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WO2025247352A1 - Forme cristalline, forme saline, solvate, hydrate de composé et utilisation associée - Google Patents

Forme cristalline, forme saline, solvate, hydrate de composé et utilisation associée

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Publication number
WO2025247352A1
WO2025247352A1 PCT/CN2025/098195 CN2025098195W WO2025247352A1 WO 2025247352 A1 WO2025247352 A1 WO 2025247352A1 CN 2025098195 W CN2025098195 W CN 2025098195W WO 2025247352 A1 WO2025247352 A1 WO 2025247352A1
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angles
ray powder
expressed
powder diffraction
diffraction pattern
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English (en)
Chinese (zh)
Inventor
陈洁
刘志强
张腾
甘伟
邹冬玉
陈斌
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Shenzhen Zhongge Biological Technology Co Ltd
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Shenzhen Zhongge Biological Technology Co Ltd
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Definitions

  • 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.
  • CIN Chromosomal instability
  • 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.
  • 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.
  • 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.
  • SAC spindle assembly checkpoint
  • 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.
  • therapies targeting CIN making KIF18A a highly promising new anti-tumor target.
  • 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.
  • This application also provides a salt form of the compound shown in formula (I).
  • This application also provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • this application provides the crystal form of the compound shown in formula (I),
  • the crystal form is crystal form I
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angle using Cu-K ⁇ radiation has a diffraction peak at 8.93° ⁇ 0.2°.
  • the crystal form I using Cu-K ⁇ radiation, has a diffraction peak at 17.89° ⁇ 0.2° in the X-ray powder diffraction pattern expressed in 2 ⁇ angle.
  • 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 2 ⁇ angles are obtained using Cu-K ⁇ radiation.
  • the crystal form I of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 11.77° ⁇ 0.2°, 15.73° ⁇ 0.2°, 16.76° ⁇ 0.2°, and 20.73° ⁇ 0.2°.
  • the crystal form I of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns at 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form I of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 17.50° ⁇ 0.2°, 18.08° ⁇ 0.2°, 21.27° ⁇ 0.2°, 23.62° ⁇ 0.2°, and 26.96° ⁇ 0.2°.
  • the crystal form I of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form I of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the crystal form I of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form I of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the crystal form I of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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.
  • the crystal form I of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2 ⁇ angles, which is substantially the same as that in Figure 1, when irradiated with Cu-K ⁇ .
  • 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.
  • 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.
  • the crystal form I of the compound represented by formula (I) is the amorphous form.
  • the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2 ⁇ angles using Cu-K ⁇ 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 2 ⁇ angles using Cu-K ⁇ radiation has a diffraction peak at 19.29° ⁇ 0.2°.
  • the crystal form is crystal form II, and the X-ray powder diffraction pattern expressed in 2 ⁇ angles using Cu-K ⁇ radiation has diffraction peaks at 16.31° ⁇ 0.2° and 19.29° ⁇ 0.2°.
  • the crystal form is crystal form II
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angles using Cu-K ⁇ radiation also has diffraction peaks at one or more of the following 2 ⁇ angles: 11.09° ⁇ 0.2°, 18.47° ⁇ 0.2°, 21.44° ⁇ 0.2°, and 23.82° ⁇ 0.2°.
  • the crystal form is crystal form II
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angles using Cu-K ⁇ radiation has diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 17.21° ⁇ 0.2°, 17.83° ⁇ 0.2°, and 19.70° ⁇ 0.2°.
  • the crystal form II of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns at 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction peaks at the following 2 ⁇ 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.
  • the crystal form II of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the crystal form II of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2 ⁇ angles, which is substantially the same as that in Figure 5, when irradiated with Cu-K ⁇ .
  • 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.
  • 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.
  • the crystal form II of the compound represented by formula (I) is the amorphous form.
  • the second aspect of this application provides a salt form of the compound shown in formula (I).
  • the salt type is an inorganic acid or organic acid salt of the compound shown in formula (I).
  • 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).
