H NMR such as Figure 10 As shown, deuterated dimethyl sulfoxide was used as the solvent.

[0276] The compound shown in Formula I has a crystal form A, which is amorphous.

[0277] Table 2: X-ray powder diffraction data of crystal form A of the compound shown in Formula I Example 4: Preparation of crystal form B of the compound shown in Formula I Weigh 1400 mg of crystal form C of the compound of formula I obtained by the preparation method in Example 1 into a 50 mL reaction flask, add 14 mL of anhydrous ethanol / water (1:1.25) mixed solvent, and heat to 50°C to dissolve. After filtration, slowly cool to 40°C and stir for 2 hours. Then cool to 20°C at a rate of 5°C / hour and maintain at 20°C with stirring for 12 hours to precipitate a solid. Then cool to 5°C at a rate of 5°C / hour and continue stirring for 4 hours. Separate the solid by vacuum filtration, and place the wet sample in a vacuum dryer at 40°C overnight to obtain crystal form B of the compound of formula I.

[0278] The X-ray powder diffraction pattern of crystal form B of compound shown in Formula I is as follows: Figure 11 As shown, its X-ray powder diffraction data are shown in Table 3.

[0279] The TGA image of crystal form B of compound I is shown below. Figure 12 As shown, when heated to 150 °C, there is a mass loss of approximately 1.1%.

[0280] The DSC diagram of crystal form B of compound I is shown below. Figure 13 As shown, an endothermic peak begins to appear when it is heated to around 188 °C.

[0281] The crystal form B of the compound shown in Formula I 1 H NMR such as Figure 14 As shown, deuterated dimethyl sulfoxide was used as the solvent.

[0282] The compound shown in Formula I has a crystal form B that is amorphous.

[0283] Table 3: X-ray powder diffraction data of crystal form B of the compound shown in Formula I Example 5: Preparation of the amorphous form of the compound shown in Formula I Weigh 1209.1 mg of the solid B crystal of the compound of formula I obtained by the preparation method in Example 4 into a 100 mL round-bottom flask, and dissolve it in 20 mL of trifluoroethanol. Resolve the solvent by rotary evaporation in a 50 ºC water bath. Dry the wet sample under vacuum at room temperature for approximately 7 hours to obtain the amorphous form of the compound of formula I. The X-ray powder diffraction pattern of the amorphous form of the compound of formula I is shown below. Figure 15 As shown.

[0284] Example 6: Preparation of crystal form H of the compound shown in Formula I 209.8 mg of the amorphous solid of the compound of formula I obtained by the preparation method in Example 5 was weighed into a 5 mL vial, and 3.3 mL of pure water was added to obtain a suspension. The suspension was magnetically stirred at 5 °C for approximately 7 days, then the solid was separated by filtration. The wet sample was dried overnight at 25 °C using a forced-air drying method to obtain crystal form H of the compound of formula I. The X-ray powder diffraction pattern of crystal form H of the compound of formula I is shown below. Figure 16 As shown.

[0285] Example 7: Preparation of crystal form H of the compound shown in Formula I Weigh 3300 mg of the amorphous solid of the compound of formula I obtained by the preparation method of Example 5 into a blue-mouthed flask, add 45 mL of pure water, and add an appropriate amount of the solid of crystalline form H of the compound of formula I obtained by the preparation method of Example 6 as a seed crystal. Place the suspension in a 5°C container and stir magnetically overnight. Add 20 mL of pure water and continue stirring magnetically at 5°C. After stirring overnight, add 20 mL of pure water and continue stirring magnetically at 5°C for approximately 6 days. Centrifuge to separate the solid, remove the supernatant, and dry the wet sample overnight in a forced-air dryer at 25°C to obtain the crystalline form H of the compound of formula I.

[0286] The X-ray powder diffraction pattern of the compound of crystal form H shown in Formula I is as follows: Figure 17 As shown, its X-ray powder diffraction data are shown in Table 4.

[0287] The TGA diagram of crystal form H of the compound shown in Formula I is as follows: Figure 18 As shown, when heated to 130 °C, there is a mass loss of approximately 13.1%.

[0288] The DSC diagram of the crystal form H of the compound shown in Formula I is as follows: Figure 19 As shown, endothermic peaks begin to appear when heated to around 46 °C, 86 °C and 152 °C.

