Salt of aza-aryl compound, crystal form of salt, preparation method and application of salt

Abstract

The invention provides a salt of an aza-aryl compound, and a crystal form, a preparation method and application of the salt. The invention provides p-toluenesulfonate or hydrochloride of a compound as shown in a formula (I). The salt of the compound shown in the formula (I) is higher in AUC and Cmax, the in-vivo peak reaching time is shorter, the exposure amount is higher, and the pharmacokinetic property is good. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a salt of a nitrogen heteroaryl compound, a crystal form of the salt, a preparation method thereof, and an application thereof. Background Art

[0002] EED (Embryonic ectoderm Development) and EZH2 (Enhancer of Zeste Homolog2) are two core proteins of the PRC2 complex (Polycomb Repressive Complex 2). PRC2 inhibits the expression of related genes by methylating lysine 27 of histone 3 (H3K27) in chromatin. The binding of EED to trimethylated H3K27Me3 can allosterically promote the enzymatic catalytic function of EZH2 on the one hand, and on the other hand, it can also localize the PCR2 complex on the chromatin that needs to be modified. Abnormal functions of PRC2, such as overexpression or gain-of-function mutations of EZH2, are associated with many clinical tumor diseases, including lung cancer, breast cancer, rectal cancer, prostate cancer, bladder cancer, pancreatic cancer, sarcoma, and lymphoma, etc. PRC2 is also related to various cellular immune functions. For example, EZH2 participates in regulating lymphocyte activation and can also promote the response of T cells to tumor cells together with glycolysis. Therefore, the research and development of small molecule inhibitors of PRC2 have important and broad drug development value.

[0003] The research and development of PRC2 inhibitors mainly focuses on two strategies: developing EZH2 inhibitors and EED inhibitors. Currently, EZH2 inhibitors that have entered clinical trials include EPZ-6438 (Epizyme, clinical phase II), GSK2816126 (GSK, clinical phase I), and CPI-1205 (Constellation, clinical phase I), etc. Although the research and development of EZH2 inhibitors have entered the clinical research stage, these inhibitors all contain a common 2-pyridone pharmacophore. Moreover, in the clinical treatment with existing EZH2 inhibitors, secondary mutations have begun to appear. EED inhibitors have an allosteric inhibitory effect on the enzymatic function of EZH2 and can achieve the same or similar biological functions as EZH2. On the one hand, EED inhibitors can well overcome the drug resistance problem of EZH2, and on the other hand, EED inhibitors can be used in combination with EZH2 inhibitors to achieve better synergistic effects. Currently, the only EED inhibitor that has entered clinical trials is MAK683 (Novatis, clinical phase II). Therefore, it is of great significance to develop new solid forms of EED inhibitors and conduct drug research. Summary of the Invention

[0004] The present invention discloses a salt of a nitrogen heteroaryl compound, a crystal form of the salt, a preparation method thereof and an application. The salt of the nitrogen heteroaryl compound of the present invention has good pharmacokinetic properties, and its crystal form has good solubility and physicochemical stability, and has good prospects for drug development.

[0005] The present invention provides a p-toluenesulfonate of a compound represented by formula (I),

[0006]

[0007] The molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1.

[0008] The present invention provides a crystal form I of a p-toluenesulfonate of a compound represented by formula (I), and its X-ray powder diffraction (XRPD) pattern represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 6.63±0.20°, 11.91±0.20°, 13.24±0.20°, 14.03±0.20°, 15.71±0.20° and 18.14±0.20°.

[0009]

[0010] The molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1.

[0011] In one embodiment, the X-ray powder diffraction (XRPD) pattern represented by 2θ angle of the crystal form I of the p-toluenesulfonate of the compound represented by formula (I) using Cu-Kα radiation further has diffraction peaks at one or more of 17.24±0.20°, 21.92±0.20°, 22.54±0.20°, 24.79±0.20°, 25.06±0.20° and 26.63±0.20°.

[0012] In one embodiment, the X-ray powder diffraction (XRPD) pattern represented by 2θ angle of the crystal form I of the p-toluenesulfonate of the compound represented by formula (I) using Cu-Kα radiation further has diffraction peaks at one or more of 10.87±0.20°, 14.29±0.20°, 17.70±0.20°, 18.99±0.20°, 21.63±0.20° and 33.21±0.20°.

[0013] In one embodiment, the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) has diffraction peaks in the X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation at 6.63±0.20°, 10.87±0.20°, 11.91±0.20°, 13.24±0.20°, 14.03±0.20°, 14.29±0.20°, 15.71±0.20°, 17.24±0.20°, 18.14±0.20°, 22.54±0.20°, 24.79±0.20°, 25.06±0.20° and 26.63±0.20°.

[0014] In one embodiment, the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation, and the diffraction peak positions are shown in the following table:

[0015]

[0016]

[0017] In one embodiment, the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) has an X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation, and the diffraction peak positions and relative intensities are shown in the following table:

[0018]

[0019]

[0020] In one embodiment, the X-ray powder diffraction (XRPD) pattern expressed in 2θ angle using Cu-Kα radiation of the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) is substantially as Figure 1 shown.

[0021] In one embodiment, the differential scanning calorimetry (DSC) curve of the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) has an endothermic peak onset at 266.75±3 °C, and / or the differential scanning calorimetry (DSC) curve of the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) reaches a peak temperature at 269.39±3 °C.

[0022] In one embodiment, the differential scanning calorimetry (DSC) curve of the Form I of the p-toluenesulfonate salt of the compound represented by formula (I) is substantially as Figure 2 shown.

[0023] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) shows no weight loss before 100 ± 3 °C (for example, in the range of 25 ± 3 °C to 100 ± 3 °C, or in the range of 50 ± 3 °C to 100 ± 3 °C).

[0024] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the p-toluenesulfonate shows decomposition after 250 ± 3 °C.

[0025] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) is substantially as Figure 3 shown.

[0026] The present invention provides a hydrochloride salt of the compound represented by formula (I),

[0027]

[0028] wherein the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:1.

[0029] The present invention provides crystalline form I of a hydrochloride salt of the compound represented by formula (I), the X-ray powder diffraction (XRPD) pattern of which, using Cu-Kα radiation and expressed in terms of 2θ angle, has diffraction peaks at 7.89 ± 0.20 °, 11.61 ± 0.20 °, 15.89 ± 0.20 °, 25.58 ± 0.20 ° and 26.45 ± 0.20 °,

[0030]

[0031] wherein the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:1.

