Pharmaceutically acceptable salt and crystal form of KIF18a inhibitor, and preparation method therefor and use thereof

Abstract

The present invention provides a pharmaceutically acceptable salt and crystal form of a KIF18A inhibitor, and a preparation method therefor and a use thereof. The pharmaceutically acceptable salt is selected from one or more of a sodium salt, a potassium salt, a hydrochloride, a p-toluenesulfonate, a maleate, a methanesulfonate, an ethanesulfonate, and a hydrobromide of a compound represented by formula (I). The present invention provides the pharmaceutically acceptable salt of the compound represented by formula (I) and a crystal of the salt, which exhibit excellent hygroscopicity, solubility, and / or stability, and are suitable for pharmaceutical use.

Description

A pharmaceutically acceptable salt, crystal form, preparation method, and application of a KIF18A inhibitor

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

[0002] The prior application, patent application number 202410265587.2, filed with the State Intellectual Property Office of China on March 7, 2024, entitled “A pharmaceutically acceptable salt, crystal form, preparation method and use thereof of a KIF18A inhibitor”; and the prior application, patent application number 202510227785.4, filed with the State Intellectual Property Office of China on February 27, 2025, entitled “A pharmaceutically acceptable salt, crystal form, preparation method and use thereof of a KIF18A inhibitor”;

[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 pharmaceutically acceptable salt, crystal form, preparation method and application of a KIF18A inhibitor. 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 exhibits good KIF18A inhibition and OVCAR-3 cell activity in vitro, but also exhibits significantly improved physicochemical properties (solubility and permeability), significantly enhanced OVCAR-3 in vivo efficacy, and a good safety profile. This compound can be used to treat KIF18A-mediated conditions and / or diseases, such as tumors, and to prepare medicaments for treating such conditions or diseases.

[0006] Salt formation is one of the effective means to improve the physicochemical properties of drug molecules and enhance their drugability. It can change the solubility of the drug, improve its compliance, enhance its stability and bioavailability, and reduce its adverse reactions. Generally speaking, the crystal structure of the active ingredient of the drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the difficulty of subsequent drug preparation and production costs. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound and its salt, and sometimes are accompanied by the production of other morphologies. Therefore, from the perspectives of stability, the difficulty of the drug preparation process, and production costs, we need to conduct in-depth research on the crystal structure of the compound and its salt, so as to find a crystal form that is stable, high in purity, easy to prepare, and low in production cost. Summary of the Invention

[0007] The present invention provides a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from one or more of the sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate, methanesulfonate, ethanesulfonate and hydrobromide of the compound represented by formula (I);

[0008] According to an embodiment of the present invention, in the p-toluenesulfonate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the p-toluenesulfonic acid molecule is 1:1.8 to 1:2.5, for example, about 1:1.9, 1:2, 1:2.1, or 1:2.2.

[0009] According to an embodiment of the present invention, in the hydrochloride of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrogen chloride is 1:0.4 to 1:2.5, for example, about 1:0.7, 1:1.5, or 1:1.7.

[0010] According to an embodiment of the present invention, in the maleate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to maleic acid is 1:0.9 to 1:1.3, for example, about 1:1.

[0011] According to an embodiment of the present invention, in the sodium salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to sodium ions is 1:1.8 to 1:2.5, for example, about 1:1.9.

[0012] According to an embodiment of the present invention, in the methanesulfonate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to methanesulfonic acid is 1:0.9 to 1:2.5, for example, about 1:1.1 or 1:2.

[0013] According to an embodiment of the present invention, in the ethanesulfonate of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to ethanesulfonic acid is 1:0.9 to 1:1.3, for example, about 1:1, 1:1.1, or 1:1.2.

[0014] According to an embodiment of the present invention, in the hydrobromide salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrogen bromide is 1:0.9 to 1:2.5, for example, about 1:1.1 or 1:2.1.

