Salt of phthalazinone derivative and crystal form thereof, preparation method therefor and use thereof

Abstract

Provided in the present invention are a pharmaceutically acceptable salt form of a compound of formula (I) and a crystal form thereof, a preparation method therefor, and the use thereof in the preparation of related drugs.

Description

A salt of an phthalazinone derivative, its crystal form, preparation method and uses Technical Field

[0001] This invention provides multiple crystal forms of salts of a compound, their preparation methods, and applications. Specifically, it relates to a salt of an phthalazinone derivative, its crystal form, its preparation method, and its uses, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Protein arginine methyltransferases (PRMTs) catalyze protein arginine methylation, an important post-translational modification that uses S-adenosylmethionine (SAM) as a methyl donor to methylate the nitrogen atom of the protein arginine side chain. Based on the arginine methylation state, the nine identified human PRMTs (PRMT1–9) are further subdivided into types I, II, and III. Type I PRMTs catalyze the formation of monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA), including PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8; type II PRMTs catalyze the formation of MMA and symmetric dimethylarginine (sDMA), including PRMT5 and PRMT9; and type III PRMTs catalyze the formation of MMA, including PRMT7. PRMT5 belongs to type II PRMT, which transfers methyl groups from SAM to the guanidine nitrogen of arginine residues to generate MMA and sDMA. It regulates the expression of target genes through this epigenetic mechanism or modulates key signaling molecules through post-translational methylation modification pathways.

[0003] Homozygous deletions of pl6 / CDKN2a are prevalent in cancer. These mutations often involve the co-deletion of adjacent genes, including those encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of human cancers have homozygous deletions of the MTAP gene (e.g., see Firestone & Schramm (2017) J. Am. Chem Soc. 139(39): 13754-13760. doi: 10.1021 / jacs.7b05803. Epub 2017 Sep 20).

[0004] In MTAP-deficient cells, methylthioadenosine (MTA) accumulates excessively, forming the PRMT5·MTA complex with PRMT5. This complex partially inhibits PRMT5 enzyme activity, leading to increased cell proliferation sensitivity to PRMT5 deficiency or loss of activity. Therefore, MTAP deficiency reduces PRMT5 methylation activity, making cells selectively dependent on PRMT5 activity. In MTAP-deficient cancers, the synergistic inhibition of PRMT5 activity by MTA could offer therapeutic benefits for various cancers.

[0005] Therefore, it is necessary to develop new MTA-synergistic PRMT5 inhibitors that can inhibit PRMT5 activity in the presence of elevated MTA concentrations, especially in MTAP-deficient cells.

[0006] WO2024008176 discloses a compound of formula (I) that exhibits excellent PRMT5 inhibitory activity. Summary of the Invention

[0007] This invention provides a pharmaceutically acceptable salt of a compound of formula (I).

[0008] In some embodiments, the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonate, fumarate, hydrohalate (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucilage, succinate, lactate, orotate, pamoate, glycine, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline, ferulic acid, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentianate, salicylate, succinate, glutamate, ethylsulfonate, gluconate, adipate, oxalate, or glutarate;

[0009] In some embodiments, the pharmaceutically acceptable salt is selected from benzenesulfonate, succinate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, benzoate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate.

[0010] In some embodiments, the pharmaceutically acceptable salt is selected from benzenesulfonate, maleate, 1,5-naphthalenedisulfonate, oxalate, and benzoate;

[0011] In some implementation schemes, the pharmaceutically acceptable salt may be selected from benzenesulfonate and benzoate;

[0012] In some implementations, the molar ratio of compound (I) to pharmaceutically acceptable salt is 1:0.5 to 1:3.5;

[0013] In some implementations, the molar ratio of compound (I) to pharmaceutically acceptable salt is 1:1, 1:2, or 1:3;

[0014] In some embodiments, the pharmaceutically acceptable salt is selected from fumarate, wherein the molar ratio of compound (I) to fumarate is 1:1;

[0015] In some embodiments, the pharmaceutically acceptable salt is selected from maleate salts, wherein the molar ratio of compound (I) to maleic acid is 1:2 or 1:1;

[0016] In some embodiments, the pharmaceutically acceptable salt is selected from succinate, wherein the molar ratio of compound (I) to succinic acid is 1:1;

[0017] In some embodiments, the pharmaceutically acceptable salt is selected from oxalates, with a molar ratio of compound (I) to oxalic acid of 1:1;

[0018] In some embodiments, the pharmaceutically acceptable salt is selected from benzenesulfonates, wherein the molar ratio of compound (I) to benzenesulfonic acid is 1:1;

[0019] In some implementation schemes, the pharmaceutical salt may be selected as benzoate, and the molar ratio of compound (I) to benzoic acid is 1:1 or 1:2;

[0020] In some embodiments, the pharmaceutically acceptable salt is selected from hydrochloride salts, wherein the molar ratio of compound (I) to hydrochloric acid is 1:1;

[0021] In some embodiments, the pharmaceutically acceptable salt is selected from sulfates, wherein the molar ratio of compound (I) to sulfuric acid is 1:1;

[0022] In some embodiments, the pharmaceutically acceptable salt is selected from p-toluenesulfonate, wherein the molar ratio of compound (I) to p-toluenesulfonic acid is 1:1 or 1:2;

[0023] In some embodiments, the pharmaceutically acceptable salt is selected from methanesulfonates, wherein the molar ratio of compound (I) to methanesulfonic acid is 1:1;

[0024] In some embodiments, the pharmaceutically acceptable salt is selected from citrates, wherein the molar ratio of compound (I) to citric acid is 1:1;

[0025] In some embodiments, the pharmaceutically acceptable salt is selected from ethyl sulfonate, wherein the molar ratio of compound (I) to ethyl sulfonate is 1:1 or 1:2;

[0026] In some embodiments, the pharmaceutically acceptable salt is selected from 1,5-naphthalenedisulfonic acid salts, wherein the molar ratio of compound (I) to 1,5-naphthalenedisulfonic acid is 1:1;

[0027] In some implementations, the aforementioned medicinal salts are amorphous.

[0028] This invention provides a maleate crystal form A of a compound of formula (I). In some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.40°±0.2°, 7.66°±0.2°, 10.64°±0.2°, 17.84°±0.2°, 21.08°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.40°±0.2°, 7.66°±0.2°, 10.64°±0.2°, 12.98°±0.2°, 17.84°±0.2°, 19.59°±0.2°, 21.08°±0.2°. 2°, 23.23°±0.2°; In some embodiments, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.40°±0.2°, 6.42°±0.2°, 7.66°±0.2°, 8.75°±0.2°, 10.64°±0.2°, 11.84°±0.2°, 12.98°±0.2°, 13.67°±0.2°, 15.97°±0.2°, 17.84°±0.2°, 19.59°±0.2°, 21.08°±0.2°, 23.23°±0.2°, 26.17±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 1-A.

[0029] In some embodiments, the differential scanning calorimetry (DSC) curves of maleate crystal form A show peak temperatures of 129.09 °C and 173.31 °C, respectively; its thermogravimetric analysis (TGA) curves show a weight loss of approximately 4.27% before 120 °C; its thermogravimetric analysis curves and differential scanning calorimetry curves are shown in Figures 1-B and 1-C.

[0030] This invention provides a crystalline form A of a 1,5-naphthalene disulfonate of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 3.61°±0.2°, 4.58°±0.2°, 14.78°±0.2°, 15.35°±0.2°, 18.56°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 3.61°±0.2°, 4.58°±0.2°, 9.12°±0.2°, 10.03°±0.2°, 14.78°±0.2°, 15.35°±0.2°, 18.56° ±0.2°, 23.69°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.61°±0.2°, 4.58°±0.2°, 9.12±0.2°, 10.03°±0.2°, 11.62°±0.2°, 13.82°±0.2°, 14.78°±0.2°, 15.35°±0.2°, 16.97°±0.2°, 18.56°±0.2°, 22.11°±0.2°, 23.69°±0.2°, 25.39°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 2-A.

[0031] This invention provides a crystalline form B of 1,5-naphthalenedisulfonate of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 5.96°±0.2°, 11.93°±0.2°, 14.38°±0.2°, 16.81°±0.2°, 26.39°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 3.41°±0.2°, 5.96°±0.2°, 11.93°±0.2°, 14.38°±0.2°, 16.81°±0.2°, 22.19°±0.2°, 25.93°±0.2°, 26.39°±0.2°. °±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.41°±0.2°, 4.36°±0.2°, 5.96±0.2°, 11.93°±0.2°, 13.26°±0.2°, 14.38°±0.2°, 16.81°±0.2°, 17.76°±0.2°, 19.25°±0.2°, 22.19°±0.2°, 23.85°±0.2°, 24.97°±0.2°, 25.93°±0.2°, 26.39°±0.2°, 27.14°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 3-A.

[0032] In some embodiments, the differential scanning calorimetry (DSC) curve of 1,5-naphthalene disulfonate crystal form B shows a peak temperature of 183.61 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 3.57% before 110 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 3-B and 3-C.

[0033] This invention provides a succinate crystal form A of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.16°±0.2°, 15.50°±0.2°, 19.96°±0.2°, 20.76°±0.2°, 23.07°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.16°±0.2°, 15.50°±0.2°, 18.22°±0.2°, 18.95°±0.2°, 19.96°±0.2°, 20.76°±0.2°, 23.07°±0.2°. 0.2°, 23.71°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.84°±0.2°, 8.29°±0.2°, 9.16±0.2°, 12.54°±0.2°, 14.46°±0.2°, 15.50°±0.2°, 18.22°±0.2°, 18.95°±0.2°, 19.96°±0.2°, 20.76°±0.2°, 23.07°±0.2°, 23.71°±0.2°, 25.99°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 4-A.

[0034] In some embodiments, the differential scanning calorimetry (DSC) curve of succinate crystal form A shows peak temperatures of 156.63 °C and 188.79 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 2.51% before 150 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 4-B and 4-C.