[0032] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in terms of 2θ angle, further has diffraction peaks at one or more of 6.87 ± 0.20 °, 16.94 ± 0.20 °, 18.72 ± 0.20 °, 23.34 ± 0.20 ° and 23.96 ± 0.20 °.

[0033] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in terms of 2θ angle, further has diffraction peaks at one or more of 15.57 ± 0.20 °, 28.97 ± 0.20 °, 31.46 ± 0.20 ° and 39.23 ± 0.20 °.

[0034] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound of formula (I) using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 6.87 ± 0.20°, 7.89 ± 0.20°, 9.25 ± 0.20°, 11.61 ± 0.20°, 12.52 ± 0.20°, 12.98 ± 0.20°, 14.34 ± 0.20°, 15.57 ± 0.20°, 15.89 ± 0.20°, 16.94 ± 0.20°, 17.44 ± 0.20°, 18.72 ± 0.20°, 19.23 ± 0.20°, 20.55 ± 0.20°, 22.22 ± 0.20°, 23.34 ± 0.20°, 23.96 ± 0.20°, 24.46 ± 0.20°, 24.81 ± 0.20°, 25.27 ± 0.20°, 25.58 ± 0.20°, 26.45 ± 0.20°, 27.48 ± 0.20°, 27.92 ± 0.20°, 28.97 ± 0.20° and 31.46 ± 0.20°.

[0035] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound of formula (I) using Cu-Kα radiation and expressed in 2θ angles, the diffraction peak positions are shown in the following table:

[0036]

[0037]

[0038] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound of formula (I) using Cu-Kα radiation and expressed in 2θ angles, the diffraction peak positions and relative intensities are shown in the following table:

[0039]

[0040]

[0041] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound of formula (I) using Cu-Kα radiation and expressed in 2θ angles is substantially as Figure 4 shown.

[0042] In one embodiment, the differential scanning calorimetry (DSC) curve of crystalline form I of the hydrochloride salt of the compound of formula (I) has no endothermic peak before 250 ± 3 °C (for example, in the range of 40 ± 3 °C to 250 ± 3 °C, or in the range of 80 ± 3 °C to 250 ± 3 °C).

[0043] In one embodiment, the differential scanning calorimetry (DSC) curve of crystalline form I of the hydrochloride salt of the compound of formula (I) is substantially as Figure 5 shown.

[0044] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the hydrochloride salt of the compound of formula (I) shows a weight loss of 0.625% at 101.04 ± 3 °C (for example, in the range of 25 ± 3 °C to 101.04 ± 3 °C).

[0045] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form I of the hydrochloride salt of the compound of formula (I) is substantially as Figure 6 shown.

[0046] The present invention provides a crystalline form B of the compound of formula (I), the X-ray powder diffraction (XRPD) pattern of which, using Cu-Kα radiation and expressed in terms of 2θ angle, has diffraction peaks at 8.39 ± 0.20 °, 9.56 ± 0.20 °, 16.78 ± 0.20 °, 17.19 ± 0.20 °, 22.22 ± 0.20 ° and 25.15 ± 0.20 °,

[0047]

[0048] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form B of the compound of formula (I), using Cu-Kα radiation and expressed in terms of 2θ angle, further has diffraction peaks at one or more of 11.78 ± 0.20 °, 13.35 ± 0.20 °, 19.21 ± 0.20 °, 20.14 ± 0.20 °, 26.13 ± 0.20 ° and 31.12 ± 0.20 °.

[0049] In one embodiment, the X-ray powder diffraction (XRPD) pattern of crystalline form B of the compound of formula (I), using Cu-Kα radiation and expressed in terms of 2θ angle, further has diffraction peaks at one or more of 6.65 ± 0.20 °, 12.91 ± 0.20 °, 14.00 ± 0.20 °, 16.17 ± 0.20 °, 27.77 ± 0.20 ° and 27.98 ± 0.20 °.

[0050] In a certain embodiment, the crystalline form B of the compound represented by formula (I) uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles is 6.65±0.20°, 8.39±0.20°, 9.56±0.20°, 11.78±0.20°, 12.91±0.20°, 13.35±0.20°, 14.00±0.20°, 14.63±0.20°, 16.17±0.20°, 16.78±0.20°, 17.19±0.20°, 19.21±0.20°. There are diffraction peaks at 20.14±0.20°, 22.22±0.20°, 23.39±0.20°, 23.85±0.20°, 24.14±0.20°, 25.15±0.20°, 26.13±0.20°, 26.82±0.20°, 27.19±0.20°, 27.77±0.20°, 27.98±0.20°, 28.34±0.20°, 30.58±0.20°, 31.12±0.20°, 33.08±0.20° and 34.26±0.20°.

[0051] In a certain embodiment, the crystal form B of the compound represented by formula (I) uses Cu-Kα radiation and an X-ray powder diffraction (XRPD) pattern represented by a 2θ angle, and the diffraction peak positions are shown in the following table:

[0052]

[0053]

[0054] In one embodiment, the crystal form B of the compound represented by formula (I) uses Cu-Kα radiation and an X-ray powder diffraction (XRPD) pattern represented by a 2θ angle, and the diffraction peak positions and relative intensities thereof are shown in the following table:

[0055] Serial number 2θ (°) Relative intensity Serial number 2θ (°) Relative intensity 1 6.65 18.0％ 29 25.15 66.1％ 2 7.95 1.4％ 30 25.65 6.5％ 3 8.39 95.1％ 31 26.13 35.5％ 4 9.56 60.6％ 32 26.82 7.6％ 5 11.78 33.8％ 33 27.19 7.4％ 6 12.55 1.0％ 34 27.77 11.8％ 7 12.91 15.7％ 35 27.98 10.3％ 8 13.35 34.6％ 36 28.34 9.7％ 9 14.00 16.1％ 37 28.99 0.5％ 10 14.63 5.9％ 38 29.57 2.5％ 11 15.13 0.3％ 39 30.25 1.7％ 12 15.54 0.4％ 40 30.58 7.1％ 13 16.17 11.1％ 41 31.12 20.7％ 14 16.78 100.0％ 42 31.74 0.3％ 15 17.19 57.9％ 43 32.51 3.0％ 16 18.03 2.9％ 44 33.08 8.9％ 17 18.54 0.9％ 45 33.87 0.9％ 18 19.21 33.7％ 46 34.26 8.4％ 19 20.14 22.5％ 47 34.95 1.4％ 20 20.54 0.8％ 48 35.40 0.6％ 21 21.59 0.2％ 49 35.84 0.6％ 22 22.22 77.8％ 50 36.80 0.3％ 23 22.48 5.6％ 51 37.17 0.5％ 24 22.99 0.6％ 52 37.61 3.9％ 25 23.39 7.2％ 53 37.69 2.9％ 26 23.85 8.1％ 54 39.00 0.5％ 27 24.14 6.0％ 55 39.25 1.0％ 28 24.87 4.7％ 56 39.70 1.9％ .