[0289] The crystal form H of the compound shown in Formula I 1 H NMR such as Figure 20 As shown, deuterated dimethyl sulfoxide was used as the solvent.

[0290] The compound shown in Formula I has a crystal form H that is a hydrate.

[0291] Table 4: X-ray powder diffraction data of crystal form H of the compound shown in Formula I Example 8: Preparation of crystal form N of compound shown in Formula I Take an appropriate amount of the wet sample of the compound of formula I, obtained by the preparation method of Example 7, and place it in a vacuum dryer at 50 ºC overnight to obtain the compound of formula I, crystal form N.

[0292] The X-ray powder diffraction pattern of the compound N with crystal form shown in Formula I is as follows: Figure 21 As shown, its X-ray powder diffraction data are shown in Table 5.

[0293] The TGA diagram of the crystal form N of the compound shown in Formula I is as follows: Figure 22 As shown, when heated to 130 °C, there is a mass loss of approximately 2.6%.

[0294] The DSC diagram of the crystal form N of the compound shown in Formula I is as follows: Figure 23 As shown, an endothermic peak begins to appear when it is heated to around 152 °C.

[0295] The compound N shown in Formula I has crystal form N 1 H NMR such as Figure 24 As shown, deuterated dimethyl sulfoxide was used as the solvent.

[0296] The compound shown in Formula I has a crystal form N that is amorphous.

[0297] Table 5: X-ray powder diffraction data of crystal form N of compound I Example 9: Preparation of crystal form O of the compound shown in Formula I Weigh 961.6 mg of the solid of compound C (formula I) obtained by the preparation method in Example 1 into a 20 mL vial and add 10 mL of pure water. After sealing, mix using a rotary mixer at 25 rpm for about 2 hours at room temperature. After removing the aqueous phase, dry the wet sample under vacuum at room temperature for about 16 hours, collect the solid, and obtain the solid of compound O (formula I).

[0298] The X-ray powder diffraction pattern of the compound O with crystal form shown in Formula I is as follows: Figure 25 As shown, its X-ray powder diffraction data are shown in Table 6.

[0299] The TGA image of the crystal form O of the compound shown in Formula I is as follows: Figure 26 As shown, when heated to 110 °C, there is a mass loss of approximately 5.0%.

[0300] The DSC diagram of the compound O shown in Formula I is as follows: Figure 27As shown, endothermic peaks begin to appear when heated to around 93 °C and 126 °C.

[0301] The compound shown in Formula I has crystal form O. 1 H NMR such as Figures 28-32 As shown, deuterated dimethyl sulfoxide was used as the solvent.

[0302] The compound shown in Formula I, crystal form O, is a hydrate.

[0303] Table 6: X-ray powder diffraction data of crystal form O of the compound shown in Formula I Example 10: Study on the humidity stability of different crystal forms Using a dynamic moisture adsorption analyzer, 10-20 mg of each of the following compounds (formulas A, B, C, and N) were cycled once under humidity conditions of 0%RH-95%RH-0%RH, and the same compound (formula O) was cycled once under humidity conditions of 60%RH-95%RH-0%RH-95%RH. XRPD values ​​of the solids before and after the test were collected, and the overlay images are shown below. Figures 33-47 As shown in the figure. The results show that after the DVS test, the crystal forms A, B, N, and O of the compound shown in Formula I did not change in crystal form, while the crystal form C of the compound shown in Formula I underwent a crystal transformation. This indicates that compared to the crystal form C of the compound shown in Formula I, the crystal forms A, B, N, and O of the compound shown in Formula I have better humidity stability.

[0304] Example 11: Study on the physical stability of different crystal forms in a medium Approximately 40 mg of each of the following compounds (forms A, B, C, H, and O) were dispersed in 4 mL of FaSSIF (artificial intestinal fluid under fasting conditions), FeSSIF (artificial intestinal fluid under satiated conditions), and pure water to prepare suspensions. After equilibration at 37 °C for 1 hour, 2 hours, and 4 hours, the solids were separated by centrifugation, and the XRPD of the remaining solids was monitored. The results are shown below. Figures 48-53 As shown.

[0305] The results showed that in pure water, FaSSIF, and FeSSIF, the crystal forms A, B, H, and O of the compound shown in Formula I did not undergo any crystal form change, while the crystal form C of the compound shown in Formula I underwent a crystal form transformation. This indicates that, compared to the crystal form C of the compound shown in Formula I, the crystal forms A, B, H, and O of the compound shown in Formula I have better physical stability in the three media.

