Salt of nitrogen heteroaryl compound, crystal form of said salt, preparation method therefor, and use thereof

Abstract

Provided in the present invention are a salt of a nitrogen heteroaryl compound, a crystal form of said salt, a preparation method therefor, and use thereof. Provided in the present invention is a p-toluenesulfonate or hydrochloride of a compound represented by formula (I). The salt of the compound represented by formula (I) provided in the present invention has a higher AUC and Cmax, a faster in vivo peak time, a higher exposure amount, and good pharmacokinetic properties.

Description

A salt of a nitrogen heteroaryl compound, a crystal form of the salt, a preparation method thereof, and applications thereof

[0001] This application claims priority from Chinese patent application No. 202410016874X, filed on January 5, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a salt of a nitrogen heteroaryl compound, a crystal form of the salt, a preparation method and application thereof. Background Art

[0003] EED (Embryonic ectoderm Development) and EZH2 (Enhancer of Zeste Homolog 2) are two core proteins of the Polycomb Repressive Complex 2 (PRC2) complex. PRC2 represses gene expression by methylating histone 3 at position lysine 27 (H3K27) in chromatin. EED's binding to trimethylated H3K27Me3 not only significantly enhances EZH2's enzymatic activity but also localizes the PRC2 complex to chromatin sites requiring modification. PRC2 dysfunction, such as EZH2 overexpression or gain-of-function mutations, is clinically associated with numerous cancer diseases, including lung, breast, colorectal, prostate, bladder, pancreatic, sarcomas, and lymphomas. PRC2 is also involved in various cellular immune functions. For example, EZH2 regulates lymphocyte activation and, in conjunction with glycolysis, promotes T cell responses to tumor cells. Therefore, developing small molecule inhibitors of PRC2 holds significant potential for drug discovery.

[0004] The research and development of PRC2 inhibitors mainly focuses on two strategies: the development of EZH2 inhibitors and EED inhibitors. The EZH2 inhibitors currently entering the clinic include EPZ-6438 (Epizyme, clinical phase II), GSK2816126 (GSK, clinical phase I), and CPI-1205 (Constellation, clinical phase I). Although there are multiple EZH2 inhibitors entering the clinical research stage, these inhibitors all contain a common 2-pyridone pharmacophore. In addition, secondary mutations have begun to appear in the clinical treatment of existing EZH2 inhibitors. EED inhibitors have an allosteric inhibitory effect on the EZH2 enzyme function and can achieve the same or similar biological functions as EZH2. On the one hand, EED inhibitors have effectively overcome the drug resistance problem of EZH2. On the other hand, EED inhibitors can be combined with EZH2 inhibitors to achieve better synergistic effects. Currently, the only EED inhibitor entering the clinic is MAK683 (Novatis, Phase II clinical trial). Therefore, it is of great significance to develop new solid forms of EED inhibitors and conduct drug research. Summary of the Invention

[0005] The present invention discloses a salt of an azoheteroaryl compound, a crystal form of the salt, a preparation method, and applications thereof. The salt of the azoheteroaryl compound of the present invention has good pharmacokinetic properties, and its crystal form has good solubility and physicochemical stability, and has good drug development prospects.

[0006] The present invention provides a p-toluenesulfonate salt of a compound represented by formula (I),

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

[0008] The present invention provides a crystalline form I of a p-toluenesulfonate salt of a compound represented by formula (I), which 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 an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles.

[0009] The molar ratio of the compound represented by formula (I) and p-toluenesulfonic acid is 1:1.

[0010] In a certain embodiment, the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles 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°.

[0011] In a certain embodiment, the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles also 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°.

[0012] In one embodiment, the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) 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° using Cu-Kα radiation and expressed in 2θ angles.

[0013] In one embodiment, the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions are shown in the following table:

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

[0015] In one embodiment, the crystalline form I of the p-toluenesulfonate salt 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 FIG1 .

