Crystal form of kif18a inhibitor, and preparation method therefor and use thereof

Abstract

Provided in the present invention is an amorphous form or a polymorph of a compound as shown in formula (I). The amorphous form or polymorph has excellent hygroscopicity, solubility and stability, has good druggability, and is suitable for industrial production, manufacturing and storage.

Description

A crystal form of a KIF18A inhibitor, its preparation method and application

[0001] This application claims the benefit of priority of the following prior patent applications:

[0002] The applicant's prior application, patent application number 202410265564.1, filed with the State Intellectual Property Office of China on March 7, 2024, entitled "A crystal form of a KIF18A inhibitor, its preparation method, and application";

[0003] The entire contents of the above-mentioned prior patent applications are incorporated into this application by reference. Technical Field

[0004] The present invention belongs to the field of compounds, and specifically relates to a crystal form of a KIF18A inhibitor, a preparation method thereof, and an application thereof. Background Art

[0005] PCT / CN2023 / 117322 (filing date September 6, 2023) describes the compound 4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide, whose structure is shown in Formula (I). This compound not only has good KIF18A inhibition and OVCAR-3 cell activity in vitro, but also has significantly improved physicochemical properties (solubility and permeability), significantly improved OVCAR-3 in vivo efficacy, and good safety. This compound can be used to treat KIF18A-mediated conditions and / or diseases, such as tumor diseases, and to prepare drugs for treating such conditions or diseases.

[0006] The crystal structure of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystalline forms. Therefore, in-depth research into the crystal forms of the compound of formula (I) and related preparation methods is essential to improve various properties of the compound of formula (I). Summary of the Invention

[0007] The present invention provides an amorphous or polymorphic compound of a compound represented by formula (I);

[0008] According to an embodiment of the present invention, the amorphous form of the compound represented by formula (I) has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in Figure 1. According to an embodiment of the present invention, the differential scanning calorimetry pattern (DSC pattern) of the amorphous form of the compound represented by formula (I) is shown in Figure 2. According to an embodiment of the present invention, the thermogravimetric analysis pattern (TGA pattern) of the amorphous form of the compound represented by formula (I) is shown in Figure 2.

[0009] According to an embodiment of the present invention, the polymorph of the compound represented by formula (I) is selected from the Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, Form E crystal form, Form F crystal form, Form G crystal form, Form H crystal form, and Form I crystal form of the compound represented by formula (I).

[0010] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.97°±0.20°, 17.87°±0.20°, 18.82°±0.20°, 19.07°±0.20°, 19.56°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 8.87°±0.20°, 13.46°±0.20°, 24.77°±0.20°. According to an embodiment of the present invention, the Form A crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.97°±0.20°, 17.87°±0.20°, 18.82°±0.20°, 19.07°±0.20°, 19.56°±0.20°. The X-ray powder diffraction pattern of Form A further includes one, two or more of the following characteristic diffraction peaks at 2θ angles: 6.81°±0.20°, 13.20°±0.20°, 16.18°±0.20°, 20.32°±0.20°, 21.11°±0.20°, 21.56°±0.20°, 22.38°±0.20°, 22.82°±0.20°, 23.35°±0.20°, 23.78°±0.20°, 24.01°±0.20°, 25.12°±0.20°, 25.68°±0.20°, 26.48°±0.20°, 26.67°±0.20°, 27.02°±0.20°, 28.01°±0.20°, 28.75°±0.20°, 30.72°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form A crystal form of the compound represented by formula (I) are shown in Table 2, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

[0011] According to an embodiment of the present invention, the Form A crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 4. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form A crystalline form of the compound represented by formula (I) comprises an endothermic peak at 245.9°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form A crystalline form of the compound represented by formula (I) is shown in Figure 5. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form A crystalline form of the compound represented by formula (I) is shown in Figure 5.

[0012] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form B crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 7.10°±0.20°, 9.92°±0.20°, 19.13°±0.20°, 19.36°±0.20°, 20.18°±0.20°, 23.50°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form B crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 15.48°±0.20°, 17.34°±0.20°, 17.87°±0.20°, 21.13°±0.20°, 23.66°±0.20°, 26.69°±0.20°. According to an embodiment of the present invention, the Form B crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 15.48°±0.20°, 17.34°±0.20°, 17.87°±0.20°, 21.13°±0.20°, 23.66°±0.20°, 26.69°±0.20°. The X-ray powder diffraction pattern of Form B further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 9.61°±0.20°, 10.72°±0.20°, 14.10°±0.20°, 17.58°±0.20°, 19.75°±0.20°, 22.05°±0.20°, 22.40°±0.20°, 23.99°±0.20°, 24.42°±0.20°, 24.73°±0.20°, 25.90°±0.20°, 27.26°±0.20°, 28.56°±0.20°, 28.85°±0.20°, 30.27°±0.20°, 30.72°±0.20°, 32.46°±0.20°, 33.01°±0.20°, 34.43°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form B crystalline form of the compound represented by formula (I) are shown in Table 3, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

[0013] According to an embodiment of the present invention, the Form B crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 7. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC pattern) of the Form B crystalline form of the compound represented by formula (I) comprises endothermic peaks at 60.7°C ± 2.0°C, 167.0°C ± 2.0°C, and 245.8°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC pattern) of the Form B crystalline form of the compound represented by formula (I) comprises an exothermic peak at 172.1°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC pattern) of the Form B crystalline form of the compound represented by formula (I) is shown in Figure 8. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA pattern) of the Form B crystalline form of the compound represented by formula (I) is shown in Figure 8.

[0014] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form C crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.51°±0.20°, 18.32°±0.20°, 19.09°±0.20°, 19.35°±0.20°, 23.10°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form C crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 16.51°±0.20°, 17.58°±0.20°, 20.24°±0.20°, 23.97°±0.20°, 25.51°±0.20°, 30.99°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 4, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°.

[0015] According to an embodiment of the present invention, the Form C crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 10. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form C crystalline form of the compound represented by formula (I) comprises endothermic peaks at 91.7°C ± 2.0°C and 245.4°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form C crystalline form of the compound represented by formula (I) is shown in Figure 11. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form C crystalline form of the compound represented by formula (I) is shown in Figure 11.

[0016] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.41°±0.20°, 19.17°±0.20°, 19.93°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 6.93°±0.20°, 17.60°±0.20°, 22.94°±0.20°, 23.60°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 9.14°±0.20°, 15.21°±0.20°, 16.57°±0.20°, 17.21. ±0.20°, 20.57°±0.20°, 21.00°±0.20°, 21.81°±0.20°, 23.19±0.20°, 23.84°±0.20°, 26.46°±0.20°, 28.09°±0.20°, 30.58°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form D crystalline form of the compound represented by formula (I) are shown in Table 5, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

[0017] According to an embodiment of the present invention, the Form D crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 13. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form D crystalline form of the compound represented by formula (I) comprises endothermic peaks at 148.7°C ± 2.0°C, 166.7°C ± 2.0°C, and 246.8°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form D crystalline form of the compound represented by formula (I) comprises an exothermic peak at 176.4°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form D crystalline form of the compound represented by formula (I) is shown in Figure 14. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form D crystalline form of the compound represented by formula (I) is shown in Figure 14.

[0018] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form E crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.78°±0.20°, 19.40°±0.20°, 20.07°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form E crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 9.40°±0.20°, 15.33°±0.20°, 17.26°±0.20°, 17.48°±0.20°, 17.62°±0.20°, 18.98°±0.20°, 23.49°±0.20°, 23.66°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form E crystal form of the compound represented by formula (I) is shown in Table 6, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°.

[0019] According to an embodiment of the present invention, the Form E crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 16. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form E crystalline form of the compound represented by formula (I) comprises endothermic peaks at 58.2°C ± 2.0°C, 168.2°C ± 2.0°C, and 246.8°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form E crystalline form of the compound represented by formula (I) comprises an exothermic peak at 182.9°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form E crystalline form of the compound represented by formula (I) is shown in Figure 17. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form E crystalline form of the compound represented by formula (I) is shown in Figure 17.