[0056] In one embodiment, the crystalline form B of the compound represented by formula (I) has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles as shown in FIG. Figure 8 shown.

[0057] In a certain embodiment, the differential scanning calorimetry (DSC) curve of the crystalline form B of the compound as shown in formula (I) has an endothermic peak starting point at 213.77±3°C, and / or the differential scanning calorimetry (DSC) curve of the crystalline form B of the compound as shown in formula (I) reaches a peak temperature at 214.71±3°C.

[0058] In one embodiment, the differential scanning calorimetry (DSC) curve of crystalline form B of the compound represented by formula (I) is substantially as Figure 9 shown.

[0059] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form B of the compound represented by formula (I) shows a weight loss of 0.517% at 150.72 ± 3 °C (for example, in the range of 25 ± 3 °C to 150.72 ± 3 °C).

[0060] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form B of the compound represented by formula (I) shows that it decomposes after 210 ± 3 °C.

[0061] In one embodiment, the thermogravimetric analysis (TGA) curve of crystalline form B of the compound represented by formula (I) is substantially as Figure 10 shown.

[0062] The present invention also provides a method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), which comprises the following steps: crystallizing a mixture of p-toluenesulfonic acid, the compound represented by formula (I), and a solvent to obtain crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), and the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water.

[0063] In one embodiment, in the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the alcohol solvent is an alcohol solvent having 1 to 3 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol, and further such as ethanol.

[0064] In one embodiment, the mixed solvent of an alcohol solvent and water is a mixed solvent with a volume ratio of ethanol to water of 3:1.

[0065] In one embodiment, in the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the p-toluenesulfonic acid is conventional in the art, such as p-toluenesulfonic acid monohydrate.

[0066] In one embodiment, in the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the crystallization is a conventional crystallization operation in the art, such as cooling crystallization.

[0067] In one embodiment, in the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the preparation method further comprises filtration and drying to obtain crystalline form I of the p-toluenesulfonate of the compound represented by formula (I).

[0068] Preferably, in the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the drying is carried out under reduced pressure and vacuum at 40 - 60 °C.

[0069] The present invention also provides a method for preparing crystalline form I of the hydrochloride salt of a compound represented by formula (I), which comprises the following steps: Crystallizing a mixture of hydrochloric acid, the compound represented by formula (I), and a solvent to obtain crystalline form I of the hydrochloride salt of the compound represented by formula (I), wherein the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water.

[0070] In one embodiment, in the method for preparing crystalline form I of the hydrochloride salt of the compound represented by formula (I), the alcohol solvent is an alcohol solvent having 1 to 3 carbon atoms, such as methanol, ethanol, n-propanol or isopropanol, and for example, ethanol.

[0071] In one embodiment, in the method for preparing crystalline form I of the hydrochloride salt of the compound represented by formula (I), the mixed solvent of an alcohol solvent and water is a mixed solvent of ethanol and water with a volume ratio of 3:1.

[0072] In one embodiment, the method for preparing crystalline form I of the hydrochloride salt of the compound represented by formula (I) comprises the following steps:

[0073] Mix the compound represented by formula (I), hydrochloric acid and a solvent, crystallize, filter, and dry to obtain crystalline form I of the hydrochloride salt of the compound represented by formula (I).

[0074] Preferably, the crystallization, filtration, and drying are as described in any one of the present invention.

[0075] The present invention also provides a method for preparing crystalline form B of a compound represented by formula (I), which comprises the following steps: Crystallizing a mixture of the compound represented by formula (I) and a solvent to obtain crystalline form B of the compound represented by formula (I), wherein the solvent is an ester solvent.

[0076] In one embodiment, in the method for preparing crystalline form B of the compound represented by formula (I), the ester solvent is ethyl acetate.

[0077] In one embodiment, in the method for preparing crystalline form B of the compound represented by formula (I), the crystallization is slurrying.

[0078] In one embodiment, in the method for preparing crystalline form B of the compound represented by formula (I), the compound represented by formula (I) is crystalline form A of the compound represented by formula (I).

[0079] The present invention also provides a pharmaceutical composition, which comprises substance Z and one or more pharmaceutically acceptable excipients. Substance Z is the p-toluenesulfonate of the compound represented by formula (I) above, the hydrochloride of the compound represented by formula (I) above, polymorph I of the p-toluenesulfonate of the compound represented by formula (I) above, polymorph I of the hydrochloride of the compound represented by formula (I) above, or polymorph B of the compound represented by formula (I) above. In the above pharmaceutical composition, the p-toluenesulfonate of the compound represented by formula (I) above, the hydrochloride of the compound represented by formula (I) above, polymorph I of the p-toluenesulfonate of the compound of formula (I), polymorph I of the hydrochloride of the compound of formula (I), or polymorph B of the compound of formula (I) is included as the active ingredient.

[0080] The present invention also provides the use of substance Z or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the action mechanism of EED protein and / or PRC2 protein complex. Substance Z is the p-toluenesulfonate of the compound represented by formula (I) above, the hydrochloride of the compound represented by formula (I) above, polymorph I of the p-toluenesulfonate of the compound represented by formula (I) above, polymorph I of the hydrochloride of the compound represented by formula (I) above, or polymorph B of the compound represented by formula (I) above.

[0081] In one embodiment, the disease is a tumor (such as a malignant tumor), for example, lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma, and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, and soft tissue tumor. The lymphoma is preferably diffuse large B-cell lymphoma, follicular lymphoma, or non-Hodgkin lymphoma.