[0015] The present invention also provides crystals of the above-mentioned pharmaceutically acceptable salts, including crystal form A of the sodium salt of the compound represented by formula (I), crystal form A of the potassium salt of the compound represented by formula (I), crystal form A of the hydrochloride of the compound represented by formula (I), crystal form B of the hydrochloride of the compound represented by formula (I), crystal form C of the hydrochloride of the compound represented by formula (I), crystal form D of the hydrochloride of the compound represented by formula (I), crystal form A of the p-toluenesulfonate of the compound represented by formula (I), crystal form A of the methanesulfonate of the compound represented by formula (I), crystal form B of the methanesulfonate of the compound represented by formula (I), crystal form A of the maleate of the compound represented by formula (I), crystal form A of the ethanesulfonate of the compound represented by formula (I), crystal form B of the ethanesulfonate of the compound represented by formula (I), crystal form A of the hydrobromide of the compound represented by formula (I), and crystal form B of the hydrobromide of the compound represented by formula (I).

[0016] According to an embodiment of the present invention, the crystal form A of the sodium salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.0±0.20°, 5.3±0.20°, 6.2±0.20°, 7.0±0.20°, 16.1±0.20°, 18.3±0.20°, 18.7±0.20°, and 20.0±0.20°; further, it may also have characteristic peaks at 10.0±0.20°, 12.1±0.20°, 13.5±0.20°, 13.9±0.20°, 16.9±0.20°, 17.8±0.20°, 18.0±0.20° and / or 19.4±0.20°.

[0017] According to an embodiment of the present invention, the crystal form A of the sodium salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG3 .

[0018] According to an embodiment of the present invention, the crystal form A of the sodium salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 2.

[0019] According to an embodiment of the present invention, the weight loss of the crystal form A of the sodium salt of the compound represented by formula (I) in the range of room temperature to 230° C. is 12 to 20%, for example, 14 to 18%.

[0020] According to an embodiment of the present invention, the crystal form A of the sodium salt of the compound represented by formula (I) has at least one broad endothermic peak with an onset temperature of 45-53°C and a peak temperature of 85-95°C; for example, the onset temperature is 48.5°C and the peak temperature is 90.3°C.

[0021] Furthermore, the crystal form A of the sodium salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 222-228°C and a peak temperature of 232-238°C; for example, the onset temperature is 225.3°C and the peak temperature is 234.3°C.

[0022] According to an embodiment of the present invention, the crystal form A of the sodium salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG4 .

[0023] According to an embodiment of the present invention, the crystal form A of the sodium salt of the compound represented by formula (I) contains residual solvent, for example, the residual solvent is acetonitrile.

[0024] According to an embodiment of the present invention, the A crystal form of the potassium salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.0±0.20°, 5.4±0.20°, 6.1±0.20°, 6.6±0.20°, 10.0±0.20°, 16.0±0.20°, and 18.8±0.20°; further, it can also have characteristic peaks at 12.1±0.20°, 14.0±0.20°, 16.5±0.20°, 16.9±0.20°, 18.8±0.20°, 19.1±0.20°, 20. The invention discloses a novel nanostructured carbon foam having a nanostructured carbon foam and a nanostructured carbon foam. The nanostructured carbon foam has characteristic peaks at 0.20°, 17.2±0.20°, 17.9±0.20°, 18.3±0.20° and / or 20.0±0.20°; further, the nanostructured carbon foam may have characteristic peaks at 7.0±0.20°, 8.5±0.20°, 9.2±0.20°, 11.0±0.20°, 13.6±0.20°, 14.6±0.20°, 14.9±0.20°, 15.3±0.20°, 19.5±0.20° and / or 21.3±0.20°.

[0025] According to an embodiment of the present invention, the Form A of the potassium salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG6 .

[0026] According to an embodiment of the present invention, the crystal form A of the potassium salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 3.

[0027] According to an embodiment of the present invention, the weight loss of the potassium salt of the compound represented by formula (I) in the form A is 5-15%, for example, 7-10%, in the range of room temperature to 280°C.

[0028] According to an embodiment of the present invention, the crystal form A of the potassium salt of the compound represented by formula (I) has at least one endothermic peak with a peak temperature of 52 to 60°C; for example, the peak temperature is 57.4°C.

[0029] Furthermore, the crystal form A of the potassium salt of the compound represented by formula (I) also has an endothermic peak with a peak temperature of 193 to 202°C; for example, the peak temperature is 197.7°C.

