Crystal form of compound salt, preparation method therefor and use thereof

Abstract

Provided are a crystal form of a (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-formamide (hereinafter referred to as "compound I") salt, a preparation method therefor, a pharmaceutical composition containing the compound I salt, and a use of the compound I salt in preparation of a PRMT5 inhibitor drug.

Description

Crystal form of compound salt, preparation method and use thereof Priority Declaration This disclosure claims priority to Chinese patent application No. 202410211544.6, filed on February 26, 2024. The full text of the patent application. Technical Field

[0001] The present disclosure relates to the field of crystal chemistry, and specifically to pharmaceutically acceptable salts of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide and their crystalline forms. Background Art

[0002] (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide has the structure of formula (I), which is referred to herein as Compound I:

[0003] In the development of small molecule drugs, drug polymorphism is a common phenomenon in drug research and development and is an important factor affecting drug quality. A crystal is a solid in which compound molecules are arranged in a three-dimensional, orderly manner in a microstructure to form a crystal lattice. Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms. A compound may exist in one or more crystal forms, but its existence and properties cannot be specifically predicted. The changes in properties caused by different crystal forms can also improve the final formulation form. For example, such changes can increase solubility and thus improve bioavailability, or improve the stability of the active ingredient, or more surprisingly, increase solubility while achieving good stability and lower hygroscopicity. For the above-mentioned Compound I, it is necessary to further study and improve its different crystal forms. Summary of the Invention

[0004] The technical problem to be solved by the present disclosure is to overcome the defect of compound I lacking a pharmaceutically acceptable salt form and crystal form and to improve its physicochemical properties, thereby providing a pharmaceutically acceptable salt of the compound represented by formula (I), which may be a hydrate, anhydrous form or a crystal of a solvate.

[0005] The present disclosure provides a pharmaceutically acceptable salt formed by Compound I and a pharmaceutically acceptable acid. Further, the pharmaceutically acceptable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, oxalic acid, citric acid, tartaric acid, and the like.

[0006] The pharmaceutically acceptable salt of Compound I provided by the present disclosure has a molar ratio of the pharmaceutically acceptable acid to Compound I of preferably 1:2-2:1, more preferably 1:1 or 2:1.

[0007] The present disclosure provides pharmaceutically acceptable salts of Compound I that are physically and chemically stable under a range of storage conditions and amenable to additional processing.

[0008] The present disclosure provides a pharmaceutically acceptable salt of Compound I, preferably a p-toluenesulfonate, a maleate, a benzenesulfonate, a phosphate, an oxalate, a dibenzenesulfonate or a dihydrochloride salt.

[0009] The present disclosure provides pharmaceutically acceptable salts of Compound I, preferably the pharmaceutically acceptable salts are crystalline solids.

[0010] The present disclosure provides a pharmaceutically acceptable salt of Compound I, preferably the pharmaceutically acceptable salt is an anhydrate.

[0011] The present disclosure provides pharmaceutically acceptable salts of Compound I, including p-toluenesulfonate, maleate, benzenesulfonate, phosphate, oxalate, dibenzenesulfonate or dihydrochloride, which are preferably crystalline solids.

[0012] The p-toluenesulfonate and maleate salts provided by the present disclosure are preferably crystalline solids, more preferably anhydrous.

[0013] The present disclosure provides a maleate salt of Compound 1.

[0014] Furthermore, the present disclosure provides a crystalline form of a maleate salt of Compound I (hereinafter referred to as "maleate salt crystalline form A").

[0015] In some embodiments of the present disclosure, the maleate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 3 using Cu-kα radiation.

[0016] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of the maleate salt form A is substantially as shown in Figure 4. The results show that when the maleate salt form A is heated to 120°C, it has only a mass loss of 0.20%, and almost no mass loss; an endothermic peak begins to appear around 233.9°C.

[0017] In some embodiments of the present disclosure, the maleate salt Form A is an anhydrate.

[0018] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the maleate salt crystalline form A is 5.31°±0.2°, 10.66°±0.2°, 11.18°±0.2°, 13.37°±0.2°, 14.63°±0.2°, 15.15°±0.2°, 17.30°±0.2°, 18.87°±0.2°, 20.40°±0.2°, 21.42°±0.2°, 23. There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 of 0.2°, 23.28°±0.2°, 24.62°±0.2°, 26.84°±0.2°, 27.63°±0.2°, 30.56°±0.2°, and 32.31°±0.2°.

[0019] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the maleate salt form A has a characteristic peak at a 2θ value of 5.31±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 17.30±0.2°, 18.87±0.2°, 21.42±0.2°, 26.84±0.2°, 27.63±0.2°, and 30.56±0.2°.

[0020] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the maleate salt form A has characteristic peaks at 2θ values ​​of 5.31±0.2° and 18.87±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 17.30±0.2°, 21.42±0.2°, 26.84±0.2°, 27.63±0.2°, and 30.56±0.2°.

[0021] In some embodiments of the present disclosure, the maleate salt crystalline form A has an X-ray powder diffraction pattern with characteristic peaks at 2θ values ​​of 5.31±0.2°, 17.30±0.2°, 18.87±0.2°, 21.42±0.2° and 27.63±0.2°.

[0022] In some embodiments of the present disclosure, the single crystal data of maleate salt form A are shown in Table 1. Table 1

[0023] The present disclosure provides the hydrochloride salt of Compound 1.

[0024] Furthermore, the present disclosure provides a crystalline form of the dihydrochloride salt of Compound I (hereinafter referred to as "dihydrochloride salt crystalline form D").

[0025] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the dihydrochloride salt Form D is substantially as shown in FIG. 7 using Cu-kα radiation.

[0026] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of the dihydrochloride salt form D is substantially as shown in Figure 8. The results show that the dihydrochloride salt form D begins to lose mass at about 30°C, with multiple endothermic and exothermic signals.