[0082] Term Explanation:

[0083] It should be noted that in the X-ray powder diffraction pattern, the position of the diffraction peak or the relative intensity of the diffraction peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the peak, and the measurement error of the 2θ value is, for example, ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and the range within the error also belongs to the scope of this application.

[0084] It should be noted that for the same crystal form, the occurrence positions of DSC thermal events (such as endothermic peaks, exothermic peaks, etc.) may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the endothermic peak, and the error can be ±5°C, can be ±3°C, or can be ±2°C. Therefore, when determining each crystal form, this error should be taken into account, and within the error range also belongs to the scope of this application.

[0085] It should be noted that for the same crystal form, the occurrence position of the weight loss temperature of TGA may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the weight loss temperature, and the error can be ±5°C, can be ±3°C, or can be ±2°C. Therefore, when determining each crystal form, this error should be taken into account, and within the error range also belongs to the scope of this application.

[0086] In this application, the "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). This medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity. The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting with any component contained in the composition in an adverse manner. In this application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that has been permitted by the relevant government regulatory authorities for use in humans or livestock.

[0087] As used herein, the terms "preventive", "prevent" and "prevent from" include reducing the likelihood of the occurrence or worsening of a disease or disorder in a patient.

[0088] The terms "treat" and other similar synonyms as used herein include the following meanings: (i) preventing the occurrence of a disease or disorder in a mammal, especially when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder; (ii) inhibiting the disease or disorder, that is, curbing its development; (iii) alleviating the disease or disorder, that is, making the state of the disease or disorder subside; or (iv) relieving the symptoms caused by the disease or disorder.

[0089] As used herein and unless otherwise specified, the term "excipient" refers to those excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional drug composition, and can also provide methods to enable the active ingredient to dissolve at the desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration. Excipients can be inert fillers or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition.

[0090] As used herein, the term "room temperature" generally refers to 10°C to 35°C, such as 25°C, unless otherwise specified.

[0091] As used herein, the term "stirring" is completed by using conventional operating methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 revolutions per minute, wherein the magnetic stirring speed is 200 to 1500 revolutions per minute, preferably 300 to 1000 revolutions per minute, and the mechanical stirring speed is preferably 100 to 300 revolutions per minute.

[0092] Unless otherwise stated, the term "plural" as used herein refers to, for example, 2, 3, 4, 5 or 6.

[0093] On the basis of not violating the common sense in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0094] The reagents and raw materials used in the present invention are all commercially available.

[0095] The positive and progressive effects of the present invention are as follows: The crystal form of the salt of the compound shown in formula (I) provided by the present invention has good solubility and physicochemical stability, and has good stability under high temperature and high humidity conditions; and under the conditions of grinding, pressure and heat, the crystal form has good stability; compared with the free base, the AUC and C of the salt of the compound shown in formula (I) max are higher, the time to peak in vivo is faster, the exposure is higher, and its pharmacokinetic properties are good. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 It is the XRPD pattern of crystal form I of the p-toluenesulfonate salt of the compound shown in formula (I).

[0097] Figure 2 It is the DSC pattern of crystal form I of the p-toluenesulfonate salt of the compound shown in formula (I).

[0098] Figure 3 It is the TGA pattern of crystal form I of the p-toluenesulfonate salt of the compound shown in formula (I).

[0099] Figure 4XRPD pattern of Form I of the hydrochloride salt of the compound represented by formula (I).

[0100] Figure 5 DSC pattern of Form I of the hydrochloride salt of the compound represented by formula (I).

[0101] Figure 6 TGA pattern of Form I of the hydrochloride salt of the compound represented by formula (I).

[0102] Figure 7 XRPD pattern of Form A of the compound represented by formula (I).

[0103] Figure 8 XRPD pattern of Form B of the compound represented by formula (I).

[0104] Figure 9 DSC pattern of Form B of the compound represented by formula (I).

[0105] Figure 10 TGA pattern of Form B of the compound represented by formula (I). Detailed Description of the Invention

[0106] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples. The experimental methods not specified in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0107] Test Instruments Used in the Experiments

[0108] 1. X-ray Diffraction Spectrum

[0109] Instrument Model: Bruker D8 ADVANCE X-ray Powder Diffractometer

[0110] Ray: Monochromatic Cu-Kα ray (wavelength = 1.5418)

[0111] Scanning Mode: θ / 2θ, Scanning Range: 3 - 60°

[0112] Voltage: 40 kV, Current: 40 mA

[0113] 2. DSC Spectrum

[0114] Instrument Model: TA Discovery DSC 250

[0115] Purge Gas: Nitrogen

[0116] Heating Rate: 10 °C / min

[0117] Temperature Range: 40 °C to 285 °C

[0118] 3. TGA Spectrum

[0119] Instrument Model: TA Discovery TGA 550

[0120] Purge Gas: Nitrogen

[0121] Heating Rate: 10 °C / min

[0122] Temperature Range: Room Temperature - 300 °C

[0123] Example 1: Preparation of Crystal Form I of p-Toluenesulfonate of the Compound Shown in Formula (I)

[0124] Take (300 mg, 0.65 mmol) of the compound shown in Formula (I) (the compound was prepared according to the method disclosed in Example 115 of WO2021032004). In a 25 mL single-necked flask, add 12 mL of 75% ethanol (v / v) and p-toluenesulfonic acid monohydrate (147 mg, 0.77 mmol). Heat to dissolve, cool to 20 °C and crystallize for 2 h, filter, wash with 75% ethanol, and dry under vacuum at 50 °C to obtain 375 mg of solid with a yield of 90.92%. The obtained solid was identified by XRPD, DSC, and TGA, and it was Crystal Form I of p-toluenesulfonate. Among them, (referring to the method in General Rules 0512 of the Fourth Part of Chinese Pharmacopoeia 2020 Edition), the HPLC content test result of p-toluenesulfonic acid showed that the molar ratio of the compound shown in Formula (I) to p-toluenesulfonic acid was 1:1.

