Crystal form, salt form, solvate, hydrate of compound and use thereof

Abstract

The present application provides a crystal form, a salt form, a solvate and a hydrate of a compound as represented by formula (I), and a pharmaceutical composition containing the crystal form, the salt form, the solvate or the hydrate. The present application further provides the use of the crystal form, the salt form, the solvate or the hydrate.

Description

Crystal forms, salt forms, solvates, hydrates and their uses of compounds

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application 202410708952.2, filed on May 31, 2024, the contents of which are incorporated herein by reference in their entirety and for all purposes. Technical Field

[0003] This application belongs to the field of pharmaceutical technology, specifically relating to the crystal form, salt form, solvate, and hydrate of N-(8,8-difluoro-4-methoxy-6,7,8,9-tetrahydropyridin[1,2-a]indol-1-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide, as well as pharmaceutical compositions containing these crystal forms, salt forms, solvates, or hydrates, and also relating to the use of these crystal forms, salt forms, solvates, or hydrates. Background Technology

[0004] Chromosomal instability (CIN) is caused by errors in chromosome segregation during mitosis. CIN is a key characteristic of recurrent and metastatic advanced malignant tumors, occurring in approximately 90% of solid tumors and affecting the genome of about 25% of solid tumor cells. The causes of CIN are diverse, including mitotic errors, replication stress, homologous recombination repair, and the break-fusion-bridging cycle. CIN is closely associated with cell transformation, tumor progression and recurrence, chemotherapy resistance, and poor prognosis.

[0005] Kinesins are molecular motors that play crucial roles in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins function in multiple aspects, including spindle assembly, chromosome segregation, centrosome separation, and dynamics. Based on sequence homology within their motor domains, human kinesins are classified into 14 subfamilies. KIF18A, belonging to the kinesin-8 family, is a G2 / M phase-specific protein in mitosis. It plays a key role in maintaining the integrity of the bipolar spindle during cell division, thereby regulating chromosome localization. Intracellularly, KIF18A utilizes energy released from ATP hydrolysis to move towards the positive pole via microtubules. It is also located at the positive pole of microtubules, regulating their dynamic instability and exhibiting activity similar to microtubule depolymerases. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a crucial role in the timely alignment of chromosomes, maintaining genome stability, and successfully completing mitosis.

[0006] Studies have shown that kinesin KIF18A is a crucial factor influencing the proliferation of CIN tumor cells. KIF18A knockout leads to mitotic fragility in CIN-characteristic tumor cells, associated with spindle assembly checkpoint (SAC) activation, multipolar spindle formation, and apoptosis induction. This fragility results in mitotic arrest, cell cycle arrest, and apoptosis. KIF18A is an essential gene for abnormal somatic cell division, but CIN tumor cells are highly sensitive to KIF18A knockout. Therefore, small-molecule inhibitors of KIF18A can selectively target CIN-characteristic tumor cells. Compared to other drugs targeting mitotic mechanisms, KIF18A inhibition does not affect the proliferation of normal cells. Currently, there are no effective therapies targeting CIN, making KIF18A a highly promising new anti-tumor target.

[0007] The compound shown in formula (I) is a highly effective KIF18A inhibitor, and its free base compound is chemically named N-(8,8-difluoro-4-methoxy-6,7,8,9-tetrahydropyridin[1,2-a]indol-1-yl)-4-(2-hydroxyethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide. Further research is needed to improve the physicochemical properties of this compound, such as stability, solubility, and bioavailability, and to obtain crystal forms, salt forms, solvates, and hydrates suitable for preparing pharmaceutical formulations. Summary of the Invention

[0008] This application provides a crystal form of the compound shown in formula (I).

[0009] This application also provides a salt form of the compound shown in formula (I).

[0010] This application provides a solvate of the compound shown in formula (I),

[0011] This application provides a hydrate of the compound shown in formula (I),

[0012] This application also provides a pharmaceutical composition comprising the crystal form, salt form, solvate or hydrate of the compound shown in formula (I) above, and a pharmaceutically acceptable carrier or excipient.

[0013] This application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for treating diseases or conditions mediated by kinesin KIF18A.

[0014] This application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for reducing the size of solid tumors in subjects.

[0015] This application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for treating cell proliferation disorders in subjects.

[0016] This application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for inhibiting KIF18A in cells.

[0017] This application also provides a method for treating diseases or conditions mediated by kinesin KIF18A, comprising administering to a patient in need a therapeutically effective amount of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above.

[0018] This application also provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need a therapeutically effective amount of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound represented by formula (I) above.

[0019] This application also provides a method for treating cell proliferation disorders in a subject, the method comprising administering to a subject in need a therapeutically effective amount of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound represented by formula (I) above.

[0020] This application also provides a method for inhibiting KIF18A in cells, the method comprising contacting the cells with the crystal form, salt form, solvate, hydrate or pharmaceutical composition of the compound shown in formula (I) above.

[0021] Invention Details

[0022] In a first aspect, this application provides the crystal form of the compound shown in formula (I),

[0023] According to some embodiments of this application, the crystal form is crystal form I, and the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation has a diffraction peak at 8.93°±0.2°.

[0024] According to some embodiments of this application, the crystal form I, using Cu-Kα radiation, has a diffraction peak at 17.89°±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle.

[0025] According to some embodiments of this application, the crystal form I of the compound shown in formula (I) has diffraction peaks at 8.93°±0.2° and 17.89°±0.2° when X-ray powder diffraction patterns expressed in 2θ angles are obtained using Cu-Kα radiation.

[0026] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 11.77°±0.2°, 15.73°±0.2°, 16.76°±0.2°, and 20.73°±0.2°.

[0027] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns at 2θ angles with diffraction peaks at the following 2θ angles: 8.93°±0.2°, 11.77°±0.2°, 15.73°±0.2°, 16.76°±0.2°, 17.89°±0.2°, and 20.73°±0.2°.

[0028] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 17.50°±0.2°, 18.08°±0.2°, 21.27°±0.2°, 23.62°±0.2°, and 26.96°±0.2°.

[0029] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.93°±0.2°, 11.77°±0.2°, 15.73°±0.2°, 16.76°±0.2°, 17.89°±0.2°, 17.50°±0.2°, 18.08°±0.2°, 20.73°±0.2°, 21.27°±0.2°, 23.62°±0.2°, and 26.96°±0.2°.

[0030] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 5.35°±0.2°, 11.61°±0.2°, 14.68°±0.2°, 20.30°±0.2°, 22.18°±0.2°, 22.42°±0.2°, 23.39°±0.2°, 26.73°±0.2°, and 27.84°±0.2°.

[0031] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.35°±0.2°, 8.93°±0.2°, 11.77°±0.2°, 11.61°±0.2°, 14.68°±0.2°, 15.73°±0.2°, 16.76°±0.2°, and 17.5°. 0°±0.2°, 17.89°±0.2°, 18.08°±0.2°, 20.30°±0.2°, 20.73°±0.2°, 21.27°±0.2°, 22.18°±0.2°, 22.42°±0.2°, 23.39°±0.2°, 23.62°±0.2°, 26.73°±0.2°, 26.96°±0.2°, 27.84°±0.2°.

[0032] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 17.13°±0.2°, 19.05°±0.2°, 20.49°±0.2°, 24.34°±0.2°, 25.2°±0.2°, 25.51°±0.2°, 27.68°±0.2°, and 36.22°±0.2°.

[0033] In some embodiments, the crystal form I of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.35°±0.2°, 8.93°±0.2°, 11.77°±0.2°, 11.61°±0.2°, 14.68°±0.2°, 15.73°±0.2°, 16.76°±0.2°, 17.13°±0.2°, 17.50°±0.2°, 17.89°±0.2°, 18.08°±0.2°, 19. 0.5°±0.2°, 20.30°±0.2°, 20.49°±0.2°, 20.73°±0.2°, 21.27°±0.2°, 22.18°±0.2°, 22.42°±0.2°, 23.39°±0.2°, 23.62°±0.2°, 24.34°±0.2°, 25.2°±0.2°, 25.51°±0.2°, 26.73°±0.2°, 26.96°±0.2°, 27.68°±0.2°, 27.84°±0.2°, 36.22°±0.2°.

[0034] In some embodiments, the crystal form I of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2θ angles, which is substantially the same as that in Figure 1, when irradiated with Cu-Kα.

[0035] In some embodiments, the DSC curve of crystal form I of the compound shown in formula (I) has an endothermic peak at 237°C to 247°C. In some embodiments, the DSC curve of crystal form I of the compound shown in formula (I) is substantially the same as that in Figure 2.

[0036] In some embodiments, the TGA curve of crystal form I of the compound shown in formula (I) shows essentially zero weight loss at temperatures ranging from 20°C to 200°C. In some embodiments, the TGA curve of crystal form I of the compound shown in formula (I) is substantially the same as that in Figure 3.

[0037] In some embodiments, the crystal form I of the compound represented by formula (I) is the amorphous form.

[0038] According to some embodiments of this application, the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation has a diffraction peak at 16.31°±0.2°. According to some embodiments of this application, the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation has a diffraction peak at 19.29°±0.2°.

[0039] According to some embodiments of this application, the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation has diffraction peaks at 16.31°±0.2° and 19.29°±0.2°.

[0040] According to some embodiments of this application, the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation also has diffraction peaks at one or more of the following 2θ angles: 11.09°±0.2°, 18.47°±0.2°, 21.44°±0.2°, and 23.82°±0.2°.

[0041] According to some embodiments of this application, the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation has diffraction peaks at the following 2θ angles: 11.09°±0.2°, 16.31°±0.2°, 18.47°±0.2°, 19.29°±0.2°, 21.44°±0.2°, and 23.82°±0.2°.

[0042] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 17.21°±0.2°, 17.83°±0.2°, and 19.70°±0.2°.

[0043] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns at 2θ angles with diffraction peaks at the following 2θ angles: 11.09°±0.2°, 16.31°±0.2°, 17.21°±0.2°, 17.83°±0.2°, 18.47°±0.2°, 19.29°±0.2°, 19.70°±0.2°, 21.44°±0.2°, and 23.82°±0.2°.

[0044] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 5.62°±0.2°, 10.41°±0.2°, 20.63°±0.2°, 20.98°±0.2°, 22.69°±0.2°, and 23.17°±0.2°.

[0045] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.62°±0.2°, 10.41°±0.2°, 11.09°±0.2°, 16.31°±0.2°, 17.21°±0.2°, 17.83°±0.2°, 18.47°±0.2°, 19.29°±0.2°, 19.70°±0.2°, 20.63°±0.2°, 20.98°±0.2°, 21.44°±0.2°, 22.69°±0.2°, 23.17°±0.2°, and 23.82°±0.2°.

[0046] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 12.39°±0.2°, 16.92°±0.2°, 20.45°±0.2°, 26.32°±0.2°, 27.98°±0.2°, 28.31°±0.2°, and 28.67°±0.2°.

[0047] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.62°±0.2°, 10.41°±0.2°, 11.09°±0.2°, 12.39°±0.2°, 16.31°±0.2°, 16.92°±0.2°, 17.21°±0.2°, 17.83°±0.2°, 18. 47°±0.2°, 19.29°±0.2°, 19.70°±0.2°, 20.45°±0.2°, 20.63°±0.2°, 20.98°±0.2°, 21.44°±0.2°, 22.69°±0.2°, 23.17°±0.2°, 23.82°±0.2°, 26.32°±0.2°, 27.98°±0.2°, 28.31°±0.2°, 28.67°±0.2°.

[0048] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 9.47°±0.2°, 10.66°±0.2°, 14.33°±0.2°, 27.31°±0.2°, 29.06°±0.2°, 31.20°±0.2°, 32.48°±0.2°, and 34.66°±0.2°.

[0049] In some embodiments, the crystal form II of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.62°±0.2°, 9.47°±0.2°, 10.41°±0.2°, 10.66°±0.2°, 11.09°±0.2°, 12.39°±0.2°, 14.33°±0.2°, 16.31°±0.2°, 16.92°±0.2°, 17.21°±0.2°, 17.83°±0.2°, 18.47°±0.2°, 19.2°±0.2°. 9°±0.2°, 19.70°±0.2°, 20.45°±0.2°, 20.63°±0.2°, 20.98°±0.2°, 21.44°±0.2°, 22.69°±0.2°, 23.17°±0.2°, 23.82°±0.2°, 26.32°±0.2°, 27.31°±0.2°, 27.98°±0.2°, 28.31°±0.2°, 28.67°±0.2°, 29.06°±0.2°, 31.20°±0.2°, 32.48°±0.2°, 34.66°±0.2°.