[0027] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the dihydrochloride salt form D has characteristic peaks at any one, or two, or three, or four, or five, or six of the diffraction angle 2θ values ​​of 9.33°±0.2°, 14.05°±0.2°, 17.81°±0.2°, 18.86°±0.2°, 23.89°±0.2°, and 27.66°±0.2°.

[0028] The present disclosure provides a hydrobromide salt of Compound 1.

[0029] Furthermore, the present disclosure provides a crystalline form of the hydrobromide salt of Compound 1 (hereinafter referred to as "hydrobromide salt crystalline form A").

[0030] In some embodiments of the present disclosure, the hydrobromide salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-kα radiation.

[0031] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the hydrobromide salt form A has characteristic peaks at any one of the diffraction angles 2θ values ​​of 3.54°±0.2°, 7.23°±0.2°, 9.88°±0.2°, 10.79°±0.2°, 19.42°±0.2°, 20.17°±0.2°, 21.34°±0.2°, 25.05°±0.2°, and 32.58°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9.

[0032] Furthermore, the present disclosure provides a crystalline form of the dihydrobromide salt of Compound I (hereinafter referred to as "dihydrobromide salt crystalline form A").

[0033] In some embodiments of the present disclosure, the dihydrobromide salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 10 using Cu-ka radiation.

[0034] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the dihydrobromide salt form A has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven of the diffraction angle 2θ values ​​of 4.15°±0.2°, 7.84°±0.2°, 8.27°±0.2°, 12.43°±0.2°, 15.64°±0.2°, 16.44°±0.2°, and 16.89°±0.2°.

[0035] The present disclosure provides a phosphate salt of Compound 1.

[0036] Furthermore, the present disclosure provides a crystalline form of the phosphate salt of Compound I (hereinafter referred to as "phosphate salt crystalline form A").

[0037] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the phosphate salt Form A is substantially as shown in FIG. 11 using Cu-kα radiation.

[0038] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of the phosphate crystal form A is substantially as shown in Figure 12. The results show that the phosphate crystal form A has only a 2.83% mass loss when heated to 120°C, and the first endothermic peak begins to appear around 67.7°C.

[0039] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the phosphate crystal form A has diffraction angles 2θ of 6.26°±0.2°, 11.66°±0.2°, 12.54°±0.2°, 13.62°±0.2°, 15.95°±0.2°, 18.54°±0.2°, 18.83°±0.2°, 20.69°±0.2°, 21. There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14 of 24°±0.2°, 21.65°±0.2°, 22.32°±0.2°, 23.42°±0.2°, 24.86°±0.2°, and 27.63°±0.2°.

[0040] The present disclosure provides a besylate salt of Compound 1.

[0041] Furthermore, the present disclosure provides a crystalline form of a benzenesulfonate salt of Compound I (hereinafter referred to as "benzenesulfonate salt crystalline form A").

[0042] In some embodiments of the present disclosure, the besylate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 13 using Cu-ka radiation.

[0043] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of benzenesulfonate salt Form A is substantially as shown in Figure 14. The results show that benzenesulfonate salt Form A has only about 0.63% mass loss when heated to 120°C, and the first endothermic peak begins to appear around 218.7°C.

[0044] In some embodiments of the present disclosure, the besylate salt Form A is an anhydrate.

[0045] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the benzenesulfonate salt form A has characteristic peaks at any one of the diffraction angles 2θ values ​​of 5.48°±0.2°, 7.46°±0.2°, 10.58°±0.2°, 14.93°±0.2°, 16.09°±0.2°, 17.66°±0.2°, 21.61°±0.2°, and 30.75°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8.

[0046] The present disclosure provides a dibenzenesulfonate salt of Compound 1.

[0047] Furthermore, the present disclosure provides a crystalline form of a dibenzenesulfonate salt of Compound I (hereinafter referred to as "dibenzenesulfonate salt crystalline form A").

[0048] In some embodiments of the present disclosure, the dibenzenesulfonate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 15 using Cu-ka radiation.

[0049] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of dibenzenesulfonate salt Form A is substantially as shown in Figure 16. The results show that dibenzenesulfonate salt Form A has only about 1.15% mass loss when heated to 120°C, and an endothermic peak begins to appear around 180.2°C.

[0050] In some embodiments of the present disclosure, the dibenzenesulfonate salt Form A is an anhydrate.

[0051] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the dibenzenesulfonate salt form A has characteristic peaks at any one of the diffraction angles 2θ values ​​of 4.66°±0.2°, 5.73°±0.2°, 9.23°±0.2°, 16.44°±0.2°, 17.27°±0.2°, 19.93°±0.2°, 20.64°±0.2°, and 21.77°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8.

[0052] The present disclosure provides a p-toluenesulfonic acid salt of Compound 1.

[0053] Furthermore, the present disclosure provides a crystalline form of a p-toluenesulfonate salt of Compound I (hereinafter referred to as "p-toluenesulfonate salt crystalline form A").

[0054] In some embodiments of the present disclosure, the p-toluenesulfonate salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 17 using Cu-ka radiation.

[0055] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of the p-toluenesulfonate crystalline form A is substantially as shown in Figure 18. The results show that the p-toluenesulfonate crystalline form A has almost no mass loss when heated to 120°C, and an endothermic peak begins to appear around 259.5°C.

[0056] In some embodiments of the present disclosure, the p-toluenesulfonate salt Form A is an anhydrate.

[0057] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A has characteristic peaks at any one of the diffraction angles 2θ values ​​of 5.42°±0.2°, 10.74°±0.2°, 14.52°±0.2°, 15.18°±0.2°, 17.15°±0.2°, 17.65°±0.2°, 20.12°±0.2°, 20.65°±0.2°, 21.47°±0.2°, and 30.29°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0058] In some embodiments of the present disclosure, the p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ of 5.42±0.2°, 10.74±0.2°, and 21.47±0.2°.

[0059] The present disclosure provides an oxalate salt of Compound 1.