[0016] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) has an endothermic peak starting point at 266.75±3°C, and / or the differential scanning calorimetry (DSC) curve of the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) reaches a peak temperature at 269.39±3°C.

[0017] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) is substantially as shown in FIG2 .

[0018] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) shows no weight loss before 100±3°C (e.g., within the range of 25±3°C to 100±3°C, or further within the range of 50±3°C to 100±3°C).

[0019] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystalline form I of the p-toluenesulfonate salt shows that it decomposes after 250±3°C.

[0020] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) is substantially as shown in FIG3 .

[0021] The present invention provides a hydrochloride salt of a compound represented by formula (I),

[0022] The molar ratio of the compound represented by formula (I) and hydrochloric acid is 1:1.

[0023] The present invention provides a crystalline form I of the hydrochloride salt of a compound represented by formula (I), which 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 an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles.

[0024] The molar ratio of the compound represented by formula (I) and hydrochloric acid is 1:1.

[0025] In a certain embodiment, the crystalline form I of the hydrochloride salt of the compound represented by formula (I) uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles 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°.

[0026] In a certain embodiment, the crystalline form I of the hydrochloride salt of the compound represented by formula (I) uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles also 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°.

[0027] In a certain embodiment, the crystalline form I of the hydrochloride salt of the compound represented by formula (I) uses Cu-Kα radiation and the X-ray powder diffraction (XRPD) pattern expressed in 2θ angles is 6.87±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±0.2 There are diffraction peaks at 0°, 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°.

[0028] In one embodiment, the hydrochloride salt of the compound represented by formula (I) in Form I has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions are shown in the following table:

[0029] In one embodiment, the crystalline form I of the hydrochloride salt of the compound represented by formula (I) has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles, and the diffraction peak positions and relative intensities thereof are shown in the following table:

[0030] In one embodiment, the X-ray powder diffraction (XRPD) pattern of the hydrochloride salt of the compound represented by formula (I) using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG4 .

[0031] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline form I of the hydrochloride salt of the compound represented by formula (I) has no endothermic peak before 250±3°C (e.g., in the range of 40±3°C to 250±3°C, or in the range of 80±3°C to 250±3°C).

[0032] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline form I of the hydrochloride salt of the compound represented by formula (I) is substantially as shown in FIG5 .

[0033] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystalline form I of the hydrochloride salt of the compound represented by formula (I) shows a weight loss of 0.625% at 101.04±3°C (e.g., in the range of 25±3°C to 101.04±3°C).

[0034] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystalline form I of the hydrochloride salt of the compound represented by formula (I) is substantially as shown in FIG6 .

[0035] The present invention provides a crystalline form B of a compound represented by formula (I), which has an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation and expressed in 2θ angles 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°.

[0036] 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 also 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°.

[0037] 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 also 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°.

[0038] 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°.

[0039] In one embodiment, the crystal 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, and the diffraction peak positions are shown in the following table:

[0040] In one embodiment, the crystal 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, and the diffraction peak positions and relative intensities thereof are shown in the following table:

[0041] In one embodiment, the X-ray powder diffraction (XRPD) pattern of Form B of the compound represented by Formula (I) using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG8 .

[0042] In one embodiment, the differential scanning calorimetry (DSC) curve of the crystalline form B of the compound represented by 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 represented by formula (I) reaches a peak temperature at 214.71±3°C.

[0043] In one embodiment, the differential scanning calorimetry (DSC) curve of Form B of the compound represented by formula (I) is substantially as shown in FIG9 .

[0044] In one embodiment, the thermogravimetric analysis (TGA) curve of Form B of the compound of formula (I) shows a weight loss of 0.517% at 150.72±3°C (e.g., in the range of 25±3°C to 150.72±3°C).

[0045] In one embodiment, the thermogravimetric analysis (TGA) curve of the crystalline form B of the compound represented by formula (I) shows that it decomposes after 210±3°C.

[0046] In one embodiment, the thermogravimetric analysis (TGA) curve of Form B of the compound of formula (I) is substantially as shown in FIG10 .