[0050] In some embodiments, the crystal form II of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2θ angles, which is substantially the same as that in Figure 5, when irradiated with Cu-Kα.

[0051] In some embodiments, the DSC curve of crystal form II of the compound shown in formula (I) has an endothermic peak at 238°C to 248°C. In some embodiments, the DSC curve of crystal form II of the compound shown in formula (I) is substantially the same as that in Figure 6.

[0052] In some embodiments, the TGA curve of crystal form II of the compound shown in formula (I) shows essentially zero weight loss at temperatures ranging from 20°C to 200°C. In some embodiments, the TGA curve of crystal form II of the compound shown in formula (I) is substantially the same as that in Figure 7.

[0053] In some embodiments, the crystal form II of the compound represented by formula (I) is the amorphous form.

[0054] The second aspect of this application provides a salt form of the compound shown in formula (I).

[0055] According to some embodiments of this application, the salt type is an inorganic acid or organic acid salt of the compound shown in formula (I). In some embodiments, the inorganic acid or organic acid is selected from hydrochloric acid, toluenesulfonic acid (e.g., p-toluenesulfonic acid), sulfuric acid, hydrobromic acid, maleic acid, succinic acid, citric acid, fumaric acid, salicylic acid, L-tartaric acid, fumaric acid, acetic acid, nitric acid, phosphoric acid, oxalic acid, lactic acid, and amino acids (e.g., lysine or aspartic acid).

[0056] According to some embodiments of this application, the salt type is a hydrochloride, p-toluenesulfonate, or sulfate of the compound shown in formula (I).

[0057] According to some embodiments of this application, the salt type is the hydrochloride salt of the compound shown in formula (I).

[0058] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at 15.07° ± 0.2° in an X-ray powder diffraction pattern expressed in 2θ angle.

[0059] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at 15.98° ± 0.2° in an X-ray powder diffraction pattern expressed in 2θ angle.

[0060] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at 15.07°±0.2° and 15.98°±0.2° in X-ray powder diffraction patterns expressed in 2θ angles.

[0061] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 10.04°±0.2°, 14.54°±0.2°, 18.26°±0.2°, 18.72°±0.2°, and 24.19°±0.2°.

[0062] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns at 2θ angles with diffraction peaks at the following 2θ angles: 10.04°±0.2°, 14.54°±0.2°, 15.07°±0.2°, 15.98°±0.2°, 18.26°±0.2°, 18.72°±0.2°, and 24.19°±0.2°.

[0063] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 5.00°±0.2°, 8.64°±0.2°, 20.88°±0.2°, 23.49°±0.2°, and 28.21°±0.2°.

[0064] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns at 2θ angles with diffraction peaks at the following 2θ angles: 5.00°±0.2°, 8.64°±0.2°, 10.04°±0.2°, 14.54°±0.2°, 15.07°±0.2°, 15.98°±0.2°, 18.26°±0.2°, 18.72°±0.2°, 20.88°±0.2°, 23.49°±0.2°, 24.19°±0.2°, and 28.21°±0.2°.

[0065] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 12.02°±0.2°, 17.05°±0.2°, 17.38°±0.2°, 19.91°±0.2°, 20.12°±0.2°, 20.47°±0.2°, 22.24°±0.2°, and 25.55°±0.2°.

[0066] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction peaks at 2θ angles at the following 2θ angles: 5.00°±0.2°, 8.64°±0.2°, 10.04°±0.2°, 12.02°±0.2°, 14.54°±0.2°, 15.07°±0.2°, 15.98°±0.2°, and 17.0°. 5°±0.2°, 17.38°±0.2°, 18.26°±0.2°, 18.72°±0.2°, 19.91°±0.2°, 20.12°±0.2°, 20.47°±0.2°, 20.88°±0.2°, 22.24°±0.2°, 23.49°±0.2°, 24.19°±0.2°, 25.55°±0.2°, 28.21°±0.2°.

[0067] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 9.18°±0.2°, 21.60°±0.2°, 22.07°±0.2°, 23.84°±0.2°, 25.95°±0.2°, 27.53°±0.2°, 27.82°±0.2°, 29.32°±0.2°, and 40.98°±0.2°.

[0068] In some embodiments, the hydrochloride salt of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction peaks at 2θ angles at the following 2θ angles: 5.00°±0.2°, 8.64°±0.2°, 9.18°±0.2°, 10.04°±0.2°, 12.02°±0.2°, 14.54°±0.2°, 15.07°±0.2°, 15.98°±0.2°, 17.05°±0.2°, 17.38°±0.2°, 18.26°±0.2°, and 18.72°±0.2°. °, 19.91°±0.2°, 20.12°±0.2°, 20.47°±0.2°, 20.88°±0.2°, 21.60°±0.2°, 22.07°±0.2°, 22.24°±0.2°, 23.49°±0.2°, 23.84°±0.2°, 24.19°±0.2°, 25.55°±0.2°, 25.95°±0.2°, 27.53°±0.2°, 27.82°±0.2°, 28.21°±0.2°, 29.32°±0.2°, 40.98°±0.2°.

[0069] In some embodiments, the hydrochloride salt of the compound shown in formula (I) has an X-ray powder diffraction pattern, expressed in 2θ angles, that is substantially the same as that in Figure 9, when irradiated with Cu-Kα.

[0070] In some embodiments, the DSC curve of the hydrochloride salt of the compound shown in formula (I) has an endothermic peak at 185–225 °C (e.g., 210–220 °C). In some embodiments, the DSC curve of the hydrochloride salt of the compound shown in formula (I) is substantially the same as that in Figure 10.

[0071] In some embodiments, the TGA curve of the hydrochloride salt of the compound shown in formula (I) shows a weight loss between 20 and 170°C, with a weight loss of 0.1% to 0.5% between 20 and 100°C. In some embodiments, the TGA curve of the hydrochloride salt of the compound shown in formula (I) is substantially the same as that in Figure 11.

[0072] According to some embodiments of this application, the salt type is a p-toluenesulfonate of the compound shown in formula (I).

[0073] In some embodiments, the p-toluenesulfonate of the compound represented by formula (I) has crystal form III.

[0074] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I) has a diffraction peak at 7.59°±0.2° when X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0075] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles, which also has diffraction peaks at one or more of the following 2θ angles: 3.80°±0.2°, 15.96°±0.2°, and 17.50°±0.2°.

[0076] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at the following 2θ angles: 3.80°±0.2°, 7.59°±0.2°, 15.96°±0.2°, and 17.50°±0.2°.

[0077] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 5.31°±0.2°, 19.42°±0.2°, 19.83°±0.2°, 20.73°±0.2°, 22.79°±0.2°, 24.13°±0.2°, and 24.28°±0.2°.

[0078] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 3.80°±0.2°, 5.31°±0.2°, 7.59°±0.2°, 15.96°±0.2°, 17.50°±0.2°, 19.42°±0.2°, 19.83°±0.2°, 20.73°±0.2°, 22.79°±0.2°, 24.13°±0.2°, and 24.28°±0.2°.

[0079] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 12.23°±0.2°, 18.18°±0.2°, 18.41°±0.2°, 18.65°±0.2°, 21.56°±0.2°, and 23.50°±0.2°.

[0080] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when subjected to Cu-Kα radiation, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 3.80°±0.2°, 5.31°±0.2°, 7.59°±0.2°, 12.23°±0.2°, 15.96°±0.2°, and 17.50°±0.2°. 0.2°, 18.18°±0.2°, 18.41°±0.2°, 18.65°±0.2°, 19.42°±0.2°, 19.83°±0.2°, 20.73°±0.2°, 21.56°±0.2°, 22.79°±0.2°, 23.50°±0.2°, 24.13°±0.2°, 24.28°±0.2°.

[0081] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns at 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 8.62°±0.2°, 9.28°±0.2°, 11.78°±0.2°, 16.88°±0.2°, 20.28°±0.2°, 26.48°±0.2°, and 28.11°±0.2°.

[0082] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction peaks at one or more of the following 2θ angles in its 2θ angle X-ray powder diffraction pattern: 3.80°±0.2°, 5.31°±0.2°, 7.59°±0.2°, 8.62°±0.2°, 9.28°±0.2°, 11.78°±0.2°, 12.23°±0.2°, 15.96°±0.2°, 16.88°±0.2°, 1 7.50°±0.2°, 18.18°±0.2°, 18.41°±0.2°, 18.65°±0.2°, 19.42°±0.2°, 19.83°±0.2°, 20.28°±0.2°, 20.73°±0.2°, 21.56°±0.2°, 22.79°±0.2°, 23.50°±0.2°, 24.13°±0.2°, 24.28°±0.2°, 26.48°±0.2°, 28.11°±0.2°.

[0083] In some embodiments, the p-toluenesulfonate crystal form III of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2θ angles using Cu-Kα radiation that is substantially the same as that in Figure 13.

[0084] In some embodiments, the DSC curve of p-toluenesulfonate crystal form III of the compound shown in formula (I) has an endothermic peak at 160°C to 200°C (e.g., 170°C to 185°C). In some embodiments, the DSC curve of p-toluenesulfonate crystal form III of the compound shown in formula (I) is substantially the same as that in Figure 14.

[0085] In some embodiments, the TGA curves of p-toluenesulfonate crystal form III of the compound shown in formula (I) show a weight loss of 3.0% to 4.0% at 20°C to 150°C and a weight loss of 4.0% to 5.0% at 150°C to 215°C. In some embodiments, the TGA curves of p-toluenesulfonate crystal form III of the compound shown in formula (I) are substantially the same as those in Figure 15.

[0086] According to some embodiments of this application, the p-toluenesulfonate of the compound shown in formula (I) has crystal form IV.

[0087] In some embodiments, the p-toluenesulfonate crystal form IV of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles: 3.80°±0.2°, 4.13°±0.2°, 9.39°±0.2°, 17.48°±0.2°, 19.09°±0.2°, and 21.83°±0.2°.

[0088] In some embodiments, the p-toluenesulfonate crystal form IV of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 5.25°±0.2°, 6.67°±0.2°, 7.90°±0.2°, 17.99°±0.2°, 19.42°±0.2°, 20.63°±0.2°, 22.12°±0.2°, and 23.33°±0.2°.

[0089] In some embodiments, the p-toluenesulfonate crystal form IV of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 3.80°±0.2°, 4.13°±0.2°, 5.25°±0.2°, 6.67°±0.2°, 7.90°±0.2°, 9.39°±0.2°, 17.48°±0.2°, 17.99°±0.2°, 19.09°±0.2°, 19.42°±0.2°, 20.63°±0.2°, 21.83°±0.2°, 22.12°±0.2°, and 23.33°±0.2°.

[0090] In some embodiments, the p-toluenesulfonate crystal form IV of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 15.75°±0.2°, 16.00°±0.2°, 16.35°±0.2°, 17.05°±0.2°, 19.58°±0.2°, 20.26°±0.2°, 21.11°±0.2°, 22.53°±0.2°, 24.61°±0.2°, and 27.12°±0.2°.

[0091] In some embodiments, the p-toluenesulfonate crystal form IV of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 3.80°±0.2°, 4.13°±0.2°, 5.25°±0.2°, 6.67°±0.2°, 7.90°±0.2°, 9.39°±0.2°, 15.75°±0.2°, 16.00°±0.2°, 16.35°±0.2°, 17. 0.5°±0.2°, 17.48°±0.2°, 17.99°±0.2°, 19.09°±0.2°, 19.42°±0.2°, 19.58°±0.2°, 20.26°±0.2°, 20.63°±0.2°, 21.11°±0.2°, 21.83°±0.2°, 22.12°±0.2°, 22.53°±0.2°, 23.33°±0.2°, 24.61°±0.2°, 27.12°±0.2°.

[0092] In some embodiments, the p-toluenesulfonate crystal form IV of the compound shown in formula (I) is substantially the same as the X-ray powder diffraction pattern in Figure 17 when irradiated with Cu-Kα at an angle of 2θ.

[0093] In some embodiments, the DSC curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) exhibits an endothermic peak at 50°C to 60°C. In some embodiments, the DSC curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) exhibits an endothermic peak at 135°C to 175°C (e.g., 160°C to 170°C). In some embodiments, the DSC curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) exhibits endothermic peaks at both 50°C to 60°C and 135°C to 175°C (e.g., 160°C to 170°C). In some embodiments, the DSC curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) is substantially the same as that in Figure 18.

[0094] In some embodiments, the TGA curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) shows a weight loss of 1.5% to 2.5% at 20°C to 100°C. In some embodiments, the TGA curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) shows a weight loss of 6.0% to 7.0% at 100°C to 200°C. In some embodiments, the TGA curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) shows a weight loss of 1.5% to 2.5% at 20°C to 100°C and a weight loss of 6.0% to 7.0% at 100°C to 200°C. In some embodiments, the TGA curve of p-toluenesulfonate crystal form IV of the compound shown in formula (I) is substantially the same as that in Figure 19.