[0020] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form F crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.71°±0.20°, 17.65°±0.20°, 18.79°±0.20°, 19.44°±0.20°, 20.01°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form F crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 9.31°±0.20°, 15.36°±0.20°, 17.01°±0.20°, 17.31°±0.20°, 20.87°±0.20°, 23.36°±0.20°, 23.66°±0.20°, 23.82°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form F crystalline form of the compound represented by formula (I) are shown in Table 7, wherein the error range of each characteristic diffraction peak 2θ is ±0.2°.

[0021] According to an embodiment of the present invention, the Form F crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 19. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) comprises endothermic peaks at 56.4°C ± 2.0°C, 150.7°C ± 2.0°C, 167.8°C ± 2.0°C, and 247.1°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) comprises an exothermic peak at 171.7°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form F crystalline form of the compound represented by formula (I) is shown in Figure 20. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form F crystalline form of the compound represented by formula (I) is shown in Figure 20.

[0022] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form G crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.61°±0.20°, 17.62°±0.20°, 19.54°±0.20°, 20.30°±0.20°, 24.09°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form G crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 7.06°±0.20°, 16.70°±0.20°, 18.49°±0.20°, 19.31°±0.20°, 23.31°±0.20°, 26.89°±0.20°, 28.60°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form G crystal form of the compound represented by formula (I) is shown in Table 8, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°.

[0023] According to an embodiment of the present invention, the Form G crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 22. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form G crystalline form of the compound represented by formula (I) comprises endothermic peaks at 97.5°C ± 2.0°C and 246.4°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC spectrum) of the Form G crystalline form of the compound represented by formula (I) is shown in Figure 23. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form G crystalline form of the compound represented by formula (I) is shown in Figure 23.

[0024] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form H crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.37°±0.20°, 19.15°±0.20°, 20.01°±0.20°, 22.98°±0.20°, and 23.70°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form H crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 6.95°±0.20°, 9.14°±0.20°, 16.57°±0.20°, 17.30°±0.20°, 17.54°±0.20°, 20.59°±0.20°, 21.08°±0.20°, 25.60°±0.20°, 26.26°±0.20°, 28.19°±0.20°, 30.56°±0.20°.

[0025] According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form H crystal form of the compound represented by formula (I) are shown in Table 9, wherein the error range of each characteristic diffraction peak 2θ is ± 0.2°. According to an embodiment of the present invention, the Form H crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form H crystal form of the compound represented by formula (I) includes endothermic peaks at 123.6°C ± 2.0°C, 165.6°C ± 2.0°C, and 246.6°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form H crystal form of the compound represented by formula (I) includes an exothermic peak at 173.0°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC diagram) of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA spectrum) of the Form H crystal form of the compound represented by formula (I) is shown in FIG26 .

[0026] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 13.55°±0.20°, 17.22°±0.20°, 18.27°±0.20°, 18.91°±0.20°, 20.8°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 5.11°±0.20°, 7.91°±0.20°, 11.63°±0.20°, 14.34°±0.20°, 14.98°±0.20°, 15.68°±0.20°, 19.69°±0.20°, 21.9°±0.20°, 22.57°±0.20°, 23.53°±0.20°, 24.17°±0.20°, 25.72°±0.20°, 28.02°±0.20°, and 32.21°±0.20°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the Form I crystal form of the compound represented by formula (I) is shown in Table 10, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°.

[0027] According to an embodiment of the present invention, the Form I crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 28. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC pattern) of the Form I crystalline form of the compound represented by formula (I) comprises endothermic peaks at 210.4°C ± 2.0°C and 245.8°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC pattern) of the Form I crystalline form of the compound represented by formula (I) comprises an exothermic peak at 210.4°C ± 2.0°C. According to an embodiment of the present invention, the differential scanning calorimetry analysis spectrum (DSC pattern) of the Form I crystalline form of the compound represented by formula (I) is shown in Figure 29. According to an embodiment of the present invention, the thermogravimetric analysis spectrum (TGA pattern) of the Form I crystalline form of the compound represented by formula (I) is shown in Figure 30.

[0028] The present invention also provides a method for preparing the amorphous or polymorphic form of the compound represented by the above formula (I), wherein:

[0029] The preparation method of the amorphous form of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a first solvent and freeze-drying to obtain the amorphous form of the compound represented by formula (I);

[0030] The preparation method of the polymorph of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a solvent and crystallizing to obtain the polymorph of the compound represented by formula (I).

[0031] According to an embodiment of the present invention, in the method for preparing the amorphous form of the compound represented by formula (I), the first solvent is selected from a mixed solvent of an organic solvent (such as acetonitrile) and water.

[0032] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is selected from the following method A or method B:

[0033] Method A): dissolving the amorphous form of the compound of formula (I) in a second solvent, adding a third solvent, stirring, and crystallizing to obtain Form A of the compound of formula (I);

[0034] Method B): The amorphous form of the compound of formula (I) is dissolved in a fourth solvent, suspended, and crystallized to obtain Form A of the compound of formula (I).

[0035] According to an embodiment of the present invention, the method for preparing the amorphous form of the compound represented by formula (I) is as described above.

[0036] According to an embodiment of the present invention, the method A is specifically as follows: dissolving the amorphous form of the compound of formula (I) in a second solvent, adding a third solvent, stirring, crystallizing, centrifuging, and drying to obtain the Form A crystal form of the compound represented by formula (I).

[0037] According to an embodiment of the present invention, the second solvent is selected from dichloromethane and acetone. According to an embodiment of the present invention, the third solvent is selected from methyl tert-butyl ether. According to an embodiment of the present invention, the volume ratio of the second solvent to the third solvent is 1:1-20, for example, 1:15, 1:10, 1:8, 1:5, 1:2. According to an embodiment of the present invention, the mass volume ratio of the amorphous form of the compound of formula (I) to the second solvent is 1g:10mL-50mL, for example, 1g:40mL, 1g:30mL, 1g:20mL, 1g:15mL, 1g:10mL.

[0038] According to an embodiment of the present invention, the method B is specifically as follows: dissolving the amorphous form of the compound of formula (I) in a fourth solvent, suspending, crystallizing, centrifuging, and drying to obtain the Form A crystal form of the compound of formula (I).

[0039] According to an embodiment of the present invention, the fourth solvent is selected from n-hexane. According to an embodiment of the present invention, the suspension temperature is 40-60° C., for example, 50° C. According to an embodiment of the present invention, the suspension time is 10 h-50 h, for example, 24 h.

[0040] According to an embodiment of the present invention, the mass volume ratio of the amorphous form of the compound of formula (I) to the fourth solvent is 1g:50mL-200mL, for example, 1g:80mL, 1g:100mL, 1g:120mL, 1g:150mL.

[0041] According to an embodiment of the present invention, the preparation method of the Form B crystal form of the compound represented by formula (I) is as follows:

[0042] The Form A crystal form of the compound of formula (I) is dissolved in a fifth solvent, and then a sixth solvent is added, stirred, and crystallized to obtain the Form B crystal form of the compound of formula (I).

[0043] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0044] According to an embodiment of the present invention, the preparation method of the Form B crystal form is as follows: dissolving the Form A crystal form of the compound of formula (I) in a fifth solvent, adding a sixth solvent, stirring, crystallizing, centrifuging, and drying to obtain the Form B crystal form of the compound represented by formula (I).

[0045] According to an embodiment of the present invention, the fifth solvent is selected from dichloromethane. According to an embodiment of the present invention, the sixth solvent is selected from n-heptane. According to an embodiment of the present invention, the volume ratio of the fifth solvent to the sixth solvent is 1:1-20, for example, 1:5, 1:8, 1:10, 1:12, 1:15. According to an embodiment of the present invention, the mass volume ratio of Form A crystalline form of the compound of formula (I) to the fifth solvent is 1g:10mL-50mL, for example, 1g:40mL, 1g:30mL, 1g:20mL, 1g:10mL.