[0030] Furthermore, the crystal form A of the potassium salt of the compound represented by formula (I) has an exothermic peak with a peak temperature of 295 to 305°C; for example, the peak temperature is 299.5°C.

[0031] According to an embodiment of the present invention, the crystal form A of the potassium salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG7 .

[0032] According to an embodiment of the present invention, the crystal form A of the hydrochloride of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.3±0.20°, 12.6±0.20°, 19.0±0.20°, and 19.5±0.20°; further, it may also have characteristic peaks at 14.1±0.20°, 16.3±0.20° and / or 28.4±0.20°.

[0033] According to an embodiment of the present invention, the Form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG9 .

[0034] According to an embodiment of the present invention, the Form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 4.

[0035] According to an embodiment of the present invention, the weight loss of form A of the hydrochloride salt of the compound represented by formula (I) in the range of room temperature to 110°C is 4 to 8%, for example, 5 to 7%; and / or, the weight loss in the range of 110 to 210°C is 4 to 8%, for example, 5 to 7%.

[0036] According to an embodiment of the present invention, the crystal form A of the hydrochloride of the compound represented by formula (I) has at least one endothermic peak with a peak temperature of 72 to 85°C, for example, a peak temperature of 77.1°C.

[0037] Furthermore, the crystal form A of the hydrochloride salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 172-180°C and a peak temperature of 193-202°C; for example, the onset temperature is 175.6°C and the peak temperature is 197.1°C.

[0038] According to an embodiment of the present invention, the Form A of the hydrochloride salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG10 .

[0039] According to an embodiment of the present invention, the crystal form A of the hydrochloride salt of the compound represented by formula (I) contains a solvent, for example, the solvent is ethanol.

[0040] According to an embodiment of the present invention, the B crystal form of the hydrochloride of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.7±0.20°, 18.4±0.20°, 20.4±0.20°, 21.1±0.20° and 23.2±0.20°; further, it can also have characteristic peaks at 15.1±0.20°, 16.1±0.20°, 27.6±0.20°. and / or a characteristic peak at 32.7±0.20°; further, characteristic peaks may also be present at 10.4±0.20°, 12.8±0.20°, 24.6±0.20°, 25.7±0.20°, 30.2±0.20°, 32.1±0.20°, 33.1±0.20°, 35.6±0.20°, 37.1±0.20°, 38.3±0.20° and / or 43.6±0.20°.

[0041] According to an embodiment of the present invention, the Form B of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG12 .

[0042] According to an embodiment of the present invention, the Form B of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 5.

[0043] According to an embodiment of the present invention, the weight loss of form B of the hydrochloride salt of the compound represented by formula (I) in the range of room temperature to 60°C is 1 to 5%, for example, 2 to 4%; and / or, the weight loss in the range of greater than 60°C and less than 125°C is 1.5 to 4%, for example, 2 to 3.5%; and / or, the weight loss in the range of 125 to 210°C is 5 to 8%, for example, 6 to 7%.

[0044] According to an embodiment of the present invention, the B crystal form of the hydrochloride of the compound represented by formula (I) has at least one endothermic peak with an onset temperature of 80-90°C and a peak temperature of 105-115°C; for example, the onset temperature is 85.9°C and the peak temperature is 109.3°C;

[0045] Furthermore, the B crystal form of the hydrochloride salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 165-180°C and a peak temperature of 183-193°C; for example, the onset temperature is 172.3°C and the peak temperature is 188.1°C.

[0046] According to an embodiment of the present invention, the Form B of the hydrochloride salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG13 .

[0047] According to an embodiment of the present invention, the C crystalline form of the hydrochloride of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.6±0.20°, 18.8±0.20°, 20.7±0.20°, 22.2±0.20°, 23.0±0.20° and 24.8±0.20°; further, it can also have characteristic peaks at 3.1±0.20°, 8.3±0.20°, 12.2±0.20°, 14.4±0.20°, 16.9±0.20°, 18.8±0.20°, 20.7±0.20°, 22.2±0.20°, 23.0±0.20° and 24.8±0.20°. °, 15.2±0.20°, 17.5±0.20°, 19.4±0.20°, 22.7±0.20° and / or 29.9±0.20°; further, characteristic peaks may also be present at 2.3±0.20°, 5.2±0.20°, 7.3±0.20°, 10.4±0.20°, 21.5±0.20°, 25.5±0.20°, 27.8±0.20° and / or 31.6±0.20°.