[0095] According to some embodiments of this application, the salt type is a sulfate of the compound shown in formula (I).

[0096] According to some embodiments of this application, the sulfate of the compound shown in formula (I) is a solvate. In some embodiments, the sulfate of the compound shown in formula (I) is an acetone solvate.

[0097] In some embodiments, the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at the following 2θ angles: 9.34°±0.2°, 21.04°±0.2°, and 26.15°±0.2°.

[0098] In some embodiments, the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at one or more of the following 2θ angles in its X-ray powder diffraction pattern expressed in 2θ angles: 8.50°±0.2°, 19.93°±0.2°, 20.16°±0.2°.

[0099] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at the following 2θ angles: 8.50°±0.2°, 9.34°±0.2°, 19.93°±0.2°, 20.16°±0.2°, 21.04°±0.2°, and 26.15°±0.2°.

[0100] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 16.26°±0.2°, 18.45°±0.2°, 20.55°±0.2°, 22.44°±0.2°, and 25.86°±0.2°.

[0101] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.50°±0.2°, 9.34°±0.2°, 16.26°±0.2°, 18.45°±0.2°, 19.93°±0.2°, 20.16°±0.2°, 20.55°±0.2°, 21.04°±0.2°, 22.44°±0.2°, 25.86°±0.2°, and 26.15°±0.2°.

[0102] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 12.50°±0.2°, 13.85°±0.2°, 16.47°±0.2°, 16.64°±0.2°, 17.21°±0.2°, 19.56°±0.2°, 24.24°±0.2°, 24.48°±0.2°, and 24.83°±0.2°.

[0103] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.50°±0.2°, 9.34°±0.2°, 12.50°±0.2°, 13.85°±0.2°, 16.26°±0.2°, 16.47°±0.2°, 16.64°±0.2°, 17°±0.2°. 0.21°±0.2°, 18.45°±0.2°, 19.56°±0.2°, 19.93°±0.2°, 20.16°±0.2°, 20.55°±0.2°, 21.04°±0.2°, 22.44°±0.2°, 24.24°±0.2°, 24.48°±0.2°, 24.83°±0.2°, 25.86°±0.2°, 26.15°±0.2°.

[0104] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2θ angles using Cu-Kα radiation that is substantially the same as that in Figure 25.

[0105] In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) has an endothermic peak at 125°C to 175°C (e.g., 160°C to 170°C). In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) has an endothermic peak at 245°C to 255°C. In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) has endothermic peaks at 125°C to 175°C (e.g., 160°C to 170°C) and 245°C to 255°C. In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) is substantially the same as that in Figure 26.

[0106] In some embodiments, the TGA curve of the acetone sulfate solvate of the compound shown in formula (I) shows a weight loss of 7.0% to 8.0% between 20°C and 180°C. In some embodiments, the TGA curve of the acetone sulfate solvate of the compound shown in formula (I) is substantially the same as that in Figure 27.

[0107] According to some embodiments of this application, the sulfate of the compound shown in formula (I) is a hydrate.

[0108] In some embodiments of this application, the sulfate hydrate of the compound shown in formula (I) has a diffraction peak at 17.87°±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0109] In some embodiments, the sulfate hydrate of the compound shown in formula (I) has a diffraction peak at 18.80° ± 0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0110] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at 17.87°±0.2° and 18.80°±0.2°.

[0111] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, and 22.16°±0.2°.

[0112] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at one or more of the following 2θ angles in its X-ray powder diffraction pattern expressed in 2θ angles: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, 17.87°±0.2°, 18.80°±0.2°, and 22.16°±0.2°.

[0113] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 19.02°±0.2°, 20.28°±0.2°, 22.44°±0.2°, 26.65°±0.2°, and 28.36°±0.2°.

[0114] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, 17.87°±0.2°, 18.80°±0.2°, 19.02°±0.2°, 20.28°±0.2°, 22.16°±0.2°, 22.44°±0.2°, 26.65°±0.2°, and 28.36°±0.2°.

[0115] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 6.71°±0.2°, 13.36°±0.2°, 24.42°±0.2°, 27.31°±0.2°, 36.18°±0.2°, and 36.99°±0.2°.

[0116] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.71°±0.2°, 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 13.36°±0.2°, 17.54°±0.2°, and 17.8°±0.2°. 7°±0.2°, 18.80°±0.2°, 19.02°±0.2°, 20.28°±0.2°, 22.16°±0.2°, 22.44°±0.2°, 24.42°±0.2°, 26.65°±0.2°, 27.31°±0.2°, 28.36°±0.2°, 36.18°±0.2°, 36.99°±0.2°.

[0117] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 23.19°±0.2°, 25.68°±0.2°, 27.99°±0.2°, 29.70°±0.2°, 30.29°±0.2°, 31.86°±0.2°, and 35.67°±0.2°.

[0118] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.71°±0.2°, 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 13.36°±0.2°, 17.54°±0.2°, 17.87°±0.2°, 18.80°±0.2°, 19.02°±0.2°, and 20.28°±0.2°. °, 22.16°±0.2°, 22.44°±0.2°, 23.19°±0.2°, 24.42°±0.2°, 25.68°±0.2°, 26.65°±0.2°, 27.31°±0.2°, 27.99°±0.2°, 28.36°±0.2°, 29.70°±0.2°, 30.29°±0.2°, 31.86°±0.2°, 35.67°±0.2°, 36.18°±0.2°, 36.99°±0.2°.

[0119] In some embodiments, the sulfate hydrate of the compound shown in formula (I) has an X-ray powder diffraction pattern, expressed in 2θ angles, that is substantially the same as that in Figure 29, when irradiated with Cu-Kα.

[0120] In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) has an endothermic peak at 110°C to 150°C (e.g., 125°C to 135°C). In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) has an endothermic peak at 170°C to 200°C (e.g., 175°C to 185°C). In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) has endothermic peaks at 110°C to 150°C (e.g., 125°C to 135°C) and 170°C to 200°C (e.g., 175°C to 185°C). In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) is substantially the same as that in Figure 30.

[0121] In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) shows a weight loss of 5.0% to 6.0% at 20°C to 120°C. In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) shows a weight loss of 4.0% to 5.0% at 120°C to 210°C. In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) shows a weight loss of 5.0% to 6.0% at 20°C to 120°C and a weight loss of 4.0% to 5.0% at 120°C to 210°C. In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) is substantially the same as that in Figure 31.

[0122] According to some embodiments of this application, the salt type is a metal salt of the compound shown in formula (I), such as an alkali metal salt, an alkaline earth metal salt, etc. In some embodiments, the salt type is a sodium salt, potassium salt, magnesium salt, or calcium salt of the compound shown in formula (I).

[0123] According to some embodiments of this application, the salt type is a potassium salt of the compound shown in formula (I).

[0124] In some embodiments, using Cu-Kα radiation, the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at the following 2θ angles: 11.18°±0.2°, 16.22°±0.2°, and 18.08°±0.2°.

[0125] In some embodiments, using Cu-Kα radiation, the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles that also have diffraction peaks at one or more of the following 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 13.71°±0.2°, and 14.97°±0.2°.

[0126] In some embodiments, using Cu-Kα radiation, the potassium salt of the compound shown in formula (I) exhibits X-ray powder diffraction patterns at 2θ angles with diffraction peaks at the following 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 13.71°±0.2°, 14.97°±0.2°, 16.22°±0.2°, and 18.08°±0.2°.

[0127] In some embodiments, using Cu-Kα radiation, the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles that also have diffraction peaks at one or more of the following 2θ angles: 16.66°±0.2°, 18.84°±0.2°, 21.35°±0.2°, 23.06°±0.2°, and 25.06°±0.2°.

[0128] In some embodiments, using Cu-Kα radiation, the potassium salt of the compound shown in formula (I) exhibits X-ray powder diffraction patterns at 2θ angles with diffraction peaks at the following 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 13.71°±0.2°, 14.97°±0.2°, 16.22°±0.2°, 16.66°±0.2°, 18.08°±0.2°, 18.84°±0.2°, 21.35°±0.2°, 23.06°±0.2°, and 25.06°±0.2°.

[0129] In some embodiments, using Cu-Kα radiation, the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles that also have diffraction peaks at one or more of the following 2θ angles: 7.00°±0.2°, 17.79°±0.2°, 20.47°±0.2°, 22.59°±0.2°, and 23.87°±0.2°.

[0130] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2θ angles, exhibits diffraction peaks at the following 2θ angles: 3.45°±0.2°, 7.00°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 13.71°±0.2°, and 14.97°±0.2°. 16.22°±0.2°, 16.66°±0.2°, 17.79°±0.2°, 18.08°±0.2°, 18.84°±0.2°, 20.47°±0.2°, 21.35°±0.2°, 22.59°±0.2°, 23.06°±0.2°, 23.87°±0.2°, 25.06°±0.2°.

[0131] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.15°±0.2°, 15.81°±0.2°, 17.64°±0.2°, 18.39°±0.2°, 19.70°±0.2°, 23.50°±0.2°, 25.47°±0.2°, and 26.48°±0.2°.

[0132] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2θ angles, exhibits diffraction peaks at the following 2θ angles: 3.45°±0.2°, 7.00°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 12.15°±0.2°, 13.71°±0.2°, 14.97°±0.2°, 15.81°±0.2°, 16.22°±0.2°, 16.66°±0.2°. 17.64°±0.2°, 17.79°±0.2°, 18.08°±0.2°, 18.39°±0.2°, 18.84°±0.2°, 19.70°±0.2°, 20.47°±0.2°, 21.35°±0.2°, 22.59°±0.2°, 23.06°±0.2°, 23.50°±0.2°, 23.87°±0.2°, 25.06°±0.2°, 25.47°±0.2°, 26.48°±0.2°.

[0133] In some embodiments, Cu-Kα radiation is used, and the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2θ angle, is substantially the same as that in Figure 21.

[0134] In some embodiments, the DSC curve of the potassium salt of the compound shown in formula (I) has an endothermic peak at 110°C to 160°C (e.g., 140°C to 150°C). In some embodiments, the DSC curve of the potassium salt of the compound shown in formula (I) has an endothermic peak at 220°C to 250°C (e.g., 225°C to 240°C). In some embodiments, the DSC curve of the potassium salt of the compound shown in formula (I) has endothermic peaks at 110°C to 160°C (e.g., 140°C to 150°C) and 220°C to 250°C (e.g., 225°C to 240°C). In some embodiments, the DSC curve of the potassium salt of the compound shown in formula (I) is substantially the same as that in Figure 22.

[0135] In some embodiments, the TGA curve of the potassium salt of the compound shown in formula (I) shows a weight loss of 13.0% to 15.0% at temperatures ranging from 20°C to 200°C. In some embodiments, the TGA curve of the potassium salt of the compound shown in formula (I) is substantially the same as that in Figure 23.

[0136] The third aspect of this application provides a solvate of the compound shown in formula (I).

[0137] According to some embodiments of this application, the solvent is selected from alcohols, carboxylic acids, ketones, ethers, esters, sulfoxides, or nitrile organic solvents, such as methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetone, ethylene glycol dimethyl ether, ethyl formate, DMSO, or acetonitrile.

[0138] According to some embodiments of this application, the solvate is an acetone solvate.

[0139] According to some embodiments of this application, the solvate is a sulfate acetone solvate.

[0140] In some embodiments, the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at one or more of the following 2θ angles in its X-ray powder diffraction pattern in terms of 2θ angles: 9.34°±0.2°, 21.04°±0.2°, and 26.15°±0.2°.

[0141] In some embodiments, the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at one or more of the following 2θ angles in its X-ray powder diffraction pattern expressed in 2θ angles: 8.50°±0.2°, 19.93°±0.2°, 20.16°±0.2°.

[0142] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at the following 2θ angles: 8.50°±0.2°, 9.34°±0.2°, 19.93°±0.2°, 20.16°±0.2°, 21.04°±0.2°, and 26.15°±0.2°.

[0143] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 16.26°±0.2°, 18.45°±0.2°, 20.55°±0.2°, 22.44°±0.2°, and 25.86°±0.2°.

[0144] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.50°±0.2°, 9.34°±0.2°, 16.26°±0.2°, 18.45°±0.2°, 19.93°±0.2°, 20.16°±0.2°, 20.55°±0.2°, 21.04°±0.2°, 22.44°±0.2°, 25.86°±0.2°, and 26.15°±0.2°.