[0306] Example 12: Study on the stability of solids with different crystal forms Approximately 5 mg of each of the following compounds (polymorphs A, B, C, N, O, and H) from Formula I were placed in open conditions at 25 °C / 60%RH and 40 °C / 75%RH for 4 weeks, respectively. The crystal forms of the resulting solids were then determined using XRPD. The results are summarized in Table 7, and the XRPD comparison charts are shown below. Figures 54-58 As shown.

[0307] The results show that the crystal forms A, B, N, O, and H of the compound shown in Formula I are stable for at least 4 weeks under the conditions of 25 ℃ / 60%RH and 40 ℃ / 75%RH, while the crystal form C of the compound shown in Formula I undergoes a crystal transformation. This indicates that the crystal forms A, B, N, O, and H of the compound shown in Formula I have better physical stability than the crystal form C of the compound shown in Formula I.

[0308] Table 7: Solid stability studies of different crystal forms Example 13: Grinding stability of different crystal forms Approximately 10 mg of each of the following compounds (crystal form A, B, C, H, and O) from Formula I were placed in centrifuge tubes. 10 μL of pure water was added to each tube, and the mixtures were then wet-milled at 500 rpm for 10 minutes. The XRPD of the solids before and after milling was measured, and the overlay images are shown below. Figures 59-63 As shown.

[0309] The results showed that after wet grinding, the crystal forms A, B, H, and O of the compound shown in Formula I did not change, while the crystal form C of the compound shown in Formula I underwent a crystal transformation. This indicates that compared to the crystal form C of the compound shown in Formula I, the crystal forms A, B, H, and O of the compound shown in Formula I have better grinding stability.

[0310] Example 14: Pressure stability of different crystal forms Approximately 20 mg of each of the following compounds (forms A, B, N, O, and H) from Formula I were taken and compressed using a 6 mm tableting mold under pressures of 5 kN and 10 kN, respectively. XRPD tests were performed before and after tableting. The test results are as follows: Figures 64-66 As shown.

[0311] The results showed that after being pressed under pressure of 5 kN or 10 kN, the crystal forms of compounds A, B, N, O, and H of Formula I did not undergo any crystal form change, indicating that these compounds have good pressure stability.

[0312] Example 15: Fluidity Study of Different Crystal Forms Approximately 500 mg of each of the three compounds (crystal form B, C, and N) shown in Formula I were weighed and gently added to a 5 mL graduated cylinder. The initial volume V0 was measured, and the loose density ρ0 was calculated using the formula: "Loose density ρ0 = Powder mass / Initial volume". After vibrating the powder 1250 times using a ZS-2E vibratory compactor, the volume V after compaction was recorded. t Using the formula "tap density ρ t = Powder mass / Tapped volume" to calculate tapped density ρ t Compressibility (c), also known as the compressibility index or Carr index, is calculated based on the measured bulk density and tap density of the sample using the formula c = (V0 - V). t The result can be calculated by multiplying V0 by 100%. A smaller Cartesian coefficient indicates better liquidity. The results are summarized in Table 8.

[0313] The results show that the Karl coefficients of compound crystal forms B and N shown in Formula I are smaller than those of compound crystal form C shown in Formula I; indicating that, compared with compound crystal form C shown in Formula I, compound crystal forms B and N shown in Formula I have better fluidity.

[0314] Table 8: Fluidity Study of Different Crystal Forms Example 16: Adhesion Study of Different Crystal Forms Tableting was performed using a manual tablet press. Approximately 30 mg of each of the following compounds (crystal forms A, B, C, N, and O) from Formula I were added to an 8 mm circular punch. A pressure of 10 kN was applied for tableting, followed by a dwell time of approximately half a minute. The mass of the punch before and after tableting was measured, and the amount of adhesion was calculated. The results are summarized in Table 9.

[0315] The results showed that after tableting, the adhesion of compound crystal forms A, B, N, and O in Formula I was lower than that of compound crystal form C in Formula I, and they were less prone to sticking.