[0060] Furthermore, the present disclosure provides a crystalline form of the oxalate salt of Compound I (hereinafter referred to as "oxalate salt crystalline form A").

[0061] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the oxalate salt Form A is substantially as shown in FIG. 20 using Cu-kα radiation.

[0062] In some embodiments of the present disclosure, the thermogravimetric analysis / differential scanning calorimetry analysis diagram of the oxalate salt form A is substantially as shown in Figure 21. The results show that the oxalate salt form A loses about 2.24% of its mass when heated to 120°C, and the first endothermic peak begins to appear around 35.8°C.

[0063] In some embodiments of the present disclosure, the X-ray powder diffraction pattern of the oxalate salt form A has characteristic peaks at any one of the diffraction angles 2θ of 5.20°±0.2°, 7.85±0.2°, 10.46°±0.2°, 13.11°±0.2°, 15.52°±0.2°, 16.51°±0.2°, 17.46°±0.2°, 18.29°±0.2°, 19.56°±0.2°, 20.98°±0.2°, 25.95°±0.2°, 27.11°±0.2°, and 28.46°±0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13.

[0064] The present disclosure provides a pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of a pharmaceutically acceptable salt of Compound I of the present disclosure, and a pharmaceutically acceptable excipient.

[0065] The present disclosure provides the use of a pharmaceutically acceptable salt of Compound I in the preparation of a pharmaceutical preparation for treating diseases associated with PRMT5 inhibitors.

[0066] This application studies the reaction of Compound I with sulfuric acid, methanesulfonic acid, fumaric acid, citric acid and tartaric acid to form corresponding salts and crystals. The experimental results show that only a mixture of salts formed by Compound I and the corresponding acids can be obtained, which is not suitable for further development. For example, Compound I and sulfuric acid do not form sulfate crystals in an ethanol system; in the process of Compound I reacting with methanesulfonic acid, different feed molar ratios can produce different crystal forms, and controlling the formation of a specific crystal form becomes very challenging; when the feed ratio of Compound I to fumaric acid is 1:1, only a mixture of Compound I and fumarate can be obtained. Even if other methods are tried, only a fumarate crystal form with very low crystallinity can be obtained, and its XRPD is shown in Figure 19; Compound I and citric acid can only form a mixture of Compound I and citrate, 1 The H-NMR results are shown in FIG22 ; Compound I and tartaric acid can also only form a mixture of Compound I and tartaric acid salt. 1 The H-NMR results are shown in FIG23 .

[0067] To obtain suitable salt forms and crystals of Compound I, the inventors further studied the reaction products of Compound I with acids such as maleic acid, p-toluenesulfonic acid, phosphoric acid, and oxalic acid. The studies revealed that the salts formed with the aforementioned acid ligands and Compound I exhibited good stability. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Powder appearance of maleate salt form A Figure 2 PLM diagram of maleate salt form A Figure 3 XRPD pattern of maleate salt form A Figure 4 TGA and DSC curves of maleate salt form A Figure 5 Maleate salt crystal form A 1 H NMR spectra Figure 6 Ellipsoid diagram of the molecular structure of maleate salt form A Figure 7 XRPD pattern of dihydrochloride salt form D Figure 8 TGA and DSC curves of dihydrochloride form D Figure 9 XRPD pattern of hydrobromide salt form A Figure 10 XRPD pattern of dihydrobromide salt form A Figure 11 XRPD pattern of phosphate crystal form A Figure 12 TGA and DSC diagrams of phosphate crystal form A Figure 13 XRPD pattern of benzenesulfonate salt form A Figure 14 TGA and DSC curves of benzenesulfonate Form A Figure 15 XRPD pattern of dibenzenesulfonate salt form A Figure 16 TGA and DSC curves of dibenzenesulfonate Form A Figure 17 XRPD pattern of p-toluenesulfonate Form A Figure 18 TGA and DSC curves of p-toluenesulfonate Form A Figure 19 XRPD pattern of fumarate salt form A Figure 20 XRPD pattern of oxalate salt form A Figure 21 TGA and DSC curves of oxalate crystal form A Figure 22: Mixture of citrate and free base 1 H NMR spectra Figure 23: Mixture of tartrate and free base 1 HNMR spectra Figure 24 DVS diagram of maleate salt form A Figure 25 XRPD comparison of maleate salt form A after DVS test (top: after DVS test, bottom: before DVS test) Figure 26 Comparison of the stability of maleate crystal form A after storage under different conditions (from top to bottom: 25°C / 60% RH for 4 weeks, 2 weeks at 25°C / 60% RH, 4 weeks at 60°C, 2 weeks at 60°C, 4 weeks at 40°C / 75% RH, 2 weeks at 40°C / 75% RH, maleate crystal form A as a control) Figure 27 XRPD comparison of maleate salt form A before and after airflow crushing (top: after crushing; bottom: before crushing) Figure 28 PLM image of maleate crystal form A after airflow crushing Figure 29 Stability of maleate crystal form A in the formulation (from top to bottom: 9.2 kN pressure, 4.2 kN pressure, maleate crystal form A and Microcrystalline cellulose powder mix, microcrystalline cellulose, maleate crystal form A control) Figure 30 XRPD comparison of p-toluenesulfonate Form A after DVS test (top: after DVS test, bottom: before DVS test) Figure 31 Comparison of the stability of p-toluenesulfonate Form A after storage under different conditions (from top to bottom: 25°C / 60% RH for 4 weeks, 25℃ / 60%RH for 2 weeks, 60℃ for 4 weeks, 60℃ for 2 weeks, 40℃ / 75%RH for 4 weeks, 40℃ / 75%RH for 2 weeks, p-toluenesulfonate Form A as control) DETAILED DESCRIPTION

[0068] The present disclosure is further described in conjunction with the following examples, which describe in detail the preparation and use of the disclosed crystalline forms. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the present disclosure.