[0035] This invention provides a citrate crystal form A of a compound of formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.20°±0.2°, 13.99°±0.2°, 20.70°±0.2°, 21.98°±0.2°, 25.40°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.20°±0.2°, 10.93°±0.2°, 13.99°±0.2°, 16.94°±0.2°, 18.64°±0.2°, 20.70°±0.2°, 21.98°±0.2°, 25.40°±0.2°. 0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.20°±0.2°, 10.93°±0.2°, 12.38±0.2°, 12.95°±0.2°, 13.68°±0.2°, 13.99°±0.2°, 16.94°±0.2°, 18.64°±0.2°, 18.92°±0.2°, 20.21°±0.2°, 20.70°±0.2°, 21.98°±0.2°, 24.46°±0.2°, 25.40°±0.2°, 26.05°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 5-A.

[0036] In some embodiments, the differential scanning calorimetry (DSC) curve of citrate crystal form A shows peak temperatures of 141.62 °C and 170.81 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 4.82% before 150 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 5-B and 5-C.

[0037] This invention provides a p-toluenesulfonate crystal form A of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.69°±0.2°, 10.97°±0.2°, 13.18°±0.2°, 16.33°±0.2°, 19.72°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.69°±0.2°, 8.14°±0.2°, 9.84°±0.2°, 10.97°±0.2°, 13.18°±0.2°, 14.57°±0.2°, 16.33°±0.2°, 19.72°±0.2°. 9.72°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.69°±0.2°, 5.19°±0.2°, 8.14±0.2°, 9.84°±0.2°, 10.35°±0.2°, 10.97°±0.2°, 13.18°±0.2°, 14.57°±0.2°, 15.07°±0.2°, 16.33°±0.2°, 19.72°±0.2°, 21.33°±0.2°, 23.18°±0.2°, 25.96°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 6-A.

[0038] In some embodiments, the differential scanning calorimetry (DSC) curve of p-toluenesulfonate crystal form A shows peak temperatures of 144.96 °C and 179.21 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 4.72% before 200 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 6-B and 6-C.

[0039] This invention provides a p-toluenesulfonate crystal form B of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.30°±0.2°, 9.00°±0.2°, 12.50°±0.2°, 18.34°±0.2°, 23.53°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.30°±0.2°, 9.00°±0.2°, 12.50°±0.2°, 14.54°±0.2°, 18.34°±0.2°, 23.53°±0.2°, 24.66°± 0.2°, 26.76°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.61°±0.2°, 5.30°±0.2°, 9.00±0.2°, 12.50°±0.2°, 14.54°±0.2°, 18.34°±0.2°, 22.41°±0.2°, 23.53°±0.2°, 24.66°±0.2°, 26.76°±0.2°, 27.47°±0.2°, 32.03°±0.2°, 36.81°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 7-A.

[0040] In some embodiments, the differential scanning calorimetry (DSC) curve of p-toluenesulfonate crystal form B shows a peak temperature of 186.72 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 5.62% before 210 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 7-B and 7-C.

[0041] This invention provides an oxalate crystal form A of a compound of formula (I); in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 7.15°±0.2°, 9.94°±0.2°, 12.09°±0.2°, 23.39°±0.2°; in some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 7.15°±0.2°, 9.16°±0.2°, 9.94°±0.2°, 12.09°±0.2°, 16.31°±0.2°, 19.76°±0.2°, 23.39°±0.2°; in some embodiments, Cu-K... Alpha radiation, its X-ray powder diffraction pattern shows characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 7.15°±0.2°, 8.19±0.2°, 9.16°±0.2°, 9.94°±0.2°, 10.42°±0.2°, 12.09°±0.2°, 12.54°±0.2°, 16.31°±0.2°, 17.66° ±0.2°, 19.76°±0.2°, 21.30°±0.2°, 22.62°±0.2°, 23.39°±0.2°, 24.19°±0.2°, 24.60°±0.2°, 25.51°±0.2°, 26.18°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 8-A.

[0042] In some embodiments, the differential scanning calorimetry (DSC) curves of oxalate crystal form A show peak temperatures of 102.51 °C and 166.10 °C; its thermogravimetric analysis (TGA) curves show a weight loss of approximately 1.60% before 90 °C and approximately 2.35% between 90 and 150 °C; its thermogravimetric analysis curves and differential scanning calorimetry curves are shown in Figures 8-B and 8-C.

[0043] This invention provides a benzoate crystal form A of compound of formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.64°±0.2°, 15.33°±0.2°, 18.71°±0.2°, 19.32°±0.2°, 25.19°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.64°±0.2°, 7.28°±0.2°, 10.96°±0.2°, 15.33°±0.2°, 18.71°±0.2°, 19.32°±0.2°, 21.90°±0.2°. 0.2°, 25.19°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.64°±0.2°, 7.28°±0.2°, 7.62±0.2°, 10.96°±0.2°, 13.43°±0.2°, 15.33°±0.2°, 16.41°±0.2°, 17.43°±0.2°, 18.71°±0.2°, 19.32°±0.2°, 21.90°±0.2°, 22.90°±0.2°, 25.19°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 9-A.

[0044] In some embodiments, the differential scanning calorimetry (DSC) curve of benzoate crystal form A shows a peak temperature of 117.72 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of 1.92% before 110 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 9-B and 9-C.

[0045] This invention provides a benzoate crystal form B of a compound of formula (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.45°±0.2°, 12.91°±0.2°, 15.99°±0.2°, 20.10°±0.2°, 25.84°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.93°±0.2°, 6.45°±0.2°, 12.91°±0.2°, 15.99°±0.2°, 19.27°±0.2°, 20.10°±0.2°, 21.62°±0.2°, 25.84°±0.2°; in In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.93°±0.2°, 6.45°±0.2°, 8.55±0.2°, 12.28°±0.2°, 12.91°±0.2°, 13.53°±0.2°, 15.99°±0.2°, 16.63°±0.2°, 18.28°±0.2°, 19.27°±0.2°, 20.10°±0.2°, 21.62°±0.2°, 23.05°±0.2°, 23.49°±0.2°, 25.84°±0.2°, and 27.36°±0.2°. In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 10-A.

[0046] In some embodiments, the differential scanning calorimetry (DSC) curve of benzoate crystal form B shows a peak temperature of 117.24 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of 1.75% before 110 °C; its thermogravimetric analysis curve, differential scanning calorimetry curve and DVS curve are shown in Figures 10-B, 10-C and 10-D.

[0047] This invention provides a benzoate crystal form C of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 4.30°±0.2°, 7.79°±0.2°, 9.43°±0.2°, 25.11°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 4.30°±0.2°, 7.79°±0.2°, 9.43°±0.2°, 10.11°±0.2°, 12.59°±0.2°. 13.19°±0.2°, 25.11°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 4.30°±0.2°, 7.79°±0.2°, 9.43°±0.2°, 10.11°±0.2°, 11.20°±0.2°, 12.59°±0.2°, 13.19°±0.2°, 15.20°±0.2°, 16.82°±0.2°, 25.11°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 11-A.

[0048] In some embodiments, the differential scanning calorimetry (DSC) curve of benzoate crystal form C shows a peak temperature of 123.31 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of 2.76% before 110 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 11-B and 11-C.

[0049] This invention provides an ethyl sulfonate crystal form A of a compound of formula (I); in some embodiments, using Cu-Kα radiation, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 4.76°±0.2°, 5.56°±0.2°, 6.77°±0.2°, 13.45°±0.2°, 13.73°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.76°±0.2°, 5.56°±0.2°, 6.77°±0.2°, 13.45°±0.2°, 13.73°±0.2°, 18.56°±0.2°, 18.98°±0.2°, 20.21°±0.2°; in a In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.76°±0.2°, 5.56°±0.2°, 6.77°±0.2°, 7.55°±0.2°, 7.83°±0.2°, 13.45°±0.2°, 13.73°±0.2°, 15.69°±0.2°, and 17.98°. ±0.2°, 18.56°±0.2°, 18.98°±0.2°, 20.21°±0.2°, 21.00°±0.2°, 21.64°±0.2°, 23.06°±0.2°, 24.98°±0.2°, 25.77°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 12-A.

[0050] In some embodiments, the differential scanning calorimetry (DSC) curve of ethyl sulfonate crystal form A shows a peak temperature of 186.73 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of 3.55% before 170 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 12-B and 12-C.

[0051] This invention provides an ethyl sulfonate crystal form B of compound (I); in some embodiments, using Cu-Kα radiation, characterized by its X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions (2θ±0.2°): 3.99°±0.2°, 4.72°±0.2°, 7.69°±0.2°, 14.99°±0.2°, 21.63°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.99°±0.2°, 4.72°±0.2°, 6.49°±0.2°, 7.69°±0.2°, 11.87°±0.2°, 12 0.99°±0.2°, 14.99°±0.2°, 21.63°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.99°±0.2°, 4.72°±0.2°, 6.49°±0.2°, 7.69°±0.2°, 9.91°±0.2°, 10.64°±0.2°, 11.87°±0.2°, 12.99°±0.2°, 14.99°±0.2°, 17.16°±0.2°, 21.63°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 13-A.

[0052] In some embodiments, the differential scanning calorimetry (DSC) curve of ethyl sulfonate crystal form B shows a peak temperature of 152.40 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of 2.56% before 140 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 13-B and 13-C.

[0053] This invention provides a benzenesulfonate crystal form A of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.66°±0.2°, 5.16°±0.2°, 10.93°±0.2°, 16.50°±0.2°, 26.08°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.66°±0.2°, 5.16°±0.2°, 8.15°±0.2°, 10.93°±0.2°, 13.14°±0.2°, 16.50°±0.2°, 25.25°±0.2°, 26.08°±0.2°; in some embodiments, Using Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 3.66°±0.2°, 5.16°±0.2°, 8.15±0.2°, 10.34°±0.2°, 10.93°±0.2°, 13.14°±0.2°, 14.76°±0.2°, 15.52°±0.2°, and 16.06°±0.2°. 2°, 16.50°±0.2°, 18.04°±0.2°, 19.60°±0.2°, 19.91°±0.2°, 23.32°±0.2°, 25.25°±0.2°, 26.08°±0.2°, 26.62°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 14-A.

[0054] In some embodiments, the differential scanning calorimetry (DSC) curves of benzenesulfonate crystal form A show peak temperatures of 144.27 °C and 178.48 °C; its thermogravimetric analysis (TGA) curves show a weight loss of approximately 1.36% before 100 °C; its thermogravimetric analysis curves and differential scanning calorimetry curves are shown in Figures 14-B and 14-C.