[0125] Table 1 XRPD Peak List of Crystal Form I of p-Toluenesulfonate

[0126]

[0127]

[0128] The X-ray diffraction pattern of Crystal Form I of p-toluenesulfonate of the compound shown in Formula (I) is shown in Figure 1 ... It has characteristic absorption peaks at approximately 6.63, 10.87, 11.91, 13.24, 14.03, 14.29, 15.71, 17.24, 18.14, 22.54, 24.79, 25.06, and 26.63. It has the diffraction peaks shown in Table 1, and the DSC spectrum is shown in Figure 2 ... It has a sharp endothermic peak at 269.39 °C and the starting point of an endothermic peak at 266.75 °C, with an enthalpy value of 77.660 J / g. The TGA spectrum is shown in Figure 3 ... There is basically no weight loss before 100 °C, basically no weight loss before 150.48 °C, and it gradually melts and decomposes after 250 °C.

[0129] Example 2: Preparation of Crystal Form I of the Hydrochloride Salt of the Compound Shown by Formula (I)

[0130] Take the compound shown by formula (I) (100 mg, 0.22 mmol), place it in a 25 mL single-neck flask, add 4 mL of 75% ethanol aqueous solution (v / v) and hydrochloric acid (10 mg, 0.27 mmol), heat and stir to dissolve, cool to room temperature and crystallize for 24 h, filter, wash with ethanol aqueous solution, and dry under vacuum at 50 °C to obtain 102 mg of solid, with a yield of 94.50%. The obtained solid was identified by XRPD, DSC, and TGA, and it was Crystal Form I of the hydrochloride salt of the compound shown by formula (I). The titration test result of the hydrochloric acid content showed that the molar ratio of the compound shown by formula (I) to hydrochloric acid was 1:1.

[0131] Table 2 XRPD Peak List of Crystal Form I of the Hydrochloride Salt

[0132]

[0133]

[0134] The X-ray diffraction of Crystal Form I of the hydrochloride salt of the compound shown by formula (I) is shown in Figure 4 , where characteristic absorption peaks are present at 2θ angles of 6.87, 7.89, 9.25, 11.61, 12.52, 12.98, 14.34, 15.57, 15.89, 16.94, 17.44, 18.72, 19.23, 20.55, 22.22, 23.34, 23.96, 24.46, 24.81, 25.27, 25.58, 26.45, 27.48, 27.92, 28.97, and 31.46. The error range of the 2θ angle of each characteristic peak is ±0.2. It has the diffraction peaks shown in Table 2, and the DSC pattern is shown in Figure 5 , and there is no endothermic melting peak before 250 °C. The TGA pattern is shown in Figure 6 , and there is almost no weight loss before 100 °C. At 101.04 °C, the weight loss is about 0.625% (99.375% by weight).

[0135] Example 3: Preparation of Crystal Form A of the Compound Shown by Formula (I)

[0136] The compound shown by formula (I) was prepared according to the method disclosed in Example 115 of WO2021032004. The obtained product after preparation was concentrated to be a crystalline compound. The obtained solid was identified by XRPD and TGA, and it was Crystal Form A of the compound of formula (I).

[0137] Table 3 XRPD Peak List of Crystal Form A of the Compound Shown by Formula (I)

[0138]

[0139]

[0140] The XRPD of crystalline form A of the compound shown in formula (I) is shown in Table 3, and the XRPD pattern is shown in Figure 7 . Its diffraction 2θ angles have characteristic absorption peaks at 6.11, 6.94, 10.44, 12.31, 13.97, 14.58, 15.68, 16.20, 16.72, 17.09, 17.97, 18.55, 18.94, 19.41, 20.30, 20.89, 21.53, 23.09, 23.92, 25.57, 26.14, 26.78, 28.09 and 29.19, and the error range of the 2θ angle of each characteristic peak is ±0.2. TGA shows a weight loss of about 5.92% before 100 °C.

[0141] Example 4: Crystalline form B of the free base compound shown in formula (I)

[0142] 100 mg of the solid of crystalline form A of the compound shown in formula (I) was taken and added to 5 mL of ethyl acetate for a slurry experiment to obtain crystalline form B of the compound shown in formula (I).

[0143] Table 4 List of XRPD peaks of crystalline form B

[0144]

[0145] The X-ray diffraction pattern of crystalline form B of the compound shown in formula (I) is shown in Table 4, see Figure 8 . Using Cu-Kα radiation, its diffraction 2θ angles have characteristic absorption peaks at 6.65, 8.39, 9.56, 11.78, 12.91, 13.35, 14.00, 14.63, 16.17, 16.78, 17.19, 19.21, 20.14, 22.22, 23.39, 23.85, 24.14, 25.15, 26.13, 26.82, 27.19, 27.77, 27.98, 28.34, 30.58, 31.12, 33.08 and 34.26, and the error range of the 2θ angle of each characteristic peak is ±0.2. The DSC pattern shows an absorption peak starting point at 213.77 °C, a sharp endothermic peak at 214.71 °C, and an enthalpy value of 88.316 J / g, see Figure 9 . TGA shows basically no weight loss before 100 °C, a weight loss of about 0.517% (weight 99.483%) at 150.72 °C, and gradual melting and decomposition after 210 °C, see Figure 10 .

[0146] Example 5

[0147] Samples of polymorph A of the compound represented by formula (I), polymorph B of the compound represented by formula (I), polymorph I of the p-toluenesulfonate of the compound represented by formula (I), and polymorph I of the hydrochloride were each placed open and flat, and were examined for 10 days and 30 days under the conditions of light (5000 Lux ± 500 Lux), high temperature of 60 °C, and high humidity (25 °C, RH 90% ± 5%) to investigate the stability of the polymorphs. The specific research data are shown in Table 5.

[0148] Table 5. Comparison of polymorph stability data after being placed for 30 days under different conditions

[0149]

[0150] The research data on polymorph stability indicate that except for the poor stability of polymorph A of the compound represented by formula (I) under high humidity conditions, the other polymorph samples have good polymorph stability under the conditions of light, high temperature, and high humidity.

[0151] Example 6

[0152] Samples of polymorph A of the compound represented by formula (I), polymorph B of the compound represented by formula (I), polymorph I of the p-toluenesulfonate, and polymorph I of the hydrochloride were each placed open and flat, and were examined for 10 days and 30 days under the conditions of light (5000 Lux ± 500 Lux), high temperature of 60 °C, and high humidity (25 °C, RH 90% ± 5%) to investigate the stability of related substances. The specific research data are shown in Table 6.