[0069] The abbreviations used in this disclosure are explained as follows:

[0070] XRPD: X-ray powder diffraction

[0071] DSC: Differential Scanning Calorimetry

[0072] TGA: Thermogravimetric analysis

[0073] 1 HNMR: Liquid-state hydrogen nuclear magnetic spectroscopy

[0074] RH: relative humidity

[0075] PLM: Polarized Light Microscopy

[0076] DVS: Dynamic Water Sorption

[0077] HPLC: High Performance Liquid Chromatography

[0078] XRPD patterns were obtained using a Bruker D8 Advance diffractometer. Before the experiment, the voltage was set to 40 kV and the current was set to 40 mA. The sample was loaded onto a zero-background sample holder and scanned over an angle range of 2° to 40°. The scan step was set to 0.01°, and the wavelength of the X-ray used in the measurement was

[0079] Single crystal data of maleate were obtained using a Bruker D8 Venture. The instrument parameters are shown in Table 2:

[0080] The diffraction data were integrated and reduced using the SAINT program, and then empirically corrected for absorption using the SADABS program. The single crystal structure was solved directly using SHELXT2014 and refined using the least squares method. Hydrogen atoms were refined using isotropic calculations. The CH hydrogen atoms were obtained by computational hydrogenation and refined using the riding model. The Flack constant was 0.05 (12), and C8 was an S configuration.

[0081] Differential scanning calorimetry experiments were performed using a Mettler-Toledo DSC3 differential scanning calorimeter (DSC). Prior to the experiment, the heating rate and melting enthalpy were calibrated using indium as a reference material. The sample was placed in a standard 40 μL aluminum crucible and then covered with a perforated lid. The weight of the sample was accurately recorded. The sample pan containing the sample was placed in the sample cavity. At the reference position, a standard 40 μL aluminum crucible was placed, which was configured identically to the sample pan except that it did not contain the sample. DSC measurements were performed by heating the sample from 30°C to 300°C at a heating rate of 10°C / min. Nitrogen was purged during the experiment at a flow rate of 50 mL / min.

[0082] TGA data were acquired using a Mettler-Toledo TGA 2. Prior to sample analysis, the TGA 2 was calibrated with nickel. Samples were placed in an open aluminum pan, automatically weighed, and then placed in the TGA furnace. The furnace was heated from 31°C to 300°C at a heating rate of 10°C / min, with a nitrogen flow rate of 20 mL / min.

[0083] Moisture sorption and desorption data were acquired using a dynamic vapor sorption instrument (Model TA Discovery SA). At the beginning of the experiment, the sample was equilibrated at 25°C / 0% RH for 300 minutes. Subsequently, the humidity level was controlled and maintained over a range of 0% to 95% RH in 5% steps using nitrogen. A mass change rate of less than 0.02% / min over 10 minutes was considered equilibrium during testing, with a maximum equilibration time of 120 minutes.

[0084] The data of the samples were collected using a Bruker 400 MHz nuclear magnetic resonance spectrometer with DMSO-d6 as the solvent.

[0085] The preparation method of the simulated gastrointestinal fluid involved in the present disclosure is:

[0086] SGF: Weigh 2.02 g of sodium chloride into a 1000 mL beaker and dissolve it in 950 mL of purified water. Next, adjust the pH to 1.2 with 12 N hydrochloric acid. Transfer the solution to a 1000 mL volumetric flask and bring the volume to 1000 mL with purified water.

[0087] FeSSIF: Weigh 4.04 g of sodium hydroxide, 8.65 g of acetic acid, and 11.87 g of sodium chloride into a 1000 mL volumetric flask and dissolve in 950 mL of purified water. Titrate the resulting solution to pH 5.0 with 1 M sodium hydroxide or 1 M aqueous hydrochloric acid, then bring the volume to 1000 mL with purified water. Finally, weigh 11.20 g of SIF powder and add it to 1000 mL of the pH 5.0 solution. Stir magnetically until clear.

[0088] FaSSIF: Weigh 0.42g sodium hydroxide, 3.44g anhydrous sodium dihydrogen phosphate, and 6.19g sodium chloride into a 1000mL volumetric flask and dissolve in 950mL of purified water. Titrate the resulting solution to pH 6.5 with 1M sodium hydroxide or 1M aqueous hydrochloric acid, then bring the volume to 1000mL with purified water. Finally, weigh 2.240g SIF powder and add it to 1000mL of the pH 6.5 solution. Stir magnetically until dissolved.

[0089] The air flow milling process parameters are shown in Table 3. Table 3

[0090] The solubility detection method described in this application is shown in Table 4. Table 4

[0091] The HPLC analysis method for the enantiomeric excess percentage described in this application is shown in Table 5. Table 5

[0092] The purity detection method described in this application is shown in Table 6.

[0093] The "centrifugation" is performed by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a speed of 10,000 rpm until all solids sink to the bottom of the centrifuge tube.

[0094] The drying is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2 to 48 hours, or, alternatively, drying is performed in a fume hood, forced air oven, or vacuum oven.

[0095] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

[0096] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0097] The "anhydrous substance" refers to a solid substance that does not contain crystal water or crystallization solvent.

[0098] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Ka radiation, the peak position can usually have an error of ±0.2°.

[0099] In this disclosure, "crystal" or "crystal form" may be characterized by X-ray powder diffraction. The XRPD diffraction data of a crystal has fingerprint characteristics. In the art, different crystal forms are identified based on XRPD diffraction data. Those skilled in the art will select several representative peaks in the XRPD pattern as characteristic peaks to characterize the crystal.

[0100] When selecting characteristic peaks, the peak position, peak intensity, and peak shape are comprehensively considered. However, it will be understood by those skilled in the art that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample, and the purity of the sample. The peak intensity of the diffraction peak in the X-ray powder diffraction pattern may also change with changes in the experimental conditions. In fact, the peak intensity of the diffraction peak in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal. The diffraction peak intensity shown in the present disclosure is illustrative rather than for absolute comparison. Therefore, when identifying whether the crystal forms are the same, the matching of the peak positions within the above-mentioned error range is the first priority.