[0048] According to an embodiment of the present invention, the Form C of the hydrochloride of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 39 .

[0049] According to an embodiment of the present invention, the Form C of the hydrochloride of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 10.

[0050] According to an embodiment of the present invention, the hydrochloride salt of the compound represented by formula (I) in form C loses 8 to 11% of its weight in the range of room temperature to 210° C., for example, loses 9 to 10.5% of its weight.

[0051] According to an embodiment of the present invention, the C crystal form of the hydrochloride of the compound represented by formula (I) has at least one endothermic peak with an onset temperature of 42 to 48°C and a peak temperature of 80 to 85°C; for example, the onset temperature is 45.03°C and the peak temperature is 83.14°C;

[0052] Furthermore, the C crystal form of the hydrochloride salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 174-180°C and a peak temperature of 188-192°C; for example, the onset temperature is 177.23°C and the peak temperature is 190.51°C.

[0053] According to an embodiment of the present invention, the Form C of the hydrochloride of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG40 .

[0054] According to an embodiment of the present invention, the Form C of the hydrochloride of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG41 .

[0055] According to an embodiment of the present invention, the D crystal form of the hydrochloride of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.2±0.20°, 16.3±0.20°, 19.3±0.20°, 20.1±0.20°, 20.9±0.20° and 27.0±0.20°; further, it can also have characteristic peaks at 13.3±0.20°, 15.1±0.20°, 18.2±0. The invention discloses a novel nanostructured carbon foam having a nanostructured carbon foam and a nanostructured carbon foam. The nanostructured carbon foam has characteristic peaks at 20°, 22.5±0.20°, 23.2±0.20°, 24.8±0.20° and / or 28.2±0.20°; further, the nanostructured carbon foam may have characteristic peaks at 5.7±0.20°, 8.8±0.20°, 9.6±0.20°, 10±0.20°, 10.5±0.20°, 11.2±0.20°, 12.4±0.20°, 24±0.20° and / or 26.1±0.20°.

[0056] According to an embodiment of the present invention, the D crystal form of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 42.

[0057] According to an embodiment of the present invention, the D crystal form of the hydrochloride salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 11.

[0058] According to an embodiment of the present invention, the D-type hydrochloride of the compound represented by formula (I) loses 4-7% of its weight at room temperature to 200° C., for example, loses 5-6% of its weight.

[0059] According to an embodiment of the present invention, the D crystal form of the hydrochloride salt of the compound represented by formula (I) has one, two or three of the following endothermic peaks:

[0060] First endothermic peak: the onset temperature is 33-38°C and the peak temperature is 60-65°C; for example, the onset temperature is 35.10°C and the peak temperature is 63.18°C;

[0061] Second endothermic peak: the onset temperature is 112-116°C and the peak temperature is 120-125°C; for example, the onset temperature is 114.32°C and the peak temperature is 122.52°C;

[0062] The third endothermic peak: the onset temperature is 155-160°C, and the peak temperature is 162-167°C; for example, the onset temperature is 157.36°C and the peak temperature is 164.36°C.

[0063] According to an embodiment of the present invention, the D crystal form of the hydrochloride salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in Figure 43.

[0064] According to an embodiment of the present invention, the D crystal form of the hydrochloride salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 44.

[0065] According to an embodiment of the present invention, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.7±0.20°, 8.3±0.20°, 15.8±0.20°, (17.3~17.6)±0.20° (for example, 17.3±0.20° or 17.6±0.20°), 20.0±0.20°, 20.6±0.20° and 21.8±0.20°.