[0153] Table 6. Comparison of related substance stability data under different conditions

[0154]

[0155]

[0156] The results of the investigation on the stability of related substances indicate that after salification, the chemical stability has been improved to varying degrees. Under the condition of light, all four samples have degraded to varying degrees, suggesting that the samples need to be stored away from light. The stability of polymorph I of the p-toluenesulfonate of the compound represented by formula (I) under high temperature conditions is better than that of polymorph I of the hydrochloride.

[0157] Example 7

[0158] Samples of crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (I), crystalline form I of the p-toluenesulfonate of the compound of formula (I) obtained according to Example 1, and crystalline form I of the hydrochloride of the compound of formula (I) obtained according to Example 2 were tested for their saturated solubility in water and at different pH values. The results showed that the solubility of the free base in water and at pH 1.0 was greatly increased after salt formation. In the selected dissolution medium at pH 1.0, the solubility of the p-toluenesulfonate of the compound of formula (I) increased the most. The specific research data are shown in Table 7.

[0159] Table 7 Solubility data (mg / mL) under different conditions

[0160]

[0161] Example 8

[0162] Crystalline form I of the p-toluenesulfonate of the compound of formula (I) prepared according to the method of Example 1 was ground, heated, and tableted. The research results showed that the crystalline form was stable. The detailed experimental data are shown in Table 8 below.

[0163] Table 8 Stability study of crystalline form I of p-toluenesulfonate

[0164]

[0165] The results showed that crystalline form I of the p-toluenesulfonate of the compound of formula (I) obtained in this application had good stability.

[0166] Example 9

[0167] Referring to the operation of Example 1 of this application, the compound of formula (I) was mixed with the acids and solvents shown in the following table, and no crystalline form of the salt could be obtained.

[0168]

[0169] The results showed that sulfuric acid, acetic acid, and L-lactic acid at a molar ratio of 0.5 did not form salts; the crystalline forms obtained from the other salts had problems such as strong hygroscopicity, poor product properties, and poor crystalline purity.

[0170] Example 10 Pharmacokinetic experiment

[0171] 10.1 Experimental animals

[0172] Number of animals: 6 Beagle dogs in each group, with 3 males and 3 females;

[0173] Grouping method: Randomly grouped by gender according to the body weight of the dogs.

[0174] 10.2 Reagent preparation

[0175] A sample of crystalline form B of the compound represented by formula (I) is added to a Solutol HS15:20% HP-β-CD mixed solution, sonicated, and vortexed to mix evenly, thus obtaining the solution. Storage conditions and expiration date after preparation: It can be stored for 3 h when temporarily placed in a refrigerator at 2-8 °C after preparation.

[0176] A sample of crystalline form I of the tosylate of the compound represented by formula (I) is added to a Solutol HS15:20% HP-β-CD mixed solution, sonicated, and vortexed to mix evenly, thus obtaining the solution.

[0177] A sample of crystalline form I of the tosylate of the compound represented by formula (I) is added to an SBE-β-CD / 50 mM sodium acetate mixed solution with a pH of 4.61, sonicated, and vortexed to mix evenly, thus obtaining the solution. Storage conditions and expiration date after preparation: It can be stored for 3 h when temporarily placed in a refrigerator at 2-8 °C after preparation.

[0178] 10.3 Experimental operations

[0179] The administration dose is 10 mg / kg, and the dose here is calculated based on the content of the compound represented by formula (I);

[0180] The administration concentration is 2 mg / mL;

[0181] The administration volume is 5 mL / kg;

[0182] Administration frequency: single administration;

[0183] Administration route: oral gavage;

[0184] Sampling time: before administration and at 15 minutes (±1 minute), 30 minutes (±1 minute), 1 hour (±2 minutes), 2 hours (±2 minutes), 4 hours (±5 minutes), 8 hours (±5 minutes), and 24 hours (±20 minutes) after administration;

[0185] Sampling animals: all surviving dogs in each group;

[0186] Sampling site: anterior limb vein or other suitable vein;

[0187] Sampling volume: approximately 0.5 mL, anticoagulated with sodium heparin;

[0188] Blood sample treatment: The collected blood is added to a centrifuge tube containing an anticoagulant, and gently shaken to fully mix the blood with the anticoagulant. The whole blood sample is placed in the dark in an ice box before centrifugation and centrifuged at 2-8 °C and 1800 rpm for 10 minutes within 2 hours to separate the plasma, which is divided into 2 tubes and stored at -66 °C or below for testing.

[0189] Data processing and analysis: Non-compartmental models are used to calculate the pharmacokinetic parameters C max 、T max 、AUC last 、AUC0-∞ ;

[0190] T max and C max adopt measured values;

[0191] AUC 0-t : calculated by the linear trapezoidal method, where t is the time of the last quantifiable plasma drug concentration;

[0192] AUC 0-∞ = AUC 0-t + C t / λ z and C t is the plasma drug concentration at the last quantifiable time point, and λ z is the terminal elimination rate constant.

[0193] 10.4 Experimental results

[0194] The results are shown in Table 9 below.

[0195] Table 9 Pharmacokinetic data

[0196]

[0197] The results showed that in the oral gavage experiment of Beagle dogs, compared with the free base, the AUC and C of the p-toluenesulfonate salt of the compound of formula (I) max were higher, the time to peak in vivo was faster, and the exposure was higher, indicating that the p-toluenesulfonate salt of the compound of formula (I) had good pharmacokinetic properties.

Claims

1. The p-toluenesulfonate or hydrochloride of a compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1; wherein the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:

1.

2. A crystalline form of a compound of formula (I) or a salt thereof, characterized in that, It is polymorph I of the p-toluenesulfonate of the compound represented by formula (I), polymorph I of the hydrochloride of the compound represented by formula (I), or polymorph B of the compound represented by formula (I); Among them, the structure of the compound shown in formula (I) is as follows: For polymorph I of the p-toluenesulfonate of the compound represented by formula (I), the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 6.63±0.20°, 11.91±0.20°, 13.24±0.20°, 14.03±0.20°, 15.71±0.20° and 18.14±0.20°; In polymorph I of the p-toluenesulfonate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:1; For polymorph I of the hydrochloride of the compound represented by formula (I), the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 7.89±0.20°, 11.61±0.20°, 15.89±0.20°, 25.58±0.20° and 26.45±0.20°; In polymorph I of the hydrochloride of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrochloric acid is 1:1; For polymorph B of the compound represented by formula (I), the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation has diffraction peaks at 8.39±0.20°, 9.56±0.20°, 16.78±0.20°, 17.19±0.20°, 22.22±0.20° and 25.15±0.20°.