[0055] This invention provides a benzenesulfonate crystal form B of compound (I); in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.03°±0.2°, 12.65°±0.2°, 14.78°±0.2°, 18.26°±0.2°, 25.01°±0.2°; in some embodiments, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.27°±0.2°, 9.03°±0.2°, 12.65°±0.2°, 14.78°±0.2°, 18.26°±0.2°, 23.54°±0.2°, 25.01°±0.2°, 25.62°±0.2°; in some In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.27°±0.2°, 9.03°±0.2°, 12.65±0.2°, 13.92°±0.2°, 14.78°±0.2°, 16.67°±0.2°, 17.61°±0.2°, 18.26°±0.2°, 18.79°±0.2°, 22.31°±0.2°, 23.54°±0.2°, 23.91°±0.2°, 25.01°±0.2°, 25.62°±0.2°, 27.23°±0.2°, and 28.23°±0.2°. In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 15-A.

[0056] In some embodiments, the differential scanning calorimetry (DSC) curve of benzenesulfonate crystal form B shows a peak temperature of 194.63 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 3.40% before 180 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 15-B and 15-C; the DVS curve is shown in Figure 15-D, and the X-ray powder diffraction patterns before and after DVS testing are shown in Figure 15-E. The results show that the crystal form remains stable before and after the DVS test.

[0057] This invention provides a benzenesulfonate crystal form C of compound (I), whose X-ray powder diffraction pattern, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ positions: 3.33°±0.2°, 3.76°±0.2°, 4.66°±0.2°, 7.59°±0.2°, 7.89°±0.2°; in some embodiments, when irradiated with Cu-Kα, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 3.33°±0.2°, 3.76°±0.2°, 4.66°±0.2°, 7.59°±0.2°, 7.89°±0.2°, 11.45°±0.2°, 12.24°±0.2°, 15. 98°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.33°±0.2°, 3.76°±0.2°, 4.66°±0.2°, 6.54°±0.2°, 7.59°±0.2°, 7.89°±0.2°, 10.10°±0.2°, 11.45°±0.2°, 12.24°±0.2°, 14.03°±0.2°, 15.98°±0.2°, 19.07°±0.2°, 23.96°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 16-A.

[0058] In some embodiments, the differential scanning calorimetry (DSC) curve of benzenesulfonate crystal form C shows a peak temperature of 171.86 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 3.09% before 120 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 16-B and 16-C.

[0059] This invention provides a benzenesulfonate crystal form D of compound (I) that exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern using Cu-Kα radiation: 7.81°±0.2°, 15.37°±0.2°, 17.88°±0.2°, 19.28°±0.2°, 25.69°±0.2°; in some embodiments, the X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions in its Cu-Kα radiation pattern: 7.81°±0.2°, 13.80°±0.2°, 15.37°±0.2°, 17.88°±0.2°, 19.28°±0.2°, 19.48°±0.2°, 23.35°±0.2°, 25.69°±0.2°. 0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.81°±0.2°, 13.80°±0.2°, 14.23°±0.2°, 15.37°±0.2°, 15.61°±0.2°, 17.88°±0.2°, 18.32°±0.2°, 19.28°±0.2°, 19.48°±0.2°, 22.13°±0.2°, 23.35°±0.2°, 23.65°±0.2°, 25.69°±0.2°, 26.55°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 17-A.

[0060] In some embodiments, the differential scanning calorimetry (DSC) curves of benzenesulfonate crystal form D show peak temperatures of 121.36 °C and 189.79 °C, respectively; its thermogravimetric analysis (TGA) curves show a weight loss of approximately 3.60% before 120 °C; its thermogravimetric analysis curves and differential scanning calorimetry curves are shown in Figures 17-B and 17-C; its variable temperature XRD is shown in Figure 17-D.

[0061] This invention provides a benzenesulfonate crystal form E of compound (I), whose X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 7.77°±0.2°, 11.35°±0.2°, 15.91°±0.2°, and 25.66°±0.2°; in some embodiments, when subjected to Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions. Diffraction peaks: 3.73°±0.2°, 4.52°±0.2°, 7.77°±0.2°, 11.35°±0.2°, 12.13°±0.2°, 14.14°±0.2°, 15.91°±0.2°, 18.90°±0.2°, 23.60°±0.2°, 25.66°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 18-A.

[0062] In some embodiments, the differential scanning calorimetry (DSC) curve of the benzenesulfonate crystal form E shows a peak temperature of 163.58 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 1.74% before 100 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 18-B and 18-C.

[0063] This invention provides a benzenesulfonate crystal form F of compound (I), whose X-ray powder diffraction pattern, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ positions: 5.31°±0.2°, 7.22°±0.2°, 7.90°±0.2°, 9.07°±0.2°, 15.82°±0.2°; in some embodiments, when irradiated with Cu-Kα, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 5.31°±0.2°, 7.22°±0.2°, 7.54°±0.2°, 7.90°±0.2°, 9.07°±0.2°, 10.19°±0.2°, 15.82°±0.2°, 23.55°±0.2°; in some In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.31°±0.2°, 6.57°±0.2°, 7.22°±0.2°, 7.54°±0.2°, 7.90°±0.2°, 9.07°±0.2°, 10.19°±0.2°, 12.13°±0.2°, 14.09°±0.2°, 15.82°±0.2°, 18.25°±0.2°, 19.01°±0.2°, 20.39°±0.2°, 23.55°±0.2°, and 23.86°±0.2°. In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 19-A.

[0064] This invention provides a benzenesulfonate crystal form G of compound (I), whose X-ray powder diffraction pattern, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ positions: 4.13°±0.2°, 5.37°±0.2°, 9.15°±0.2°, 14.85°±0.2°, 25.08°±0.2°; in some embodiments, when irradiated with Cu-Kα, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 4.13°±0.2°, 5.37°±0.2°, 9.15°±0.2°, 11.95°±0.2°, 12.78°±0.2°, 14.85°±0.2°, 18.48°±0.2°, 25.08°±0.2°; in a In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.13°±0.2°, 5.37°±0.2°, 7.42°±0.2°, 9.15°±0.2°, 10.70°±0.2°, 10.85°±0.2°, 11.95°±0.2°, 12.78°±0.2°, 14.00°±0.2°, 14.85°±0.2°, 15.33°±0.2°, 18.48°±0.2°, 20.72°±0.2°, 25.08°±0.2°, and 25.64°±0.2°. In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 20-A.

[0065] In some embodiments, the differential scanning calorimetry (DSC) curve of benzenesulfonate crystal form G shows a peak temperature of 199.15 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 4.99% before 190 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 20-B and 20-C.

[0066] The present invention also provides a crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern, when irradiated with Cu-Kα, exhibits characteristic diffraction peaks at the following 2θ positions: 3.63°±0.2°, 5.93°±0.2°, 6.95°±0.2°, 13.78°±0.2°, 15.01°±0.2°; in some embodiments, when irradiated with Cu-Kα, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 3.63°±0.2°, 5.93°±0.2°, 6.95°±0.2°, 10.91°±0.2°, 13.78°±0.2°, 15.01°±0.2°, 25.03 ... 78°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.63°±0.2°, 4.19°±0.2°, 5.93°±0.2°, 6.95°±0.2°, 7.26°±0.2°, 10.91°±0.2°, 13.78°±0.2°, 15.01°±0.2°, 16.82°±0.2°, 20.99°±0.2°, 25.03°±0.2°, 25.78°±0.2°, 26.91°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 21-A.

[0067] The present invention also provides a crystal form B of the compound of formula (I), whose X-ray powder diffraction pattern, when irradiated with Cu-Kα, has characteristic diffraction peaks at the following 2θ positions: 15.23°±0.2°, 20.57°±0.2°, 22.47°±0.2°, 23.30°±0.2°, 24.15°±0.2°; in some embodiments, when irradiated with Cu-Kα, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.12°±0.2°, 15.23°±0.2°, 18.35°±0.2°, 19.89°±0.2°, 20.57°±0.2°, 22.47°±0.2°, 23.30°±0.2°, 24. 15°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.12°±0.2°, 14.30°±0.2°, 14.76°±0.2°, 15.23°±0.2°, 16.83°±0.2°, 18.35°±0.2°, 19.89°±0.2°, 20.57°±0.2°, 21.41°±0.2°, 22.47°±0.2°, 23.30°±0.2°, 24.15°±0.2°, 27.18°±0.2°; In some embodiments, Cu-Kα radiation is used, and its X-ray powder diffraction pattern is shown in Figure 22-A.

[0068] In some embodiments, the differential scanning calorimetry (DSC) curve of crystal form B of compound (I) shows a peak temperature of 229.53 °C; its thermogravimetric analysis (TGA) curve shows a weight loss of approximately 4.33% before 200 °C; its thermogravimetric analysis curve and differential scanning calorimetry curve are shown in Figures 22-B and 22-C.

[0069] This invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula (I), comprising the steps of obtaining the compound of formula (I) and forming a salt with an acid; wherein the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, fumarate, hydrohalate (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucilage, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, etc. Triphenylacetate, L-proline, ferulic acid salt, 2-hydroxyethanesulfonate, mandelic acid salt, nitrate, methanesulfonate, malonate, gentianate, salicylate, succinate, glutamate, ethylsulfonate, gluconate, adipate, oxalate, or glutamate; preferably from benzenesulfonate, succinate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, benzoate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate; more preferably from benzenesulfonate and benzoate;

[0070] This invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula (I), wherein the method comprises: a step of forming a salt with a compound of formula (I) and an acid; in some embodiments, the solvent used is selected from C 1-6 Halogenated alkane solvents, C 2-6 Ester solvents, C 2-6 Ether solvents, C 1-6 One or more of an alcohol solvent or water; in some embodiments, the solvent used is selected from one or more of dichloromethane, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, propanol, diethyl ether, tetrahydrofuran, and water.

[0071] The crystalline form of the present invention can be prepared by the following method:

[0072] 1. Volatilization experiment: Add the compound of formula (I) to the selected single solvent or binary solvent to form a clear solution of the sample, and volatilize it in the open at different temperatures until the solvent is dry.