[0066] According to an embodiment of the present invention, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.7±0.20°, 8.3±0.20°, 15.8±0.20°, 17.3±0.20°, 20.0±0.20°, 20.6±0.20° and 21.8±0.20°; further, it may also have characteristic peaks at 15.5±0.20°, 17.6±0.20° and / or 18.7±0.20°; further, it may also have characteristic peaks at 6.2±0.20°, 7.1 ±0.20°, 12.0±0.20°, 12.4±0.20°, 14.1±0.20°, 14.7±0.20°, 15.3±0.20°, 16.7±0.20°, 18.3±0.20°, 18.9±0.20°, 19.2±0.20°, 19.7±0.20°, 21.2±0.20°, 21.5±0.20°, 22.1±0.20°, 23.1±0.20°, 23.5±0.20°, 24.3±0.20°, 26.9±0.20° and / or 28.7±0.20°.

[0067] According to an embodiment of the present invention, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG15 .

[0068] According to an embodiment of the present invention, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 6.

[0069] According to an embodiment of the present invention, the weight loss of the p-toluenesulfonate salt of the compound represented by formula (I) in the crystal form A at room temperature to 140° C. is 0.5 to 5%, for example, 1 to 3%.

[0070] According to an embodiment of the present invention, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) also has an endothermic peak with an onset temperature of 205-210°C and a peak temperature of 210.5-215°C; for example, the onset temperature is 208.6°C and the peak temperature is 212.4°C.

[0071] According to an embodiment of the present invention, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG16 .

[0072] According to an embodiment of the present invention, the crystal form A of the methanesulfonate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.3±0.20°, 18.5±0.20°, 18.6±0.20°, 20.4±0.20°, 21.5±0.20° and 21.6±0.20°; further, it can also have characteristic peaks at 18.7±0.20°, 18.9±0.20°, 20.0±0.20°, 21. The invention discloses a novel nanostructured carbon foam having characteristic peaks at 0±0.20°, 22.0±0.20° and / or 23.0±0.20°; further, the nanostructured carbon foam may have characteristic peaks at 7.1±0.20°, 10.8±0.20°, 11.4±0.20°, 14.0±0.20°, 14.8±0.20°, 16.2±0.20°, 17.9±0.20°, 22.3±0.20°, 22.8±0.20°, 24.0±0.20° and / or 27.8±0.20°.

[0073] According to an embodiment of the present invention, the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG18 .

[0074] According to an embodiment of the present invention, the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 7.

[0075] According to an embodiment of the present invention, the weight loss of the crystal form A of the methanesulfonate of the compound represented by formula (I) at room temperature to 145° C. does not exceed 0.3%, for example, does not exceed 0.1%.

[0076] According to an embodiment of the present invention, the crystal form A of the methanesulfonate of the compound represented by formula (I) has an endothermic peak with an onset temperature of 210-213°C and a peak temperature of 213.5-216°C; for example, the onset temperature is 212.7°C and the peak temperature is 214.3°C.

[0077] According to an embodiment of the present invention, the crystal form A of the methanesulfonate salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG19 .

[0078] According to an embodiment of the present invention, the B crystalline form of the methanesulfonate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.9±0.20°, 20.3±0.20°, 21±0.20° and 28.5±0.20°; further, it can also have characteristic peaks at 8.5±0.20°, 15.4±0.20°, 17.4± It has characteristic peaks at 0.20° and / or 18.6±0.20°; further, it may also have characteristic peaks at 10.4±0.20°, 11.4±0.20°, 12.7±0.20°, 14.5±0.20°, 23.1±0.20°, 24.3±0.20°, 25.6±0.20°, 30.1±0.20° and / or 31.1±0.20°.

[0079] According to an embodiment of the present invention, the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 45 .

[0080] According to an embodiment of the present invention, the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 12.

[0081] According to an embodiment of the present invention, the crystal form B of the methanesulfonate of the compound represented by formula (I) loses no more than 1.3% of its weight at room temperature to 160° C., for example, loses 0.8 to 1.0% of its weight.

[0082] According to an embodiment of the present invention, the crystal form B of the methanesulfonate of the compound represented by formula (I) has one or two of the following endothermic peaks:

[0083] Endothermic peak 1: the onset temperature is 173-180°C, and the peak temperature is 181-185°C; for example, the onset temperature is 176.10°C and the peak temperature is 183.61°C;

[0084] Endothermic peak 2: the onset temperature is 207-210°C, and the peak temperature is 211-214°C; for example, the onset temperature is 208.90°C, and the peak temperature is 212.53°C.