  • the salt type is a hydrochloride, p-toluenesulfonate, or sulfate of the compound shown in formula (I).
  • the salt type is the hydrochloride salt of the compound shown in formula (I).
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at 15.07° ⁇ 0.2° and 15.98° ⁇ 0.2° in X-ray powder diffraction patterns expressed in 2 ⁇ angles.
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns at 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns at 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction peaks at 2 ⁇ angles at the following 2 ⁇ 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°.
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the hydrochloride salt of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction peaks at 2 ⁇ angles at the following 2 ⁇ 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°.
  • the hydrochloride salt of the compound shown in formula (I) has an X-ray powder diffraction pattern, expressed in 2 ⁇ angles, that is substantially the same as that in Figure 9, when irradiated with Cu-K ⁇ .
  • 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.
  • 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.
  • the salt type is a p-toluenesulfonate of the compound shown in formula (I).
  • the p-toluenesulfonate of the compound represented by formula (I) has crystal form III.
  • 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 2 ⁇ angle using Cu-K ⁇ radiation.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles, which also has diffraction peaks at one or more of the following 2 ⁇ angles: 3.80° ⁇ 0.2°, 15.96° ⁇ 0.2°, and 17.50° ⁇ 0.2°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at the following 2 ⁇ angles: 3.80° ⁇ 0.2°, 7.59° ⁇ 0.2°, 15.96° ⁇ 0.2°, and 17.50° ⁇ 0.2°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when subjected to Cu-K ⁇ radiation, exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns at 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction peaks at one or more of the following 2 ⁇ angles in its 2 ⁇ 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
  • the p-toluenesulfonate crystal form III of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2 ⁇ angles using Cu-K ⁇ radiation that is substantially the same as that in Figure 13.
  • 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.
  • 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.
  • 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.
  • the p-toluenesulfonate of the compound shown in formula (I) has crystal form IV.
  • the p-toluenesulfonate crystal form IV of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form IV of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form IV of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form IV of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the p-toluenesulfonate crystal form IV of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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.
  • 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-K ⁇ at an angle of 2 ⁇ .
  • 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).
  • 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).
  • 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.
  • 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.
  • the salt type is a sulfate of the compound shown in formula (I).
  • 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.
  • the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at the following 2 ⁇ angles: 9.34° ⁇ 0.2°, 21.04° ⁇ 0.2°, and 26.15° ⁇ 0.2°.
  • the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has a diffraction peak at one or more of the following 2 ⁇ angles in its X-ray powder diffraction pattern expressed in 2 ⁇ angles: 8.50° ⁇ 0.2°, 19.93° ⁇ 0.2°, 20.16° ⁇ 0.2°.
  • the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ angles: 16.26° ⁇ 0.2°, 18.45° ⁇ 0.2°, 20.55° ⁇ 0.2°, 22.44° ⁇ 0.2°, and 25.86° ⁇ 0.2°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2 ⁇ angles using Cu-K ⁇ radiation that is substantially the same as that in Figure 25.
  • 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.
  • 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.
  • the sulfate of the compound shown in formula (I) is a hydrate.
  • 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 2 ⁇ angle using Cu-K ⁇ radiation.
  • 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 2 ⁇ angle using Cu-K ⁇ radiation.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at 17.87° ⁇ 0.2° and 18.80° ⁇ 0.2°.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 8.73° ⁇ 0.2°, 9.37° ⁇ 0.2°, 11.03° ⁇ 0.2°, 17.54° ⁇ 0.2°, and 22.16° ⁇ 0.2°.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 19.02° ⁇ 0.2°, 20.28° ⁇ 0.2°, 22.44° ⁇ 0.2°, 26.65° ⁇ 0.2°, and 28.36° ⁇ 0.2°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) has an X-ray powder diffraction pattern, expressed in 2 ⁇ angles, that is substantially the same as that in Figure 29, when irradiated with Cu-K ⁇ .
  • 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).
  • 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.
  • 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.
  • 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.
  • the salt type is a sodium salt, potassium salt, magnesium salt, or calcium salt of the compound shown in formula (I).