[0145] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 12.50°±0.2°, 13.85°±0.2°, 16.47°±0.2°, 16.64°±0.2°, 17.21°±0.2°, 19.56°±0.2°, 24.24°±0.2°, 24.48°±0.2°, and 24.83°±0.2°.

[0146] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction peaks at one or more of the following 2θ angles in its 2θ angle: 8.50°±0.2°, 9.34°±0.2°, 12.50°±0.2°, 13.85°±0.2°, 16.26°±0.2°, 16.47°±0.2°, and 16.64°±0.2°. 17.21°±0.2°, 18.45°±0.2°, 19.56°±0.2°, 19.93°±0.2°, 20.16°±0.2°, 20.55°±0.2°, 21.04°±0.2°, 22.44°±0.2°, 24.24°±0.2°, 24.48°±0.2°, 24.83°±0.2°, 25.86°±0.2°, 26.15°±0.2°.

[0147] In some embodiments, the acetone sulfate solvate of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2θ angles using Cu-Kα radiation that is substantially the same as that in Figure 25.

[0148] In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) has an endothermic peak at 125°C to 175°C (e.g., 160°C to 170°C). In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) has an endothermic peak at 245°C to 255°C. In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) has endothermic peaks at 125°C to 175°C (e.g., 160°C to 170°C) and 245°C to 255°C. In some embodiments, the DSC curve of the acetone sulfate solvate of the compound shown in formula (I) is substantially the same as that in Figure 26.

[0149] In some embodiments, the TGA curve of the acetone sulfate solvate of the compound shown in formula (I) shows a weight loss of 7.0% to 8.0% between 20°C and 180°C. In some embodiments, the TGA curve of the acetone sulfate solvate of the compound shown in formula (I) is substantially the same as that in Figure 27.

[0150] According to some embodiments of this application, the solvate is a potassium salt acetone solvate.

[0151] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at the following 2θ angles: 11.18°±0.2°, 16.22°±0.2°, and 18.08°±0.2°.

[0152] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles that also have diffraction peaks at one or more of the following 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 13.71°±0.2°, and 14.97°±0.2°.

[0153] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) exhibits X-ray powder diffraction peaks at the following 2θ angles in the form of: 3.45°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 13.71°±0.2°, 14.97°±0.2°, 16.22°±0.2°, and 18.08°±0.2°.

[0154] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles that also have diffraction peaks at one or more of the following 2θ angles: 16.66°±0.2°, 18.84°±0.2°, 21.35°±0.2°, 23.06°±0.2°, and 25.06°±0.2°.

[0155] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) exhibits X-ray powder diffraction peaks at the following 2θ angles in terms of 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 13.71°±0.2°, 14.97°±0.2°, 16.22°±0.2°, 16.66°±0.2°, 18.08°±0.2°, 18.84°±0.2°, 21.35°±0.2°, 23.06°±0.2°, and 25.06°±0.2°.

[0156] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2θ angles that also have diffraction peaks at one or more of the following 2θ angles: 7.00°±0.2°, 17.79°±0.2°, 20.47°±0.2°, 22.59°±0.2°, and 23.87°±0.2°.

[0157] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the potassium salt acetone solvate of the compound shown in formula (I), expressed in 2θ angles, has diffraction peaks at the following 2θ angles: 3.45°±0.2°, 7.00°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 13.71°±0.2°, and 14.97°±0.2°. 2°, 16.22°±0.2°, 16.66°±0.2°, 17.79°±0.2°, 18.08°±0.2°, 18.84°±0.2°, 20.47°±0.2°, 21.35°±0.2°, 22.59°±0.2°, 23.06°±0.2°, 23.87°±0.2°, 25.06°±0.2°.

[0158] In some embodiments, using Cu-Kα radiation, the potassium salt acetone solvate of the compound shown in formula (I) exhibits X-ray powder diffraction patterns at 2θ angles, with diffraction peaks at one or more of the following 2θ angles: 12.15°±0.2°, 15.81°±0.2°, 17.64°±0.2°, 18.39°±0.2°, 19.70°±0.2°, 23.50°±0.2°, 25.47°±0.2°, and 26.48°±0.2°.

[0159] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the potassium salt acetone solvate of the compound shown in formula (I), expressed in 2θ angles, exhibits diffraction peaks at one or more of the following 2θ angles: 3.45°±0.2°, 7.00°±0.2°, 9.32°±0.2°, 11.18°±0.2°, 12.15°±0.2°, 13.71°±0.2°, 14.97°±0.2°, 15.81°±0.2°, 16.22°±0.2°, and 16.66°. ±0.2°, 17.64°±0.2°, 17.79°±0.2°, 18.08°±0.2°, 18.39°±0.2°, 18.84°±0.2°, 19.70°±0.2°, 20.47°±0.2°, 21.35°±0.2°, 22.59°±0.2°, 23.06°±0.2°, 23.50°±0.2°, 23.87°±0.2°, 25.06°±0.2°, 25.47°±0.2°, 26.48°±0.2°.

[0160] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the potassium salt acetone solvate of the compound shown in formula (I), expressed in 2θ angle, is substantially the same as that in Figure 21.

[0161] In some embodiments, the DSC curve of the potassium acetone solvate of the compound shown in formula (I) has an endothermic peak at 110°C to 160°C (e.g., 140°C to 150°C). In some embodiments, the DSC curve of the potassium acetone solvate of the compound shown in formula (I) has an endothermic peak at 220°C to 250°C (e.g., 225°C to 240°C). In some embodiments, the DSC curve of the potassium acetone solvate of the compound shown in formula (I) has endothermic peaks at 110°C to 160°C (e.g., 140°C to 150°C) and 220°C to 250°C (e.g., 225°C to 240°C). In some embodiments, the DSC curve of the potassium acetone solvate of the compound shown in formula (I) is substantially the same as that in Figure 22.

[0162] In some embodiments, the TGA curve of the potassium salt acetone solvate of the compound shown in formula (I) shows a weight loss of 13.0% to 15.0% between 20°C and 200°C. In some embodiments, the TGA curve of the potassium salt acetone solvate of the compound shown in formula (I) is substantially the same as that in Figure 23.

[0163] Fourthly, this application provides a hydrate of the compound shown in formula (I).

[0164] According to some embodiments of this application, the hydrate is a sulfate hydrate.

[0165] In some embodiments, the sulfate hydrate of the compound shown in formula (I) has a diffraction peak at 17.87° ± 0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0166] In some embodiments, the sulfate hydrate of the compound shown in formula (I) has a diffraction peak at 18.80° ± 0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0167] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has X-ray powder diffraction patterns in 2θ angles with diffraction peaks at 17.87°±0.2° and 18.80°±0.2°.

[0168] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, and 22.16°±0.2°.

[0169] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has a diffraction peak at one or more of the following 2θ angles in its X-ray powder diffraction pattern expressed in 2θ angles: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, 17.87°±0.2°, 18.80°±0.2°, and 22.16°±0.2°.

[0170] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 19.02°±0.2°, 20.28°±0.2°, 22.44°±0.2°, 26.65°±0.2°, and 28.36°±0.2°.

[0171] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, 17.87°±0.2°, 18.80°±0.2°, 19.02°±0.2°, 20.28°±0.2°, 22.16°±0.2°, 22.44°±0.2°, 26.65°±0.2°, and 28.36°±0.2°.

[0172] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern in 2θ angles that also has diffraction peaks at one or more of the following 2θ angles: 6.71°±0.2°, 13.36°±0.2°, 24.42°±0.2°, 27.31°±0.2°, 36.18°±0.2°, and 36.99°±0.2°.

[0173] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.71°±0.2°, 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 13.36°±0.2°, 17.54°±0.2°, and 17.8°±0.2°. 7°±0.2°, 18.80°±0.2°, 19.02°±0.2°, 20.28°±0.2°, 22.16°±0.2°, 22.44°±0.2°, 24.42°±0.2°, 26.65°±0.2°, 27.31°±0.2°, 28.36°±0.2°, 36.18°±0.2°, 36.99°±0.2°.

[0174] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits X-ray powder diffraction patterns in 2θ angles with diffraction peaks at one or more of the following 2θ angles: 23.19°±0.2°, 25.68°±0.2°, 27.99°±0.2°, 29.70°±0.2°, 30.29°±0.2°, 31.86°±0.2°, and 35.67°±0.2°.

[0175] In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, exhibits diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.71°±0.2°, 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 13.36°±0.2°, 17.54°±0.2°, 17.87°±0.2°, 18.80°±0.2°, 19.02°±0.2°, and 20.28°±0.2°. °, 22.16°±0.2°, 22.44°±0.2°, 23.19°±0.2°, 24.42°±0.2°, 25.68°±0.2°, 26.65°±0.2°, 27.31°±0.2°, 27.99°±0.2°, 28.36°±0.2°, 29.70°±0.2°, 30.29°±0.2°, 31.86°±0.2°, 35.67°±0.2°, 36.18°±0.2°, 36.99°±0.2°. In some embodiments, the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-Kα, has an X-ray powder diffraction pattern expressed in 2θ angles that is substantially the same as that in Figure 29.

[0176] In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) has an endothermic peak at 110°C to 150°C, for example (125°C to 135°C). In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) has an endothermic peak at 170°C to 200°C, for example (175°C to 185°C). In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) has endothermic peaks at 110°C to 150°C (for example, 125°C to 135°C) and 170°C to 200°C, for example (175°C to 185°C). In some embodiments, the DSC curve of the sulfate hydrate of the compound shown in formula (I) is substantially the same as that in Figure 30.

[0177] In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) shows a weight loss of 5.0% to 6.0% at 20°C to 120°C. In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) shows a weight loss of 4.0% to 5.0% at 120°C to 210°C. In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) shows a weight loss of 5.0% to 6.0% at 20°C to 120°C and a weight loss of 4.0% to 5.0% at 120°C to 210°C. In some embodiments, the TGA curve of the sulfate hydrate of the compound shown in formula (I) is substantially the same as that in Figure 31.

[0178] The fifth aspect of this application provides a pharmaceutical composition comprising a crystal form, salt form, solvate or hydrate of the compound represented by formula (I) above, and a pharmaceutically acceptable carrier or excipient.

[0179] The sixth aspect of this application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for treating diseases or conditions mediated by kinesin KIF18A.

[0180] In some embodiments, the disease or condition is a tumor. In some embodiments, the disease or condition is cancer.

[0181] In some embodiments, the disease or symptom is selected from the group consisting of: (a) solid tumors or hematopoietic tumors selected from the following cancers: bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) hematopoietic tumors selected from the following lymphatic system: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, etc. (c) Hematopoietic tumors of the bone marrow lineage selected from: acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (d) stromal tumors selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous systems selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0182] The seventh aspect of this application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for reducing the size of solid tumors in a subject.

[0183] In some embodiments, the solid tumor is selected from solid tumors of the following cancers: bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.

[0184] The eighth aspect of this application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for treating cell proliferation disorders in a subject.

[0185] The ninth aspect of this application also provides the use of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above in the preparation of a medicament for inhibiting KIF18A in cells.

[0186] The tenth aspect of this application also provides a method for treating diseases or conditions mediated by kinesin KIF18A, comprising administering to a patient in need a therapeutically effective amount of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above.

[0187] The eleventh aspect of this application also provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need a therapeutically effective amount of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound represented by formula (I) above.

[0188] The twelfth aspect of this application also provides a method for treating cell proliferation disorders in a subject, the method comprising administering to a subject in need a therapeutically effective amount of the crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound represented by formula (I) above.

[0189] The thirteenth aspect of this application also provides a method for inhibiting KIF18A in cells, the method comprising contacting the cells with a crystal form, salt form, solvate, hydrate, or pharmaceutical composition of the compound shown in formula (I) above. Beneficial effects

[0190] The crystal form, salt form, solvate, or hydrate of the compound shown in formula (I) provided in this application has one or more of the following advantages:

[0191] (1) High temperature resistance;

[0192] (2) Resistant to high humidity;

[0193] (3) Light resistance;

[0194] (4) Good stability;

[0195] (5) Low hygroscopicity (slightly hygroscopic);

[0196] (6) High solubility;

[0197] (7) High in vitro dissolution rate;

[0198] (8) Good pharmacokinetic properties, such as high relative bioavailability in vivo;

[0199] (9) It has good KIF18A inhibitory activity. Attached Figure Description

[0200] Figure 1 shows the XRPD pattern of crystal form I of the compound of formula I prepared in Example 1 of this application.

[0201] Figure 2 shows the differential scanning calorimetry (DSC) curve of crystal form I of the compound of formula I prepared in Example 1 of this application.

[0202] Figure 3 shows the thermogravimetric analysis (TGA) curve of crystal form I of the compound of formula I prepared in Example 1 of this application.