[0046] According to an embodiment of the present invention, the preparation method of the Form C crystal form of the compound represented by formula (I) is as follows:

[0047] The Form A crystal form of the compound of formula (I) is dissolved in a seventh solvent, the seventh solvent is evaporated open, and crystallization is performed to obtain the Form C crystal form of the compound of formula (I).

[0048] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0049] According to an embodiment of the present invention, the preparation method of the Form C crystal form is as follows: dissolving the Form A crystal form of the compound of formula (I) in a seventh solvent, evaporating the seventh solvent at room temperature, and crystallizing to obtain the Form C crystal form of the compound represented by formula (I).

[0050] According to an embodiment of the present invention, the seventh solvent is selected from ethyl acetate. According to an embodiment of the present invention, the mass volume ratio of Form A crystalline form of the compound of formula (I) to the seventh solvent is 5 mg-20 mg:1 mL, for example, 5 mg:1 mL, 8 mg:1 mL, 10 mg:1 mL, 15 mg:1 mL.

[0051] According to an embodiment of the present invention, the preparation method of the Form D crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in an eighth solvent, suspended, and crystallized to obtain the Form D crystal form of the compound represented by formula (I).

[0052] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0053] According to an embodiment of the present invention, the preparation method of the Form D crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in an eighth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form D crystal form of the compound represented by formula (I).

[0054] According to an embodiment of the present invention, the eighth solvent is selected from ethanol. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the suspension time is 5min-60min, for example, 20min. According to an embodiment of the present invention, the mass volume ratio of Form A crystalline form of the compound of formula (I) to the eighth solvent is 10mg-30mg:1mL, for example, 12mg:1mL, 15mg:1mL, 16mg:1mL, 20mg:1mL.

[0055] According to an embodiment of the present invention, the preparation method of the Form E crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a ninth solvent, suspended, and crystallized to obtain the Form E crystal form of the compound represented by formula (I).

[0056] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0057] According to an embodiment of the present invention, the preparation method of the Form E crystal form is as follows: dissolving the Form A crystal form of the compound of formula (I) in a ninth solvent, suspending, crystallizing, centrifuging, and drying to obtain the Form E crystal form of the compound of formula (I).

[0058] According to an embodiment of the present invention, the ninth solvent is selected from methanol. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the mass volume ratio of the Form A crystalline form of the compound of formula (I) to the ninth solvent is 5 mg-30 mg:1 mL, for example, 8 mg:1 mL, 10 mg:1 mL, 10.2 mg:1 mL, 12 mg:1 mL, 15 mg:1 mL.

[0059] According to an embodiment of the present invention, the preparation method of the Form F crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in a tenth solvent, suspended, and crystallized to obtain the Form F crystal form of the compound represented by formula (I).

[0060] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0061] According to an embodiment of the present invention, the preparation method of the Form F crystal form is as follows: the Form A crystal form of the compound of formula (I) is dissolved in a tenth solvent, suspended, crystallized, centrifuged, and dried to obtain the Form F crystal form of the compound represented by formula (I).

[0062] According to an embodiment of the present invention, the tenth solvent is selected from acetonitrile. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the mass volume ratio of Form A crystalline form of the compound of formula (I) to the tenth solvent is 5 mg-30 mg:1 mL, for example, 8 mg:1 mL, 10 mg:1 mL, 10.2 mg:1 mL, 12 mg:1 mL, 15 mg:1 mL.

[0063] According to an embodiment of the present invention, the preparation method of the Form G crystal form of the compound represented by formula (I) is as follows: the Form A crystal form of the compound represented by formula (I) is dissolved in an eleventh solvent, suspended, and crystallized to obtain the Form G crystal form of the compound represented by formula (I).

[0064] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0065] According to an embodiment of the present invention, the preparation method of the Form G crystalline form is as follows: the Form A crystalline form of the compound of formula (I) is dissolved (completely dissolved) in an eleventh solvent, suspended, crystallized, centrifuged, and dried to obtain the Form G crystalline form of the compound of formula (I). According to an embodiment of the present invention, the eleventh solvent is selected from ethylene glycol dimethyl ether. According to an embodiment of the present invention, the suspension temperature is 10°C-30°C, for example, room temperature.

[0066] According to an embodiment of the present invention, the preparation method of the Form H crystalline form of the compound represented by formula (I) is as follows:

[0067] The Form A crystal form of the compound of formula (I) is dissolved in a twelfth solvent, and the temperature is lowered for crystallization to obtain the Form H crystal form of the compound of formula (I).

[0068] According to an embodiment of the present invention, the preparation method of the Form A crystal form of the compound represented by formula (I) is as described above.

[0069] According to an embodiment of the present invention, the preparation method of the Form H crystalline form is as follows: dissolving the Form A crystalline form of the compound of formula (I) in a twelfth solvent (using a minimum amount of the twelfth solvent), cooling the solution to crystallize, centrifuging, and drying to obtain the Form H crystalline form of the compound of formula (I). According to an embodiment of the present invention, the twelfth solvent is selected from ethyl formate.

[0070] According to an embodiment of the present invention, the preparation method of the Form I crystal form of the compound represented by formula (I) is as follows:

[0071] The Form D crystal form of the compound of formula (I) is dissolved in a thirteenth solvent, and the temperature is lowered to crystallize to obtain the Form I crystal form of the compound of formula (I).

[0072] According to an embodiment of the present invention, the preparation method of Form D crystal form of the compound represented by formula (I) is as described above.

[0073] According to an embodiment of the present invention, the preparation method of the Form I crystal form is as follows: Form D crystal form of the compound of formula (I) is dissolved in a thirteenth solvent with stirring, cooled and stirred, suspended, centrifuged, and dried to obtain Form I crystal form of the compound of formula (I). According to an embodiment of the present invention, the thirteenth solvent is selected from one or more of isopropyl alcohol, isopropyl acetate, acetone, methyl tert-butyl ether, and the like. According to an embodiment of the present invention, the mass volume ratio of Form D crystal form of the compound of formula (I) to the thirteenth solvent is 50 mg-200 mg:1 mL, for example, 80 mg:1 mL, 100 mg:1 mL, 125 mg:1 mL, 150 mg:1 mL, or 180 mg:1 mL. According to an embodiment of the present invention, the temperature for stirring and dissolving is 40°C-60°C, for example, 50°C. According to an embodiment of the present invention, the stirring and dissolving time is 1 hour-3 hours, for example, 2 hours. According to an embodiment of the present invention, the temperature for stirring and cooling is 10°C-30°C, for example, room temperature. According to an embodiment of the present invention, the stirring and cooling time is 1 day-3 days, for example, 2 days. According to an embodiment of the present invention, the drying method is vacuum drying. According to an embodiment of the present invention, the drying temperature is 40°C-60°C, for example 50°C.

[0074] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by the above formula (I).

[0075] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0076] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0077] The present invention also provides a method for treating tumor diseases, which comprises administering to a patient a preventive or therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by formula (I) or the pharmaceutical composition.

[0078] According to an embodiment of the present invention, the tumor disease includes colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer. According to an embodiment of the present invention, the patient includes a mammal, preferably a human.

[0079] The present invention also provides a method for treating KIF18A-mediated disorders and / or diseases, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the amorphous or polymorphic forms of the compound represented by formula (I) or the pharmaceutical composition.

[0080] According to an embodiment of the present invention, the KIF18A-mediated disorder and / or disease is cancer, such as bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

[0081] The present invention also provides an amorphous or polymorphic compound of the compound represented by the above formula (I) or the above pharmaceutical composition for treating tumor diseases.

[0082] The present invention also provides use of the amorphous or polymorphic form of the compound represented by the above formula (I) or the above pharmaceutical composition in preparing medicines.

[0083] According to an embodiment of the present invention, the use may be use in preparing a medicament for treating KIF18A-mediated disorders and / or diseases, such as use in preparing a KIF18A inhibitor drug.