[0316] Table 9: Adhesion studies of different crystal forms Example 17: Particle size distribution of different crystal forms After the samples were thoroughly mixed, approximately 10 mg of each of the following compounds (forms A, B, and C) were placed in 20 mL vials: one containing Isopar G (containing 0.2% lecithin). The mixture was then added to the SDC injection system, ensuring adequate light shielding. After sonication for 30 seconds, the particle size distribution was measured. The results are summarized in Table 10, and the particle size distribution diagrams are shown below. Figure 3 As shown in the figure. The results show that the crystal forms A and B of the compound shown in Formula I are both unimodal, while the crystal form C of the compound shown in Formula I is multimodal. This indicates that compared with the crystal form C of the compound shown in Formula I, the crystal forms A and B of the compound shown in Formula I have more uniform particle size distribution.

[0317] Table 10: Particle size distribution of different crystal forms Example 18: Comparison of DSC values ​​for different crystal forms pass Figure 8It can be seen that the compound crystal form C shown in Formula I has one endothermic peak, the peak temperature of which is 136.1 °C. The compound crystal form C shown in Formula I is a methanol solvent compound crystal form, and the endothermic peak with a peak temperature of 136.1 °C corresponds to the methanol removal process.

[0318] pass Figure 12 It can be seen that the compound crystal form A shown in Formula I has one endothermic peak, the peak temperature of which is 178.6 ℃. The compound crystal form A shown in Formula I is a solvent-free crystal form, and the endothermic peak with a peak temperature of 178.6 ℃ corresponds to the melting process.

[0319] pass Figure 18 It can be seen that the compound B shown in Formula I has one endothermic peak, the peak temperature of which is 188.3 °C. The compound B shown in Formula I is a solvent-free crystal form, and the endothermic peak with a peak temperature of 188.3 °C corresponds to the melting process.

[0320] pass Figure 22 It can be seen that the compound H shown in Formula I has three endothermic peaks, with peak temperatures of 45.8 ℃, 86.2 ℃, and 152.3 ℃, respectively. Compound H shown in Formula I is a hydrate crystal form. The endothermic peaks with peak temperatures of 45.8 ℃ and 86.2 ℃ correspond to the dehydration process, while the endothermic peak with peak temperature of 152.3 ℃ corresponds to the melting process.

[0321] pass Figure 26 It can be seen that the compound N represented by Formula I has one endothermic peak, the peak temperature of which is 152.0 °C. The compound N represented by Formula I is a solvent-free crystal form, and the endothermic peak with a peak temperature of 152.0 °C corresponds to the melting process.

[0322] pass Figure 2 It can be seen that the compound O shown in Formula I has two endothermic peaks, with peak temperatures of 92.8 ℃ and 126.4 ℃, respectively. The compound O shown in Formula I is a hydrate crystal form. The endothermic peak with a peak temperature of 92.8 ℃ corresponds to the dehydration process, and the endothermic peak with a peak temperature of 126.4 ℃ corresponds to the melting process.

[0323] When heated in DSC at a rate of 10 K / min using a sample pan with pinholes, the melting point of crystal form A of compound I is approximately 175 °C. When heated in DSC at a rate of 10 K / min using a sample pan with pinholes, the melting point of crystal form B of compound I is approximately 183 °C. The melting point of crystal form B of compound I is higher than that of crystal form A of compound I.

[0324] Example 19 Comparison of TGA with different crystal forms pass Figure 7 It can be seen that the compound crystal form C shown in Formula I loses about 5.6% of its weight at 150℃ (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss), and the curve remains basically horizontal in the range of 150.0 to 300.0℃, indicating that there is no further significant weight loss.

[0325] pass Figure 11 It can be seen that the compound crystal form A shown in Formula I loses about 1.8% of its weight at 150℃ (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss), and the curve remains basically horizontal in the range of 150.0 to 300.0℃, indicating that there is no further significant weight loss.

[0326] pass Figure 17 It can be seen that the compound B shown in Formula I loses about 1.1% of its weight at 150℃ (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss), and the curve remains basically horizontal in the range of 150.0 to 300.0℃, indicating that there is no further significant weight loss.

[0327] Through the diagram Figure 21 It can be seen that the compound H shown in Formula I loses about 13.1% of its weight at 130℃ (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss), and the curve remains basically horizontal in the range of 130.0 to 300.0℃, indicating that there is no further significant weight loss.

[0328] pass Figure 25 It can be seen that the compound N shown in Formula I loses about 2.6% of its weight at 130℃ (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss), and the curve remains basically horizontal in the range of 130.0 to 300.0℃, indicating that there is no further significant weight loss.