  • the salt type is a potassium salt of the compound shown in formula (I).
  • the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at the following 2 ⁇ angles: 11.18° ⁇ 0.2°, 16.22° ⁇ 0.2°, and 18.08° ⁇ 0.2°.
  • the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles that also have diffraction peaks at one or more of the following 2 ⁇ angles: 3.45° ⁇ 0.2°, 9.32° ⁇ 0.2°, 13.71° ⁇ 0.2°, and 14.97° ⁇ 0.2°.
  • the potassium salt of the compound shown in formula (I) exhibits X-ray powder diffraction patterns at 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles that also have diffraction peaks at one or more of the following 2 ⁇ angles: 16.66° ⁇ 0.2°, 18.84° ⁇ 0.2°, 21.35° ⁇ 0.2°, 23.06° ⁇ 0.2°, and 25.06° ⁇ 0.2°.
  • the potassium salt of the compound shown in formula (I) exhibits X-ray powder diffraction patterns at 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the potassium salt of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles that also have diffraction peaks at one or more of the following 2 ⁇ angles: 7.00° ⁇ 0.2°, 17.79° ⁇ 0.2°, 20.47° ⁇ 0.2°, 22.59° ⁇ 0.2°, and 23.87° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2 ⁇ angles exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2 ⁇ angles also has diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2 ⁇ angles exhibits diffraction peaks at the following 2 ⁇ 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°.
  • Cu-K ⁇ radiation is used, and the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in 2 ⁇ angle, is substantially the same as that in Figure 21.
  • 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.
  • 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.
  • the third aspect of this application provides a solvate of the compound shown in formula (I).
  • 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.
  • organic solvents such as methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetone, ethylene glycol dimethyl ether, ethyl formate, DMSO, or acetonitrile.
  • the solvate is an acetone solvate.
  • the solvate is a sulfate acetone solvate.
  • the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has a diffraction peak at one or more of the following 2 ⁇ angles in its X-ray powder diffraction pattern in terms of 2 ⁇ angles: 9.34° ⁇ 0.2°, 21.04° ⁇ 0.2°, and 26.15° ⁇ 0.2°.
  • the sulfate acetone solvate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has a diffraction peak at one or more of the following 2 ⁇ angles in its X-ray powder diffraction pattern expressed in 2 ⁇ angles: 8.50° ⁇ 0.2°, 19.93° ⁇ 0.2°, 20.16° ⁇ 0.2°.
  • the acetone sulfate solvate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ angles: 16.26° ⁇ 0.2°, 18.45° ⁇ 0.2°, 20.55° ⁇ 0.2°, 22.44° ⁇ 0.2°, and 25.86° ⁇ 0.2°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction peaks at one or more of the following 2 ⁇ angles in its 2 ⁇ 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°.
  • the acetone sulfate solvate of the compound shown in formula (I) has an X-ray powder diffraction pattern in 2 ⁇ angles using Cu-K ⁇ radiation that is substantially the same as that in Figure 25.
  • 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.
  • 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.
  • the solvate is a potassium salt acetone solvate.
  • the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at the following 2 ⁇ angles: 11.18° ⁇ 0.2°, 16.22° ⁇ 0.2°, and 18.08° ⁇ 0.2°.
  • the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles that also have diffraction peaks at one or more of the following 2 ⁇ angles: 3.45° ⁇ 0.2°, 9.32° ⁇ 0.2°, 13.71° ⁇ 0.2°, and 14.97° ⁇ 0.2°.
  • the potassium salt acetone solvate of the compound shown in formula (I) exhibits X-ray powder diffraction peaks at the following 2 ⁇ 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°.
  • the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles that also have diffraction peaks at one or more of the following 2 ⁇ angles: 16.66° ⁇ 0.2°, 18.84° ⁇ 0.2°, 21.35° ⁇ 0.2°, 23.06° ⁇ 0.2°, and 25.06° ⁇ 0.2°.