[0047] The present invention also provides a method for preparing the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), comprising the following steps: crystallizing a mixture of p-toluenesulfonic acid, the compound represented by formula (I) and a solvent to obtain the crystalline form I of the p-toluenesulfonate 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.

[0048] In one embodiment, in the method for preparing the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), the alcohol solvent is a C1-C3 alcohol solvent, such as methanol, ethanol, n-propanol or isopropanol, and also ethanol.

[0049] In one embodiment, the alcohol solvent and water mixed solvent is a mixed solvent with a volume ratio of ethanol to water of 3:1.

[0050] In one embodiment, in the method for preparing the crystalline form I of the p-toluenesulfonic acid salt of the compound represented by formula (I), the p-toluenesulfonic acid is conventional in the art, such as p-toluenesulfonic acid monohydrate.

[0051] In one embodiment, in the method for preparing the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), the crystallization is a conventional crystallization operation in the art, such as cooling crystallization.

[0052] In one embodiment, the method for preparing the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) further comprises filtering and drying to obtain the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I).

[0053] Preferably, in the method for preparing the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), the drying is performed at 40-60° C. under reduced pressure and vacuum drying.

[0054] The present invention also provides a method for preparing the crystalline form I of the hydrochloride salt of the compound represented by formula (I), comprising the following steps: crystallizing a mixture of hydrochloric acid, the compound represented by formula (I) and a solvent to obtain the 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.

[0055] In one embodiment, in the method for preparing the crystalline form I of the hydrochloride salt of the compound represented by formula (I), the alcohol solvent is a C1-C3 alcohol solvent, such as methanol, ethanol, n-propanol or isopropanol, and another example is ethanol.

[0056] In one embodiment, in the method for preparing the crystalline form I of the hydrochloride salt of the compound represented by formula (I), the alcohol solvent and water mixed solvent is a mixed solvent with a volume ratio of ethanol to water of 3:1.

[0057] In one embodiment, the method for preparing the crystalline form I of the hydrochloride salt of the compound represented by formula (I) comprises the following steps:

[0058] The compound represented by formula (I), hydrochloric acid and a solvent are mixed, crystallized, filtered and dried to obtain the hydrochloride form I of the compound represented by formula (I).

[0059] Preferably, the crystallization, filtration and drying are as described in any one of the present invention.

[0060] The present invention also provides a method for preparing the crystalline form B of the compound represented by formula (I), comprising the following steps: crystallizing a mixture of the compound represented by formula (I) and a solvent to obtain the crystalline form B of the compound represented by formula (I), wherein the solvent is an ester solvent.

[0061] In one embodiment, in the method for preparing the crystalline form B of the compound represented by formula (I), the ester solvent is ethyl acetate.

[0062] In one embodiment, in the method for preparing the crystalline form B of the compound represented by formula (I), the crystallization is slurrying.

[0063] In one embodiment, in the method for preparing the crystalline form B of the compound represented by formula (I), the compound represented by formula (I) is the crystalline form A of the compound represented by formula (I).

[0064] The present invention also provides a pharmaceutical composition comprising a substance Z and one or more pharmaceutically acceptable excipients, wherein the substance Z is the p-toluenesulfonate salt of the compound represented by formula (I), the hydrochloride salt of the compound represented by formula (I), the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), the crystalline form I of the hydrochloride salt of the compound represented by formula (I), or the crystalline form B of the compound represented by formula (I). The pharmaceutical composition comprises the p-toluenesulfonate salt of the compound represented by formula (I), the hydrochloride salt of the compound represented by formula (I), the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), the crystalline form I of the hydrochloride salt of the compound represented by formula (I), or the crystalline form B of the compound represented by formula (I) as an active ingredient.

[0065] The present invention also provides a use of a substance Z or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the action mechanism of the EED protein and / or PRC2 protein complex, wherein the substance Z is the p-toluenesulfonate salt of the compound represented by formula (I), the hydrochloride salt of the compound represented by formula (I), the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I), the crystalline form I of the hydrochloride salt of the compound represented by formula (I), or the crystalline form B of the compound represented by formula (I).