[0084] According to an embodiment of the present invention, the disease is cancer, for example including bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

[0085] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0086] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. Beneficial effects

[0087] The present invention provides an amorphous or polymorphic form of a compound represented by formula (I). The amorphous and polymorphic forms have excellent hygroscopicity, solubility and stability, excellent drugability, and are suitable for industrial production, manufacturing and storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1: XRPD pattern of the amorphous form of the compound represented by formula (I);

[0089] Figure 2: Overlay of DSC and TGA images of the amorphous form of the compound represented by formula (I);

[0090] Figure 3: NMR spectrum of the amorphous form of the compound represented by formula (I);

[0091] Figure 4: XRPD pattern of Form A of the compound represented by formula (I);

[0092] Figure 5: Overlay of DSC and TGA images of Form A of the compound represented by formula (I);

[0093] Figure 6: NMR spectrum of Form A crystalline form of the compound represented by formula (I);

[0094] Figure 7: XRPD pattern of Form B of the compound represented by formula (I);

[0095] Figure 8: Overlay of DSC and TGA images of Form B of the compound represented by formula (I);

[0096] Figure 9: NMR spectrum of Form B crystalline form of the compound represented by formula (I);

[0097] Figure 10: XRPD pattern of Form C of the compound represented by formula (I);

[0098] Figure 11: Overlay of DSC and TGA images of Form C of the compound represented by formula (I);

[0099] Figure 12: NMR spectrum of Form C of the compound represented by formula (I);

[0100] Figure 13: XRPD pattern of Form D crystalline form of the compound represented by formula (I);

[0101] Figure 14: Overlay of DSC and TGA images of Form D of the compound represented by formula (I);

[0102] Figure 15: NMR spectrum of Form D crystalline form of the compound represented by formula (I);

[0103] Figure 16: XRPD pattern of Form E crystalline form of the compound represented by formula (I);

[0104] Figure 17: Overlay of DSC and TGA images of Form E of the compound represented by formula (I);

[0105] Figure 18: NMR spectrum of Form E crystalline form of the compound represented by formula (I);

[0106] Figure 19: XRPD pattern of Form F crystalline form of the compound represented by formula (I);

[0107] Figure 20: Overlay of DSC and TGA images of Form F, a crystalline form of the compound represented by formula (I);

[0108] Figure 21: NMR spectrum of Form F crystalline form of the compound represented by formula (I);

[0109] Figure 22: XRPD pattern of Form G crystalline form of the compound represented by formula (I);

[0110] Figure 23: Overlay of DSC and TGA images of Form G of the compound represented by formula (I);

[0111] Figure 24: NMR spectrum of Form G crystalline form of the compound represented by formula (I);

[0112] Figure 25: XRPD pattern of Form H crystalline form of the compound represented by formula (I);

[0113] Figure 26: Overlay of DSC and TGA images of Form H of the compound represented by formula (I);

[0114] Figure 27: NMR spectrum of Form H crystalline form of the compound represented by formula (I);

[0115] Figure 28: XRPD pattern of Form I crystalline form of the compound represented by formula (I);

[0116] Figure 29: DSC graph of Form I crystalline form of the compound represented by formula (I);

[0117] Figure 30: TGA chart of Form I crystal form of the compound represented by formula (I);

[0118] Figure 31: NMR spectrum of Form I crystalline form of the compound represented by formula (I);

[0119] Figure 32: DVS image of Form A crystalline form of the compound represented by formula (I);

[0120] Figure 33: XRPD comparison of Form A of the compound represented by formula (I) before and after DVS testing;

[0121] Figure 34: DVS image of Form E crystalline form of the compound represented by formula (I);

[0122] Figure 35: XRPD comparison of Form E of the compound of formula (I) before and after DVS testing;

[0123] Figure 36: XRPD comparison chart of the stability study of Form A crystal form of the compound represented by formula (I). DETAILED DESCRIPTION

[0124] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0125] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0126] The following are the instruments, parameters, characterizations, and test methods used in the examples:

[0127] (1) NMR analysis 1 H NMR)

[0128] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 or deuterated methanol solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE NEO 400 (Bruker, Germany).

[0129] (2) X-ray powder diffraction (XRPD)

[0130] Solid samples obtained in some experiments were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 s. The measurements were performed using Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[0131] Solid samples obtained in some experiments were analyzed using an X-ray powder diffractometer (PANalytical EMPYREAN, UK). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.013°, for a total measurement time of 3 minutes and 30 seconds. The measurement method used Kα1 radiation from a Cu target, a voltage of 45 kV, a current of 40 mA, and a zero-background sample pan.

[0132] (3) Thermogravimetric analysis (TGA)

[0133] The thermogravimetric analyzer (TA Discovery 550, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0134] (4) Differential Scanning Calorimetry (DSC)

[0135] The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 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 purge rate of 50 mL / min.

[0136] (5) Dynamic moisture adsorption and desorption analysis (DVS)

[0137] Dynamic moisture sorption / desorption analysis (DVS Intrinsic Plus, SMS, UK) was used to perform preliminary hygroscopicity assessments. The test used a gradient mode with humidity changes from 50% to 95% to 50%, with each step increasing by 15%. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 60 minutes per step. After the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0138] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic Plus (SMS, UK). The test used a gradient mode with humidity changes from 0% to 95% to 0%, with each gradient increasing by 10% within the 0% to 95% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per gradient. After the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0139] (6) High performance liquid chromatography (HPLC)

[0140] The high performance liquid chromatography model was SHIMADZU LC-20A (Shimadzu, JP), and the test conditions were shown in the table.

[0141] Table 1 HPLC test conditions

[0142] Example 1

[0143] Step 1 Synthesis of (1S,4R)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptane-3-imine (Compound 2c)

[0144] Under a nitrogen atmosphere, (1S,4R)-2-azabicyclo[2.2.1]heptane-3-one 2b (2.76 g, 25 mmol, 1.0 eq.) was dissolved in 60 mL of acetonitrile, the reaction temperature was lowered to 0°C, POCl3 (3.73 g, 25 mmol, 1.0 eq.) was added dropwise, and the reaction was maintained at 0°C for 2 h. 2,6-dibromoaniline 2a (6.20 g, 25 mmol, 1.0 eq.) was added and the reaction was continued for 2 h. After TLC detection, the reaction was completed, and 20 mL of saturated NaHCO3 was added to quench the reaction solution. 2×20 mL of ethyl acetate was added for extraction, the liquids were separated, the organic layers were combined, and the mixture was washed with 2×20 mL of brine. The organic phase was spin-dried and slurried with a 1 / 1 mixture of ethyl acetate / petroleum ether to give the crude product compound 2c (5.60 g), which was used directly in the next reaction without purification.

[0145] Compound 2c was characterized as follows:

[0146] 1 H NMR (400MHz, CDCl3) δ7.52-7.49 (m, 2H), 6.5 (t, J=8.0, 1H), 3.85 (d, 1H), 3.20 (s, 1H) , 1.98-1.95(m, 2H), 1.85(t, 1H), 1.48(d, 1H), 1.46-1.44(m, 1H), 1.37-1.36(m, 2H);

[0147] MS: (ESI, m / z): 345.1 [M+H] + .

[0148] Step 2 Synthesis of (1S,4R)-6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (Compound 2d)

[0149] The crude product of compound 2c (1.50 g, 4.4 mmol, 1.0 eq.) was weighed and dissolved in 30 mL of DMSO. Potassium carbonate (1.21 g, 8.8 mmol, 2 eq.) and cuprous iodide (0.08 g, 0.44 mmol, 0.1 eq.) were added. The mixture was heated to 80°C for 2 h. The reaction was completed by HPLC. The mixture was cooled to room temperature, and 600 mL of water was added. The mixture was extracted with 2 × 30 mL of ethyl acetate. The organic layers were combined and concentrated to dryness to give the crude product 2d (0.48 g).