  • the potassium salt acetone solvate of the compound shown in formula (I) exhibits X-ray powder diffraction peaks at the following 2 ⁇ angles in terms of 2 ⁇ 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°.
  • the potassium salt acetone solvate of the compound shown in formula (I) has X-ray powder diffraction patterns in 2 ⁇ angles that also have diffraction peaks at one or more of the following 2 ⁇ angles: 7.00° ⁇ 0.2°, 17.79° ⁇ 0.2°, 20.47° ⁇ 0.2°, 22.59° ⁇ 0.2°, and 23.87° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the potassium salt acetone solvate of the compound shown in formula (I), expressed in 2 ⁇ angles has diffraction peaks at the following 2 ⁇ 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°.
  • the potassium salt acetone solvate of the compound shown in formula (I) exhibits X-ray powder diffraction patterns at 2 ⁇ angles, with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the potassium salt acetone solvate of the compound shown in formula (I), expressed in 2 ⁇ angles exhibits diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the potassium salt acetone solvate of the compound shown in formula (I), expressed in 2 ⁇ angle, is substantially the same as that in Figure 21.
  • 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).
  • 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.
  • 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.
  • the hydrate is a sulfate hydrate.
  • 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 2 ⁇ angle using Cu-K ⁇ radiation.
  • 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 2 ⁇ angle using Cu-K ⁇ radiation.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at 17.87° ⁇ 0.2° and 18.80° ⁇ 0.2°.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 8.73° ⁇ 0.2°, 9.37° ⁇ 0.2°, 11.03° ⁇ 0.2°, 17.54° ⁇ 0.2°, and 22.16° ⁇ 0.2°.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern in 2 ⁇ angles that also has diffraction peaks at one or more of the following 2 ⁇ angles: 19.02° ⁇ 0.2°, 20.28° ⁇ 0.2°, 22.44° ⁇ 0.2°, 26.65° ⁇ 0.2°, and 28.36° ⁇ 0.2°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits X-ray powder diffraction patterns in 2 ⁇ angles with diffraction peaks at one or more of the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I) when irradiated with Cu-K ⁇ , exhibits diffraction peaks at the following 2 ⁇ 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°.
  • the sulfate hydrate of the compound shown in formula (I), when irradiated with Cu-K ⁇ , has an X-ray powder diffraction pattern expressed in 2 ⁇ angles that is substantially the same as that in Figure 29.
  • 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.
  • 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.
  • the fifth aspect of this application provides a pharmaceutical composition
  • 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.
  • 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.
  • the disease or condition is a tumor. In some embodiments, the disease or condition is cancer.
  • 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.
  • 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
  • Hematopoietic tumors of the bone marrow lineage selected from: acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia;
  • stromal tumors selected from fibrosarcoma and rhabdomyosarcoma;
  • tumors of the central and peripheral nervous systems selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Figure 1 shows the XRPD pattern of crystal form I of the compound of formula I prepared in Example 1 of this application.
  • FIG. 1 shows the differential scanning calorimetry (DSC) curve of crystal form I of the compound of formula I prepared in Example 1 of this application.
  • FIG. 3 shows the thermogravimetric analysis (TGA) curve of crystal form I of the compound of formula I prepared in Example 1 of this application.
  • Figure 4 shows the NMR spectrum of crystal form I of the compound of formula I prepared in Example 1 of this application.
  • Figure 5 shows the XRPD pattern of crystal form II of the compound of formula I prepared in Example 2 of this application.
  • FIG. 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.
  • FIG. 7 shows the thermogravimetric analysis (TGA) curve of crystal form II of the compound of formula I prepared in Example 2 of this application.
  • Figure 8 shows the NMR spectrum of crystal form II of the compound of formula I prepared in Example 2 of this application.
  • Figure 9 shows the XRPD spectrum of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.
  • FIG 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.
  • FIG 11 shows the thermogravimetric analysis (TGA) curves of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.
  • Figure 12 shows the NMR spectrum of the hydrochloride salt of the compound of formula I prepared in Example 3 of this application.
  • 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.
  • 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.
  • FIG. 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.