[0066] In one embodiment, the disease is a tumor (e.g., a malignant tumor), such as 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, and the lymphoma is preferably diffuse large B-cell lymphoma, follicular lymphoma or non-Hodgkinson lymphoma.

[0067] Explanation of terms:

[0068] It should be noted that the positions or relative intensities of diffraction peaks in X-ray powder diffraction patterns may vary due to factors such as the measuring instrument, measurement method, and conditions. For any particular crystal form, the peak positions may have errors, with the measurement error of the 2θ value being, for example, ±0.2°. Therefore, this error should be taken into account when determining each crystal form, and determinations within this error are within the scope of this application.

[0069] It should be noted that for the same crystal form, the location 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, the position of the endothermic peak may have an error, which may be ±5°C, ±3°C, or ±2°C. Therefore, when determining each crystal form, this error should be taken into account, and within the error is also within the scope of this application.

[0070] It should be noted that for the same crystal form, the location of the weight loss temperature on TGA may vary due to factors such as the measuring instrument, measurement method / conditions, etc. For any specific crystal form, the location of the weight loss temperature may have an error of ±5°C, ±3°C, or even ±2°C. Therefore, this error should be taken into account when determining each crystal form, and any error within this error is within the scope of this application.

[0071] In the present application, "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredient, and thus exert 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, i.e., the substance can be applied to an individual without causing adverse biological reactions or interacting with any component contained in the composition in an adverse manner. In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the relevant government regulatory authorities as acceptable for use by humans or livestock.

[0072] As used herein, the terms "prophylactic," "prevention," and "preventing" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

[0073] As used herein, the terms "treat," "treat," "treat," "treat," and similar synonyms include the following: (i) preventing the disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing the disease or condition to regress; or (iv) alleviating the symptoms caused by the disease or condition.

[0074] As used herein, and unless otherwise specified, the term "excipient" refers to those excipients widely used in pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They may also provide a method for dissolving the active ingredient at a desired rate after administration to a subject, or promote effective absorption of the active ingredient after administration of the composition to a subject. Excipients may be inert fillers or provide a specific function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition.

[0075] As used herein, the term "room temperature" generally refers to 10°C to 35°C, such as 25°C, unless otherwise specified.

[0076] As used herein, the term "stirring" refers to stirring performed using conventional operating methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 rpm, wherein the magnetic stirring speed is 200 to 1500 rpm, preferably 300 to 1000 rpm, and the mechanical stirring speed is preferably 100 to 300 rpm.

[0077] Unless otherwise specified, the term "plurality" used herein refers to, for example, 2, 3, 4, 5 or 6 instances.

[0078] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0079] The reagents and raw materials used in the present invention are commercially available.

[0080] The positive progress of the present invention is that the crystal form of the compound salt represented by formula (I) provided by the present invention has good solubility and physicochemical stability, and is stable under high temperature and high humidity conditions; and is stable under grinding, pressure and heating conditions; compared with the free base, the AUC and C of the compound salt represented by formula (I) are significantly higher than those of the free base. max Higher, faster time to peak in vivo, higher exposure, and good pharmacokinetic properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] FIG1 is an XRPD pattern of the crystalline form I of the p-toluenesulfonic acid salt of the compound represented by formula (I).

[0082] FIG2 is a DSC spectrum of the crystalline form I of the p-toluenesulfonic acid salt of the compound represented by formula (I).

[0083] FIG3 is a TGA spectrum of the crystalline form I of the p-toluenesulfonic acid salt of the compound represented by formula (I).

[0084] FIG4 is an XRPD pattern of Form I of the hydrochloride salt of the compound represented by formula (I).

[0085] FIG5 is a DSC spectrum of the crystalline form I of the hydrochloride salt of the compound represented by formula (I).

[0086] FIG6 is a TGA spectrum of the crystalline form I of the hydrochloride salt of the compound represented by formula (I).