3. The crystalline form of the compound of formula (I) or its salt according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation of polymorph I of the p-toluenesulfonate of the compound represented by formula (I) also has diffraction peaks at one or more of 17.24±0.20°, 21.92±0.20°, 22.54±0.20°, 24.79±0.20°, 25.06±0.20° and 26.63±0.20°; (2) The X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation of polymorph I of the hydrochloride of the compound represented by formula (I) also has diffraction peaks at one or more of 6.87±0.20°, 16.94±0.20°, 18.72±0.20°, 23.34±0.20° and 23.96±0.20°; (3) The X-ray powder diffraction pattern of crystalline form B of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angles, further has diffraction peaks at one or more of 11.78 ± 0.20°, 13.35 ± 0.20°, 19.21 ± 0.20°, 20.14 ± 0.20°, 26.13 ± 0.20° and 31.12 ± 0.20°; Preferably, the crystalline form of the compound represented by formula (I) or its salt satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angles, further has diffraction peaks at one or more of 10.87 ± 0.20°, 14.29 ± 0.20°, 17.70 ± 0.20°, 18.99 ± 0.20°, 21.63 ± 0.20° and 33.21 ± 0.20°; (2) The X-ray powder diffraction pattern of crystalline form I of the hydrochloride salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angles, further has diffraction peaks at one or more of 15.57 ± 0.20°, 28.97 ± 0.20°, 31.46 ± 0.20° and 39.23 ± 0.20°; (3) The X-ray powder diffraction pattern of crystalline form B of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angles, further has diffraction peaks at one or more of 6.65 ± 0.20°, 12.91 ± 0.20°, 14.00 ± 0.20°, 16.17 ± 0.20°, 27.77 ± 0.20° and 27.98 ± 0.20°.

4. The crystalline form of the compound of formula (I) or its salt according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angles, has diffraction peaks at 6.63 ± 0.20°, 10.87 ± 0.20°, 11.91 ± 0.20°, 13.24 ± 0.20°, 14.03 ± 0.20°, 14.29 ± 0.20°, 15.71 ± 0.20°, 17.24 ± 0.20°, 18.14 ± 0.20°, 22.54 ± 0.20°, 24.79 ± 0.20°, 25.06 ± 0.20° and 26.63 ± 0.20°; (2) The X-ray powder diffraction pattern of Form I of the hydrochloride salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.87 ± 0.20°, 7.89 ± 0.20°, 9.25 ± 0.20°, 11.61 ± 0.20°, 12.52 ± 0.20°, 12.98 ± 0.20°, 14.34 ± 0.20°, 15.57 ± 0.20°, 15.89 ± 0.20°, 16.94 ± 0.20°, 17.44 ± 0.20°, 18.72 ± 0.20°, 19.23 ± 0.20°, 20.55 ± 0.20°, 22.22 ± 0.20°, 23.34 ± 0.20°, 23.96 ± 0.20°, 24.46 ± 0.20°, 24.81 ± 0.20°, 25.27 ± 0.20°, 25.58 ± 0.20°, 26.45 ± 0.20°, 27.48 ± 0.20°, 27.92 ± 0.20°, 28.97 ± 0.20° and 31.46 ± 0.20°; (3) The X-ray powder diffraction pattern of Form B of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.65 ± 0.20°, 8.39 ± 0.20°, 9.56 ± 0.20°, 11.78 ± 0.20°, 12.91 ± 0.20°, 13.35 ± 0.20°, 14.00 ± 0.20°, 14.63 ± 0.20°, 16.17 ± 0.20°, 16.78 ± 0.20°, 17.19 ± 0.20°, 19.21 ± 0.20°, 20.14 ± 0.20°, 22.22 ± 0.20°, 23.39 ± 0.20°, 23.85 ± 0.20°, 24.14 ± 0.20°, 25.15 ± 0.20°, 26.13 ± 0.20°, 26.82 ± 0.20°, 27.19 ± 0.20°, 27.77 ± 0.20°, 27.98 ± 0.20°, 28.34 ± 0.20°, 30.58 ± 0.20°, 31.12 ± 0.20°, 33.08 ± 0.20° and 34.26 ± 0.20°.

5. The crystal form of the compound represented by formula (I) or its salt according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of Form I of the p-toluenesulfonate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: (2) The X-ray powder diffraction pattern of Form I of the hydrochloride salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: (3) The X-ray powder diffraction pattern of Form B of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: Preferably, the crystal form of the compound represented by formula (I) or its salt satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of polymorph I of the p-toluenesulfonate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions and relative intensities as shown in the following table: (2) The X-ray powder diffraction pattern of polymorph I of the hydrochloride salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions and relative intensities as shown in the following table: (3) The X-ray powder diffraction pattern of polymorph B of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, has diffraction peak positions and relative intensities as shown in the following table: Preferably, the polymorph of the compound represented by formula (I) or its salt satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of polymorph I of the p-toluenesulfonate salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, is substantially as shown in Figure 1; (2) The X-ray powder diffraction pattern of polymorph I of the hydrochloride salt of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, is substantially as shown in Figure 4; (3) The X-ray powder diffraction pattern of polymorph B of the compound represented by formula (I), expressed in 2θ angle using Cu-Kα radiation, is substantially as shown in Figure 8.