  • 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.
  • 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.
  • 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.
  • FIG 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.
  • 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.
  • Figure 21 shows the XRPD pattern of the potassium salt of the compound of Formula I prepared in Example 6 of this application.
  • FIG. 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.
  • FIG. 23 shows the thermogravimetric analysis (TGA) curves of the potassium salt of the compound of Formula I prepared in Example 6 of this application.
  • Figure 24 shows the NMR spectrum of the potassium salt of the compound of formula I prepared in Example 6 of this application.
  • Figure 25 shows the XRPD spectrum of the sulfate solvate of the compound of formula I prepared in Example 7 of this application.
  • 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.
  • 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.
  • Figure 28 shows the NMR spectrum of the sulfate solvate of the compound of formula I prepared in Example 7 of this application.
  • Figure 29 shows the XRPD spectrum of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.
  • 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.
  • 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.
  • Figure 32 shows the NMR spectrum of the sulfate hydrate of the compound of formula I prepared in Example 8 of this application.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • two X-ray diffraction patterns are considered substantially identical when the 2 ⁇ angle of the characteristic peaks of the two X-ray diffraction patterns varies by no more than ⁇ 0.3°, ⁇ 0.2°, or ⁇ 0.1°.
  • 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.
  • 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”.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the obtained solid samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER).
  • the 2 ⁇ 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 K ⁇ 1 radiation, voltage 40 kV, current 40 mA, and a zero-background sample disk.
  • 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.
  • 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.
  • 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.
  • the high-performance liquid chromatograph was a SHIMADZU LC-20A (Shimadzu, JP), and the test conditions are shown in Table 1 below.
  • the ion chromatograph was a 925ECO IC (Metrohm, Swiss), and the instrument parameters are shown in Table 2 below.
  • EA Ethyl acetate
  • PE Petroleum ether
  • NMP N-methylpyrrolidone
  • DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
  • TLC Thin-layer chromatography
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DMF N,N-dimethylformamide
  • DIPEA N,N-diisopropylethylamine.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m), 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.
  • 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°C, but may decompose after 240°C.
  • the DSC results showed that crystal form I had a melting endothermic peak at approximately 242°C.
  • 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 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.
  • 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°C, but may decompose after 240°C.
  • the DSC results showed that crystal form II exhibited a melting endothermic peak at approximately 243°C.
  • the crystal form II of the compound shown in Formula I using Cu-K ⁇ radiation, has an XRPD pattern expressed in 2 ⁇ angles, which includes characteristic peaks at the diffraction angles (2 ⁇ ) shown in Table 4.
  • Preparation method Weigh 200.2 mg of the crystal form I of the compound shown in Formula I and 0.187 ⁇ L 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.
  • hydrochloric acid acid solution diluted with 2 mol/L ethanol
  • 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.
  • TGA results showed that the hydrochloride salt experienced a 0.3% weight loss upon heating to 100°C, continued to lose weight after 100°C, and may decompose after 170°C.
  • the DSC results showed an endothermic signal of melting and decomposition of the hydrochloride salt at approximately 214°C.
  • 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.
  • the salt formation ratio of the compound and hydrochloric acid is approximately 1:1.
  • hydrochloride salt of the compound shown in Formula I XRPD spectra expressed in 2 ⁇ angles using Cu-K ⁇ radiation, include characteristic peaks at the diffraction angles (2 ⁇ ) shown in Table 5.
  • Example 4 The p-toluenesulfonate crystal form III of the compound shown in Formula I
  • 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.
  • 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.
  • TGA results showed that p-toluenesulfonate crystal form III experienced a 3.4% weight loss upon heating to 150°C, and a 4.7% weight loss between 150°C and 215°C, and may decompose after 230°C.
  • the DSC results showed an endothermic signal at approximately 178°C 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.
  • the p-toluenesulfonate crystal form III of the compound shown in Formula I, with Cu-K ⁇ radiation, has an XRPD pattern expressed in 2 ⁇ angles, including characteristic peaks at the diffraction angles (2 ⁇ ) shown in Table 6.