[0203] Figure 4 shows the NMR spectrum of crystal form I of the compound of formula I prepared in Example 1 of this application.

[0204] Figure 5 shows the XRPD pattern of crystal form II of the compound of formula I prepared in Example 2 of this application.

[0205] Figure 6 shows the differential scanning calorimetry (DSC) curve of crystal form II of the compound of formula I prepared in Example 2 of this application.

[0206] Figure 7 shows the thermogravimetric analysis (TGA) curve of crystal form II of the compound of formula I prepared in Example 2 of this application.

[0207] Figure 8 shows the NMR spectrum of crystal form II of the compound of formula I prepared in Example 2 of this application.

[0208] Figure 9 shows the XRPD spectrum of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.

[0209] Figure 10 shows the differential scanning calorimetry (DSC) curve of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.

[0210] Figure 11 shows the thermogravimetric analysis (TGA) curves of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.

[0211] Figure 12 shows the NMR spectrum of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.

[0212] Figure 13 shows the XRPD pattern of p-toluenesulfonate crystal form III of the compound of formula I prepared in Example 4 of this application.

[0213] Figure 14 shows the differential scanning calorimetry (DSC) curve of p-toluenesulfonate crystal form III of the compound of formula I prepared in Example 4 of this application.

[0214] Figure 15 shows the thermogravimetric analysis (TGA) curves of p-toluenesulfonate crystal form III of the compound of formula I prepared in Example 4 of this application.

[0215] Figure 16 shows the NMR spectrum of p-toluenesulfonate crystal form III of the compound of formula I prepared in Example 4 of this application.

[0216] Figure 17 shows the XRPD pattern of the p-toluenesulfonate crystal form IV of the compound of formula I prepared in Example 5 of this application.

[0217] Figure 18 shows the differential scanning calorimetry (DSC) curve of the p-toluenesulfonate crystal form IV of the compound of formula I prepared in Example 5 of this application.

[0218] Figure 19 shows the thermogravimetric analysis (TGA) curves of p-toluenesulfonate crystal form IV of the compound of formula I prepared in Example 5 of this application.

[0219] Figure 20 shows the NMR spectrum of p-toluenesulfonate crystal form IV of the compound of formula I prepared in Example 5 of this application.

[0220] Figure 21 shows the XRPD pattern of the potassium salt of the compound of Formula I prepared in Example 6 of this application.

[0221] Figure 22 shows the differential scanning calorimetry (DSC) curve of the potassium salt of the compound of formula I prepared in Example 6 of this application.

[0222] Figure 23 shows the thermogravimetric analysis (TGA) curves of the potassium salt of the compound of Formula I prepared in Example 6 of this application.

[0223] Figure 24 shows the NMR spectrum of the potassium salt of the compound of formula I prepared in Example 6 of this application.

[0224] Figure 25 shows the XRPD spectrum of the sulfate solvate of the compound of formula I prepared in Example 7 of this application.

[0225] Figure 26 shows the differential scanning calorimetry (DSC) curve of the sulfate solvate of the compound of formula I prepared in Example 7 of this application.

[0226] Figure 27 shows the thermogravimetric analysis (TGA) curves of the sulfate solvate of the compound of Formula I prepared in Example 7 of this application.

[0227] Figure 28 shows the NMR spectrum of the sulfate solvate of the compound of formula I prepared in Example 7 of this application.

[0228] Figure 29 shows the XRPD spectrum of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0229] Figure 30 shows the differential scanning calorimetry (DSC) curve of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0230] Figure 31 shows the thermogravimetric analysis (TGA) curves of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0231] Figure 32 shows the NMR spectrum of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0232] Figure 33 shows a comparison of the XRPD of the remaining solid after shaking in FaSSIF and water for 2 hours on crystal form I of the compound of formula I prepared in Example 1 of this application.

[0233] Figure 34 shows a comparison of the residual solid XRPD of the hydrochloride of the compound of formula I prepared in Example 3 of this application after shaking in FaSSIF and water for 2 hours.

[0234] Figure 35 shows a comparison of the residual solid XRPD of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application after shaking in FaSSIF and water for 2 hours.

[0235] Figure 36 shows a comparison of the XRPD of the remaining solid after shaking in FaSSIF and water for 2 hours on the p-toluenesulfonate crystal form IV of the compound of formula I prepared in Example 5 of this application.

[0236] Figure 37 shows the DVS curve (50%-95%-50%) of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.

[0237] Figure 38 shows the DVS curve (50%-95%-50%) of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0238] Figure 39 shows the XRPD (50%-95%-50%) of the hydrochloride DVS test of the compound of Formula I prepared in Example 3 of this application.

[0239] Figure 40 shows the XRPD (50%-95%-50%) before and after the DVS test of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0240] Figure 41 shows the DVS curve (50%-95%-0%-50%) of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.

[0241] Figure 42 shows the XRPD plots (50%-95%-0%-50%) of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application before and after the DVS test.

[0242] Figure 43 shows an XRPD plot of the sulfate hydrate stability study of the compound of Formula I prepared in Example 8 of this application. Detailed Implementation

[0243] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with embodiments and accompanying drawings. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of this application in any way.

[0244] the term

[0245] As used herein, the term "substantially identical" used to define patterns is intended to mean that, given acceptable deviations in the art, those skilled in the art would consider the pattern identical to the reference pattern. Such deviations may be caused by factors known in the art related to instrumentation, operating conditions, and human factors. For example, those skilled in the art will understand that the endothermic onset and peak temperatures measured by differential scanning calorimetry (DSC) can vary significantly with experiments. In some embodiments, two patterns are considered substantially identical when the positions of the characteristic peaks of the two patterns vary by no more than ±5%, ±4%, ±3%, ±2%, or ±1%. For example, those skilled in the art can readily determine whether two X-ray diffraction patterns or two DSC patterns are substantially identical. In some embodiments, two X-ray diffraction patterns are considered substantially identical when the 2θ angle of the characteristic peaks of the two X-ray diffraction patterns varies by no more than ±0.3°, ±0.2°, or ±0.1°. As used herein, the term "substantially zero" used to define weight loss is intended to mean that, given acceptable deviations in the art, those skilled in the art would consider the weight loss value to be equivalent to 0, i.e., substantially no weight loss. In some implementations, a weight loss of no more than 0.01% is considered substantially zero.

[0246] As used herein, the term “about” should be understood as being within the normal tolerance range in the field, for example, “about” can be understood as being within ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.1%, ±0.05%, or ±0.01% of the value. Unless otherwise apparent from the context, all numerical values ​​provided herein are modified by the term “about”.

[0247] As used herein, the term “pharmaceuticalally acceptable carrier or excipient” means a diluent, adjuvant, or mediator that is administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0248] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this application include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain, as needed, small amounts of wetting agents, emulsifiers, pH buffers, preservatives, antioxidants, flavoring agents, fragrances, solubilizers, osmotic pressure regulators, colorants, etc. Oral formulations may contain standard carriers such as binders, fillers, disintegrants, lubricants, etc.

[0249] The pharmaceutical composition described in this application can be administered by methods known in the art, such as, but not limited to, any of the following: oral, spray inhalation, rectal, nasal, buccal, topical, and extracorporeal administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or administration via an external implantation device. Oral, intramuscular, or intravenous administration is preferred.

[0250] For these routes of administration, the pharmaceutical compositions of this application can be administered in suitable dosage forms. The dosage forms may be solid, semi-solid, liquid, or gaseous preparations, including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, and syrups.

[0251] The pharmaceutical composition described in this application can be prepared by any method well known in the art, such as by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, etc.

[0252] Unless otherwise specified, all reagents used in the following experiments in this application are commercially available products or reagents prepared according to conventional methods. Unless otherwise specified, all methods used in the experiments are conventional experimental methods. Unless otherwise specified, all instruments used in the experiments are commercially available.

[0253] The detection method used in the following embodiments of this application is as follows:

[0254] 1. Nuclear magnetic resonance analysis (NMR) 1 H NMR)

[0255] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE NEO 400 (Bruker, GER).

[0256] 2. X-ray powder diffraction (XRPD)

[0257] The solid samples obtained in the experiment were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The testing method was Cu target Kα1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk.

[0258] 3. Thermogravimetric analysis (TGA)

[0259] The thermogravimetric analyzer was a TA Discovery 55 (TA, US). Samples of 2 mg to 5 mg were placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at 60 mL / min at the sample location and 40 mL / min at the balance location.

[0260] 4. Differential Scanning Calorimetry (DSC)

[0261] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1 mg to 2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0262] 5. Dynamic moisture adsorption-desorption analysis (DVS)

[0263] Preliminary assessment method: Dynamic moisture adsorption-desorption analysis for preliminary assessment of hygroscopicity was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-50%, each gradient representing a 15% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint, or a maximum duration of 60 minutes for each gradient. After testing, XRPD analysis was performed on the samples to confirm whether the solid form had changed.

[0264] Comprehensive evaluation method: Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-0%-50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint, or each gradient maintained for a maximum of 180 minutes. After the test, XRPD analysis was performed on the samples to confirm whether the solid form had changed.

[0265] 6. High-performance liquid chromatography (HPLC)

[0266] The high-performance liquid chromatograph used was a SHIMADZU LC-20A (Shimadzu, JP), and the test conditions are shown in Table 1 below.

[0267] Table 1

[0268] 7. Ion chromatography (IC)

[0269] The ion chromatograph was model 925ECO IC (Metrohm, Swiss), and the instrument parameters are shown in Table 2 below.

[0270] Table 2

[0271] Abbreviation:

[0272] EA: Ethyl acetate; PE: Petroleum ether; NMP: N-methylpyrrolidone; DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone; TLC: Thin-layer chromatography; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine.

[0273] Example 1 Crystal form I of the compound shown in Formula I

[0274] Step 1: 2-Bromo-5-methoxy-6-fluorobenzaldehyde (2 g, 8.5 mmol), 4,4-difluoropiperidine (1.25 g, 10.3 mmol), and DIPEA (2.21 g, 17.16 mmol) were dissolved in NMP (10 mL) and reacted at 100 °C for 12 hours under nitrogen protection. The reaction solution was quenched with water (20 mL), separated with EA (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0-20 / 1) to give compound 2.

[0275] Step 2: Compound 2 (1100 mg, 3.29 mmol) and N-amino-4-toluenesulfonamide (613 mg, 3.29 mmol) were dissolved in toluene (10 mL) and reacted at room temperature for 0.5 hours. The reaction solution was quenched with water (10 mL), separated with EA (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was used directly in the next step without purification to obtain compound 3.

[0276] Step 3: Compound 3 (1653 mg, 3.29 mmol) and sodium hydride (158 mg, 3.95 mmol) were dissolved in toluene (40 mL). After reacting at room temperature for 0.5 hours, the reaction was carried out at 135 °C for 25 min. After the reaction was confirmed to be complete by TLC, the reaction solution was quenched with water (10 mL), separated by EA (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0-10 / 1) to obtain compound 4.

[0277] Step 4: Compound 4 (480 mg, 1.51 mmol) was dissolved in 1,4-dioxane (10 mL), then cooled to 0 °C, and DDQ (685 mg, 3.01 mmol) was slowly added. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was confirmed to be complete by TLC, water (10 mL) was added to quench the reaction, and the mixture was filtered. The filtrate was extracted with EA (30 mL), separated, and the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 -20 / 1) to obtain compound 5.

[0278] Step 5: Compound 5 (330 mg, 1.04 mmol), tert-butyl carbamate (244 mg, 2.08 mmol), cesium carbonate (1000 mg, 3.13 mmol), and palladium catalyst (CAS: 1599466-85-9; 88 mg, 0.1 mmol) were dissolved in 1,4-dioxane (8 mL) and reacted at 90 °C for 12 hours under nitrogen protection. The reaction solution was quenched with water (10 mL), separated with EA (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0-10 / 1) to obtain compound 6.

[0279] Step 6: Compound 6 (160 mg, 0.32 mmol) was dissolved in hydrochloric acid-dioxane (1 mL) solution and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized, extracted, dried, and concentrated to obtain compound 7. No purification was required for use in the next step.

[0280] Step 8: Compound 7 (55 mg, 0.22 mmol), 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (75 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), and DIPEA (112 mmol, 0.87 mmol) were dissolved in DMF (4 mL) and reacted at room temperature under nitrogen protection for 2 hours. The reaction solution was quenched with water (10 mL), separated with EA (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 1 / 0-10 / 1) to obtain compound 8.