[0101] It will be understood by those skilled in the art that the X-ray powder diffraction pattern of the crystal form protected by the present disclosure does not have to be completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is identical or similar to the characteristic peaks in these patterns falls within the scope of the present disclosure. For example, when peaks are marked in an X-ray powder diffraction pattern, it refers to any X-ray powder diffraction pattern that has an error within the range of ±0.2° from the peaks in these patterns. Those skilled in the art can compare the X-ray powder diffraction patterns listed in the present disclosure with the X-ray powder diffraction patterns of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0102] In some embodiments, the pharmaceutically acceptable salts of Compound 1 and crystalline forms thereof disclosed herein are pure and substantially free of any other crystalline forms. In this disclosure, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.

[0103] The term "about" in this disclosure, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0104] Example 1 Preparation of Maleate Crystalline Form A

[0105] 500 mg of Compound I was weighed and added to a clean, dry 40 mL glass vial. 10 mL of anhydrous ethanol was added to the vial and stirred at 800 rpm at room temperature for 1 hour to obtain a clear solution. A 2 mol / L maleic acid solution (614 μL) was slowly added and stirred at room temperature for 24 hours. The solid was then centrifuged and vacuum dried at 40°C for 3 days to obtain the maleate salt, Form A.

[0106] Example 2 Characterization of Maleate Crystal Form A

[0107] The appearance and PLM image of maleate salt form A are shown in Figures 1 and 2, respectively.

[0108] The XRPD pattern of maleate salt Form A is shown in FIG3 , and the XRPD data are shown in Table 7.

[0109] The TGA and DSC curves of maleate salt form A are shown in FIG4 . The results show that when heated from 31° C. to 120° C., its weight loss is 0.20%. The DSC spectrum shows an endothermic peak with an onset temperature of 233.89° C., which is a melting peak.

[0110] Maleate salt form A 1 The HNMR results are shown in Figure 5. The results show that the molar ratio of compound I to maleic acid is 1:1 (mol:mol), and there is no obvious solvent residue. Table 7

[0111] Example 3 Dihydrochloride Form D

[0112] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of toluene, and stir for 1 hour. Subsequently, slowly add 71.95 μL of 2N aqueous hydrochloric acid to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain the dihydrochloride salt, Form D.

[0113] The XRPD pattern of dihydrochloride Form D is shown in Figure 7, which has characteristic peaks at 9.33°±0.2°, 14.05°±0.2°, 17.81°±0.2°, 18.86°±0.2°, 23.89°±0.2°, and 27.66°±0.2°.

[0114] The TGA and DSC curves of dihydrochloride Form D are shown in FIG8 . The results show that dihydrochloride Form D begins to lose mass at about 30° C., with multiple endothermic and exothermic signals.

[0115] Example 4 Preparation of Hydrobromide Form A

[0116] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of ethanol, and stir for 1 hour. Subsequently, slowly add 36.85 μL of 2N aqueous hydrobromic acid to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain the hydrobromide salt, Form A.

[0117] The XRPD pattern of hydrobromide salt form A is shown in Figure 9, which has characteristic peaks at 3.54°±0.2°, 7.23°±0.2°, 9.88°±0.2°, 10.79°±0.2°, 19.42°±0.2°, 20.17°±0.2°, 21.34°±0.2°, 25.05°±0.2°, and 32.58°±0.2°.

[0118] Example 5 Preparation of Dihydrobromide Crystalline Form A

[0119] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of acetonitrile, and stir for 1 hour. Subsequently, slowly add 71.95 μL of 2N aqueous hydrobromic acid to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain the dihydrobromide salt, Form A.

[0120] The XRPD pattern of dihydrobromide salt form A is shown in Figure 10, which has characteristic peaks at 4.15°±0.2°, 7.84°±0.2°, 8.27°±0.2°, 12.43°±0.2°, 15.64°±0.2°, 16.44°±0.2°, and 16.89°±0.2°.

[0121] Example 6 Preparation of Phosphate Crystalline Form A

[0122] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of acetonitrile, and stir for 1 hour. Subsequently, slowly add 36.85 μL of 2N aqueous phosphoric acid to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain Form A, the phosphate salt.

[0123] The XRPD pattern of phosphate crystal form A is shown in Figure 11, and the XRPD data are shown in Table 8.

[0124] The TGA and DSC curves of phosphate crystal form A are shown in Figure 12. The results show that when heated from 31°C to 120°C, phosphate crystal form A has a mass loss of 2.83%, and the first endothermic peak begins to appear around 67.7°C. Table 8

[0125] Example 7 Preparation of Benzenesulfonate Form A

[0126] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of ethanol, and stir for 1 hour. Subsequently, slowly add 36.85 μL of a 2N benzenesulfonic acid methanol solution to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain Form A of the benzenesulfonate salt.

[0127] The XRPD pattern of benzenesulfonate salt Form A is shown in Figure 13, and the XRPD data are shown in Table 9.

[0128] The TGA and DSC curves of benzenesulfonate crystal form A are shown in Figure 14. The results show that the weight loss of benzenesulfonate crystal form A when heated from 31°C to 120°C is 0.6296%. The DSC spectrum shows an endothermic peak that begins to appear at around 218.7°C. Table 9

[0129] Example 8 Preparation of Dibenzenesulfonate Crystalline Form A

[0130] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of acetonitrile, and stir for 1 hour. Subsequently, slowly add 71.95 μL of a 2N benzenesulfonic acid methanol solution to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain Form A of the dibenzenesulfonate salt.

[0131] The XRPD pattern of dibenzenesulfonate Form A is shown in Figure 15, and the XRPD data are shown in Table 10.