[0073] 2. Suspension method: Add the compound of formula (I) to the selected single solvent or binary solvent until a suspension is formed. After suspending and stirring at room temperature to 50°C for a certain period of time (e.g., 1h to 10 days, or 2h to 24h, or 2h to 12h, or 3 to 5h), centrifuge the suspension and dry it to obtain the product.

[0074] 3. Dissolution and crystallization method: Dissolve the compound of formula (I) in a good solvent, take a certain amount of the solution and add it dropwise to a poor solvent, or add the poor solvent dropwise to the solution, stir to precipitate the solid, separate and dry to obtain the product.

[0075] 4. Cooling method: Dissolve a certain amount of sample in the corresponding solvent at high temperature, transfer the solution to room temperature to cool, let it stand or stir to crystallize, separate, and dry to obtain the final product.

[0076] 5. Thermal crystallization method experiment: Take a certain amount of sample, place it on a glass slide and put it on a hot stage. Heat it to the target temperature at a certain rate (e.g., 5-20℃ / min, or 10-15℃ / min) and keep it at a constant temperature for a period of time (e.g., 0.5-5min, or 1-3min, or 1-2min). Then let it cool naturally to room temperature to obtain a solid.

[0077] 6. Gas-phase diffusion experiment: Add a certain amount of compound (I) dropwise to a suitable amount of good solvent at room temperature to completely dissolve the sample or prepare a saturated solution of good solvent; take a certain amount of solution, place the clear solution in a poor solvent atmosphere and let it stand at room temperature until a solid precipitates out, then separate it to obtain the product. Alternatively, place the solid of compound (I) in a solvent atmosphere and let it stand at room temperature for 1 to 7 days to obtain the product.

[0078] 7. Polymer-induced volatilization method: A clear solution with a small amount of polymer added is left to stand at room temperature in an open container until the solvent has completely evaporated to obtain a solid.

[0079] The terms "good solvent" and "bad solvent" in this invention are relative. In a pair of solvents, the one with higher solubility is considered a good solvent, and the one with lower solubility is considered a bad solvent. In some embodiments, the good solvent is selected from those with higher solubility among ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethanol, n-propanol, 4-methyl-2-pentanone, tetrahydrofuran, isopropanol, ethyl acetate, n-heptane, dichloromethane, isopropyl ether, water, acetonitrile, toluene, chloroform, acetone, ethyl formate, MTBE, MIBK, and cyclohexane, while the bad solvent is selected from those with lower solubility. In some embodiments, the good solvent is selected from acetone, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, dichloromethane, tetrahydrofuran, ethyl acetate, ethyl formate, acetonitrile, chloroform, or mixtures thereof. In some embodiments, the bad solvent is selected from n-propanol, isopropyl ether, n-heptane, ethanol, water, toluene, MTBE, cyclohexane, isopropanol, or mixtures thereof.

[0080] In some implementations, the solvents for the evaporation method are methanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, dioxane, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, DMF, DMSO, dichloromethane, chloroform, and tetrahydrofuran.

[0081] In some implementations, the solvent used in the cooling method is methanol, ethyl acetate, isopropyl acetate, butyl formate, acetonitrile, ethylene glycol methyl ether, 4-methyl-2-pentanone, dioxane, ethanol, acetonitrile, DMF, tetrahydrofuran, isopropanol, n-propanol, ethylene glycol dimethyl ether, DMSO, or a mixture thereof.

[0082] In some implementations, the solvent used in the suspension method is ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethanol, n-propanol, 4-methyl-2-pentanone, tetrahydrofuran, isopropanol, ethyl acetate, n-heptane, dichloromethane, isopropyl ether, water, methanol, isopropyl acetate, butyl formate, acetonitrile, toluene, chloroform, acetone, ethyl formate, MTBE, cyclohexane, or mixtures thereof.

[0083] In some implementations, the gas phase diffusion method employs gas phase diffusion in cyclohexane, MTBE, ethanol, n-heptane, isopropyl ether, isopropanol, and toluene.

[0084] In some implementations, the polymers used in the polymer-induced volatilization method are polyvinyl alcohol, polyacrylamide, polyisobutyl methacrylate, polyethylene glycol, cellulose acetate, polyvinylpyrrolidone PVP10, polyvinylpyrrolidone K88-96, high-viscosity hydroxyethyl cellulose HEC-100000, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose.

[0085] The terms "good solvent" and "bad solvent" in this invention are relative. In a pair of solvents, the one with higher solubility is a good solvent, and the one with lower solubility is a bad solvent.

[0086] Unless otherwise specified, the solvent used in the above preparation method may be a single solvent or a combination of two or more solvents.

[0087] The crystal form of the salt of the compound of formula (I) of the present invention has advantages including, but not limited to, ease of processing and crystallization, convenient handling, easy purification, easy industrialization, low hygroscopicity, good flowability, easy micronization, high solubility, good pharmacokinetic characteristics and good stability, making it suitable for the preparation of pharmaceutical formulations.

[0088] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the aforementioned salts or crystal forms, and a pharmaceutically acceptable carrier and / or excipient, preferably wherein the therapeutically effective amount is 1-1500 mg. The pharmaceutical composition may be in unit dosage form (unit dosage is also referred to as a “dosage strength”).

[0089] The present invention also provides the use of the salt or crystal form or composition described in any of the foregoing embodiments in the preparation of a medicament for treating PRMT5-mediated diseases.

[0090] The present invention also provides a method for treating or preventing PRMT5-mediated diseases, the method comprising administering to a subject a therapeutically effective amount of the salt or crystalline form or a combination thereof described in any of the foregoing embodiments, said therapeutically effective amount being 1-1500 mg. In some embodiments, the mammals described in the present invention include humans.

[0091] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the crystalline form disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the crystalline form disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0092] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of the salt or crystal form of the present invention.

[0093] This invention relates to a pharmaceutical composition or formulation comprising a therapeutically effective amount of the salt or crystal form described herein, as well as a carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, etc. The salts or crystal forms of the present invention in g, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, and 1500mg.

[0094] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the crystalline form of the invention, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg, wherein the disease is a CYP11A1-mediated disease, preferably prostate cancer.

[0095] A method for treating a disease in a mammal, the method comprising administering a salt or crystal form of the drug of the present invention, along with a pharmaceutically acceptable carrier and / or excipient, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, and 100-1000 mg / day. / day, 200-1000mg / day, 25-800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, and 1500mg / day.

[0096] The present invention relates to a kit that may include a single-dose or multi-dose form of a crystal, the kit containing the crystal of the present invention in an amount identical to that in the above-described pharmaceutical composition.

[0097] In this invention, the amount of the crystal form of the invention is converted in the form of free alkali in each case.

[0098] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0099] The crystalline form of the present invention is present in the form of about 5% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 10% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 15% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 20% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 25% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 30% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 35% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 40% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 45% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 50% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 55% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, it is present at about 60% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 65% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 70% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 75% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 80% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 85% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 90% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 95% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 98% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 99% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, substantially all of the active pharmaceutical ingredient is substantially pure crystal.

[0100] The crystalline form of the compound of formula (I) described in this invention possesses excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, and high humidity resistance. For example, the crystalline form described in this invention can significantly reduce filtration time, shorten the production cycle, and save costs during formulation. The crystalline form described in this invention also has good photostability, thermal stability, and moisture stability, ensuring the reliability of the crystalline form during storage and transportation, thereby guaranteeing the safety of the formulation. Furthermore, the crystalline form does not require special packaging to prevent the effects of light, temperature, and humidity, thus reducing costs. The crystalline form will not degrade due to light, high temperature, and high humidity, improving the safety of the formulation and its effectiveness after long-term storage. Patients taking the crystalline form will not worry about photosensitivity reactions caused by exposure to sunlight.

[0101] It is understood that the values ​​described and protected in this invention are approximate. Variations within these values ​​may be attributed to equipment calibration, equipment errors, crystal purity, crystal size, sample size, and other factors.

[0102] The crystal structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to X-ray powder diffraction (XRD), ion chromatography (IC), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0103] It is understood that the crystal forms of the present invention are not limited to those that are exactly the same as the characteristic spectra described in the accompanying drawings, such as XRD, DSC, and TGA. Any crystal form that has a characteristic spectra that is substantially the same or essentially the same as those described in the accompanying drawings falls within the scope of the present invention.

[0104] It is understood that, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of the present invention are characterized by DSC plots with characteristic peak positions, possessing substantially the same properties as the DSC plots provided in the accompanying drawings of the present invention, with an error tolerance of ±3°C.

[0105] Unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When a quantity, concentration, or other value or parameter is expressed as a range, preferred range, or preferred upper and lower numerical limits, it should be understood that this is equivalent to specifically disclosing any range by combining any pair of upper or preferred values ​​with any lower or preferred value, regardless of whether the range is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within that range.

[0106] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0107] The terms "optional" or "optionally" used in this invention refer to events or circumstances that may, but are not required to, occur as described below, including situations in which the event or circumstance may or may not occur.

[0108] When used in conjunction with a numerical variable, the terms "about" or "approximately" in this invention typically refer to the value of the variable and all values ​​of the variable being within the experimental error range (e.g., within a 95% confidence interval for the average value) or within ±10% of the specified value, or a wider range.

[0109] Unless otherwise stated, all percentages, parts, etc. in this document are by weight.

[0110] The term "amorphous" as used in this invention refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystal diffraction analysis, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination of these techniques. As explained below, XRPD spectra generated by amorphous solids do not exhibit obvious diffraction characteristic peaks.

[0111] The “crystal form” or “crystal” mentioned in this invention refers to any solid substance exhibiting a three-dimensional arrangement, which, in contrast to amorphous solid substances, produces a characteristic XRPD pattern with clearly defined peaks.

[0112] The "seed crystal" mentioned in this invention refers to the crystal nucleus formed by adding insoluble additives in the crystallization process, which accelerates or promotes the growth of enantiomers with the same crystal form or stereostructure.

[0113] The “pharmaceutical composition” described in this invention refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and excipients.