[0281] Step 9: Compound 8 (80 mg, 0.15 mmol), 2-hydroxyethylsulfonamide (55 mg, 0.44 mmol), cesium carbonate (143 mg, 0.44 mmol) and palladium catalyst (CAS: 1599466-89-3; 12 mg, 0.01 mmol) were dissolved in 1,4-dioxane (4 mL), and reacted at 90 °C for 3 hours under nitrogen protection. The reaction solution was quenched with water (10 mL), separated with EA (40 mL), and the organic phase was washed with saturated saline (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound I. Compound I was purified by Prep-HPLC (AZZOTA-C18 column (50×250 mm, 10 μm), mobile phase of acetonitrile (B) and 1‰ formic acid-water solution (A), gradient elution: 0–2 min, 45%–51% B; 2–20 min, 51%–61% B; 20–28 min, 95% B; flow rate 80 mL / min, injection volume 5 mL) to obtain a white solid.

[0282] Basic Characterization: The obtained white solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 1. The white solid was found to be a highly crystalline solid, i.e., crystal form I of the compound represented by Formula I in this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 2 and 3, respectively. The TGA results showed that crystal form I exhibited almost no weight loss during heating to 200℃, but may decompose after 240℃. The DSC results showed that crystal form I had a melting endothermic peak at approximately 242℃. NMR analysis of crystal form I was performed, and the resulting NMR spectrum is shown in Figure 4. The NMR spectrum showed that the structure of the compound represented by Formula I remained unchanged. Combined with the thermal analysis data, it was determined that crystal form I of the compound represented by Formula I is an amorphous form.

[0283] The XRPD pattern of the compound of Formula I, crystal form I, using Cu-Kα radiation and expressed in 2θ angles, includes characteristic peaks at the diffraction angles (2θ) shown in Table 3.

[0284] Table 3. Crystal form I peak position data of the compound represented by Formula I.

[0285] Example 2 Crystal form II of the compound shown in Formula I

[0286] Preparation method: Weigh 23.4 mg of the crystal form I of the compound shown in Formula I, add it to 1.0 mL of acetone solvent, stir magnetically at room temperature for a period of time, then transfer it to 10 °C and stir for 3 days. After centrifuging the turbid liquid, dry the solid under vacuum at room temperature to obtain a white solid.

[0287] Basic Characterization: The obtained white solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 5. The white solid was found to be a highly crystalline solid, i.e., crystal form II of the compound represented by Formula I in this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 6 and 7, respectively. The TGA results showed that crystal form II experienced almost no weight loss when heated to 200℃, but may decompose after 240℃. The DSC results showed that crystal form II exhibited a melting endothermic peak at approximately 243℃. NMR analysis of crystal form II was performed, and the resulting NMR spectrum is shown in Figure 8. The NMR spectrum showed that the structure of the compound represented by Formula I remained unchanged. Combined with the thermal analysis data, it can be determined that crystal form II of the compound represented by Formula I is an amorphous form.

[0288] The crystal form II of the compound shown in Formula I, using Cu-Kα radiation, has an XRPD pattern expressed in 2θ angles, which includes characteristic peaks at the diffraction angles (2θ) shown in Table 4.

[0289] Table 4. Crystal form II peak position data of the compound represented by Formula I.

[0290] Example 3: Hydrochloride salt of the compound shown in Formula I

[0291] Preparation method: Weigh 200.2 mg of the crystal form I of the compound shown in Formula I and 0.187 μL of hydrochloric acid (acid solution diluted with 2 mol / L ethanol), add 8.5 mL of acetone, stir at room temperature for 2.5 h, then transfer to 5 °C for suspension for 12 h, centrifuge the turbid liquid and dry the solid under vacuum at room temperature to obtain a light yellow solid.

[0292] Basic Characterization: The obtained light yellow solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 9. The solid was found to be a well-crystallized solid, i.e., the hydrochloride salt of the compound represented by Formula I in this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 10 and 11, respectively. The TGA results showed that the hydrochloride salt experienced a 0.3% weight loss upon heating to 100℃, continued to lose weight after 100℃, and may decompose after 170℃. The DSC results showed an endothermic signal of melting and decomposition of the hydrochloride salt at approximately 214℃. NMR analysis of the hydrochloride salt was performed, and the resulting NMR spectrum is shown in Figure 12. The NMR spectrum showed a shift in peak positions at 3.0 ppm, 6.4-7.8 ppm, 10.1 ppm, and 11.0 ppm compared to the compound represented by Formula I, indicating salt formation in this sample. An acetone signal peak was observed at 2.09 ppm, indicating the presence of a small amount of acetone solvent residue. According to IC testing, the salt formation ratio of the compound and hydrochloric acid is approximately 1:1.

[0293] The hydrochloride salt of the compound shown in Formula I, XRPD spectra expressed in 2θ angles using Cu-Kα radiation, include characteristic peaks at the diffraction angles (2θ) shown in Table 5.

[0294] Table 5. Data on the hydrochloride peak positions of the compounds shown in Formula I.

[0295] Example 4: The p-toluenesulfonate crystal form III of the compound shown in Formula I

[0296] Preparation method: Weigh 23.8 mg of the crystal form I of the compound shown in Formula I and 8.5 mg of p-toluenesulfonic acid, add 1.0 mL of acetone, stir at room temperature for a period of time, then transfer to 10 °C and stir for 3 days. No solid precipitates. Add 0.8 mL of antisolvent n-heptane to form an oil, then add 0.4 mL of ethanol to redissolve and then evaporate at room temperature to obtain a yellow solid.

[0297] Basic characterization: The obtained yellow solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 13. The obtained solid was identified as p-toluenesulfonate crystal form III of the compound represented by Formula I of this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 14 and 15, respectively. The TGA results showed that p-toluenesulfonate crystal form III experienced a 3.4% weight loss upon heating to 150℃, and a 4.7% weight loss between 150℃ and 215℃, and may decompose after 230℃. The DSC results showed an endothermic signal at approximately 178℃ for p-toluenesulfonate crystal form III. NMR analysis of p-toluenesulfonate crystal form III yielded the NMR spectrum shown in Figure 16. The NMR spectrum revealed a shift in peak positions at 3.0 ppm, 6.4-7.8 ppm, 10.1 ppm, and 11.0 ppm compared to the compound shown in Formula I, indicating salt formation. Signal peaks for p-toluenesulfonic acid were observed at 2.29 ppm, 7.12 ppm, and 7.46 ppm, suggesting a salt formation ratio of approximately 1:1 between the compound and p-toluenesulfonic acid. A signal peak for acetone was observed at 2.09 ppm, and signal peaks for ethanol were observed at 1.06 ppm and 3.43 ppm, indicating the presence of small amounts of various solvents.

[0298] The p-toluenesulfonate crystal form III of the compound shown in Formula I, with Cu-Kα radiation, has an XRPD pattern expressed in 2θ angles, including characteristic peaks at the diffraction angles (2θ) shown in Table 6.

[0299] Table 6 shows the peak position data for p-toluenesulfonate crystal form III of the compound represented by Formula I.

[0300] Example 5: Crystal form IV of p-toluenesulfonate of the compound shown in Formula I

[0301] Preparation method: Weigh 200.6 mg of the crystal form I of the compound shown in Formula I and 71.6 mg of p-toluenesulfonic acid, add 8.5 mL of acetone, stir at room temperature for 3 h, no solid precipitates, transfer, volatilize at room temperature to obtain a gel, dry under vacuum at room temperature, add 10 mL of acetone:ethanol (v / v, 2:1) mixed solvent to the obtained gel to redissolve, stir at room temperature and volatilize overnight to obtain a yellow solid.

[0302] Basic characterization: The obtained yellow solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 17. The obtained solid was identified as p-toluenesulfonate crystal form IV of the compound represented by Formula I of this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 18 and 19, respectively. The TGA results showed that p-toluenesulfonate crystal form IV experienced a 1.7% weight loss upon heating to 100℃, a 6.3% weight loss between 100℃ and 200℃, and may decompose after 230℃. The DSC results showed endothermic signals at approximately 53℃ and 162℃ for p-toluenesulfonate crystal form IV. NMR analysis of p-toluenesulfonate crystal form IV yielded the NMR spectrum shown in Figure 20. The NMR spectrum showed a shift in peak positions at 3.0 ppm, 6.4-7.8 ppm, 10.1 ppm, and 11.0 ppm compared to the compound shown in Formula I, indicating salt formation in the sample. Signal peaks of p-toluenesulfonic acid were observed at 2.29 ppm, 7.12 ppm, and 7.46 ppm, suggesting a salt formation ratio of approximately 1:1 between the compound and p-toluenesulfonic acid. A signal peak of acetone was observed at 2.09 ppm, and signal peaks of ethanol were observed at 1.06 ppm and 3.43 ppm, indicating the presence of small amounts of various solvents.

[0303] The p-toluenesulfonate crystal form IV of the compound shown in Formula I, with Cu-Kα radiation, has an XRPD pattern expressed in 2θ angles, including characteristic peaks at the diffraction angles (2θ) shown in Table 7.

[0304] Table 7. Data on the IV peak positions of the p-toluenesulfonate crystal form of the compound shown in Formula I.

[0305] Example 6 Potassium salt of the compound shown in Formula I

[0306] Preparation method: Weigh 23.8 mg of the crystal form I of the compound shown in Formula I and 22 μL of 2M potassium hydroxide aqueous solution, add 1.0 mL of acetone, stir at room temperature for a period of time, then transfer to 10℃ and stir for 3 days to obtain a white solid.

[0307] Basic Characterization: The obtained white solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 21. The obtained solid was identified as the potassium salt of the compound represented by Formula I of this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 22 and 23, respectively. The TGA results showed that the potassium salt experienced a 14.0% weight loss during heating to 200℃, which basically corresponds to the solvent removal process. The DSC results showed that the potassium salt exhibited endothermic signals at approximately 145℃ and 232℃. NMR analysis of the potassium salt was performed, and the resulting NMR spectrum is shown in Figure 24. The NMR spectrum showed that compared with the compound represented by Formula I, the peak positions shifted at multiple locations, including 3.0 ppm, 3.3 ppm, 4.9 ppm, 6.4-7.8 ppm, and 11.0 ppm, indicating that the sample formed a salt. An acetone signal peak was observed at 2.09 ppm, and the molar ratio of the compound to acetone was approximately 1:1.2, indicating that the potassium salt is an acetone solvate. According to IC testing, the salt formation ratio of the compound and potassium ions is approximately 1:0.8.

[0308] The potassium salt of the compound shown in Formula I, when irradiated with Cu-Kα, has an XRPD pattern represented at a 2θ angle, which includes the characteristic peaks at the diffraction angle (2θ) shown in Table 8.

[0309] Table 8 shows the potassium salt peak positions of the compounds represented by Formula I.

[0310] Example 7: Sulfate solvate of the compound shown in Formula I

[0311] Preparation method: Weigh 47.4 mg of the crystal form I of the compound shown in Formula I and 88 μL of 1M acetone sulfuric acid solution, add 2.0 mL of acetone, stir at room temperature for 1 day, centrifuge the turbid liquid and dry the solid under vacuum at room temperature to obtain a yellow solid.

[0312] Basic characterization: The obtained yellow solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 25. The obtained solid was identified as the sulfate solvate of the compound represented by Formula I of this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 26 and 27, respectively. The TGA results showed that the sulfate solvate experienced a 7.4% weight loss upon heating to 180℃ and may decompose after 250℃. The DSC results showed endothermic signals at approximately 163℃ and 250℃. NMR analysis of the sulfate solvate yielded the NMR spectrum shown in Figure 28. The NMR spectrum revealed peak shifts at multiple locations (3.0 ppm, 6.4-7.8 ppm, 10.1 ppm, and 11.0 ppm) compared to the compound shown in Formula I, indicating salt formation. An acetone signal peak was observed at 2.09 ppm, suggesting a molar ratio of 1:0.5 between the compound and acetone. IC analysis indicated a salt formation ratio of approximately 1:1 between the compound and sulfuric acid. Combined with thermal analysis results, this sulfate is identified as an acetone solvate.

[0313] The sulfate solvates of the compounds shown in Formula I, XRPD spectra expressed in 2θ angles using Cu-Kα radiation, include characteristic peaks at the diffraction angles (2θ) shown in Table 9.

[0314] Table 9 shows the peak positions of the sulfate solvates of the compounds represented by Formula I.

[0315] Example 8: Sulfate salt hydrate of the compound shown in Formula I

[0316] Preparation method: Weigh 200.8 mg of the crystal form I of the compound shown in Formula I and 374 μL of 1M sulfuric acid aqueous solution, add 8.5 mL of acetone, stir at room temperature for 2.5 h, then transfer to 5 °C for overnight suspension, centrifuge the turbid liquid and dry the solid under vacuum at room temperature to obtain an off-white solid.