[0132] The TGA and DSC curves of dibenzenesulfonate Form A are shown in Figure 16. The results show that the weight loss is 1.1497% when heated from 31°C to 120°C. The DSC spectrum shows an endothermic peak, which begins to appear around 180.20°C. Table 10

[0133] Example 9 Preparation of p-toluenesulfonate Form A

[0134] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of ethanol, and stir for 1 hour. Subsequently, slowly add 36.85 μL of a 2N p-toluenesulfonic acid solution in methanol to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain the p-toluenesulfonate salt, Form A.

[0135] The XRPD pattern of p-toluenesulfonate Form A is shown in Figure 17, and the XRPD data are shown in Table 11.

[0136] The TGA and DSC curves of p-toluenesulfonate Form A are shown in FIG18 . The results show that there is almost no mass loss when heated to 120° C., and an endothermic peak begins to appear at 259.5° C.

[0137] Without limitation, the p-toluenesulfonate crystalline form A is an anhydrate. Table 11

[0138] Example 10 Preparation of Oxalate Form A

[0139] Weigh 30 mg of Compound I into a 2 mL glass vial, add 1 mL of acetonitrile, and stir for 1 hour. Subsequently, slowly add 36.85 μL of a 2N oxalic acid methanol solution to the reaction system. Stir at room temperature for 24 hours, then separate the solid. Dry the resulting solid under vacuum at 40°C for approximately 16 hours to obtain para-oxalate salt Form A.

[0140] The XRPD pattern of oxalate salt form A is shown in Figure 20, and the XRPD data are shown in Table 12.

[0141] The TGA and DSC curves of oxalate crystal form A are shown in Figure 21. The results show that when heated from 31°C to 120°C, the weight loss of oxalate crystal form A is 2.2386%. The DSC spectrum shows three endothermic events, with endothermic peaks starting at around 35.8°C, around 220.14°C, and around 228.7°C. Table 12

[0142] Example 11 Hygroscopicity of Maleate Crystal Form A

[0143] High hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, directly impacting their physicochemical stability. Furthermore, high hygroscopicity can reduce API flowability, impacting API processing. Furthermore, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring significant costs.

[0144] The maleate salt Form A was subjected to a DVS test. The results are shown in Figure 24. From 0% to 80% relative humidity, the maleate salt Form A experienced a moisture absorption weight gain of approximately 0.25%, demonstrating very low hygroscopicity. XRPD characterization of the sample after DVS testing, as shown in Figure 25, demonstrates that the crystal form remained unchanged after the DVS test, demonstrating that the maleate salt Form A exhibits good humidity stability.

[0145] Example 12 Physicochemical Stability of Maleate Crystal Form A

[0146] 1. Experimental Methods

[0147] For chemical stability studies, two open-top samples were prepared for each time point under each condition. Approximately 2 mg of maleate Form A was transferred to a 20 mL glass vial. The vial was then covered with perforated aluminum foil to serve as the open-top sample. The samples were stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C.

[0148] For physical stability studies, two open-dose samples were prepared for each time point under each condition. Approximately 10 mg of maleate Form A was transferred to a 20 mL glass vial and covered with perforated aluminum foil to serve as the open-dose sample. Samples were stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C.

[0149] All samples were stored under the specified storage conditions for 4 weeks. At predetermined time points (initial, 2 weeks, and 4 weeks), the corresponding samples were taken out and subjected to chemical and physical evaluations. The physical and chemical stability of the samples was tested by XRPD and HPLC.

[0150] 2. Experimental Results

[0151] The physical and chemical stability results of maleate crystal form A stored at 25°C / 60%RH, 40°C / 75%RH and 60°C are shown in Table 13, and the XRPD patterns before and after the test are shown in Figure 26.

[0152] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs. Maleate Form A exhibits good physicochemical stability when stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C for four weeks, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage.

[0153] Example 13 Mechanical Stability of Maleate Crystal Form A

[0154] Airflow Milling: Maleate Form A powder was airflow milled using the process parameters listed in Table 3. The airflow milled powder was subsequently subjected to XRPD and PLM analysis, with the results shown in Figures 27 and 28, respectively. The results indicate that after airflow milling, the crystalline form of the maleate Form A remained unchanged, while the crystal size was significantly reduced.

[0155] Pressurization method: The maleate salt Form A was weighed and transferred into a 5 mm diameter die. The upper piston was then manually lowered into the die orifice until a pressure of 40 MPa was reached, which was maintained for 1 minute. The sample was then removed and manually pulverized into a powder. Finally, the resulting powder was subjected to XRPD analysis. The results showed that the maleate salt Form A did not change in crystalline form after pressurization.

[0156] Example 14 Stability of Maleate Form A in Formulation

[0157] Weigh equal amounts of maleate crystalline form A and microcrystalline cellulose PH102 to obtain a 50% (w / w) maleate crystalline form A powder formulation of each component. Mix the two ingredients evenly.

[0158] 200 mg of the mixed powder was transferred to the die of a rotary tablet press with a diameter of 8 mm. One tablet was compressed at a pressure of 4.2 kN and the other tablet was compressed at a pressure of 9.2 kN.

[0159] The resulting tablets were characterized for weight and hardness. Two tablets were then manually ground into powder. XRPD analysis was then performed, and the results are shown in Figure 29.

[0160] The results showed that even with the application of higher pressure, the crystallinity of maleate Form A in the formulation remained relatively stable.

[0161] Example 15 Solubility of Maleate Salt Form A

[0162] 1. Experimental Methods

[0163] Weigh 10 mg of maleate salt Form A and add it to a clean, dry 4 mL glass vial. Then, add 1 mL of simulated gastric fluid (SGF), fed simulated intestinal fluid (FeSSIF), or purified water. Place all vials on a shaker at 200 rpm at 37°C.

[0164] At the predetermined time point (24 h), 200 μL of sample was taken from the vial and transferred to a centrifuge tube. The tube was centrifuged at 90,000 rpm for 5 minutes. An appropriate amount of the supernatant was diluted and analyzed for solubility using high performance liquid chromatography.