[0085] According to an embodiment of the present invention, the Form B of the methanesulfonate of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG46 .

[0086] According to an embodiment of the present invention, the Form B of the methanesulfonate salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG47 .

[0087] According to an embodiment of the present invention, the crystalline form A of the maleate salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.7±0.20°, 18.6±0.20°, 19.4±0.20°, 19.9±0.20° and 20.2±0.20°; further, it also has characteristic peaks at 11.4±0.20°, 13.8±0.20°, 14.9±0.20°, 15.4±0.20°, 15.6±0.20°, 21.1±0.20°, 25.4±0.20° and / or 27.9±0.20°.

[0088] According to an embodiment of the present invention, the crystalline form A of the maleate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG21 .

[0089] According to an embodiment of the present invention, the crystalline form A of the maleate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 8.

[0090] According to an embodiment of the present invention, the crystalline form A of the maleate salt of the compound represented by formula (I) loses no more than 0.5% of its weight at room temperature to 110° C., for example, the weight loss is about 0;

[0091] Furthermore, the maleate salt of the compound represented by formula (I) in Form A loses 13-20% of its weight at a temperature greater than 110° C. and not exceeding 250° C., for example, loses 15-18% of its weight.

[0092] According to an embodiment of the present invention, the maleate form A of the compound represented by formula (I) has an endothermic peak with an onset temperature of 128-134°C and a peak temperature of 135-140°C; for example, the onset temperature is 131.1°C and the peak temperature is 137.1°C.

[0093] According to an embodiment of the present invention, the maleate crystal form A of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG22 .

[0094] According to an embodiment of the present invention, the crystalline form A of the ethanesulfonate of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 15.1±0.20°, 16.8±0.20°, 19.8±0.20° and 20.5±0.20°; further, it may also have characteristic peaks at 8.3±0.20°, 22.6±0.20°, 23.6±0.20°, 27.2±0.20° and / or 28.2±0.20°; further, it may also have characteristic peaks at 10.3±0.20°, 12.4±0.20°, 18.1±0.20°, 25.0±0.20°, 29.7±0.20° and / or 30.5±0.20°.

[0095] According to an embodiment of the present invention, the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 48 .

[0096] According to an embodiment of the present invention, the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 13.

[0097] According to an embodiment of the present invention, the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) loses no more than 1.0% of its weight at room temperature to 150° C., for example, loses 0.5 to 0.7% of its weight.

[0098] According to an embodiment of the present invention, the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has one or two of the following endothermic peaks:

[0099] Endothermic peak 1: the onset temperature is 165-169°C, and the peak temperature is 170-175°C; for example, the onset temperature is 168.23°C and the peak temperature is 171.09°C;

[0100] Endothermic peak 2: the onset temperature is 207-210°C, and the peak temperature is 214-219°C; for example, the onset temperature is 209.37°C, and the peak temperature is 216.61°C.

[0101] According to an embodiment of the present invention, the crystal form A of the ethanesulfonic acid salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in Figure 49.

[0102] According to an embodiment of the present invention, the crystal form A of the ethanesulfonic acid salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 50.

[0103] According to an embodiment of the present invention, the B crystalline form of the ethanesulfonate salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.5±0.20°, 15.2±0.20° and 17.5±0.20°; further, it may also have characteristic peaks at 20.8±0.20°, 22.8±0.20° and / or 23.6±0.20°; further, it may also have characteristic peaks at 9.9±0.20°, 10.8±0.20°, 14.7±0.20°, 19.0±0.20°, 19.5±0.20°, 21.4±0.20°, 22.1±0.20°, 24.9±0.20° and / or 26.8±0.20°.

[0104] According to an embodiment of the present invention, the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG51 .

[0105] According to an embodiment of the present invention, the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 14.

[0106] According to an embodiment of the present invention, the crystalline form B of the ethanesulfonate salt of the compound represented by formula (I) loses 1.3-2.3% of its weight at room temperature to 160° C., for example, loses 1.5-1.9% of its weight.