[0150] Compound 2d was characterized as follows: MS: (ESI, m / z): 262.8 [M+H]+ .

[0151] Step 3 Synthesis of Compound 2

[0152] Compound 2d (0.50 g, 1.9 mmol, 1.0 eq.), cuprous oxide (100 mg, 0.07 mmol, 0.35 eq.), potassium hydroxide (0.12 g, 1.9 mmol, 1.0 eq.), and 10 mL of ethanolic ammonia solution (20% ammonia in ethanol) were stirred at 80°C for 12 hours. HPLC confirmed the reaction was complete, and the filtrate was filtered and concentrated to dryness under reduced pressure. 20 mL of water was added, and the mixture was extracted with dichloromethane (2 × 10 mL). The organic phase was concentrated to dryness and crystallized by adding ethyl acetate / n-heptane (1 / 3) to afford compound 2 (250 mg, 66% yield).

[0153] Compound 2 is characterized as follows:

[0154] 1 H NMR (400MHz, CDCl3) δ7.18 (t, 1H), 6.83 (dd, 1H), 6.54 (dd, 1H), 4.95 (qd, 1H), 4. 31(s, 2H), 3.62(d, 1H), 2.22-2.16(m, 1H), 2.10-2.07(m, 3H), 1.37-1.36(m, 2H);

[0155] MS: (ESI, m / z): 199.9 [M+H] + .

[0156] Step 4: Synthesis of 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (Compound 3a)

[0157] Under nitrogen, 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (Compound 1a) (6.70 g, 21.6 mmol, 1.0 eq.), Compound 2 (4.38 g, 22 mmol, 1.02 eq.), and DMF (33.5 mL) were added to a reaction vessel. The temperature was controlled at 25±5°C, and DIEA (5.42 g, 47 mmol, 2.2 eq.) was added dropwise. After the addition was complete, HATU (10.36 g, 27 mmol, 1.3 eq.) and EDCI (5.22 g, 27 mmol, 1.3 eq.) were added to the reaction vessel. The temperature was controlled at 25±5°C and stirred for at least 10 hours. After the reaction was completed by HPLC, the temperature in the reaction vessel was controlled at 25±5°C, and H2O (40.2 mL) was added dropwise. The mixture was stirred for at least 1 hour and centrifuged. The filter cake was rinsed with H2O (13.4 mL) and collected. The wet filter cake and H₂O (33.5 mL) were added to a reaction vessel. The reaction mixture was stirred for at least 1 hour at a temperature of 25±5°C. The mixture was centrifuged and rinsed with H₂O (13.4 mL). The filter cake was collected and dried under vacuum at 45±5°C to afford 3a (9.88 g, 93% yield), a brown solid.

[0158] Compound 3a was characterized as follows:

[0159] 1 H NMR (400MHz, CDCl3) δ12.28 (s, 1H), 8.46 (d, 1H), 8.10 (d, 1H), 7.44-7.39 (m, 1H), 7.36-7. 30(m, 1H), 7.24(dd, 1H), 7.14-7.12(m, 1H), 4.97(s, 1H), 3.79(t, 1H), 3.67(s, 1H), 3.13- 3.11(m, 4H), 2.40(d, 1H), 2.38-2.37(m, 1H), 2.36-2.35(m, 2H), 2.16-2.13(m, 2H), 2.02- 1.96(m, 3H), 1.94-1.58(m, 4H), 1.22-1.14(m, 4H), 0.31(s, 4H).MS(EI, m / z): 492.5[M+H] + .

[0160] Step 5: Synthesis of the compound of formula (I)

[0161] Under nitrogen protection, compound 3a (9.50 g, 1.9 mmol, 1.0 eq.), 2-hydroxyethane-1-sulfonamide (compound 4) (3.14 g, 2.5 mmol, 1.3 eq.), K3PO4 (10.26 g, 4.8 mmol, 2.5 eq.), DMF (38 mL), and trans-NN-dimethyl-1,2-cyclohexanediamine (2.75 g, 1.9 mmol, 1.0 eq.) were added to the reactor. The atmosphere was replaced with nitrogen three times. CuI (1.84 g, 0.95 mmol, 0.5 eq.) was added to the system. The reactor was rinsed with DMF (9.5 mL), replaced with nitrogen three times, and the temperature was raised to 85°C for reaction, with stirring for at least 2 hours. After the reaction was completed under HPLC monitoring, the temperature was lowered to 25° C. The reaction solution was treated and purified by column chromatography to obtain the compound of formula (I) (white solid, 7.55 g, purity 99.0%, ee value 99.5%, yield 73%).

[0162] The compound of formula (I) is characterized as follows:

[0163] 1 H NMR (400MHz, Methanol-d4) δ12.28 (s, 1H), 10.16 (s, 1H), 8.20 (d, 1H), 8.00 (d, 1 H), 7.30-7.25(m, 2H), 7.19-7.15(m, 1H), 7.08(dd, 1H), 5.18(s, 1H), 3.77(t, 2H) , 3.63(d, 1H), 3.36(t, 2H), 2.98(q, 4H), 2.51-2.49(m, 1H), 2.25(d, 1H), 2.16-2. 13(m, 1H), 2.02-1.96(m, 2H), 1.94-1.58(m, 3H), 1.22-1.14(m, 2H), 0.28(s, 4H);

[0164] HPLC: Chiralpak IC column, 254 nm, 35°C, 0.1% diethylamine (n-hexane:ethanol:dichloromethane=75:15:10) / ethanol=70 / 30, flow rate=1.0 mL / min, retention times 9.4 min and 12.0 min (main peak);

[0165] MS (EI, m / z): 536.6 [M+H] + .

[0166] The compound represented by the above formula (I) was dissolved in a certain amount of acetonitrile / water mixed solvent and lyophilized to obtain a white solid. XRPD characterization of the solid was performed, and the XRPD pattern was shown in FIG1 . The results showed that the obtained white solid was amorphous.

[0167] The amorphous form of the compound represented by formula (I) was subjected to TGA, DSC, and NMR detection, and the spectra are shown in Figures 2 and 3.

[0168] Example 2 Preparation and Characterization of Form A

[0169] 2 g of the amorphous raw material of the compound of formula (I) was weighed, and 60 mL of dichloromethane was added dropwise at room temperature to completely dissolve the sample. The solution was then added dropwise to 10 volumes of methyl tert-butyl ether and stirred for approximately 30 min. The system with precipitated solid was centrifuged and then dried under vacuum at room temperature to obtain Form A. The XRPD pattern is shown in FIG4 , and the analytical data are shown in Table 2.

[0170] Table 2

[0171] The obtained Form A crystalline form of the compound represented by formula (I) was subjected to TGA, DSC, and NMR detection, and the spectra are shown in Figures 5 and 6. The NMR results showed that there was no obvious solvent signal peak, and the sample was solvent-free.

[0172] Example 3

[0173] 2 g of the amorphous raw material of the compound of formula (I) was weighed and 30 mL of acetone was added dropwise at room temperature to completely dissolve the sample. 60 mL of methyl tert-butyl ether was slowly added dropwise and stirred for approximately 30 minutes. The resulting solid was centrifuged and then dried under vacuum at room temperature to collect the solid. XRPD analysis of the solid revealed that the XRPD spectrum was substantially consistent with that of Form A in Example 2, indicating that the resulting crystals were Form A.

[0174] Example 4

[0175] 2 g of the amorphous starting material of the compound of formula (I) was weighed and added to 200 mL of cyclohexane. The mixture was suspended at 50°C for 24 h. The precipitated solid was centrifuged and then dried under vacuum at room temperature. The solid was collected. XRPD analysis of the solid revealed that the XRPD spectrum was substantially consistent with that of Form A in Example 2, indicating that the resulting crystals were Form A.