[0329] pass ​ It can be seen that the compound O shown in Formula I loses about 5.0% of its weight at 110℃ (the percentage of weight loss is the percentage of the weight reduction of the sample to the weight of the sample before this weight loss), and the curve remains basically horizontal in the range of 110.0 to 300.0℃, indicating that there is no further significant weight loss.

[0330] In summary, the weight loss of crystal forms B and A of the compound shown in Formula I is relatively small, while the weight loss of crystal forms C, N and O of the compound shown in Formula I is relatively high, and the weight loss of crystal form H of the compound shown in Formula I is the highest.

[0331] The foregoing description of specific exemplary embodiments of this disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit this disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of this disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of this disclosure, as well as various different choices and variations. The scope of this disclosure is intended to be defined by the claims and their equivalents.

Claims

1. A crystal form of the compound shown in formula (I), (I) The compound shown in formula (I) has a crystal form of B, and the XRPD spectrum of crystal form B has characteristic peaks at the 2θ values ​​in the lower group: 7.0°±0.2°, 15.0°±0.2°, 21.4°±0.2°; or, The compound shown in formula (I) has a crystal form of crystal form A, and the XRPD spectrum of crystal form A has characteristic peaks at the 2θ values ​​in the lower group: 12.6°±0.2°, 18.7°±0.2°, 23.0°±0.2°; or, The compound shown in formula (I) has a crystal form of H, and the XRPD spectrum of crystal form H has characteristic peaks at the 2θ values ​​in the lower group: 5.4°±0.2°, 10.2°±0.2°, 18.5°±0.2°; or, The compound shown in formula (I) has crystal form N, and the XRPD spectrum of crystal form N has characteristic peaks at the 2θ values ​​in the lower group: 9.9°±0.2°, 11.7°±0.2°, 14.8°±0.2°; or, The compound shown in formula (I) has a crystal form of O, and the XRPD spectrum of crystal form O has characteristic peaks at the 2θ values ​​in the lower group: 10.8°±0.2°, 12.3°±0.2°, and 17.3°±0.2°.

2. The crystal form of the compound of formula (I) according to claim 1, wherein, The XRPD spectrum of crystal form B has characteristic peaks at the 2θ values ​​in the lower group: 7.0°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 19.7°±0.2°, 20.5°±0.2°, 21.4°±0.2°; or, The XRPD spectrum of crystal form A has characteristic peaks at the 2θ values ​​in the lower group: 12.6°±0.2°, 16.8°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 20.6°±0.2°, 23.0°±0.2°; or, The XRPD spectrum of crystal form H has characteristic peaks at the 2θ values ​​in the lower group: 5.4°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 18.5°±0.2°, 19.4°±0.2°, 22.0°±0.2°; or, The XRPD spectrum of the N crystal form has characteristic peaks at the 2θ values ​​in the lower group: 9.9°±0.2°, 11.7°±0.2°, 12.7°±0.2°, 14.8°±0.2°, 18.1°±0.2°, 21.3°±0.2°; or, The XRPD spectrum of the crystal form O has characteristic peaks at the 2θ values ​​in the lower group: 10.8°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 16.1°±0.2°, 17.3°±0.2°, and 25.5°±0.2°.

3. The crystal form of the compound of formula (I) according to claim 1 or 2, wherein, The XRPD spectrum of crystal form B has characteristic peaks at the 2θ values ​​in the lower group: 7.0°±0.2°, 12.1°±0.2°, 14.0°±0.2°, 15.0°±0.2°, 15.5°±0.2°, 16.9°±0.2°, 19.7°±0.2°, 20.5°±0.2°, 21.4°±0.2°; or, The XRPD spectrum of crystal form A has characteristic peaks at the 2θ values ​​in the lower group: 9.5°±0.2°, 11.3°±0.2°, 12.6°±0.2°, 16.8°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 20.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°; or, The XRPD spectrum of crystal form H has characteristic peaks at the 2θ values ​​in the lower group: 5.4°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 12.3°±0.2°, 15.2°±0.2°, 18.5°±0.2°, 19.4°±0.2°, 22.0°±0.2°; or, The XRPD spectrum of the N crystal form has characteristic peaks at the 2θ values ​​in the lower group: 9.9°±0.2°, 11.7°±0.2°, 12.7°±0.2°, 13.4°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 21.3°±0.2°; or, The XRPD spectrum of the crystal form O has characteristic peaks at the 2θ values ​​in the lower group: 10.8°±0.2°, 12.3°±0.2°, 13.1°±0.2°, 16.1°±0.2°, 17.3°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 24.2°±0.2°, and 25.5°±0.2°.