[0107] According to an embodiment of the present invention, the crystalline form B of the ethanesulfonate salt of the compound represented by formula (I) has one or two of the following endothermic peaks:

[0108] Endothermic peak 1: The onset temperature is 15-20°C and the peak temperature is 50-55°C; for example, the onset temperature is 17.23°C and the peak temperature is 52.50°C;

[0109] Endothermic peak 2: the onset temperature is 215-220°C, and the peak temperature is 221-225°C; for example, the onset temperature is 218.89°C, and the peak temperature is 222.29°C.

[0110] According to an embodiment of the present invention, the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG52 .

[0111] According to an embodiment of the present invention, the Form B of the ethanesulfonic acid salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in FIG53 .

[0112] According to an embodiment of the present invention, the A crystal form of the hydrobromide salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 15.6±0.20°, 20.9±0.20°, 25.5±0.20° and 28.2±0.20°; further, it can also have characteristic peaks at 8.0±0.20°, 11.4±0.20°, 17.0±0.20°, 18.0±0.20°, 20.0±0.20°, 25.0±0.20°, 26.0±0.20°, 27.0±0.20°, 28.0±0.20°, 29.0±0.20°, 30.0±0.20°, 31.0±0.20°, 32.0±0.20°, 33.0±0.20°, 34.0±0.20°, 35.0±0.20°, 36.0±0.20°, 37.0±0.20°, 38.0±0.20°, 39.0±0.20°, 40.0±0.20°, 41.0±0.20°, 42.0±0.20°, 43.0±0.20°, 44.0±0.20°, 45.0±0.20°, 47.0±0.20°, 48.0±0.20°, 49.0±0.20°, 50.0±0.20°, 51.0±0.20°, 52.0±0.20°, 53.0±0.20°, °, 17.6±0.20°, 24.5±0.20°, 26.4±0.20° and / or 29.9±0.20°; further, characteristic peaks may also be present at 6.9±0.20°, 10.5±0.20°, 14.2±0.20°, 18.6±0.20°, 22.8±0.20°, 23.5±0.20° and / or 31.6±0.20°.

[0113] According to an embodiment of the present invention, the Form A of the hydrobromide salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG54 .

[0114] According to an embodiment of the present invention, the crystal form A of the hydrobromide salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 15.

[0115] According to an embodiment of the present invention, the crystal form A of the hydrobromide salt of the compound represented by formula (I) loses 4.0-5.0% of its weight at room temperature to 170° C., for example, loses 4.3-4.8% of its weight.

[0116] According to an embodiment of the present invention, the crystalline form A of the hydrobromide salt of the compound represented by formula (I) has one or two of the following endothermic peaks:

[0117] Endothermic peak 1: the onset temperature is 35-40°C, and the peak temperature is 58-63°C; for example, the onset temperature is 38.99°C and the peak temperature is 60.49°C;

[0118] Endothermic peak 2: the onset temperature is 178-184°C, and the peak temperature is 190-195°C; for example, the onset temperature is 181.71°C, and the peak temperature is 192.83°C.

[0119] According to an embodiment of the present invention, the Form A of the hydrobromide salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in FIG55 .

[0120] According to an embodiment of the present invention, the crystal form A of the hydrobromide salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 56.

[0121] According to an embodiment of the present invention, the B crystalline form of the hydrobromide salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.5±0.20°, 6.4±0.20°, 11.9±0.20°, 17.4±0.20°, 18.3±0.20°, 22.0±0.20° and 23.8±0.20°; further, it may also have characteristic peaks at 5.2±0.20°, 17.7±0.20°, 19.3±0.20°, 20.8±0.20° and / or 28. further, it may also have characteristic peaks at 6.8±0.20°, 13.0±0.20°, 13.8±0.20°, 14.9±0.20°, 15.9±0.20°, 20.0±0.20°, 22.9±0.20°, 24.3±0.20°, 24.8±0.20°, 25.5±0.20°, 26.3±0.20°, 26.7±0.20°, 27.3±0.20°, 29.1±0.20° and / or 29.8±0.20°.