[0176] Example 5 Preparation and Characterization of Form B

[0177] 2 g of the compound of formula (I) Form A raw material was weighed and 60 mL of dichloromethane was added dropwise at room temperature to completely dissolve the sample. The solution was then added dropwise to 10 volumes of n-heptane and stirred for approximately 30 min. The precipitated solid was centrifuged and dried under vacuum at room temperature to obtain Form B. The XRPD pattern is shown in Figure 7, and the analytical data are shown in Table 3.

[0178] Table 3

[0179] The resulting Form B crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 8 and 9. The NMR results showed a dichloromethane signal peak at 5.49 ppm. Based on the integration results, the molar ratio of the compound to dichloromethane was 1:0.3, with a rough estimate of approximately 4.5% by mass.

[0180] Example 6 Preparation and Characterization of Form C

[0181] 20 mg of the compound of formula (I) Form A starting material was weighed and 2.5 mL of ethyl acetate was added dropwise until completely dissolved. The solution was allowed to evaporate at room temperature in an open atmosphere until sufficient solid precipitated to obtain Form C. The XRPD pattern is shown in Figure 10, and the analytical data are shown in Table 4.

[0182] Table 4

[0183] The resulting Form C crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 11 and 12. The NMR results showed that ethyl acetate signal peaks were visible at 1.24 ppm, 2.01 ppm, and 4.09 ppm. Based on the integration results, the ratio of compound to ethyl acetate was 1:0.6, with a rough estimate of approximately 9.0% by mass.

[0184] Example 7 Preparation and Characterization of Form D

[0185] 20.4 mg of the compound of formula (I) Form A starting material was weighed and 1.3 mL of ethanol was added to the sample to completely dissolve the sample. After suspending at room temperature for 20 minutes, a sufficient amount of white solid precipitated. The suspension was centrifuged, and the solid was dried under vacuum at room temperature and characterized to obtain Form D. The XRPD pattern is shown in Figure 13, and the analytical data are shown in Table 5.

[0186] Table 5

[0187] The resulting Form D crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 14 and 15. The NMR results revealed visible ethanol signal peaks at 1.18 ppm and 3.60 ppm. Based on the integration results, the compound-to-ethanol ratio was 1:0.9, with a rough estimate of approximately 7.2% by mass.

[0188] Example 8 Preparation and Characterization of Form E

[0189] 20.4 mg of Form A of the compound of formula (I) was weighed, 2 mL of methanol was added to the sample to completely dissolve the sample, and the sample was suspended at room temperature until sufficient white solid precipitated. The suspension was centrifuged, and the solid was dried under vacuum at room temperature and characterized to obtain Form E. The XRPD pattern is shown in Figure 16, and the analytical data are shown in Table 6.

[0190] Table 6

[0191] The obtained Form E crystalline form of the compound represented by formula (I) was subjected to TGA, DSC, and NMR analysis, and the spectra are shown in Figures 17 and 18. The NMR results showed no obvious solvent signal peak.

[0192] Example 9 Preparation and Characterization of Form F

[0193] 20.4 mg of the compound of formula (I) Form A starting material was weighed, 2 mL of acetonitrile was added to the sample to completely dissolve the sample, and the sample was suspended at room temperature until sufficient white solid precipitated. The suspension was centrifuged, and the solid was vacuum-dried at room temperature and characterized to obtain Form F. The XRPD pattern is shown in Figure 19, and the analytical data are shown in Table 7.

[0194] Table 7

[0195] The resulting Form F crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 20 and 21. The NMR results showed an acetonitrile signal peak at 2.07 ppm. Based on the integration results, the ratio of compound to acetonitrile was 1:0.5, with a rough estimate of approximately 3.7% by mass.

[0196] Example 10 Preparation and Characterization of Form G

[0197] 20.4 mg of the compound of formula (I) Form A starting material was weighed and sufficient ethylene glycol dimethyl ether was added to the sample to completely dissolve the sample. The sample was suspended and evaporated at room temperature until a sufficient amount of white solid precipitated. The suspension was centrifuged and the solid was vacuum dried at room temperature and characterized to obtain Form G. The XRPD pattern is shown in Figure 22, and the analytical data are shown in Table 8.

[0198] Table 8

[0199] The resulting Form G crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 23 and 24. The NMR results showed that signal peaks of ethylene glycol dimethyl ether were visible at 3.65 ppm, 3.47 ppm, and 3.37 ppm. Based on the integration results, the ratio of compound to ethylene glycol dimethyl ether was 1:0.45, with a rough estimate of approximately 6.0% by mass.

[0200] Example 11 Preparation and Characterization of Form H

[0201] 134.0 mg of the compound of formula (I) Form A starting material was weighed and completely dissolved in a minimal amount of ethyl formate. The mixture was then cooled to allow crystallization and centrifuged. The solid was dried under vacuum at room temperature overnight to obtain Form H. The XRPD pattern is shown in Figure 25, and the analytical data are shown in Table 9.

[0202] Table 9

[0203] The resulting Form H crystalline form of the compound represented by Formula (I) was subjected to TGA, DSC, and NMR analysis, with the spectra shown in Figures 26 and 27. The NMR results revealed peaks of ethyl formate at 8.06 ppm, 4.23 ppm, 4.17 ppm, and 1.28 ppm, with peaks at 1.18 ppm and 3.60 ppm likely representing ethanol, suggesting decomposition of ethyl formate during the experiment. The sample may be a solvate or hydrate.

[0204] Example 12 Preparation and Characterization of Form I

[0205] Preparation method: Weigh 50 mg of Form D of the compound of Formula I, add 0.4 mL of isopropyl acetate, stir at 50°C for 2 hours, then cool to room temperature and stir for 2 days. After centrifugation, the sample is vacuum-dried at 50°C to obtain Form I of the compound of Formula I. The XRPD pattern is shown in Figure 28, and the analytical data are shown in Table 10. The DSC, TGA, and NMR spectra of Form I are shown in Figures 29-31, respectively.

[0206] The NMR data of the Form I crystalline form of the compound are as follows: 1H NMR (400MHz, DMSO-d6) δ12.32 (s, 1H), 10.16 (s, 1H), 8.27 (dd, J=7.9, 1.0Hz, 1H), 8.00 (d, J=8. 5Hz, 1H), 7.31-7.17 (m, 2H), 7.17-7.03 (m, 2H), 5.15 (d, J=2.2Hz, 1H), 4.95 (t, J=5.7Hz, 1H), 3 .76 (q, J=6.3Hz, 2H), 3.58 (d, J=3.7Hz, 1H), 3.37-3.36 (m, 4H), 2.99 (d, J=9.8Hz, 3H), 2.23 (d, J=9.5Hz, 1H), 2.18-2.08 (m, 1H), 1.98 (dd, J=13.8, 8.4Hz, 2H), 1.34-1.06 (m, 4H), 0.29 (s, 4H).

[0207] Table 10

[0208] Summary of properties of different crystal forms

[0209] Table 11

[0210] Example 13 Biological Evaluation

[0211] (1) Test name: KIF18A enzyme activity assay

[0212] (2) Operation steps:

[0213] 1) Compound dilution and treatment: The final test concentrations of AM-5308 are: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM, and the final test concentrations of the test compounds are: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM.

[0214] 2) Transfer 100 nL of the diluted compound stock solution to each well of the reaction plate using an Echo 655. The final DMSO concentration is 1%.

[0215] 3) Seal the reaction plate with sealing film and centrifuge at 1000g for 1 minute.

[0216] 4) Prepare 2× enzyme solution using 1× reaction buffer.

[0217] 5) Add 5 μL of 2× enzyme solution to each well of the reaction plate. Seal the plate with film and centrifuge at 1000 g for 1 minute. Incubate at room temperature for 15 minutes.

[0218] 6) Prepare 2× ATP solution using 1× reaction buffer.

[0219] 7) Add 5 μL of 2× ATP solution to the reaction plate and centrifuge at 1000 g for 1 minute to start the reaction.

[0220] 8) React at room temperature for 60 minutes.

[0221] 9) Add 10 μL of ADP Glo reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

[0222] 10) Add 20 μL of kinase assay reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

[0223] 11) Centrifuge at 1000g for 1 minute.