4. The crystal form of the compound of formula (I) according to any one of claims 1-3, wherein, The compound B shown in formula (I) has an XRPD pattern that is substantially the same as that in Figure 10; and / or, The TGA spectrum of crystal form B of the compound shown in formula (I) shows a weight loss of 1.1 ± 0.5% at 150 ± 2 °C; and / or, The compound B represented by formula (I) has a TGA spectrum that is substantially the same as that shown in Figure 11; and / or, The DSC spectrum of the compound of crystal form B shown in formula (I) has an endothermic peak at 188±2℃; and / or, The compound B shown in formula (I) has a DSC spectrum that is essentially the same as that in Figure 12; Preferably, the compound A represented by formula (I) has an XRPD pattern that is substantially the same as that in Figure 5 or Figure 6; and / or, The TGA spectrum of crystal form A of the compound shown in formula (I) shows a weight loss of 1.8 ± 0.5% at 150 ± 2 °C; and / or, The compound A shown in formula (I) has a TGA spectrum that is substantially the same as that in Figure 7; and / or, The DSC spectrum of crystal form A of the compound shown in formula (I) has an endothermic peak at 179±2℃; and / or, The compound of formula (I) in crystal form A has a DSC spectrum that is substantially the same as that in Figure 8; and / or, Preferably, the compound H represented by formula (I) has an XRPD pattern that is substantially the same as that in Figure 15 or Figure 16; and / or, The TGA spectrum of the compound of crystal form H shown in formula (I) shows a weight loss of 13.1 ± 0.5% at 130 ± 2 °C; and / or, The compound H represented by formula (I) has a TGA spectrum that is substantially the same as that shown in Figure 17; and / or, The DSC spectrum of the compound H, as shown in formula (I), exhibits endothermic peaks at 46±2 ℃, 86±2 ℃, and 152±2 ℃; and / or, The compound H shown in formula (I) has a DSC spectrum that is essentially the same as that in Figure 18; Preferably, the compound N represented by formula (I) has an XRPD pattern that is substantially the same as that in Figure 20; and / or, The TGA spectrum of the compound N, as shown in formula (I), indicates a weight loss of 2.6 ± 0.5% at 130 ± 2 °C; and / or, The compound N represented by formula (I) has a TGA spectrum that is substantially the same as that in Figure 21; and / or, The DSC spectrum of the compound N, as shown in formula (I), has an endothermic peak at 152±2 °C; and / or, The compound N represented by formula (I) has a DSC spectrum that is essentially the same as that in Figure 22; Preferably, the compound O represented by formula (I) has an XRPD pattern that is substantially the same as that in Figure 24; and / or, The TGA spectrum of the compound O represented by formula (I) shows a weight loss of 5.0 ± 0.5% at 110 ± 2 °C; and / or, The compound of formula (I) with crystal form O has a TGA spectrum that is substantially the same as that in Figure 25; and / or, The DSC spectrum of the compound O shown in formula (I) exhibits endothermic peaks at 93±2 ℃ and 126±2 ℃; and / or, The compound O shown in formula (I) has a DSC spectrum that is essentially the same as that in Figure 26.

5. A method for preparing the crystal form of the compound of formula (I) as described in any one of claims 1-4, characterized in that, The preparation method of the compound B represented by formula (I) includes the following steps: (B-1-1) Add a mixed solvent to crystal form C of the compound shown in Formula I and heat to 35–65°C to dissolve; after filtration, first cool to 25–55°C and maintain the temperature with stirring for 0.5–4 hours; second cool to 5–35°C and maintain the temperature with stirring for 8–16 hours to precipitate a solid; third cool to -10–20°C and maintain the temperature with stirring for 1–8 hours; separate the solid to obtain a wet sample; (B-1-2) The wet sample was placed in a vacuum at 25-55°C and dried overnight to obtain the compound B shown in Formula I.