[0114] The "carrier" as used in this invention refers to a carrier or diluent that does not cause significant irritation to organisms and does not eliminate the biological activity and properties of the given compound.

[0115] The term "excipient" as used in this invention refers to an inert substance added to a pharmaceutical composition for further administration dependent on the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrants, etc.

[0116] The “carrier” as described in this invention refers to a system that does not cause significant stimulation to the organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0117] The "IC" described in this invention 50"Half-inhibition concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0118] The "ether solvents" mentioned in this invention refer to chain or cyclic compounds containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to, tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane.

[0119] The "alcohol solvent" mentioned in this invention refers to one or more "hydroxyl groups" replacing "C". 1-6 A group derived from one or more hydrogen atoms on an alkyl group, wherein the hydroxyl group and the C 1-6 "Alkyl" as defined above, specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.

[0120] The "ester solvent" mentioned in this invention refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms. Specific examples include, but are not limited to, ethyl acetate, isopropyl acetate, or butyl acetate.

[0121] The "ketone solvents" mentioned in this invention refer to compounds in which a carbonyl group (-C(O)-) is attached to two hydrocarbon groups. Depending on the hydrocarbon groups in the molecule, ketones can be classified into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones, and unsaturated ketones. Specific examples include, but are not limited to, acetone, acetophenone, and 4-methyl-2-pentanone.

[0122] The "nitrile solvent" mentioned in this invention refers to one or more "cyano" groups replacing "C". 1-6 A group derived from one or more hydrogen atoms on an alkyl group, wherein the "cyano" and "C" 1-6 "Alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.

[0123] The "halogenated hydrocarbon solvent" described in this invention refers to one or more "halogen atoms" replacing "C". 1-6 A group derived from one or more hydrogen atoms on an alkyl group, wherein the halogen atom and the C 1-6 "Alkyl" is defined above, and specific examples include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform, or carbon tetrachloride.

[0124] The terms "crystal of the present invention", "crystal form of the present invention", and "polymorph of the present invention" used in this invention are interchangeable.

[0125] The "room temperature" mentioned in this invention generally refers to 4 to 30°C, and preferably to 20±5°C.

[0126] The drying temperature described in this invention is generally 20–100°C, preferably 25–70°C. It can be performed under normal pressure or under reduced pressure (vacuum drying). Preferably, the drying is carried out under reduced pressure.

[0127] The "X-ray powder diffraction pattern (XRPD pattern)" mentioned in this invention refers to an experimentally observed diffraction pattern or parameters, data, or values ​​derived from it. XRPD patterns are typically characterized by peak position (horizontal axis) and / or peak intensity (vertical axis).

[0128] The "2θ or 2θ angle" mentioned in this invention refers to the diffraction angle, where θ is the Bragg angle, a peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is typically the horizontal axis unit in a diffraction pattern. If the incident beam is diffracted when it forms an angle θ with a certain lattice plane, the experimental setup needs to record the reflected beam at a 2θ angle. It should be understood that the specific 2θ value for a particular crystal form mentioned herein is intended to represent a 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, with an error range of ±0.3, which can be ±0.3, ±0.2, or ±0.1.

[0129] The term "substantially identical" as used in this invention means taking into account representative peak positions and intensity variations. For example, those skilled in the art will understand that peak positions (2θ) will exhibit some variation, typically up to 0.1–0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. Furthermore, those skilled in the art will understand that relative peak intensities will vary due to differences between instruments, as well as the degree of crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered as qualitative measurements only.

[0130] The "differential scanning calorimetry or DSC" described in this invention refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0131] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guidelines for Hygroscopicity of Drugs" (9103) of the 2020 edition of the Chinese Pharmacopoeia, Volume IV:

[0132] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0133] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0134] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0135] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0136] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0137] The crystal form disclosed in this invention can be prepared using the following common methods for preparing crystal forms:

[0138] 1. The evaporation experiment involves evaporating a clear solution of the sample in an open container at different temperatures until the solvent is dry.

[0139] 2. The crystal slurry experiment involves stirring a supersaturated solution of the sample (containing insoluble solids) in different solvent systems at a certain temperature.

[0140] 3. The solvent resistance test involves dissolving the sample in a good solvent, adding the solvent, stirring the precipitated solid briefly, and then filtering it immediately.

[0141] 4. The cooling crystallization experiment involves dissolving a certain amount of sample into a corresponding solvent at high temperature, and then directly stirring and crystallizing at room temperature or low temperature.

[0142] 5. The polymer template experiment involves adding different types of polymer materials to a clear solution of the sample and leaving it at room temperature to evaporate until the solvent is dry.

[0143] 6. Thermal method experiments involve treating the sample under specific thermal crystallization conditions and then cooling it to room temperature.

[0144] 7. The water vapor diffusion experiment involves placing the sample in an environment with a certain humidity at room temperature.

[0145] Definitions of abbreviations and key terms in this invention: Attached Figure Description

[0146] Figure 1-A shows the X-ray powder diffraction pattern of maleate crystal form A of compound (I).

[0147] Figure 1-B shows the thermogravimetric analysis (TGA) spectrum of maleate crystal form A of compound (I).

[0148] Figure 1-C shows the differential scanning calorimetry curve of maleate crystal form A of compound (I).

[0149] Figure 2-A shows the X-ray powder diffraction pattern of crystal form A of compound (I) 1,5-naphthalene disulfonate.

[0150] Figure 3-A shows the X-ray powder diffraction pattern of crystal form B of compound (I) 1,5-naphthalene disulfonate.

[0151] Figure 3-B shows the thermogravimetric analysis (TGA) spectrum of 1,5-naphthalene disulfonate crystal form B of compound (I).

[0152] Figure 3-C shows the differential scanning calorimetry curve of crystal form B of compound (I) 1,5-naphthalene disulfonate.

[0153] Figure 4-A shows the X-ray powder diffraction pattern of succinate form A of compound (I).

[0154] Figure 4-B shows the thermogravimetric analysis spectrum of succinate form A of compound (I).

[0155] Figure 4-C shows the differential scanning calorimetry curve of succinate form A of compound (I).

[0156] Figure 5-A shows the X-ray powder diffraction pattern of citrate crystal form A of compound (I).

[0157] Figure 5-B shows the thermogravimetric analysis spectrum of citrate form A of compound (I).

[0158] Figure 5-C shows the differential scanning calorimetry curve of citrate form A of compound (I).

[0159] Figure 6-A shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form A of compound (I).

[0160] Figure 6-B shows the thermogravimetric analysis (TGA) spectrum of p-toluenesulfonate crystal form A of compound (I).

[0161] Figure 6-C shows the differential scanning calorimetry curve of p-toluenesulfonate crystal form A of compound (I).

[0162] Figure 7-A shows the X-ray powder diffraction pattern of p-toluenesulfonate crystal form B of compound (I).

[0163] Figure 7-B shows the thermogravimetric analysis (TGA) spectrum of p-toluenesulfonate crystal form B of compound (I).

[0164] Figure 7-C shows the differential scanning calorimetry curve of p-toluenesulfonate crystal form B of compound (I).

[0165] Figure 8-A shows the X-ray powder diffraction pattern of the oxalate crystal form A of compound (I).

[0166] Figure 8-B shows the thermogravimetric analysis spectrum of oxalate crystal form A of compound (I).

[0167] Figure 8-C shows the differential scanning calorimetry curve of oxalate crystal form A of compound (I).

[0168] Figure 9-A shows the X-ray powder diffraction pattern of benzoate crystal form A of compound (I).

[0169] Figure 9-B shows the thermogravimetric analysis (TGA) spectrum of benzoate crystal form A of compound (I).

[0170] Figure 9-C shows the differential scanning calorimetry curve of benzoate form A of compound (I).

[0171] Figure 10-A shows the X-ray powder diffraction pattern of benzoate crystal form B of compound (I).

[0172] Figure 10-B shows the thermogravimetric analysis (TGA) spectrum of the benzoate crystal form B of compound (I).

[0173] Figure 10-C shows the differential scanning calorimetry curve of the benzoate crystal form B of compound (I).

[0174] Figure 10-D shows the DVS curve of benzoate crystal form B of compound (I).

[0175] Figure 10 - X-ray powder diffraction patterns of the benzoate crystal form of compound E (I) before and after DVS test.

[0176] Figure 11-A shows the X-ray powder diffraction pattern of the benzoate crystal form C of compound (I).

[0177] Figure 11-B shows the thermogravimetric analysis (TGA) spectrum of the benzoate crystal form C of compound (I).

[0178] Figure 11-C shows the differential scanning calorimetry curve of the benzoate crystal form C of compound (I).

[0179] Figure 12-A shows the X-ray powder diffraction pattern of ethyl sulfonate form A of compound (I).

[0180] Figure 12-B shows the thermogravimetric analysis (TGA) spectrum of ethyl sulfonate form A of compound (I).

[0181] Figure 12-C shows the differential scanning calorimetry curve of ethyl sulfonate form A of compound (I).

[0182] Figure 13-A shows the X-ray powder diffraction pattern of ethyl sulfonate form B of compound (I).

[0183] Figure 13-B shows the thermogravimetric analysis (TGA) spectrum of the ethyl sulfonate crystal form B of compound (I).

[0184] Figure 13-C shows the differential scanning calorimetry curve of the ethyl sulfonate crystal form B of compound (I).

[0185] Figure 14-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form A of compound (I).

[0186] Figure 14-B shows the thermogravimetric analysis (TGA) spectrum of benzenesulfonate crystal form A of compound (I).

[0187] Figure 14-C shows the differential scanning calorimetry curve of benzenesulfonate crystal form A of compound (I).

[0188] Figure 15-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form B of compound (I).

[0189] Figure 15-B shows the thermogravimetric analysis (TGA) spectrum of benzenesulfonate form B of compound (I).

[0190] Figure 15-C shows the differential scanning calorimetry curve of benzenesulfonate crystal form B of compound (I).

[0191] Figure 15-D shows the DVS curve of benzenesulfonate crystal form B of compound (I).

[0192] Figure 15-E shows the X-ray powder diffraction patterns of the benzenesulfonate crystal form B of compound (I) before and after DVS detection.

[0193] Figure 15-F shows the X-ray powder diffraction patterns of benzenesulfonate crystal form B of formula (I) at different temperatures.