  • Table 6 shows the peak position data of p-toluenesulfonate crystal form III of the compound represented by Formula I.
  • Example 5 Crystal form IV of p-toluenesulfonate of the compound shown in Formula I
  • 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.
  • 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.
  • TGA results showed that p-toluenesulfonate crystal form IV experienced a 1.7% weight loss upon heating to 100°C, a 6.3% weight loss between 100°C and 200°C, and may decompose after 230°C.
  • the DSC results showed endothermic signals at approximately 53°C and 162°C 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.
  • the p-toluenesulfonate crystal form IV of the compound shown in Formula I, with Cu-K ⁇ radiation, has an XRPD pattern expressed in 2 ⁇ angles, including characteristic peaks at the diffraction angles (2 ⁇ ) shown in Table 7.
  • Table 7 shows the peak position data of p-toluenesulfonate crystal form IV of the compound represented by Formula I.
  • Preparation method Weigh 23.8 mg of the crystal form I of the compound shown in Formula I and 22 ⁇ L 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°C and stir for 3 days to obtain a white solid.
  • 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°C, which basically corresponds to the solvent removal process.
  • the DSC results showed that the potassium salt exhibited endothermic signals at approximately 145°C and 232°C.
  • 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.
  • the salt formation ratio of the compound and potassium ions is approximately 1:0.8.
  • the potassium salt of the compound shown in Formula I when irradiated with Cu-K ⁇ , has an XRPD pattern represented at a 2 ⁇ angle, which includes the characteristic peaks at the diffraction angle (2 ⁇ ) shown in Table 8.
  • Table 8 shows the potassium salt peak positions of the compounds represented by Formula I.
  • Example 7 Sulfate solvate of the compound shown in Formula I
  • Preparation method Weigh 47.4 mg of the crystal form I of the compound shown in Formula I and 88 ⁇ L 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.
  • 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.
  • TGA results showed that the sulfate solvate experienced a 7.4% weight loss upon heating to 180°C and may decompose after 250°C.
  • the DSC results showed endothermic signals at approximately 163°C and 250°C.
  • 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.
  • Table 9 shows the peak positions of the sulfate solvates of the compounds represented by Formula I.
  • Example 8 Sulfate salt hydrate of the compound shown in Formula I
  • Preparation method Weigh 200.8 mg of the crystal form I of the compound shown in Formula I and 374 ⁇ L 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.
  • the DSC results showed endothermic signals in the sulfate hydrate at approximately 130°C and 180°C.
  • 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.
  • the sulfate salt hydrate of the compound shown in Formula I XRPD spectra expressed in 2 ⁇ angles using Cu-K ⁇ radiation, include characteristic peaks at the diffraction angles (2 ⁇ ) shown in Table 10.
  • Table 10 shows the peak positions of the sulfate hydrates of the compounds represented by Formula I.
  • 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 0.22 ⁇ m 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the compound of formula I was prepared according to the method described in Example 478 of WO2024/114787A1.
  • 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.
  • mice 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.
  • test compound different crystal forms, salt forms, solvates, and hydrates of Formula I compound
  • test compound for intravenous injection, it is a clear solution; for oral administration, it is a clear solution or a homogeneous suspension.
  • a blood drug concentration-time curve was plotted.
  • 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).

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Abstract

La présente invention concerne une forme cristalline, une forme saline, un solvate et un hydrate d'un composé tel que représenté par la formule (I), et une composition pharmaceutique contenant la forme cristalline, la forme saline, le solvate ou l'hydrate. La présente invention concerne en outre l'utilisation de la forme cristalline, de la forme saline, du solvate ou de l'hydrate.
PCT/CN2025/098195 2024-05-31 2025-05-29 Forme cristalline, forme saline, solvate, hydrate de composé et utilisation associée Pending WO2025247352A1 (fr)

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CN202410708952 2024-05-31
CN202410708952.2 2024-05-31

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WO2025247352A1 true WO2025247352A1 (fr) 2025-12-04

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