[0087] FIG7 is an XRPD pattern of Form A of the compound represented by formula (I).

[0088] FIG8 is an XRPD pattern of Form B of the compound represented by formula (I).

[0089] FIG9 is a DSC spectrum of Form B of the compound represented by formula (I).

[0090] FIG10 is a TGA spectrum of Form B of the compound represented by formula (I). DETAILED DESCRIPTION

[0091] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0092] Test equipment used in the experiment

[0093] 1. X-ray diffraction spectrum

[0094] Instrument model: Bruker D8 ADVANCE X-ray powder diffractometer

[0095] Rays: Monochromatic Cu-Ka rays (wavelength = 1.5418)

[0096] Scanning mode: θ / 2θ, scanning range: 3-60°

[0097] Voltage: 40kV, Current: 40mA

[0098] 2.DSC spectrum

[0099] Instrument model: TA Discovery DSC 250

[0100] Purge gas: nitrogen

[0101] Heating rate: 10℃ / min

[0102] Temperature range: 40°C to 285°C

[0103] 3. TGA spectrum

[0104] Instrument model: TA Discovery TGA 550

[0105] Purge gas: nitrogen

[0106] Heating rate: 10℃ / min

[0107] Temperature range: room temperature-300℃

[0108] Example 1: Preparation of Form I of the p-toluenesulfonate salt of the compound represented by formula (I)

[0109] 300 mg, 0.65 mmol) of the compound represented by formula (I) (prepared according to the method disclosed in Example 115 of WO2021032004) was added to a 25 mL single-necked flask, and 12 mL of 75% ethanol (v / v) and p-toluenesulfonic acid monohydrate (147 mg, 0.77 mmol) were added. The mixture was heated to dissolve, cooled to 20°C for 2 h to crystallize, filtered, rinsed with 75% ethanol, and dried under vacuum at 50°C to obtain 375 mg of a solid with a yield of 90.92%. The obtained solid was identified by XRPD, DSC, and TGA as Form I of the p-toluenesulfonic acid salt. The HPLC content of p-toluenesulfonic acid was tested (referring to the method of 0512 of the fourth volume of the Chinese Pharmacopoeia 2020 edition) and the results showed that the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid was 1:1.

[0110] Table 1 XRPD peak list of Form I of p-toluenesulfonate

[0111] The X-ray diffraction pattern of the crystalline form I of the p-toluenesulfonate salt of the compound represented by 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. The DSC spectrum is shown in Figure 2, with a sharp endothermic peak at 269.39°C, an endothermic peak starting point at 266.75°C, and an enthalpy of 77.660 J / g. The TGA spectrum is shown in Figure 3, with essentially no weight loss before 100°C, essentially no weight loss before 150.48°C, and gradual melting and decomposition after 250°C.

[0112] Example 2: Preparation of Form I of the hydrochloride salt of the compound represented by formula (I)

[0113] 100 mg, 0.22 mmol) of the compound represented by formula (I) was placed in a 25 mL single-necked flask, and 4 mL of 75% aqueous ethanol (v / v) and hydrochloric acid (10 mg, 0.27 mmol) were added. The mixture was heated and stirred to dissolve, cooled to room temperature for crystallization for 24 h, filtered, rinsed with aqueous ethanol, and dried under vacuum at 50°C to obtain 102 mg of a solid with a yield of 94.50%. The obtained solid was identified by XRPD, DSC, and TGA to be Form I of the hydrochloride salt of the compound represented by formula (I). The results of a hydrochloric acid titration test showed that the molar ratio of the compound represented by formula (I) to hydrochloric acid was 1:1.

[0114] Table 2 XRPD peak list of Form I of hydrochloride

[0115] The X-ray diffraction pattern of the crystalline form I of the hydrochloride salt of the compound as shown in formula (I) is shown in Figure 4, wherein the 2θ angle has characteristic absorption peaks at 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, wherein 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 spectrum is shown in Figure 5. There is no melting endothermic peak before 250°C. The TGA spectrum is shown in FIG6 . There is almost no weight loss before 100° C., and at 101.04° C., the weight loss is about 0.625% (99.375% by weight).