[0317] Basic characterization: The obtained off-white solid was subjected to XRPD analysis, and the resulting XRPD spectrum is shown in Figure 29. The solid was found to be a well-crystallized solid, namely the sulfate hydrate of the compound represented by Formula I of this application. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on it, and the resulting DSC and TGA spectra are shown in Figures 30 and 31, respectively. The TGA results showed that the sulfate hydrate experienced a 5.3% weight loss when heated to 120℃, and a 4.6% weight loss between 120℃ and 210℃. The DSC results showed endothermic signals in the sulfate hydrate at approximately 130℃ and 180℃. NMR analysis of the sulfate hydrate yielded the NMR spectrum shown in Figure 32. The NMR spectrum revealed a shift in peak positions at 3.0 ppm, 6.4-7.8 ppm, 10.1 ppm, and 11.0 ppm compared to the compound shown in Formula I, indicating salt formation in this sample. An acetone signal peak was observed at 2.09 ppm, suggesting the presence of a small amount of acetone solvent residue. The salt formation ratio of the compound to sulfuric acid was approximately 1:1. Combined with the thermal analysis results, this sulfate is determined to be a hydrate.

[0318] The sulfate salt hydrate of the compound shown in Formula I, XRPD spectra expressed in 2θ angles using Cu-Kα radiation, include characteristic peaks at the diffraction angles (2θ) shown in Table 10.

[0319] Table 10 shows the peak positions of the sulfate hydrates of the compounds represented by Formula I.

[0320] Experiment Example 1: Solubility Test

[0321] Experimental Methods: A certain amount of sample was added to different media (e.g., FaSSIF, FeSSIF, FaSSGF, water, PBS buffer) to prepare suspensions. The suspensions were incubated at 37°C with shaking for different times (0.5h, 2h, 5h, 24h), and then samples were taken. The solutions were filtered through a 0.22μm filter membrane, and the peak area of ​​the solution was measured using HPLC. The concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of compound I (crystal form I), and the dilution factor. Furthermore, the pH value of the supernatant of the remaining liquid was tested at different time points (0.5h, 2h, 5h, 24h), and the remaining solids were subjected to XRPD analysis.

[0322] The solubility test results of some Formula I compounds in their crystal forms, salt forms, solvates, or hydrates are as follows: As shown in Table 11 and Figures 33 to 36, the 2-hour solubility ranking of the three salt forms (hydrochloride prepared in Example 3, sulfate hydrate prepared in Example 8, and p-toluenesulfonate crystal form IV prepared in Example 5) and crystal form I prepared in Example 1 in FaSSIF is: hydrochloride ≈ sulfate hydrate > p-toluenesulfonate crystal form IV > crystal form I. The pH of the solution did not change significantly after shaking in FaSSIF for 2 hours for the three salt forms. The remaining solid crystal forms did not change after shaking in FaSSIF and water for 2 hours for the three salt forms and crystal form I. Further 24-hour solubility tests were conducted in FaSSGF solution, with the solubility ranking being: sulfate hydrate > p-toluenesulfonate crystal form IV > hydrochloride. Table 11: Dynamic solubility tests in biological media and water. LOQ = 2 μg / mL.

[0323] Experiment Example 2: Hygroscopicity Test

[0324] (1) Preliminary assessment of the hygroscopicity of different salt forms, crystal forms, solvates, and hydrates of the compound shown in Formula I (humidity variation 50%-95%-50%), some DVS results are shown in Figures 37 and 38:

[0325] The hydrochloride prepared in Example 3 showed a weight gain of 0.49% at 95% RH; a weight gain of 0.26% at 80% RH during adsorption; a weight gain of 0.27% at 80% RH during desorption; and a weight loss of 0.04% at 50% RH. The XRPD results before and after the DVS test are shown in Figure 39, indicating that the crystal form of the hydrochloride did not change after the DVS test.

[0326] The sulfate hydrate prepared in Example 8 showed a weight gain of 1.42% at 95% RH; a weight gain of 0.37% at 80% RH during adsorption; a weight gain of 0.36% at 80% RH during desorption; and a weight loss of 0.06% at 50% RH. Figure 40 shows the XRPD results before and after the DVS test, indicating that the crystal form of the sulfate hydrate did not change after the DVS test.

[0327] (2) A comprehensive evaluation of the hygroscopicity of the compounds shown in Formula I in different salt forms, crystal forms, solvates, and hydrates (humidity variations of 50%-95%-0%-50%), with some DVS results shown in Figure 41:

[0328] The sulfate hydrate prepared in Example 8 showed an adsorption weight gain of approximately 1.82% at 95% RH, an adsorption weight gain of approximately 0.68% at 80% RH, a desorption weight gain of approximately 0.83%, and a desorption weight loss of 0.74% at 0% RH, indicating that the sulfate hydrate is slightly hygroscopic. The XRPD results before and after the DVS test are shown in Figure 42, indicating that the crystal form of the sulfate hydrate did not change before and after the DVS test.

[0329] Experiment Example 3: Stability Test Experiment

[0330] Experimental methods: Approximately 20 mg of sample (Examples 1 to 8 of this application) was weighed into a weighing bottle and placed under high temperature (60°C), high humidity (25°C / 92.5%RH), light (25°C / 4500Lux), and accelerated conditions (40°C / 75%RH), respectively. Samples were taken at 7 and 15 days for HPLC purity testing and XRPD characterization.

[0331] Some experimental results are shown in Table 12 and Figure 43. The sulfate hydrate prepared in Example 8 did not change its crystal form after being exposed to high temperature (60℃), high humidity (25℃ / 92.5%RH), light (25℃ / 4500Lux), and accelerated conditions (40℃ / 75%RH) for 15 days. Chemical purity results showed that the purity of the sulfate hydrate decreased slightly after being exposed to high temperature (60℃), light (25℃ / 4500Lux), and accelerated conditions (40℃ / 75%RH) for 15 days. However, the purity of the sample did not change significantly after being exposed to high humidity (25℃ / 92.5%RH) for 7 and 15 days.

[0332] Table 12 Summary of Solid State Stability Assessment

[0333] Experimental Example 4: In vitro inhibition assay of KIF18A activity (ADP-Glo ​​assay)

[0334] This experiment followed the method described in Test Example 1 of WO2024 / 114787A1 to detect the KIF18A ATPase activity of compound I and its different crystal forms, salt forms, solvates, and hydrates in response to tubulin stimulation. The activity was determined based on the IC50 assay. 50 The size of the compound of Formula I of this invention and its different crystal forms, salt forms, solvates and hydrates were evaluated to assess their inhibitory effect on the KIF18A target.

[0335] The compound of formula I was prepared according to the method described in Example 478 of WO2024 / 114787A1.

[0336] The detection results showed that compound I had good KIF18A inhibitory activity, IC50 50 <50nM.

[0337] Experimental Example 5: OVCAR-3 Cell Proliferation Inhibition Assay

[0338] This experiment tested the inhibitory effects of compound I and its different crystal forms, salt forms, solvates, and hydrates on the proliferation of OVCAR-3 cells according to the method described in Test Example 2 of WO2024 / 114787A1.

[0339] The test results showed that the compound of formula I had a significant inhibitory effect on the proliferation of OVCAR-3 cells, with IC50 < 50 nM.

[0340] Experimental Example 6: PK Study

[0341] 1. Laboratory animals

[0342] Six ICR mice were divided into two groups: one receiving oral administration and the other receiving intravenous administration, with three mice in each group. The mice were fasted for 10-14 hours before administration, but had free access to water.

[0343] 2. Preparation of drug formulations

[0344] Weigh the test compound (different crystal forms, salt forms, solvates, and hydrates of Formula I compound) according to the dosage, and prepare an appropriate concentration of the drug preparation. For intravenous injection, it is a clear solution; for oral administration, it is a clear solution or a homogeneous suspension.

[0345] 3. Animal drug administration and blood sample collection

[0346] Animals were administered the drug via intravenous injection and oral gavage. Blood samples were collected at 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after intravenous injection, and at the same time after oral administration. Whole blood was centrifuged at 6800g for 6 min at 4°C, and the supernatant plasma was collected and stored at -80°C for analysis.

[0347] 4. Plasma sample testing

[0348] Dilute the DMSO stock solution of the analyte with methanol or acetonitrile to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of methanol or acetonitrile containing internal standard according to the response to precipitate proteins. Centrifuge all samples at 4°C, 18000g for 10 min, and take an appropriate amount of supernatant for LC-MS / MS analysis.

[0349] 5. Parameter Calculation

[0350] Based on the test concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software, pharmacokinetic parameters were calculated according to a non-compartmental model, including: half-life (T1 / 2), area under the curve (AUC0-t), clearance (CL), steady-state volume of distribution (Vss), and bioavailability (F).

[0351] Testing revealed that some crystal forms, salt forms, solvates, and hydrates of the compound of formula I disclosed in this invention exhibit good pharmacokinetic properties. For example, under conditions of 100 mg / kg, po, the C1 of crystal form I of compound of formula I... max The concentration (ng / mL) was 16045, and the AUC (ng*h / mL) was 110579. The C60 values ​​for its sulfate salt, hydrochloride, and p-toluenesulfonate crystal form IV were... max The values ​​(ng / mL) were all greater than 20,000, and the AUC (ng*h / mL) were all greater than 150,000.

[0352] The technical solutions of this application are not limited to the specific embodiments described above. Any technical modifications made based on the technical solutions of this application shall fall within the protection scope of this application.

Claims

1. The crystal form of the compound shown in formula (I), 2. The crystal form according to claim 1, characterized in that, The crystal form is crystal form I. Using Cu-Kα radiation, its X-ray powder diffraction pattern, expressed in 2θ angles, shows diffraction peaks at 8.93°±0.2° and 17.89°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 11.77°±0.2°, 15.73°±0.2°, 16.76°±0.2°, 20.73°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 17.50°±0.2°, 18.08°±0.2°, 21.27°±0.2°, 23.62°±0.2°, and 26.96°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 5.35°±0.2°, 11.61°±0.2°, 14.68°±0.2°, 20.30°±0.2°, 22.18°±0.2°, 22.42°±0.2°, 23.39°±0.2°, 26.73°±0.2°, 27.84°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 17.13°±0.2°, 19.05°±0.2°, 20.49°±0.2°, 24.34°±0.2°, 25.2°±0.2°, 25.51°±0.2°, 27.68°±0.2°, and 36.22°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 1; Preferably, its DSC curve has an endothermic peak at 237℃ to 247℃; Preferably, its DSC curve is substantially the same as that in Figure 2; Preferably, the weight loss of its TGA curve is essentially zero at 20℃ to 200℃; Preferably, its TGA curve is basically the same as that in Figure 3.

3. The crystal form according to claim 1, characterized in that, The crystal form is crystal form II. Using Cu-Kα radiation, its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at 16.31°±0.2° and 19.29°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at one or more of the following 2θ angles: 11.09°±0.2°, 18.47°±0.2°, 21.44°±0.2°, 23.82°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 17.21°±0.2°, 17.83°±0.2°, and 19.70°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 5.62°±0.2°, 10.41°±0.2°, 20.63°±0.2°, 20.98°±0.2°, 22.69°±0.2°, and 23.17°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.39°±0.2°, 16.92°±0.2°, 20.45°±0.2°, 26.32°±0.2°, 27.98°±0.2°, 28.31°±0.2°, 28.67°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 9.47°±0.2°, 10.66°±0.2°, 14.33°±0.2°, 27.31°±0.2°, 29.06°±0.2°, 31.20°±0.2°, 32.48°±0.2°, and 34.66°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 5; Preferably, its DSC curve has an endothermic peak at 238℃ to 248℃; Preferably, its DSC curve is basically the same as that in Figure 6; Preferably, the weight loss of its TGA curve is essentially zero at 20℃ to 200℃; Preferably, its TGA curve is substantially the same as that in Figure 7.

4. The salt form of the compound shown in formula (I), 5. The salt form according to claim 4, characterized in that, The salt type is an inorganic acid or organic acid salt of the compound shown in formula (I); Preferably, the inorganic or organic acid is selected from hydrochloric acid, toluenesulfonic acid (e.g., p-toluenesulfonic acid), sulfuric acid, hydrobromic acid, maleic acid, succinic acid, citric acid, fumaric acid, salicylic acid, L-tartaric acid, fumaric acid, acetic acid, nitric acid, phosphoric acid, oxalic acid, lactic acid, and amino acids such as lysine or aspartic acid.