[0224] 12) Read the luminescence signal on Envision 2104.

[0225] (3) Data analysis:

[0226] The percentage inhibition was calculated as follows:

[0227] %inhibition=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100

[0228] Signalcmpd: Average value of test compounds on the reaction plate.

[0229] SignalAve_PC: The average value of the positive control (AM-5308) on the reaction plate.

[0230] SignalAve_VC: the average value of the negative control (DMSO) on the reaction plate.

[0231] (4) Calculate IC 50 And fitting compound dose-effect curve:

[0232] GraphPad 8.0 was used to calculate the IC50 values ​​of the compounds using a nonlinear fitting formula.

[0233] Quality control Z factor>0.5; S / B>2.

[0234] (5) Experimental results: IC of the compound KIF18A represented by formula (I) 50 is 5.35nM.

[0235] Example 14 Evaluation of Moisture Absorption

[0236] Dynamic moisture sorption / desorption analysis was performed on Form A, the compound of Formula (I) obtained in this example. XRPD analysis of the solid before and after the test is shown in Figures 32-33. The results show that Form A gained approximately 0.17% in weight upon moisture absorption at 80% relative humidity, and lost 0.01% in weight upon return to 0% relative humidity, demonstrating that Form A is virtually non-hygroscopic. Form A maintained its crystalline form after DVS analysis.

[0237] Dynamic moisture sorption / desorption analysis was performed on Form E, the compound of Formula (I) obtained in this example, to preliminarily assess its hygroscopicity. XRPD analysis of the solid before and after the test was performed, as shown in Figures 34-35. The results show that Form E gained 0.98% weight at 80% humidity during the sorption process; during the desorption process, it gained 0.93% weight at 80% humidity and lost 0.15% weight at 50% humidity. DVS analysis of Form E revealed no change in its crystalline form.

[0238] Example 15 Dynamic Solubility Test in Biological Media and Water

[0239] The preparation process of the biological medium is shown in Table 12. Samples of different crystalline forms were added to the biological medium and water and shaken at 37°C for 24 hours. Samples were taken at 0.5, 2, and 24 hours. The sampled solutions were filtered through a 0.22 μm water filter. Some samples with higher concentrations were appropriately diluted with diluent. The signal peak area of ​​the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was tested.

[0240] Table 12 Preparation process of biological medium

[0241] Dynamic solubility measurements were performed on Form A and the amorphous form in three biological media (FaSSIF, FeSSIF, and FaSSGF) and in water. The corresponding results are shown in Table 13. The results show that the 24-h solubility of Form A and the amorphous form in both biological media and water is generally consistent, with the order of FaSSGF > FeSSIF > FaSSIF > water.

[0242] Table 13 Dynamic solubility test in biological media and water

[0243] Example 16 Stability Test

[0244] Form A was subjected to stability studies under conditions of high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated exposure (40°C / 75% RH). Samples were collected for XRPD characterization and HPLC analysis after 7 and 15 days, respectively. The results are shown in Table 14 and Figure 36. XRPD results showed that Form A maintained its crystalline form after 15 days under these conditions. There was no significant change in purity after 15 days under these conditions. However, under light exposure, the purity decreased slightly after 15 days, and the sample turned yellow.

[0245] Table 14

[0246] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. an amorphous form or polymorph of the compound represented by formula (I); 2. The amorphous or polymorphic compound according to claim 1, wherein The amorphous form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG1 ; Preferably, the differential scanning calorimetry analysis spectrum of the amorphous form of the compound represented by formula (I) is shown in FIG2 . Preferably, the thermogravimetric analysis spectrum of the amorphous compound represented by formula (I) is shown in FIG2 .

3. The amorphous or polymorphic compound according to claim 1, wherein The polymorph of the compound represented by formula (I) is selected from the Form A crystal form, Form B crystal form, Form C crystal form, Form D crystal form, Form E crystal form, Form F crystal form, Form G crystal form, Form H crystal form, and Form I crystal form of the compound represented by formula (I).

4. The amorphous or polymorphic compound according to claim 3, wherein The X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.97°±0.20°, 17.87°±0.20°, 18.82°±0.20°, 19.07°±0.20°, and 19.56°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 8.87°±0.20°, 13.46°±0.20°, 24.77°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form A crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.81°±0.20°, 13.20°±0.20°, 16.18°±0.20°, 20.32°±0.20°, 21.11°±0.20°, 21.56°±0.20°, 22.38°±0.20°, 22.82°±0.20°, 23.35°±0.20°, 23.78°±0.20°, 24.01°±0.20°, 25.12°±0.20°, 25.68°±0.20°, 26.48°±0.20°, 26.67°±0.20°, 27.02°±0.20°, 28.01°±0.20°, 28.75°±0.20°, 30.72°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form A crystal form of the compound represented by formula (I) is shown in Table 2, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form A crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG4 ; Preferably, the differential scanning calorimetry analysis spectrum of the Form A crystal form of the compound represented by formula (I) comprises an endothermic peak at 245.9°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of Form A crystal form of the compound represented by formula (I) is shown in Figure 5; Preferably, the thermogravimetric analysis spectrum of the Form A crystal form of the compound represented by formula (I) is shown in Figure 5.