[0116] Example 3: Preparation of Form A of the Compound of Formula (I)

[0117] The compound represented by formula (I) was prepared according to the method disclosed in Example 115 of WO2021032004. The product obtained after preparation was concentrated to obtain a crystalline compound. The obtained solid was identified by XRPD and TGA, which was Form A of the compound of formula (I).

[0118] Table 3 XRPD peak list of Form A of the compound represented by formula (I)

[0119] The XRPD pattern of Form A of the compound represented by Formula (I) is shown in Table 3, and the XRPD pattern is shown in Figure 7. Its diffraction 2θ angles exhibit 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, with the 2θ angle error for each characteristic peak being ±0.2. TGA showed a weight loss of approximately 5.92% before 100°C.

[0120] Example 4: Crystalline Form B of the Free Base Compound of Formula (I)

[0121] 100 mg of the solid form A of the compound represented by formula (I) was added to 5 mL of ethyl acetate to perform a slurry experiment to obtain the solid form B of the compound represented by formula (I).

[0122] Table 4 XRPD peak list of Form B

[0123] The X-ray diffraction pattern of Form B of the compound represented by Formula (I) is shown in Table 4 and Figure 8. Using Cu-Ka radiation, the diffraction 2θ angle has 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, wherein the error range of the 2θ angle of each characteristic peak is ±0.2. The DSC spectrum shows an absorption peak starting at 213.77°C and a sharp endothermic peak at 214.71°C with an enthalpy of 88.316 J / g (see Figure 9). TGA shows essentially no weight loss before 100°C, a weight loss of approximately 0.517% (99.483% by weight) at 150.72°C, and gradual melting and decomposition after 210°C (see Figure 10).

[0124] Example 5

[0125] Samples of Form A of the compound represented by formula (I), Form B of the compound represented by formula (I), Form I of the p-toluenesulfonate salt of the compound represented by formula (I), and Form I of the hydrochloride salt of the compound represented by formula (I) were laid out open and observed under conditions of light (5000 Lux ± 500 Lux), high temperature of 60°C, and high humidity (25°C, RH 90% ± 5%) for 10 days and 30 days to investigate the stability of the crystal forms. Specific research data are shown in Table 5.

[0126] Table 5. Comparison of crystal stability data after 30 days of storage under different conditions

[0127] The crystal stability study data show that, except for the crystal form A of the compound represented by formula (I), which has poor stability under high humidity conditions, the other crystal form samples have good crystal stability under light, high temperature and high humidity conditions.

[0128] Example 6

[0129] Samples of Form A of the compound represented by formula (I), Form B of the compound represented by formula (I), Form I of the p-toluenesulfonate salt, and Form I of the hydrochloride salt were laid out open and examined under light (5000 Lux ± 500 Lux), high temperature of 60°C, and high humidity (25°C, RH 90% ± 5%) for 10 days and 30 days to examine the stability of the relevant substances. Specific research data are shown in Table 6.

[0130] Table 6 Comparison of stability data of relevant substances under different conditions

[0131] The results of the stability study of the relevant substances showed that the chemical stability was improved to varying degrees after salt formation. Under light conditions, all four samples showed varying degrees of degradation, suggesting that the samples should be stored in the dark. The stability of the p-toluenesulfonic acid salt of the compound represented by formula (I) in Form I under high temperature conditions was better than that of the hydrochloric acid salt in Form I.

[0132] Example 7

[0133] The saturated solubility tests of Form A of the compound of Formula (I), Form B of the compound of Formula (I), Form I of the p-toluenesulfonate salt of the compound of Formula (I) obtained in Example 1, and Form I of the hydrochloride salt of the compound of Formula (I) obtained in Example 2 in water and at different pH values ​​showed that salt formation significantly increased the solubility of the free base in water and at pH 1.0. In the selected dissolution medium at pH 1.0, the p-methanesulfonate salt of the compound of Formula (I) showed the greatest increase in solubility. Specific research data are shown in Table 7.