[0165] The remaining 800 μL of suspension in the bottle was centrifuged at 8000 rpm for 10 minutes. The pH of the resulting supernatant was measured, and the precipitated solid was dried under vacuum at 40°C for approximately 16 hours. The dried precipitated solid was then scanned using X-ray powder diffraction.

[0166] 2. Experimental Results

[0167] The dynamic solubility of maleate salt form A in different media is shown in Table 14. Table 14

[0168] The results showed that maleate salt form A had high solubility in both SGF and FeSSIF, and the crystal form did not change after 24 hours of solubility testing in SGF, FeSSIF and water, indicating that it had good physical stability in the above media.

[0169] Maleate salt form A has a higher solubility, which is beneficial to improving drug absorption in the human body and increasing bioavailability; in addition, higher solubility can reduce the dosage of the drug while ensuring the drug's efficacy, thereby reducing the drug's side effects and improving the drug's safety.

[0170] Example 16 Hygroscopicity of p-toluenesulfonate Form A

[0171] High hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, directly impacting their physicochemical stability. Furthermore, high hygroscopicity can reduce API flowability, impacting API processing. Furthermore, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring significant costs.

[0172] DVS testing of Form A, the p-toluenesulfonate salt, revealed a moisture absorption weight gain of approximately 0.37% from 0% to 80% relative humidity, indicating low hygroscopicity. XRPD characterization of the sample after DVS testing, as shown in Figure 30, demonstrates that the crystalline form remained unchanged after DVS testing, demonstrating that Form A exhibits good humidity stability.

[0173] Example 17 Solubility of p-Toluenesulfonate Form A

[0174] 1. Experimental Methods

[0175] Weigh 10 mg of p-toluenesulfonate Form A into a clean, dry 4 mL glass vial. Then, add 1 mL of simulated gastric fluid (SGF), fed simulated intestinal fluid (FeSSIF), or purified water. Place all vials on a shaker at 200 rpm at 37°C.

[0176] At the predetermined time point (24 h), 200 μL of sample was taken from the vial and transferred to a centrifuge tube. The tube was centrifuged at 90,000 rpm for 5 minutes. An appropriate amount of the supernatant was diluted and analyzed for solubility using high performance liquid chromatography.

[0177] The remaining 800 μL of suspension in the bottle was centrifuged at 8000 rpm for 10 minutes. The pH of the resulting supernatant was measured, and the precipitated solid was dried under vacuum at 40°C for approximately 16 hours. The dried precipitated solid was then scanned using X-ray powder diffraction.

[0178] 2. Experimental Results

[0179] The dynamic solubility of p-toluenesulfonate Form A in different media is shown in Table 15. Table 15

[0180] The results showed that the p-toluenesulfonate crystalline form A had high solubility in SGF, FeSSIF and water, and the crystalline form did not change after 24 hours of solubility testing in SGF, FeSSIF and water, indicating that it had good physical stability in the above media.

[0181] The p-toluenesulfonate crystalline form A has a higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

[0182] Example 18 Physicochemical Stability of Toluenesulfonate Form A

[0183] 1. Experimental Methods

[0184] For chemical stability studies, two open-top samples were prepared for each time point under each condition. Approximately 2 mg of p-toluenesulfonate Form A was transferred to a 20 mL glass vial. The vial was then covered with perforated aluminum foil to serve as the open-top sample. The samples were stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C.

[0185] For physical stability studies, two open-dose samples were prepared for each time point under each condition. Approximately 10 mg of p-toluenesulfonate Form A was placed in a 20 mL glass vial and covered with perforated aluminum foil to serve as the open-dose sample. Samples were stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C.

[0186] All samples were stored under the specified storage conditions for 4 weeks. At predetermined time points (initial, 2 weeks, and 4 weeks), the corresponding samples were taken out and subjected to chemical and physical evaluations. The physical and chemical stability of the samples was tested by XRPD and HPLC.

[0187] 2. Experimental Results

[0188] The physicochemical stability results of p-toluenesulfonate Form A stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C are shown in Table 16, and a comparison of the XRPD patterns before and after the test is shown in Figure 31.

[0189] The results showed that the p-toluenesulfonate salt form A had good physical and chemical stability when stored at 25°C / 60%RH, 40°C / 75%RH and 60°C for 4 weeks. Table 16

[0190] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs. Form A of the p-toluenesulfonate salt exhibits good physicochemical stability when stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C for four weeks, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage.

[0191] The above embodiments are intended only to illustrate the technical concepts and features of the present disclosure. Their purpose is to enable those familiar with the art to understand the contents of the present disclosure and implement them accordingly. They are not intended to limit the scope of protection of the present disclosure. Any equivalent changes or modifications made in accordance with the spirit of the present disclosure are intended to be covered by the scope of protection of the present disclosure.

Claims

1. A pharmaceutically acceptable salt of a compound of formula (I) and a pharmaceutically acceptable acid, 2. The pharmaceutically acceptable salt according to claim 1, characterized in that The molar ratio of the pharmaceutically acceptable acid to the compound of formula (I) is 1:2-2:

1.

3. The pharmaceutically acceptable salt according to claim 1, characterized in that It is a crystalline solid.

4. The pharmaceutically acceptable salt according to claim 2, characterized in that The molar ratio of the pharmaceutically acceptable acid to the compound of formula (I) is 1:

1.

5. The pharmaceutically acceptable salt according to claim 2, characterized in that The molar ratio of the pharmaceutically acceptable acid to the compound of formula (I) is 2:

1.

6. The pharmaceutically acceptable salt according to claim 3, characterized in that The crystalline solid is anhydrous.

7. The pharmaceutically acceptable salt according to claim 4, characterized in that The pharmaceutically acceptable salt is p-toluenesulfonate, maleate, benzenesulfonate, phosphate, or oxalate.