5. The amorphous or polymorphic compound according to claim 3, wherein The X-ray powder diffraction pattern of the Form B crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 7.10°±0.20°, 9.92°±0.20°, 19.13°±0.20°, 19.36°±0.20°, 20.18°±0.20°, 23.50°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form B crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 15.48°±0.20°, 17.34°±0.20°, 17.87°±0.20°, 21.13°±0.20°, 23.66°±0.20°, 26.69°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form B crystalline form of the compound represented by formula (I) further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 9.61°±0.20°, 10.72°±0.20°, 14.10°±0.20°, 17.58°±0.20°, 19.75°±0.20°, 22.05°±0.20°, 22.40°±0.20°, 23.99°±0.20°, 24.42°±0.20°, 24.73°±0.20°, 25.90°±0.20°, 27.26°±0.20°, 28.56°±0.20°, 28.85°±0.20°, 30.27°±0.20°, 30.72°±0.20°, 32.46°±0.20°, 33.01°±0.20°, 34.43°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form B crystal form of the compound represented by formula (I) is shown in Table 3, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form B crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG7 ; Preferably, the differential scanning calorimetry analysis spectrum of the Form B crystal form of the compound represented by formula (I) comprises endothermic peaks at 60.7°C±2.0°C, 167.0°C±2.0°C, and 245.8°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form B crystalline form of the compound represented by formula (I) comprises an exothermic peak at 172.1°C ± 2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form B crystal form of the compound represented by formula (I) is shown in Figure 8; Preferably, the thermogravimetric analysis spectrum of the Form B crystal form of the compound represented by formula (I) is shown in FIG8 ; Preferably, the X-ray powder diffraction pattern of the Form C crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.51°±0.20°, 18.32°±0.20°, 19.09°±0.20°, 19.35°±0.20°, 23.10°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form C crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 16.51°±0.20°, 17.58°±0.20°, 20.24°±0.20°, 23.97°±0.20°, 25.51°±0.20°, 30.99°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form C crystal form of the compound represented by formula (I) is shown in Table 4, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form C crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 10; Preferably, the differential scanning calorimetry analysis spectrum of the Form C crystal form of the compound represented by formula (I) comprises endothermic peaks at 91.7°C±2.0°C and 245.4°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form C crystal form of the compound represented by formula (I) is shown in Figure 11; Preferably, the thermogravimetric analysis spectrum of the Form C crystal form of the compound represented by formula (I) is shown in FIG11 ; Preferably, the X-ray powder diffraction pattern of the Form D crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.41°±0.20°, 19.17°±0.20°, 19.93°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.93°±0.20°, 17.60°±0.20°, 22.94°±0.20°, 23.60°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form D crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.14°±0.20°, 15.21°±0.20°, 16.57°±0.20°, 17.21°±0.20°, 20.57°±0.20°, 21.00°±0.20°, 21.81°±0.20°, 23.19±0.20°, 23.84°±0.20°, 26.46°±0.20°, 28.09°±0.20°, 30.58°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form D crystal form of the compound represented by formula (I) is shown in Table 5, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form D crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 13; Preferably, the differential scanning calorimetry analysis spectrum of the Form D crystal form of the compound represented by formula (I) comprises endothermic peaks at 148.7°C±2.0°C, 166.7°C±2.0°C, and 246.8°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form D crystal form of the compound represented by formula (I) comprises an exothermic peak at 176.4°C ± 2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form D crystal form of the compound represented by formula (I) is shown in Figure 14; Preferably, the thermogravimetric analysis spectrum of the Form D crystal form of the compound represented by formula (I) is shown in FIG14 ; Preferably, the Form E crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.78°±0.20°, 19.40°±0.20°, 20.07°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form E crystal form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.40°±0.20°, 15.33°±0.20°, 17.26°±0.20°, 17.48°±0.20°, 17.62°±0.20°, 18.98°±0.20°, 23.49°±0.20°, 23.66°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form E crystal form of the compound represented by formula (I) is shown in Table 6, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form E crystalline form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 16; Preferably, the differential scanning calorimetry analysis spectrum of the Form E crystal form of the compound represented by formula (I) comprises endothermic peaks at 58.2°C±2.0°C, 168.2°C±2.0°C, and 246.8°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form E crystal form of the compound represented by formula (I) comprises an exothermic peak at 182.9°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form E crystal form of the compound represented by formula (I) is shown in Figure 17; Preferably, the thermogravimetric analysis spectrum of the Form E crystal form of the compound represented by formula (I) is shown in FIG17 ; Preferably, the X-ray powder diffraction pattern of the Form F crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 6.88°±0.20°, 9.71°±0.20°, 17.65°±0.20°, 18.79°±0.20°, 19.44°±0.20°, 20.01°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form F crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 9.31°±0.20°, 15.36°±0.20°, 17.01°±0.20°, 17.31°±0.20°, 20.87°±0.20°, 23.36°±0.20°, 23.66°±0.20°, 23.82°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form F crystal form of the compound represented by formula (I) is shown in Table 7, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form F crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 19; Preferably, the differential scanning calorimetry analysis spectrum of the Form F crystalline form of the compound represented by formula (I) comprises endothermic peaks at 56.4°C±2.0°C, 150.7°C±2.0°C, 167.8°C±2.0°C, and 247.1°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form F crystalline form of the compound represented by formula (I) comprises an exothermic peak at 171.7°C ± 2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form F crystal form of the compound represented by formula (I) is shown in FIG20 ; Preferably, the thermogravimetric analysis spectrum of the Form F crystal form of the compound represented by formula (I) is shown in FIG20 ; Preferably, the Form G crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 9.61°±0.20°, 17.62°±0.20°, 19.54°±0.20°, 20.30°±0.20°, 24.09°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form G crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 7.06°±0.20°, 16.70°±0.20°, 18.49°±0.20°, 19.31°±0.20°, 23.31°±0.20°, 26.89°±0.20°, 28.60°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form G crystal form of the compound represented by formula (I) is shown in Table 8, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form G crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 22; Preferably, the differential scanning calorimetry analysis spectrum of the Form G crystal form of the compound represented by formula (I) comprises endothermic peaks at 97.5°C±2.0°C and 246.4°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form G crystal form of the compound represented by formula (I) is shown in Figure 23; Preferably, the thermogravimetric analysis spectrum of the Form G crystal form of the compound represented by formula (I) is shown in FIG23 ; Preferably, the X-ray powder diffraction pattern of the Form H crystalline form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 9.47°±0.20°, 18.37°±0.20°, 19.15°±0.20°, 20.01°±0.20°, 22.98°±0.20°, 23.70°±0.20°; Preferably, the X-ray powder diffraction pattern of the Form H crystalline form of the compound represented by formula (I) further includes one, two or more characteristic diffraction peaks at 2θ angles: 6.95°±0.20°, 9.14°±0.20°, 16.57°±0.20°, 17.30°±0.20°, 17.54°±0.20°, 20.59°±0.20°, 21.08°±0.20°, 25.60°±0.20°, 26.26°±0.20°, 28.19°±0.20°, 30.56°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form H crystal form of the compound represented by formula (I) is shown in Table 9, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; Preferably, the Form H crystalline form of the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 25; Preferably, the differential scanning calorimetry analysis spectrum of the Form H crystal form of the compound represented by formula (I) comprises endothermic peaks at 123.6°C±2.0°C, 165.6°C±2.0°C, and 246.6°C±2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form H crystalline form of the compound represented by formula (I) comprises an exothermic peak at 173.0°C ± 2.0°C; Preferably, the differential scanning calorimetry analysis spectrum of the Form H crystal form of the compound represented by formula (I) is shown in Figure 26; Preferably, the thermogravimetric analysis spectrum of the Form H crystal form of the compound represented by formula (I) is shown in FIG26 ; Preferably, the X-ray powder diffraction pattern of the Form I crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 13.55°±0.20°, 17.22°±0.20°, 18.27°±0.20°, 18.91°±0.20°, 20.8°±0.20°; Preferably, the Form I crystal form of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 13.55°±0.20°, 17.22°±0.20°, 18.27°±0.20°, 18.91°±0.20°, 20.8°±0.20°; The X-ray powder diffraction pattern of Form I further includes the following characteristic diffraction peaks at 2θ angles: 5.11°±0.20°, 7.91°±0.20°, 11.63°±0.20°, 14.34°±0.20°, 14.98°±0.20°, 15.68°±0.20°, 19.69°±0.20°, 21.9°±0.20°, 22.57°±0.20°, 23.53°±0.20°, 24.17°±0.20°, 25.72°±0.20°, 28.02°±0.20°, 32.21°±0.20°; Preferably, the X-ray powder diffraction pattern analysis data of the Form I crystal form of the compound represented by formula (I) are shown in Table 10, wherein the error range of 2θ of each characteristic diffraction peak is ±0.2°; preferably, the Form I crystal form of the compound represented by formula (I) has an X-ray powder diffraction pattern substantially as shown in Figure 28; preferably, the differential scanning calorimetry analysis pattern of the Form I crystal form of the compound represented by formula (I) includes endothermic peaks at 210.4°C±2.0°C and 245.8°C±2.0°C; preferably, the differential scanning calorimetry analysis pattern of the Form I crystal form of the compound represented by formula (I) includes an exothermic peak at 210.4°C±2.0°C; preferably, the differential scanning calorimetry analysis pattern of the Form I crystal form of the compound represented by formula (I) is shown in Figure 29; preferably, the thermogravimetric analysis pattern of the Form I crystal form of the compound represented by formula (I) is shown in Figure 30.

6. A method for preparing an amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, wherein: The preparation method of the amorphous form of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a first solvent and freeze-drying to obtain the amorphous form of the compound represented by formula (I); The preparation method of the polymorph of the compound represented by formula (I) is as follows: dissolving the compound represented by formula (I) in a solvent and crystallizing to obtain the polymorph of the compound represented by formula (I).

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the amorphous form or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5; Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition may further contain one or more additional therapeutic agents.

8. A method for treating a tumor disease, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7; Preferably, the tumor disease includes colorectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer and ovarian cancer.

9. An amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 7 for use in treating tumor diseases.

10. Use of the amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7 in the preparation of a medicament; Preferably, the use can be for the preparation of a medicament for treating KIF18A-mediated disorders and / or diseases, such as for the preparation of a KIF18A inhibitor drug; Preferably, the disease is cancer, including, for example, bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

11. A method for treating KIF18A-mediated disorders and / or diseases, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the amorphous or polymorphic form of the compound of formula (I) according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 7; Preferably, the KIF18A-mediated disorder and / or disease is cancer, such as bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

Images