[0194] Figure 16-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form C of compound (I).

[0195] Figure 16-B shows the thermogravimetric analysis spectrum of benzenesulfonate crystal form C of compound (I).

[0196] Figure 16-C shows the differential scanning calorimetry curve of benzenesulfonate crystal form C of compound (I).

[0197] Figure 17-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form D of compound (I).

[0198] Figure 17-B shows the thermogravimetric analysis spectrum of benzenesulfonate crystal form D of compound (I).

[0199] Figure 17-C shows the differential scanning calorimetry curve of benzenesulfonate crystal form D of compound (I).

[0200] Figure 17-D shows the X-ray powder diffraction patterns of benzenesulfonate crystal form D of compound (I) at different temperatures.

[0201] Figure 18-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form E of compound (I).

[0202] Figure 18-B shows the thermogravimetric analysis spectrum of benzenesulfonate crystal form E of compound (I).

[0203] Figure 18-C shows the differential scanning calorimetry curve of benzenesulfonate E of compound (I).

[0204] Figure 19-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form F of compound (I).

[0205] Figure 20-A shows the X-ray powder diffraction pattern of benzenesulfonate crystal form G of compound (I).

[0206] Figure 20-B shows the thermogravimetric analysis spectrum of benzenesulfonate crystal form G of compound (I).

[0207] Figure 20-C shows the differential scanning calorimetry curve of benzenesulfonate G of compound (I).

[0208] Figure 21-A shows the X-ray powder diffraction pattern of crystal form A of compound (I).

[0209] Figure 22-A shows the X-ray powder diffraction pattern of crystal form B of compound (I).

[0210] Figure 22-B shows the thermogravimetric analysis spectrum of crystal form B of compound (I).

[0211] Figure 22-C shows the differential scanning calorimetry curve of crystal form B of compound (I). Detailed Implementation

[0212] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0213] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0214] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Eclipse Plus C18, 150×4.6mm).

[0215] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0216] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0217] Crystal form preparation example

[0218] Example 1: Preparation of compound (I)

[0219] Compound (I) was prepared according to the method described in WO2024008176.

[0220] Example 2: Preparation of maleate crystal form A of compound (I)

[0221] Take about 30 mg of compound (I), add 1.1 eq of maleic acid and 0.4 mL of acetone, suspend at room temperature for 1 day, add 0.75 mL of MTBE, suspend for 1 day, filter, and dry the resulting solid under vacuum at 50 °C to obtain the maleate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 1-A, 1-B and 1-C, respectively.

[0222] Example 3: Preparation of crystalline form A of 1,5-naphthalenedisulfonate of compound (I)

[0223] Take about 30 mg of compound (I), add 1.1 eq of 1,5-naphthalenedisulfonic acid and 0.6 mL of ethanol, suspend at room temperature for 1 day and filter. Dry the resulting solid under vacuum at 50 °C to obtain the 1,5-naphthalenedisulfonate crystal form A of compound (I), whose XRD is shown in Figure 2-A.

[0224] Example 4: Preparation of crystalline form B of 1,5-naphthalenedisulfonate of compound (I)

[0225] Take about 30 mg of compound (I), add 1.1 eq of 1,5-naphthalenedisulfonic acid and 0.8 mL of tetrahydrofuran, suspend at room temperature for 1 day and filter. The resulting solid is dried under vacuum at 50 °C to obtain the 1,5-naphthalenedisulfonate crystal form B of compound (I). Its XRD, TGA and DSC are shown in Figures 3-A, 3-B and 3-C, respectively.

[0226] Example 5: Preparation of succinate crystal form A of compound (I)

[0227] Take about 30 mg of compound (I), add 1.1 eq of succinic acid and 0.8 mL of ethyl acetate, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain succinate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 4-A, 4-B and 4-C, respectively.

[0228] Example 6: Preparation of citrate crystal form A of compound (I)

[0229] Take about 30 mg of compound (I), add 1.1 eq of citric acid and 0.8 mL of ethanol, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain the citrate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 5-A, 5-B and 5-C, respectively.

[0230] Example 7: Preparation of p-toluenesulfonate crystal form A of compound (I)

[0231] Take about 30 mg of compound (I), add 1.1 eq of p-toluenesulfonic acid and 0.8 mL of acetone, suspend at room temperature for 1 day and filter. The resulting solid is dried under vacuum at 50 °C to obtain p-toluenesulfonate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 6-A, 6-B and 6-C, respectively.

[0232] Example 8: Preparation of p-toluenesulfonate crystal form B of compound (I)

[0233] Take about 30 mg of compound (I), add 1.1 eq of p-toluenesulfonic acid and 0.8 mL of acetonitrile, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain p-toluenesulfonate crystal form B of compound (I). Its XRD, TGA and DSC are shown in Figures 7-A, 7-B and 7-C, respectively.

[0234] Example 9: Preparation of oxalate crystal form A of compound (I)

[0235] Take about 30 mg of compound (I), add 1.1 eq of oxalic acid and 0.8 mL of ethanol, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain the oxalate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 8-A, 8-B and 8-C, respectively.

[0236] Example 10: Preparation of benzoate crystal form A of compound (I)

[0237] Take about 30 mg of compound (I), add 1.1 eq of benzoic acid and 0.4 mL of ethyl acetate, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain the benzoate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 9-A, 9-B and 9-C, respectively.

[0238] Example 11: Preparation of benzoate crystal form B of compound (I)

[0239] Take about 30 mg of compound (I), add 1.1 eq of benzoic acid and 0.8 mL of acetonitrile, suspend at room temperature for 1 day and filter. The resulting solid is dried under vacuum at 50 °C to obtain the benzoate crystal form B of compound (I). Its XRD, TGA, DSC, DVS, and XRD before and after DVS testing are shown in Figures 10-A, 10-B, 10-C, 10-D, and 10-E, respectively.

[0240] Example 12: Preparation of benzoate crystal form C of compound (I)

[0241] Take about 30 mg of compound (I), add 1.1 eq of benzoic acid and 0.4 mL of dichloromethane, suspend at room temperature for 1 day, add MTBE dropwise until solid precipitates, suspend for 1 day and filter, the obtained solid is dried under vacuum at 50 °C to obtain benzoate crystal form C of compound (I), its XRD, TGA and DSC are shown in Figures 11-A, 11-B and 11-C respectively.

[0242] Example 13: Preparation of ethyl sulfonate crystal form A of compound (I)

[0243] Take about 30 mg of compound (I), add 1.1 eq of ethylsulfonic acid and 0.4 mL of acetone, suspend at room temperature for 1 day and filter. The resulting solid is dried under vacuum at 50 °C to obtain the ethylsulfonate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 12-A, 12-B and 12-C, respectively.

[0244] Example 14: Preparation of ethyl sulfonate crystal form B of compound (I)

[0245] Take about 30 mg of compound (I), add 1.1 eq of ethylsulfonic acid and 0.8 mL of toluene, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain the ethylsulfonate crystal form B of compound (I). Its XRD, TGA and DSC are shown in Figures 13-A, 13-B and 13-C, respectively.

[0246] Example 15: Preparation of benzenesulfonate crystal form A of compound (I)

[0247] Take about 30 mg of compound (I), add 1.1 eq of benzenesulfonic acid and 0.8 mL of ethanol, suspend at room temperature for 1 day and filter. Dry the obtained solid under vacuum at 50 °C to obtain the benzenesulfonate crystal form A of compound (I). Its XRD, TGA and DSC are shown in Figures 14-A, 14-B and 14-C, respectively.

[0248] Example 16: Preparation of benzenesulfonate crystal form B of compound (I)

[0249] Take about 30 mg of compound (I), add 1.1 eq of benzenesulfonic acid and 0.8 mL of acetonitrile, suspend at room temperature for 1 day and filter. The resulting solid is dried under vacuum at 50 °C to obtain the benzenesulfonate crystal form B of compound (I). Its XRD, TGA, DSC, DVS, and XRD before and after DVS detection are shown in Figures 15-A, 15-B, 15-C, 15-D, and 15-E, respectively.

[0250] Example 17: Preparation of benzenesulfonate crystal form C of compound (I)

[0251] Take 30 mg of benzenesulfonate crystal form B of formula (I), add it to a mixed solvent of 1.0 mL isopropanol and 0.6 mL methanol to dissolve it, filter it, and let it stand open at room temperature until the solvent completely evaporates to obtain a solid, thus obtaining benzenesulfonate crystal form C of formula (I). Its XRD, TGA and DSC are shown in Figures 16-A, 16-B and 16-C, respectively.

[0252] Example 18: Preparation of benzenesulfonate crystal form D of compound (I)

[0253] Take 30 mg of benzenesulfonate crystal form B of formula (I), dissolve it in 0.08 mL DMSO, back-drop it into 2.0 mL MIBK, stir at RT for 24 h to obtain benzenesulfonate crystal form D of formula (I). Its XRD, TGA, DSC and temperature-dependent XRD are shown in Figures 17-A, 17-B, 17-C and 17-D, respectively.

[0254] Example 19: Preparation of benzenesulfonate crystal form E of compound (I)

[0255] Take 30 mg of benzenesulfonate crystal form B of formula (I), add it to a mixed solvent of 0.5 mL dichloromethane and 0.05 mL methanol to dissolve it, filter it, and let it stand open at room temperature until the solvent completely evaporates to obtain a solid, thus obtaining benzenesulfonate crystal form E of formula (I). Its XRD, TGA and DSC are shown in Figures 18-A, 18-B and 18-C, respectively.

[0256] Example 20: Preparation of benzenesulfonate crystal forms F and G of formula (I)

[0257] Take 30 mg of benzenesulfonate crystal form B of formula (I), add it to 0.4 mL of ethanol, stir at room temperature for 5 days, filter, and obtain benzenesulfonate crystal form F of formula (I), whose XRD is shown in Figure 19-A; after vacuum drying at 50℃ for 5 h, obtain benzenesulfonate crystal form G of formula (I), whose XRD, TGA and DSC are shown in Figures 20-A, 20-B and 20-C respectively.