8. The pharmaceutically acceptable salt according to claim 5, characterized in that The pharmaceutically acceptable salt is dibenzenesulfonate or dihydrochloride.

9. The pharmaceutically acceptable salt according to claim 6 or claim 7, characterized in that The pharmaceutically acceptable salt is maleate.

10. The pharmaceutically acceptable salt according to claim 6 or claim 7, characterized in that The pharmaceutically acceptable salt is p-toluenesulfonate.

11. The pharmaceutically acceptable salt according to claim 6 or claim 7, characterized in that The pharmaceutically acceptable salt is benzenesulfonate.

12. The pharmaceutically acceptable salt according to claim 6 or claim 7, characterized in that The pharmaceutically acceptable salt is phosphate.

13. The pharmaceutically acceptable salt according to claim 6 or claim 7, characterized in that The pharmaceutically acceptable salt is oxalate.

14. The pharmaceutically acceptable salt according to claim 6 or claim 7, characterized in that The pharmaceutically acceptable salt is dibenzenesulfonate.

15. The pharmaceutically acceptable salt according to claim 9, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 5.31±0.2°, 14.63±0.2°, 15.15±0.2°, 17.30±0.2°, 18.87±0.2°, 21.42±0.2°, 26.84±0.2°, 27.63±0.2°, and 30.56±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG3 ; (iii) an endothermic peak began to appear at 233.9°C ± 3°C; (iv) after storage at 40° C. and 75% RH for four weeks, has an X-ray powder diffraction pattern substantially the same as (i) or (ii); (v) after storage at 60°C for four weeks, has an X-ray powder diffraction pattern substantially the same as (i) or (ii); (vi) a moisture gain of less than 0.30% at 0-80% RH; (vii) a single crystal structure having unit cell parameters substantially equal to: Crystal system and space group: triclinic, P1, α＝90.17°±1° β＝101.37°±1° γ=111.41°±1° 16. The pharmaceutically acceptable salt according to claim 15, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has a characteristic peak at a 2θ value of 5.31±0.2°, and arbitrarily has two characteristic peaks at 2θ values ​​of 17.30±0.2°, 18.87±0.2°, 21.42±0.2°, 26.84±0.2°, 27.63±0.2°, and 30.56±0.2°.

17. The pharmaceutically acceptable salt according to claim 15, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.31±0.2° and 18.87±0.2°, and arbitrarily has one characteristic peak at 2θ values ​​of 17.30±0.2°, 21.42±0.2°, 26.84±0.2°, 27.63±0.2°, and 30.56±0.2°.

18. The pharmaceutically acceptable salt according to claim 15, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.31±0.2°, 17.30±0.2°, 18.87±0.2°, 21.42±0.2° and 27.63±0.2°.

19. The pharmaceutically acceptable salt according to claim 10, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 5.42°±0.2°, 10.74°±0.2°, 17.15°±0.2°, 17.65°±0.2°, 20.12°±0.2°, 20.65°±0.2°, 21.47°±0.2°, and 30.29°±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG17 ; (iii) an endothermic peak began to appear at 259.5°C ± 3°C; (iv) after storage at 40° C. and 75% RH for four weeks, has an X-ray powder diffraction pattern substantially the same as (i) or (ii); (v) after storage at 60°C for four weeks, has an X-ray powder diffraction pattern substantially the same as (i) or (ii); (vi) The weight gain due to moisture absorption under 0-80% RH conditions is less than 0.50%.

20. The pharmaceutically acceptable salt according to claim 19, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.42±0.2°, 10.74±0.2° and 21.47±0.2°.

21. The pharmaceutically acceptable salt of claim 11, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 5.48±0.2°, 7.46±0.2°, 14.93±0.2°, 16.09±0.2°, 17.66±0.2°, and 21.61±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG13 ; (iii) An endothermic peak begins to appear at 218.7℃±3℃.

22. The pharmaceutically acceptable salt according to claim 21, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at 2θ of 5.48±0.2°, 14.93±0.2° and 21.61±0.2°.

23. The pharmaceutically acceptable salt of claim 12, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 6.26±0.2°, 11.66±0.2°, 12.54±0.2°, 13.62±0.2°, 15.95±0.2°, 21.65±0.2°, 22.32±0.2°, and 23.42±0.2°; (ii) The X-ray powder diffraction pattern is substantially as shown in FIG11 .

24. The pharmaceutically acceptable salt according to claim 23, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at 2θ of 6.26±0.2°, 11.66±0.2° and 15.95±0.2°.

25. The pharmaceutically acceptable salt of claim 13, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 5.20±0.2°, 7.85±0.2°, 10.46±0.2°, 15.52±0.2°, 16.51±0.2°, 17.46±0.2°, 18.29±0.2°, 19.56±0.2°, and 20.98±0.2°; (ii) The X-ray powder diffraction pattern is substantially as shown in FIG20 .

26. The pharmaceutically acceptable salt according to claim 25, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at 2θ of 5.20±0.2°, 7.85±0.2° and 10.46±0.2°.

27. The pharmaceutically acceptable salt of claim 14, characterized by at least one of the following: (i) using Cu-ka radiation, an X-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 4.66±0.2°, 5.73±0.2°, 9.23±0.2°, 16.44±0.2°, 17.27±0.2°, 19.93±0.2°, 20.64±0.2°, and 21.77±0.2°; (ii) an X-ray powder diffraction pattern substantially as shown in FIG15 ; (vii) An endothermic peak begins to appear at 180.2℃±3℃.

28. The pharmaceutically acceptable salt according to claim 27, characterized in that Using Cu-kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ of 4.66±0.2°, 5.73±0.2° and 9.23±0.2°.

29. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of claims 1 to 28.

30. Use of the pharmaceutically acceptable salt according to any one of claims 1 to 28 or the pharmaceutical composition according to claim 29 in the preparation of a pharmaceutical preparation for treating diseases associated with PRMT5 inhibitors.

Images