[0134] Table 7 Solubility data under different conditions (mg / mL)

[0135] Example 8

[0136] The crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) prepared according to the method of Example 1 was ground, heated and tableted. The results showed that the crystalline form was stable. Detailed experimental data are shown in Table 8 below.

[0137] Table 8 Stability study of Form I of p-toluenesulfonate

[0138] The results show that the crystalline form I of the p-toluenesulfonic acid salt of the compound of formula (I) obtained in the present application has good stability.

[0139] Example 9

[0140] Referring to the operation of Example 1 of the present application, the compound represented by formula (I) was mixed with the acid and solvent shown in the table below, but no crystalline salt could be obtained.

[0141] The results showed that sulfuric acid, acetic acid and L-lactic acid at a molar ratio of 0.5 did not form salts; the crystal forms obtained from the remaining salts had problems such as strong hygroscopicity, poor product properties and crystalline purity.

[0142] Example 10 Pharmacokinetic Experiment

[0143] 10.1 Experimental Animals

[0144] Number of animals: 6 Beagle dogs per group, half male and half female;

[0145] Grouping method: Dogs were randomly divided into groups according to their weight and gender.

[0146] 10.2 Reagent Preparation

[0147] Take a sample of Form B of the compound represented by formula (I) and add it to a mixed solution of Solutol HS15:20% HP-β-CD, sonicate, and vortex to mix thoroughly. Storage conditions and shelf life after preparation: After preparation, place it in a refrigerator at 2-8°C for 3 hours.

[0148] A sample of the crystalline form I of the p-toluenesulfonate salt of the compound represented by formula (I) was added to a mixed solution of Solutol HS15:20% HP-β-CD, and the mixture was sonicated and vortexed to obtain the product.

[0149] Add a sample of Form I of the p-toluenesulfonate salt of the compound represented by Formula (I) to a mixture of SBE-β-CD and 50 mM sodium acetate at pH 4.61, sonicate, and vortex to mix thoroughly. Storage and shelf life: After preparation, refrigerate at 2-8°C for 3 hours.

[0150] 10.3 Experimental Operation

[0151] The dosage is 10 mg / kg, where the dosage is calculated based on the content of the compound represented by formula (I);

[0152] Dosing concentration 2 mg / mL;

[0153] Dosing volume 5 mL / kg;

[0154] Dosage frequency: single dose;

[0155] Route of administration: oral gavage;

[0156] Sampling time: before administration and 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;

[0157] Sampled animals: All surviving dogs in each group;

[0158] Sampling site: forelimb vein or other suitable vein;

[0159] Sampling volume: about 0.5 mL, anticoagulated with sodium heparin;

[0160] Blood Sample Processing: Collect blood and place it in a centrifuge tube containing anticoagulant. Gently shake to thoroughly mix the blood and anticoagulant. Place the whole blood sample in an ice box in the dark before centrifugation. Centrifuge at 2-8°C and 1800 rpm for 10 minutes within 2 hours to separate the plasma. Divide the sample into two tubes and store at -66°C or below until testing.

[0161] Data processing and analysis: Pharmacokinetic parameters C were calculated using a non-compartmental model. max 、T max , AUC last , AUC 0-∞ ;

[0162] T max 、C max Use measured values;

[0163] AUC 0-t : Calculated using the linear trapezoidal method, t is the time of the last quantifiable blood drug concentration;

[0164] AUC 0-∞ =AUC 0-t +C t / λ z , C t is the blood drug concentration at the last quantifiable time point, λ z is the terminal elimination rate constant.

[0165] 10.4 Experimental Results

[0166] The results are shown in Table 9 below.