6. The salt form according to claim 4 or 5, characterized in that, The salt type is the hydrochloride salt of the compound shown in formula (I); Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at 15.07°±0.2° and 15.98°±0.2°. Preferably, its X-ray powder diffraction pattern expressed in 2θ angle also has diffraction peaks at one or more of the following 2θ angles: 10.04°±0.2°, 14.54°±0.2°, 18.26°±0.2°, 18.72°±0.2°, 24.19°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 5.00°±0.2°, 8.64°±0.2°, 20.88°±0.2°, 23.49°±0.2°, and 28.21°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.02°±0.2°, 17.05°±0.2°, 17.38°±0.2°, 19.91°±0.2°, 20.12°±0.2°, 20.47°±0.2°, 22.24°±0.2°, and 25.55°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 9.18°±0.2°, 21.60°±0.2°, 22.07°±0.2°, 23.84°±0.2°, 25.95°±0.2°, 27.53°±0.2°, 27.82°±0.2°, 29.32°±0.2°, and 40.98°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 9; Preferably, its DSC curve has an endothermic peak at 185–225°C; Preferably, its DSC curve is substantially the same as that in Figure 10; Preferably, its TGA curve shows weight loss at 20–170°C, with a weight loss of 0.1–0.5% at 20–100°C; Preferably, its TGA curve is substantially the same as that in Figure 11.

7. The salt form according to claim 4 or 5, characterized in that, The salt type is p-toluenesulfonate.

8. The salt form according to claim 7, characterized in that, The p-toluenesulfonate has crystal form III; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has a diffraction peak at 7.59°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 3.80°±0.2°, 15.96°±0.2°, and 17.50°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 5.31°±0.2°, 19.42°±0.2°, 19.83°±0.2°, 20.73°±0.2°, 22.79°±0.2°, 24.13°±0.2°, and 24.28°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.23°±0.2°, 18.18°±0.2°, 18.41°±0.2°, 18.65°±0.2°, 21.56°±0.2°, and 23.50°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 8.62°±0.2°, 9.28°±0.2°, 11.78°±0.2°, 16.88°±0.2°, 20.28°±0.2°, 26.48°±0.2°, and 28.11°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 13; Preferably, its DSC curve has an endothermic peak in the range of 160℃ to 200℃; Preferably, its DSC curve is substantially the same as that in Figure 14; Preferably, its TGA curve shows a weight loss of 3.0% to 4.0% at 20℃ to 150℃ and a weight loss of 4.0% to 5.0% at 150℃ to 215℃. Preferably, its TGA curve is substantially the same as that in Figure 15.

9. The salt form according to claim 7, characterized in that, The p-toluenesulfonate has crystal form IV; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at the following 2θ angles: 3.80°±0.2°, 4.13°±0.2°, 9.39°±0.2°, 17.48°±0.2°, 19.09°±0.2°, and 21.83°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 5.25°±0.2°, 6.67°±0.2°, 7.90°±0.2°, 17.99°±0.2°, 19.42°±0.2°, 20.63°±0.2°, 22.12°±0.2°, and 23.33°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 15.75°±0.2°, 16.00°±0.2°, 16.35°±0.2°, 17.05°±0.2°, 19.58°±0.2°, 20.26°±0.2°, 21.11°±0.2°, 22.53°±0.2°, 24.61°±0.2°, and 27.12°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 17; Preferably, its DSC curve has an endothermic peak at 50℃~60℃ and / or 135℃~175℃; Preferably, its DSC curve is substantially the same as that in Figure 18; Preferably, its TGA curve shows a weight loss of 1.5% to 2.5% at 20℃ to 100℃ and a weight loss of 6.0% to 7.0% at 100℃ to 200℃. Preferably, its TGA curve is substantially the same as that in Figure 19.

10. The salt form according to claim 4 or 5, characterized in that, The salt type is the sulfate of the compound shown in formula (I).

11. The salt form according to claim 10, characterized in that, The sulfate of the compound shown in formula (I) is a solvate; preferably an acetone solvate. Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at the following 2θ angles: 9.34°±0.2°, 21.04°±0.2°, and 26.15°±0.2°; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at one or more of the following 2θ angles: 8.50°±0.2°, 19.93°±0.2°, 20.16°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 16.26°±0.2°, 18.45°±0.2°, 20.55°±0.2°, 22.44°±0.2°, and 25.86°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.50°±0.2°, 13.85°±0.2°, 16.47°±0.2°, 16.64°±0.2°, 17.21°±0.2°, 19.56°±0.2°, 24.24°±0.2°, 24.48°±0.2°, 24.83°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 25; Preferably, its DSC curve has an endothermic peak at 125℃~175℃ and / or 245℃~255℃; Preferably, its DSC curve is substantially the same as that in Figure 26; Preferably, its TGA curve shows a weight loss of 7.0% to 8.0% at temperatures ranging from 20°C to 180°C; Preferably, its TGA curve is substantially the same as that in Figure 27.

12. The salt form according to claim 10, characterized in that, The sulfate of the compound shown in formula (I) is a hydrate; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at 17.87°±0.2° and 18.80°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, and 22.16°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 19.02°±0.2°, 20.28°±0.2°, 22.44°±0.2°, 26.65°±0.2°, and 28.36°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 6.71°±0.2°, 13.36°±0.2°, 24.42°±0.2°, 27.31°±0.2°, 36.18°±0.2°, and 36.99°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 23.19°±0.2°, 25.68°±0.2°, 27.99°±0.2°, 29.70°±0.2°, 30.29°±0.2°, 31.86°±0.2°, and 35.67°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 29; Preferably, its DSC curve has an endothermic peak at 110℃~150℃ and / or 170℃~200℃; Preferably, its DSC curve is substantially the same as that in Figure 30; Preferably, its TGA curve shows a weight loss of 5.0% to 6.0% at 20℃ to 120℃ and a weight loss of 4.0% to 5.0% at 120℃ to 210℃. Preferably, its TGA curve is substantially the same as that in Figure 31.

13. The salt form according to claim 4, characterized in that, The salt type is a metal salt of a compound of formula I; Preferably, the metal salt is selected from alkali metal salts or alkaline earth metal salts; More preferably, the metal salt is selected from sodium salt, potassium salt, magnesium salt or calcium salt.

14. The salt form according to claim 4 or 13, characterized in that, The salt type is a potassium salt; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at the following 2θ angles: 11.18°±0.2°, 16.22°±0.2°, and 18.08°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 13.71°±0.2°, and 14.97°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle also has diffraction peaks at one or more of the following 2θ angles: 16.66°±0.2°, 18.84°±0.2°, 21.35°±0.2°, 23.06°±0.2°, 25.06°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 7.00°±0.2°, 17.79°±0.2°, 20.47°±0.2°, 22.59°±0.2°, and 23.87°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.15°±0.2°, 15.81°±0.2°, 17.64°±0.2°, 18.39°±0.2°, 19.70°±0.2°, 23.50°±0.2°, 25.47°±0.2°, 26.48°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 21; Preferably, its DSC curve has an endothermic peak at 110℃~160℃ and / or 220℃~250℃; Preferably, its DSC curve is substantially the same as that in Figure 22; Preferably, its TGA curve shows a weight loss of 13.0% to 15.0% at 20℃ to 200℃; Preferably, its TGA curve is substantially the same as that in Figure 23.

15. A solvate of the compound shown in formula (I), 16. The solvate according to claim 15, characterized in that, The solvent is selected from alcohols, carboxylic acids, ketones, ethers, esters, sulfoxides, or nitrile organic solvents; for example, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetone, ethylene glycol dimethyl ether, ethyl formate, DMSO, or acetonitrile.

17. The solvate according to claim 15 or 16, characterized in that, It is an acetone solvate.

18. The solvate according to claim 17, characterized in that, The acetone solvate is a sulfated acetone solvate; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at the following 2θ angles: 9.34°±0.2°, 21.04°±0.2°, and 26.15°±0.2°; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at one or more of the following 2θ angles: 8.50°±0.2°, 19.93°±0.2°, 20.16°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 16.26°±0.2°, 18.45°±0.2°, 20.55°±0.2°, 22.44°±0.2°, and 25.86°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.50°±0.2°, 13.85°±0.2°, 16.47°±0.2°, 16.64°±0.2°, 17.21°±0.2°, 19.56°±0.2°, 24.24°±0.2°, 24.48°±0.2°, 24.83°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 25; Preferably, its DSC curve has an endothermic peak at 125℃~175℃ and / or 245℃~255℃; Preferably, its DSC curve is substantially the same as that in Figure 26; Preferably, its TGA curve shows a weight loss of 7.0% to 8.0% at temperatures ranging from 20°C to 180°C; Preferably, its TGA curve is substantially the same as that in Figure 27.

19. The solvate according to claim 17, characterized in that, It is a potassium salt acetone solvate; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at the following 2θ angles: 11.18°±0.2°, 16.22°±0.2°, and 18.08°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 3.45°±0.2°, 9.32°±0.2°, 13.71°±0.2°, and 14.97°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle also has diffraction peaks at one or more of the following 2θ angles: 16.66°±0.2°, 18.84°±0.2°, 21.35°±0.2°, 23.06°±0.2°, 25.06°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 7.00°±0.2°, 17.79°±0.2°, 20.47°±0.2°, 22.59°±0.2°, and 23.87°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 12.15°±0.2°, 15.81°±0.2°, 17.64°±0.2°, 18.39°±0.2°, 19.70°±0.2°, 23.50°±0.2°, 25.47°±0.2°, 26.48°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 21; Preferably, its DSC curve has an endothermic peak at 110℃~160℃ and / or 220℃~250℃; Preferably, its DSC curve is substantially the same as that in Figure 22; Preferably, its TGA curve shows a weight loss of 13.0% to 15.0% at 20℃ to 200℃; Preferably, its TGA curve is substantially the same as that in Figure 23.

20. The hydrate of the compound shown in formula (I), 21. The hydrate according to claim 20, characterized in that, It is a sulfate salt compound; Preferably, Cu-Kα radiation is used, and its X-ray powder diffraction pattern, expressed in 2θ angles, has diffraction peaks at 17.87°±0.2° and 18.80°±0.2°. Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 8.73°±0.2°, 9.37°±0.2°, 11.03°±0.2°, 17.54°±0.2°, and 22.16°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 19.02°±0.2°, 20.28°±0.2°, 22.44°±0.2°, 26.65°±0.2°, and 28.36°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 6.71°±0.2°, 13.36°±0.2°, 24.42°±0.2°, 27.31°±0.2°, 36.18°±0.2°, and 36.99°±0.2°; Preferably, its X-ray powder diffraction pattern, expressed in 2θ angles, also has diffraction peaks at one or more of the following 2θ angles: 23.19°±0.2°, 25.68°±0.2°, 27.99°±0.2°, 29.70°±0.2°, 30.29°±0.2°, 31.86°±0.2°, and 35.67°±0.2°; Preferably, its X-ray powder diffraction pattern expressed in 2θ angle is substantially the same as that in Figure 29; Preferably, its DSC curve has an endothermic peak at 110℃~150℃ and / or 170℃~200℃; Preferably, its DSC curve is substantially the same as that in Figure 30; Preferably, its TGA curve shows a weight loss of 5.0% to 6.0% at 20℃ to 120℃ and a weight loss of 4.0% to 5.0% at 120℃ to 210℃. Preferably, its TGA curve is substantially the same as that in Figure 31.

22. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, and a pharmaceutically acceptable carrier or excipient.

23. Use of the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating diseases or conditions mediated by kinesin KIF18A.

24. The use according to claim 23, characterized in that, The disease or condition is a tumor or cancer; preferably, the disease or condition is selected from the group consisting of: (a) solid tumors or hematopoietic tumors selected from the following cancers: bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) hematopoietic tumors selected from the following lymphatic system: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma. (c) Hematopoietic tumors of the bone marrow lineage selected from: acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (d) stromal tumors selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous systems selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

25. Use of the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for reducing the size of solid tumors in a subject.

26. Use of the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating cell proliferation disorders in a subject.

27. Use of the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for inhibiting KIF18A in cells.

28. A method of treating a disease or condition mediated by kinesin KIF18A, comprising administering to a patient in need a therapeutically effective amount of the crystal form according to any one of claims 1-3, the salt form according to any one of claims 4-14, the solvate according to any one of claims 15-19, the hydrate according to any one of claims 20-21, or the pharmaceutical composition according to claim 22.

29. A method for reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need a therapeutically effective amount of the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22.

30. A method for treating cell proliferation disorders in a subject, the method comprising administering to a subject in need a therapeutically effective amount of the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22.

31. A method for inhibiting KIF18A in cells, the method comprising contacting the cells with the crystal form according to any one of claims 1 to 3, the salt form according to any one of claims 4 to 14, the solvate according to any one of claims 15 to 19, the hydrate according to any one of claims 20 to 21, or the pharmaceutical composition according to claim 22.

Images