6. The crystal form of the compound of formula (I) or its salt according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The differential scanning calorimetry curve of polymorph I of the p-toluenesulfonate salt of the compound represented by formula (I) has an endothermic peak onset at 266.75 ± 3 °C, and / or the differential scanning calorimetry curve of polymorph I of the p-toluenesulfonate salt of the compound represented by formula (I) reaches a peak temperature at 269.39 ± 3 °C; (2) The thermogravimetric analysis curve of polymorph I of the p-toluenesulfonate salt of the compound represented by formula (I) has no weight loss before 100 ± 3 °C, for example, no weight loss in the range of 25 ± 3 °C to 100 ± 3 °C, or no weight loss in the range of 50 ± 3 °C to 100 ± 3 °C; (3) The thermogravimetric analysis curve of polymorph I of the p-toluenesulfonate salt of the compound represented by formula (I) shows that it decomposes after 250 ± 3 °C; (4) The differential scanning calorimetry curve of polymorph I of the hydrochloride salt of the compound represented by formula (I) has no endothermic peak before 250 ± 3 °C, for example, no endothermic peak in the range of 40 ± 3 °C to 250 ± 3 °C, or no endothermic peak in the range of 80 ± 3 °C to 250 ± 3 °C; (5) The thermogravimetric analysis curve of polymorph I of the hydrochloride salt of the compound represented by formula (I) has a weight loss of 0.625% at 101.04 ± 3 °C, for example, a weight loss of 0.625% in the range of 25 ± 3 °C to 101.04 ± 3 °C; (6) The differential scanning calorimetry curve of polymorph B of the compound represented by formula (I) has an endothermic peak onset at 213.77 ± 3 °C, and / or the differential scanning calorimetry curve of polymorph B of the compound represented by formula (I) reaches a peak temperature at 214.71 ± 3 °C; (7) The thermogravimetric analysis curve of crystalline form B of the compound represented by formula (I) shows a weight loss of 0.517% at 150.72 ± 3 °C, for example, a weight loss of 0.517% in the range of 25 ± 3 °C to 150.72 ± 3 °C; (8) The thermogravimetric analysis curve of crystalline form B of the compound represented by formula (I) shows that it decomposes after 210 ± 3 °C; Preferably, the crystalline form of the compound represented by formula (I) or its salt satisfies one or more of the following conditions: (1) The differential scanning calorimetry curve of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) is substantially as shown in Figure 2; (2) The thermogravimetric analysis curve of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) is substantially as shown in Figure 3; (3) The differential scanning calorimetry curve of crystalline form I of the hydrochloride of the compound represented by formula (I) is substantially as shown in Figure 5; (4) The thermogravimetric analysis curve of crystalline form I of the hydrochloride of the compound represented by formula (I) is substantially as shown in Figure 6; (5) The differential scanning calorimetry curve of crystalline form B of the compound represented by formula (I) is substantially as shown in Figure 9; (6) The thermogravimetric analysis curve of crystalline form B of the compound represented by formula (I) is substantially as shown in Figure 10.

7. A method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) according to any one of claims 2-6, crystalline form I of the hydrochloride of the compound represented by formula (I) according to any one of claims 2-6, or crystalline form B of the compound represented by formula (I) according to any one of claims 2-6, characterized in that, The method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) comprises the following steps: crystallizing a mixture of p-toluenesulfonic acid, the compound represented by formula (I), and a solvent to obtain crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), and the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water; The method for preparing crystalline form I of the hydrochloride of the compound represented by formula (I) comprises the following steps: crystallizing a mixture of hydrochloric acid, the compound represented by formula (I), and a solvent to obtain crystalline form I of the hydrochloride of the compound represented by formula (I), and the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water; The method for preparing crystalline form B of the compound represented by formula (I) comprises the following steps: crystallizing a mixture of the compound represented by formula (I) and a solvent to obtain crystalline form B of the compound represented by formula (I), and the solvent is an ester solvent.

8. The preparation method of crystal form I of p-toluenesulfonate of the compound represented by formula (I), crystal form I of hydrochloride of the compound represented by formula (I), or crystal form B of the compound represented by formula (I) according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) In the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the alcohol solvent is an alcohol solvent of C1-C3, such as methanol, ethanol, n-propanol or isopropanol, and again such as ethanol; Preferably, in the method for preparing crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the mixed solvent of an alcohol solvent and water is a mixed solvent of ethanol and water with a volume ratio of 3:1; (2) In the preparation method of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate; (3) In the preparation method of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), the crystallization is cooling crystallization; (4) The preparation method of crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) further comprises filtration and drying; the drying is preferably carried out under reduced pressure and vacuum at 40 - 60 °C; (5) In the preparation method of crystalline form I of the hydrochloride of the compound represented by formula (I), the alcohol solvent is an alcohol solvent with C1 - C3, such as methanol, ethanol, n-propanol or isopropanol, and for example ethanol; Preferably, in the preparation method of crystalline form I of the hydrochloride of the compound represented by formula (I), the mixed solvent of the alcohol solvent and water is a mixed solvent with a volume ratio of ethanol to water of 3:1; (6) In the preparation method of crystalline form I of the hydrochloride of the compound represented by formula (I), the crystallization is cooling crystallization; (7) The preparation method of crystalline form I of the hydrochloride of the compound represented by formula (I) further comprises filtration and drying; the drying is preferably carried out under reduced pressure and vacuum at 40 - 60 °C; (8) In the preparation method of crystalline form B of the compound represented by formula (I), the ester solvent is ethyl acetate; (9) In the preparation method of crystalline form B of the compound represented by formula (I), the crystallization is trituration; (10) In the preparation method of crystalline form B of the compound represented by formula (I), the compound represented by formula (I) is crystalline form A of the compound represented by formula (I).

9. A pharmaceutical composition, which comprises substance Z and one or more pharmaceutically acceptable excipients, wherein the substance Z is the p-toluenesulfonate of the compound represented by formula (I) as claimed in claim 1, the hydrochloride of the compound represented by formula (I) as claimed in claim 1, crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) as claimed in any one of claims 2 - 6, crystalline form I of the hydrochloride of the compound represented by formula (I) as claimed in any one of claims 2 - 6, or crystalline form B of the compound represented by formula (I) as claimed in any one of claims 2 - 6.

10. Use of a substance Z or the pharmaceutical composition as claimed in claim 9 in the preparation of a drug for preventing and / or treating a disease related to the mechanism of action of EED protein and / or PRC2 protein complex, wherein the substance Z is the p-toluenesulfonate of the compound represented by formula (I) as claimed in claim 1, the hydrochloride of the compound represented by formula (I) as claimed in claim 1, crystalline form I of the p-toluenesulfonate of the compound represented by formula (I) as claimed in any one of claims 2 - 6, crystalline form I of the hydrochloride of the compound represented by formula (I) as claimed in any one of claims 2 - 6, or crystalline form B of the compound represented by formula (I) as claimed in any one of claims 2 - 6; Preferably, the disease is a tumor, such as a malignant tumor, such as lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumor including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue tumor, and the lymphoma is preferably diffuse large B-cell lymphoma, follicular lymphoma or non-Hodgkin lymphoma.

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