6. A method for preparing the crystal form of the compound of formula (I) as described in any one of claims 1-4, characterized in that, The preparation method of the crystal form A of the compound shown in formula (I) is either method A-1 or method A-2; The A-1 method includes the following steps: (A-1-1) An organic solvent is added to the amorphous solid of the compound shown in Formula I to obtain a suspension; (A-1-2) The suspension is stirred at -40 to 0°C for 10 to 30 days, and the solid is separated to obtain a wet sample; (A-1-3) The wet sample was placed at 5-35°C and vacuum dried for 1-6 days to obtain the crystal form A of the compound shown in Formula I; Preferably, the A-2 method includes the following steps: (A-2-1) Add a first organic solvent to the solid of crystal form B of the compound shown in Formula I, filter, add a second organic solvent to the filtrate, add crystal form A of the compound shown in Formula I as a seed crystal; continue to add the second organic solvent, place at -15 to 25°C and stir for 1 to 6 hours to precipitate a solid; separate the solid to obtain a wet sample; (A-2-2) The wet sample was placed in a vacuum at -15 to 25°C and dried overnight to obtain the compound crystal form A shown in Formula I.

7. A method for preparing the crystal form of the compound of formula (I) as described in any one of claims 1-4, characterized in that, The preparation method of the compound crystal form H shown in formula (I) is either the H-1 method or the H-2 method; The H-1 method includes the following steps: (H-1-1) Water is added to the amorphous solid of the compound shown in Formula I to obtain a suspension; (H-1-2) The suspension is stirred at -15 to 25°C for 1 to 10 days, and the solid is separated to obtain a wet sample; (H-1-3) The wet sample was dried overnight at 5-40°C by forced air drying to obtain the compound H shown in Formula I; Preferably, the H-2 method includes the following steps: (H-2-1) Water is added to the amorphous solid of the compound shown in Formula I, and solid of crystal form H of the compound shown in Formula I is added as a seed crystal to obtain a suspension. (H-2-2) The suspension is stirred overnight at -15 to 25°C, water is added, and the suspension is stirred overnight at -15 to 25°C. Water is added, and the suspension is stirred for 1 to 10 days at -15 to 25°C. The solid is separated to obtain a wet sample. (H-2-3) The wet sample was dried overnight at 5-40°C by forced air drying to obtain the compound H shown in Formula I.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one or more of the following crystal forms: B, A, H, N or O of the compound of formula (I) as claimed in any one of claims 1-4, or any one or more of the following crystal forms: B, A or H of the compound of formula (I) prepared by the preparation method of any one of claims 5-7, and optionally a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition further includes one or more other therapeutic agents; The therapeutic active agent is selected from anticancer agents, immunomodulators, anti-allergic agents, antiemetics, analgesics, and cell protectants.

9. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation comprises any one or more of the following crystal forms B, A, H, N or O of the compound of formula (I) as described in any one of claims 1-4, or any one or more of the following crystal forms B, A or H of the compound of formula (I) prepared by the preparation method described in any one of claims 5-7. Preferably, the pharmaceutical preparation comprises the pharmaceutical composition of claim 8; Preferably, the pharmaceutical preparation is a powder, tablet, lozenge, capsule, granule, pill, dispersible powder, suspension, solution, emulsion, syrup, aerosol, cream, ointment, gel, injection, lyophilized powder for injection, or suppository dosage form; Preferably, the pharmaceutical preparation is used to treat diseases or conditions mediated by Zeste homolog enhancer 2 (EZH2), multicomb inhibitory complex 2 (PRC2), or a combination of Zeste homolog enhancer 2 (EZH2) and multicomb inhibitory complex 2 (PRC2); Preferably, the disease or condition is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

10. The use of the compound of formula (I) according to any one of claims 1-4, which is a compound of crystal form B, crystal form A, crystal form H, crystal form N or crystal form O, or the compound of formula (I) prepared by the preparation method according to any one of claims 5-7, which is a compound of crystal form B, crystal form A or crystal form H, in the preparation of a drug; the use of the pharmaceutical composition of claim 8 or the pharmaceutical preparation of claim 9 in the preparation of a drug; Preferably, the drug is used to treat diseases or conditions mediated by Zeste homolog enhancer 2 (EZH2), multicomb repressor complex 2 (PRC2), or a combination of Zeste homolog enhancer 2 (EZH2) and multicomb repressor complex 2 (PRC2); Preferably, the disease or condition mediated by the combination of Zeste homolog enhancer 2 (EZH2), multicomb repressor complex 2 (PRC2), or Zeste homolog enhancer 2 (EZH2) and multicomb repressor complex 2 (PRC2) is selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

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