[0258] Example 21: Preparation of crystal form A of compound (I)

[0259] Take 30 mg of compound (I), add it to 0.2 mL of methanol and 0.2 mL of water, stir at room temperature for 4 days, filter, and obtain crystal form A of compound (I), whose XRD is shown in Figure 21-A.

[0260] Example 22: Preparation of crystal form B of compound (I)

[0261] Take 30 mg of compound (I), add it to 0.2 mL of ethanol and 0.4 mL of n-heptane, slurry at 50 °C for 4 days, filter, and vacuum dry at 50 °C to obtain crystal form B of compound (I). Its XRD, TGA and DSC are shown in Figures 22-A, 22-B and 22-C, respectively.

[0262] Performance testing methods

[0263] X-ray powder diffraction (XRD) / DSC / TGA / DVS / IC testing

[0264] See Table 1 for detailed XRD / DSC / TGA / DVS test parameters.

[0265] Table 1. XRD / DSC / TGA / DVS Test Instruments and Parameters

[0266] Ion chromatography (IC)

[0267] Crystal form parameter characterization

[0268] Tables 2-23 are lists of XRD characterization values ​​for the crystal forms of the present invention.

[0269] Table 2 lists the XRD peaks of maleate crystal form A of compound (I).

[0270] Table 3 lists the XRD peaks of 1,5-naphthalenedisulfonate crystal form A of compound (I).

[0271] Table 4 lists the XRD peaks of 1,5-naphthalenedisulfonate crystal form B of compound (I).

[0272] Table 5 lists the XRD peaks of succinate crystal form A of compound (I).

[0273] Table 6 lists the XRD peaks of citrate crystal form A of compound (I).

[0274] Table 7 lists the XRD peaks of p-toluenesulfonate crystal form A of compound (I).

[0275] Table 8 lists the XRD peaks of p-toluenesulfonate crystal form B of compound (I).

[0276] Table 9 lists the XRD peaks of oxalate crystal form A of compound (I).

[0277] Table 10 lists the XRD peaks of benzoate crystal form A of compound (I).

[0278] Table 11 lists the XRD peaks of benzoate crystal form B of compound (I).

[0279] Table 12 lists the XRD peaks of the benzoate crystal form C of compound (I).

[0280] Table 13 lists the XRD peaks of ethyl sulfonate form A of compound (I).

[0281] Table 14 lists the XRD peaks of ethyl sulfonate form B of compound (I).

[0282] Table 15 lists the XRD peaks of benzenesulfonate crystal form A of compound (I).

[0283] Table 16 lists the XRD peaks of benzenesulfonate crystal form B of compound (I).

[0284] Table 17 lists the XRD peaks of the benzenesulfonate crystal form C of compound (I).

[0285] Table 18 lists the XRD peaks of benzenesulfonate crystal form D of compound (I).

[0286] Table 19 lists the XRD peaks of benzenesulfonate crystal form E of compound (I).

[0287] Table 20 lists the XRD peaks of the benzenesulfonate crystal form F of compound (I).

[0288] Table 21 lists the XRD peaks of the benzenesulfonate crystal form G of compound (I).

[0289] Table 22 lists the XRD peaks of crystal form A of compound (I).

[0290] Table 23 lists the XRD peaks of crystal form B of compound (I).

[0291] Thermal characterization (TGA, DSC, DVS) was performed on the various crystal forms prepared in Examples 2-20, and the results are shown in Table 23-1:

[0292] Table 23-1 Characterization results of salt types of compounds of formula (I)

[0293] As can be seen from Table 23-1, considering factors such as crystallinity, TGA weight loss, and solvent residue, the benzenesulfonate crystal form B of formula (I) is relatively optimal.

[0294] Performance test results

[0295] 1. Stability test results of benzenesulfonate crystal form A, benzenesulfonate crystal form B and benzoate crystal form B of compound (I) under different conditions.

[0296] The benzenesulfonate crystal form A, benzenesulfonate crystal form B, and benzoate crystal form B of compound (I) were placed under conditions of 60℃, 92.5%RH, 5000lx, natural light, and light-proof conditions, respectively, and samples were taken at 5 days and 10 days to test their purity and properties. The results are shown in Table 24.

[0297] Table 24 shows the experimental results of factors affecting the pharmaceutically acceptable salts of compound (I).

[0298] As shown in Table 24, both benzenesulfonate crystal form B and benzoate crystal form B of formula (I) exhibit good stability, with benzenesulfonate crystal form B showing superior stability. According to Figures 10-E and 15-E, the XRD patterns of benzenesulfonate crystal form B before and after DVS testing are basically consistent, while benzoate crystal form B essentially transforms into an amorphous state after DVS testing. Benzenesulfonate crystal form A turns into a light yellow powder under light irradiation, with a significant decrease in purity, and XRD results show that it transforms into crystal form B after 10 days under high humidity conditions.

[0299] 2. Stability test results of compound (I) benzenesulfonate crystal form B under accelerated test, intermediate condition test, and long-term test conditions.

[0300] The benzenesulfonate sample (B) of formula (I) was packaged in a double-layer pharmaceutical low-density polyethylene bag (sealed with tie) as the inner packaging material and a polyester / aluminum / polyethylene pharmaceutical composite bag as the outer packaging material. Samples were taken at different time points under the following conditions: 40℃±2℃ / 75%RH±5%RH, 30℃±2℃ / 65%RH±5%RH, 25℃±2℃ / 60%RH±5%RH, and 2–8℃, respectively. The purity and crystal form were then tested. The results are shown in Table 25.

[0301] As can be seen from Table 25, the benzenesulfonate crystal form B of compound (I) maintained good stability in accelerated experiments, intermediate condition experiments, and long-term experiments.

[0302] Table 25 shows the experimental data on the stability of benzenesulfonate crystal form B of compound (I).

[0303] 3. Crystal transformation of benzenesulfonate crystal forms B and G

[0304] Equal amounts of benzenesulfonate crystals B and G were mixed and added to a pre-saturated solvent. The mixtures were then suspended and pulped at 25°C and 50°C. The test results are shown in Table 26.

[0305] It transforms into crystal form B at both 25℃ and 50℃.

[0306] Table 26 shows the competitive pulping results of benzenesulfonate crystal forms B and G of compound (I).

[0307] 4. Crystal transformation of benzenesulfonate crystal forms A, B, D, and E

[0308] Take appropriate amounts of crystal forms A, B, D, and E, mix them evenly, add them to a pre-saturated solvent, and suspend and pulp at 25℃ and 50℃. The test results are shown in Table 27: at 25℃ and 50℃, they all turn into crystal form B.

[0309] Table 27 shows the competitive beating results of benzenesulfonate crystal forms A, B, D, and E of compound (I).

[0310] As can be seen from Tables 26-27, the benzenesulfonate crystal form B of formula (I) is a thermodynamically stable crystal form at room temperature and 50°C.

[0311] 5. Solubility of benzenesulfonate crystal form B and benzoate crystal form B

[0312] Take appropriate amounts of benzenesulfonate crystal form B and benzoate crystal form B, add appropriate amounts of water respectively to prepare supersaturated solutions, suspend at 25℃ for 40h, take the supernatant for filtration, and detect the content and solubility results as shown in Table 28:

[0313] Table 28 shows the solubility test results of pharmaceutically usable salts of compound (I).

[0314] As can be seen from Table 28, the solubility of benzenesulfonate and benzoate of formula (I) is significantly higher than that of the free state, with benzenesulfonate being superior.

Claims

1. A pharmaceutically acceptable salt of a compound of formula (I), 2. The pharmaceutically acceptable salt according to claim 1, wherein the salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, fumarate, hydrohalates (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucilage, succinate, lactate, orotate, pamoate, glycine salt, alanine salt, arginine salt, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline salt, etc. The salts are ferrous sulfate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, malonate, gentianate, salicylate, succinate, glutamate, ethylsulfonate, gluconate, adipate, oxalate, or glutamate; preferably benzenesulfonate, succinate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, benzoate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate; more preferably benzenesulfonate and benzoate.

3. The medicinal salt according to claim 2, wherein, The molar ratio of the compound of formula (I) to the corresponding acid that forms the pharmaceutically acceptable salt is 1:0.5 to 1:3.5; preferably 1:1, 1:2 or 1:

3.

4. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the oxalate crystal form A of the compound of formula (I); its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 7.15°±0.2°, 9.94°±0.2°, 12.09°±0.2°, 23.39°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 4.77°±0.2°, 7.15°±0.2°, 9.16°±0.2°, 9.94°±0.2°, 12.09°±0.2°, 16.31°±0.2°, 19.76 ... The lower 2θ position has characteristic diffraction peaks: 4.77°±0.2°, 7.15°±0.2°, 8.19±0.2°, 9.16°±0.2°, 9.94°±0.2°, 10.42°±0.2°, 12.09°±0.2°, 12.54°±0.2°, 16.31°±0.2°, 17.66°±0.2°, 19.76°±0.2°, 21.30°±0.2°, 22.62°±0.2°, 23.39°±0.2°, 24.19°±0.2°, 24.60°±0.2°, 25.51°±0.2°, 26.18°±0.2°; or its X-ray powder diffraction pattern is basically shown in Figure 8-A.

5. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzoate crystal form A of the compound of formula (I); its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 3.64°±0.2°, 15.33°±0.2°, 18.71°±0.2°, 19.32°±0.2°, 25.19°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 3.64°±0.2°, 7.28°±0.2°, 10.96°±0.2°, 15.33°±0.2°, 18.71°±0.2°, 19.32°±0.2°. 0.2°, 21.90°±0.2°, 25.19°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 3.64°±0.2°, 7.28°±0.2°, 7.62±0.2°, 10.96°±0.2°, 13.43°±0.2°, 15.33°±0.2°, 16.41°±0.2°, 17.43°±0.2°, 18.71°±0.2°, 19.32°±0.2°, 21.90°±0.2°, 22.90°±0.2°, 25.19°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 9-A.

6. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzoate crystal form B of the compound of formula (I); its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.45°±0.2°, 12.91°±0.2°, 15.99°±0.2°, 20.10°±0.2°, 25.84°±0.2°; or exhibits characteristic diffraction peaks at the following 2θ positions: 3.93°±0.2°, 6.45°±0.2°, 12.91°±0.2°, 15.99°±0.2°, 19.27°±0.2°, 20.10°±0.2°, 21.62°±0.2°, 25. 0.84°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 3.93°±0.2°, 6.45°±0.2°, 8.55°±0.2°, 12.28°±0.2°, 12.91°±0.2°, 13.53°±0.2°, 15.99°±0.2°, 16.63°±0.2°, 18.28°±0.2°, 19.27°±0.2°, 20.10°±0.2°, 21.62°±0.2°, 23.05°±0.2°, 23.49°±0.2°, 25.84°±0.2°, 27.36°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 10-A.

7. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzoate crystal form C of the compound of formula (I); its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 4.30°±0.2°, 7.79°±0.2°, 9.43°±0.2°, 25.11°±0.2°; or exhibits characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 4.30°±0.2°, 7.79°±0.2°, 9.43°±0.2°, 10.11°±0.2°. 12.59°±0.2°, 13.19°±0.2°, 25.11°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 4.30°±0.2°, 7.79°±0.2°, 9.43°±0.2°, 10.11°±0.2°, 11.20°±0.2°, 12.59°±0.2°, 13.19°±0.2°, 15.20°±0.2°, 16.82°±0.2°, 25.11°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 11-A.

8. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form A of the compound of formula (I); its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 3.66°±0.2°, 5.16°±0.2°, 10.93°±0.2°, 16.50°±0.2°, 26.08°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 3.66°±0.2°, 5.16°±0.2°, 8.15°±0.2°, 10.93°±0.2°, 13.14°±0.2°, 16.50°±0.2°, 25.25°±0.2°, 26.08°±0.2°. 2°; or having characteristic diffraction peaks at the following 2θ positions: 3.66°±0.2°, 5.16°±0.2°, 8.15±0.2°, 10.34°±0.2°, 10.93°±0.2°, 13.14°±0.2°, 14.76°±0.2°, 15.52°±0.2°, 16.06°±0.2°, 16.50°±0.2°, 18.04°±0.2°, 19.60°±0.2°, 19.91°±0.2°, 23.32°±0.2°, 25.25°±0.2°, 26.08°±0.2°, 26.62°±0.2°; or having an X-ray powder diffraction pattern basically as shown in Figure 14-A.

9. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form B of the compound of formula (I); its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 9.03°±0.2°, 12.65°±0.2°, 14.78°±0.2°, 18.26°±0.2°, 25.01°±0.2°; or exhibits characteristic diffraction peaks at the following 2θ positions: 5.27°±0.2°, 9.03°±0.2°, 12.65°±0.2°, 14.78°±0.2°, 18.26°±0.2°, 23.54°±0.2°, 25.01°±0.2°, 25. 0.62°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 5.27°±0.2°, 9.03°±0.2°, 12.65°±0.2°, 13.92°±0.2°, 14.78°±0.2°, 16.67°±0.2°, 17.61°±0.2°, 18.26°±0.2°, 18.79°±0.2°, 22.31°±0.2°, 23.54°±0.2°, 23.91°±0.2°, 25.01°±0.2°, 25.62°±0.2°, 27.23°±0.2°, 28.23°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 15-A.

10. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form C of the compound of formula (I), and whose X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 3.33°±0.2°, 3.76°±0.2°, 4.66°±0.2°, 7.59°±0.2°, 7.89°±0.2°; or exhibits characteristic diffraction peaks at the following 2θ positions: 3.33°±0.2°, 3.76°±0.2°, 4.66°±0.2°, 7.59°±0.2°, 7.89°±0.2°, 11.45°±0.2°. 12.24°±0.2°, 15.98°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 3.33°±0.2°, 3.76°±0.2°, 4.66°±0.2°, 6.54°±0.2°, 7.59°±0.2°, 7.89°±0.2°, 10.10°±0.2°, 11.45°±0.2°, 12.24°±0.2°, 14.03°±0.2°, 15.98°±0.2°, 19.07°±0.2°, 23.96°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 16-A.

11. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form D of the compound of formula (I), and whose X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 7.81°±0.2°, 15.37°±0.2°, 17.88°±0.2°, 19.28°±0.2°, 25.69°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 7.81°±0.2°, 13.80°±0.2°, 15.37°±0.2°, 17.88°±0.2°, 19.28°±0.2°, 19.48°±0.2°, 23°±0.2°. 0.35°±0.2°, 25.69°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 7.81°±0.2°, 13.80°±0.2°, 14.23°±0.2°, 15.37°±0.2°, 15.61°±0.2°, 17.88°±0.2°, 18.32°±0.2°, 19.28°±0.2°, 19.48°±0.2°, 22.13°±0.2°, 23.35°±0.2°, 23.65°±0.2°, 25.69°±0.2°, 26.55°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 17-A.

12. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form E of the compound of formula (I), and whose X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 3.73°±0.2°, 7.77°±0.2°, 11.35°±0.2°, 15.91°±0.2°, 25.66°±0.2°; or has characteristic diffraction peaks at the following 2θ positions. Characteristic diffraction peaks are present: 3.73°±0.2°, 4.52°±0.2°, 7.77°±0.2°, 11.35°±0.2°, 12.13°±0.2°, 14.14°±0.2°, 15.91°±0.2°, 18.90°±0.2°, 23.60°±0.2°, 25.66°±0.2°; or their X-ray powder diffraction patterns are basically shown in Figure 18-A.

13. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form F of the compound of formula (I), and whose X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 5.31°±0.2°, 7.22°±0.2°, 7.90°±0.2°, 9.07°±0.2°, 15.82°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 5.31°±0.2°, 7.22°±0.2°, 7.54°±0.2°, 7.90°±0.2°, 9.07°±0.2°, 10.19°±0.2°, 15.82°±0.2°. 2°, 23.55°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 5.31°±0.2°, 6.57°±0.2°, 7.22°±0.2°, 7.54°±0.2°, 7.90°±0.2°, 9.07°±0.2°, 10.19°±0.2°, 12.13°±0.2°, 14.09°±0.2°, 15.82°±0.2°, 18.25°±0.2°, 19.01°±0.2°, 20.39°±0.2°, 23.55°±0.2°, 23.86°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 19-A.

14. The pharmaceutically acceptable salt according to any one of claims 1-3, which is the benzenesulfonate crystal form G of the compound of formula (I), and whose X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 4.13°±0.2°, 5.37°±0.2°, 9.15°±0.2°, 14.85°±0.2°, 25.08°±0.2°; or has characteristic diffraction peaks at the following 2θ positions: 4.13°±0.2°, 5.37°±0.2°, 9.15°±0.2°, 11.95°±0.2°, 12.78°±0.2°, 14.85°±0.2°, 18.48°±0.2°. 2°, 25.08°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 4.13°±0.2°, 5.37°±0.2°, 7.42°±0.2°, 9.15°±0.2°, 10.70°±0.2°, 10.85°±0.2°, 11.95°±0.2°, 12.78°±0.2°, 14.00°±0.2°, 14.85°±0.2°, 15.33°±0.2°, 18.48°±0.2°, 20.72°±0.2°, 25.08°±0.2°, 25.64°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 20-A.

15. A crystalline form A of a compound of formula (I), subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 3.63°±0.2°, 5.93°±0.2°, 6.95°±0.2°, 13.78°±0.2°, 15.01°±0.2°; or characteristic diffraction peaks at the following 2θ positions: 3.63°±0.2°, 5.93°±0.2°, 6.95°±0.2°, 10.91°±0.2°, 13.78°±0.2°, 15.01°±0.2°, 25.03°±0.2°. 2°, 25.78°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 3.63°±0.2°, 4.19°±0.2°, 5.93°±0.2°, 6.95°±0.2°, 7.26°±0.2°, 10.91°±0.2°, 13.78°±0.2°, 15.01°±0.2°, 16.82°±0.2°, 20.99°±0.2°, 25.03°±0.2°, 25.78°±0.2°, 26.91°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 21-A.

16. A crystalline form B of a compound of formula (I), subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions in its X-ray powder diffraction pattern: 15.23°±0.2°, 20.57°±0.2°, 22.47°±0.2°, 23.30°±0.2°, 24.15°±0.2°; or characteristic diffraction peaks at the following 2θ positions: 9.12°±0.2°, 15.23°±0.2°, 18.35°±0.2°, 19.89°±0.2°, 20.57°±0.2°, 22.47°±0.2°, 23.30°±0.2°. 0.2°, 24.15°±0.2°; or have characteristic diffraction peaks at the following 2θ positions: 9.12°±0.2°, 14.30°±0.2°, 14.76°±0.2°, 15.23°±0.2°, 16.83°±0.2°, 18.35°±0.2°, 19.89°±0.2°, 20.57°±0.2°, 21.41°±0.2°, 22.47°±0.2°, 23.30°±0.2°, 24.15°±0.2°, 27.18°±0.2°; or have an X-ray powder diffraction pattern basically as shown in Figure 22-A.

17. A method for preparing a pharmaceutically acceptable salt of a compound of formula (I), wherein, The method includes the steps of forming a salt from a compound of formula (I); the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, fumarate, hydrohalate (preferably hydrobromide and hydrochloride), sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucilage, succinate, lactate, orotate, pamoate, glycinate, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylacetate, L-proline. Salts, ferulic acid salts, 2-hydroxyethanesulfonate, mandelic acid salts, nitrates, methanesulfonate, malonate, gentianate, salicylate, succinate, glutamate, ethylsulfonate, gluconate, adipate, oxalate, or glutamate; preferably from benzenesulfonate, succinate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, benzoate, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate; more preferably from benzenesulfonate and benzoate; 18. A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of any one of claims 1-14 or a crystal form of any one of claims 15-16, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg.

19. Use of the pharmaceutically acceptable salt of any one of claims 1-14, or the crystal form of any one of claims 15-16, or the pharmaceutical composition of claim 18 in the preparation of a medicament for treating or preventing PRMT5-mediated diseases.

20. A method for treating or preventing PRMT5-mediated diseases, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt of any one of claims 1-14 or a crystal form of any one of claims 15-16, or a pharmaceutical composition of claim 18, wherein the therapeutically effective amount is preferably 1-1500 mg.

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