[0167] Table 9 Pharmacokinetic data

[0168] The results showed that in the oral gavage experiment in Beagle dogs, the AUC and C of the p-toluenesulfonate salt of the compound of formula (I) were significantly higher than those of the free base. max The results show that the p-toluenesulfonic acid salt of the compound of formula (I) has good pharmacokinetic properties.

[0169] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

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

1.

2. A crystal form of a compound of formula (I) or a salt thereof, characterized in that, It is Crystal Form I of the p-toluenesulfonate of the compound represented by formula (I), Crystal Form I of the hydrochloride of the compound represented by formula (I), or Crystal Form B of the compound represented by formula (I); Among them, the structure of the compound shown in formula (I) is as follows: For Crystal Form I of the p-toluenesulfonate of the compound represented by formula (I), the X-ray powder diffraction 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°; In Crystal Form 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 Crystal Form I of the hydrochloride of the compound represented by formula (I), the X-ray powder diffraction pattern represented by 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 Crystal Form 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 Crystal Form B of the compound represented by formula (I), the X-ray powder diffraction pattern represented by 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 represented by formula (I) or its salt according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) For Crystal Form I of the p-toluenesulfonate of the compound represented by formula (I), the X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation 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) For Crystal Form I of the hydrochloride of the compound represented by formula (I), the X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation 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) For Crystal Form B of the compound represented by formula (I), the X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation also 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 crystal form of the compound of formula (I) or its salt satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of crystal form I of the p-toluenesulfonate salt of the compound of formula (I) represented by 2θ angle 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°; (2) The X-ray powder diffraction pattern of crystal form I of the hydrochloride salt of the compound of formula (I) represented by 2θ angle using Cu-Kα radiation 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 crystal form B of the compound of formula (I) represented by 2θ angle using Cu-Kα radiation 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 crystal form of the compound represented by formula (I) or its salt as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of crystal form I of the p-toluenesulfonate salt of the compound of formula (I) represented by 2θ angle using Cu-Kα radiation 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), using Cu-Kα radiation and expressed in 2θ angle, 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), using Cu-Kα radiation and expressed in 2θ angle, 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 crystalline 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 crystalline form I of the p-toluenesulfonate of the compound represented by formula (I), expressed in 2θ angles using Cu-Kα radiation, has diffraction peak positions as shown in the following table: (2) The X-ray powder diffraction pattern of Crystal Form I of the hydrochloride salt of the compound represented by formula (I), expressed in terms of 2θ angle using Cu-Kα radiation, has diffraction peak positions as shown in the following table: (3) The X-ray powder diffraction pattern of crystalline 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 crystalline 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 and relative intensities as shown in the following table: (2) The X-ray powder diffraction pattern of crystalline 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 and relative intensities as shown in the following table: (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, has diffraction peak positions and relative intensities as shown in the following table: More 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 Form I of the p-toluenesulfonate salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angle, is substantially as shown in Figure 1; (2) The X-ray powder diffraction pattern of Form I of the hydrochloride salt of the compound represented by formula (I), using Cu-Kα radiation and expressed in 2θ angle, is substantially as shown in Figure 4; The crystalline form B of the compound represented by formula (I) has an X-ray powder diffraction pattern expressed in terms of 2θ angle using Cu-Kα radiation substantially as shown in Figure 8.

6. The crystal form of the compound of formula (I) or its salt as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The differential scanning calorimetry curve of crystalline 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 curve of crystalline form 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 crystalline form 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 crystalline form 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 crystalline form 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 crystalline form 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 crystalline form 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 crystalline form 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) has 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 salt 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 salt 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 salt 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 salt 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 polymorphic form I of the p-toluenesulfonate of the compound represented by formula (I) according to any one of claims 2-6, polymorphic form I of the hydrochloride of the compound represented by formula (I) according to any one of claims 2-6, or polymorphic form B of the compound represented by formula (I) according to any one of claims 2-6, characterized in that, The method for preparing polymorphic 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 polymorphic 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 polymorphic 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 polymorphic 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 polymorphic 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 polymorphic form B of the compound represented by formula (I), and the solvent is an ester solvent.

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