[0122] According to an embodiment of the present invention, the Form B of the hydrobromide salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG57 .

[0123] According to an embodiment of the present invention, the B crystal form of the hydrobromide salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 16.

[0124] According to an embodiment of the present invention, the B crystal form of the hydrobromide salt of the compound represented by formula (I) loses 2-5% of its weight at room temperature to 160° C., for example, loses 3-4% of its weight.

[0125] According to an embodiment of the present invention, the B crystal form of the hydrobromide salt of the compound represented by formula (I) has one or two of the following endothermic peaks:

[0126] Endothermic peak 1: The onset temperature is 75-85°C and the peak temperature is 95-105°C; for example, the onset temperature is 79.68°C and the peak temperature is 99.13°C;

[0127] Endothermic peak 2: the onset temperature is 165-175°C, and the peak temperature is 180-190°C; for example, the onset temperature is 170.54°C, and the peak temperature is 184.28°C.

[0128] According to an embodiment of the present invention, the B crystal form of the hydrobromide salt of the compound represented by formula (I) has a DSC spectrum substantially as shown in Figure 58.

[0129] According to an embodiment of the present invention, the B crystal form of the hydrobromide salt of the compound represented by formula (I) has a TGA spectrum substantially as shown in Figure 59.

[0130] The present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by the above formula (I) or a crystal of the pharmaceutically acceptable salt, comprising: reacting the compound represented by the formula (I) with sodium hydroxide, potassium hydroxide, hydrochloric acid, p-toluenesulfonic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid or hydrobromic acid in a solvent to obtain the pharmaceutically acceptable salt of the compound represented by the formula (I) or a crystal of the pharmaceutically acceptable salt.

[0131] According to an embodiment of the present invention, the compound represented by formula (I) may be in an amorphous or crystalline form, for example, in crystal form A or crystal form D of the compound represented by formula (I).

[0132] According to an embodiment of the present invention, the crystal form A of the compound represented by formula (I) substantially has an XRPD pattern as shown in FIG2 .

[0133] According to an embodiment of the present invention, the crystal form A of the compound represented by formula (I) is prepared by the following method: the amorphous form of the compound represented by formula (I) is dissolved in dichloromethane, methyl tert-butyl ether is added to the solution, stirred until a solid precipitates, separated, and dried to obtain the crystal form A of the compound represented by formula (I).

[0134] According to an embodiment of the present invention, the D crystal form of the compound represented by formula (I) substantially has an XRPD pattern as shown in FIG. 38 .

[0135] According to an embodiment of the present invention, the crystal form D of the compound represented by formula (I) is prepared by the following method: the crystal form A of the compound represented by formula (I) is dissolved in ethanol, suspended and crystallized at room temperature to obtain the crystal form D of the compound represented by formula (I).

[0136] According to an embodiment of the present invention, the solvent contains at least an organic solvent, such as one or more of acetonitrile, ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate, acetone and methyl tert-butyl ether. Further, the solvent may also contain water.

[0137] The present invention also provides a method for preparing the crystal form A of the p-toluenesulfonate of the compound represented by formula (I), comprising: mixing the compound represented by formula (I), a first solvent, and p-toluenesulfonic acid, suspending at room temperature, centrifuging, and drying to obtain the crystal form A of the p-toluenesulfonate;

[0138] Preferably, the compound represented by formula (I) may be in the form of an amorphous or crystalline form, for example, the crystal form A of the compound represented by formula (I);

[0139] Preferably, the first solvent is selected from ethanol, n-propanol, dimethylformamide, ethylene glycol dimethyl ether and dimethyl sulfoxide, or dichloromethane and chloroform, for example, ethyl acetate;

[0140] Preferably, the mass volume ratio of the compound represented by formula (I) (e.g., crystal form A of the compound represented by formula (I)) to the first solvent is (100-200) mg:10 mL;

[0141] Preferably, the suspension time at room temperature is 1 to 3 days;

[0142] Preferably, the drying is vacuum drying at room temperature.

[0143] The present invention also provides a method for preparing the crystal form A of the methanesulfonate of the compound represented by formula (I), comprising: mixing the compound represented by formula (I), a second solvent, and methanesulfonic acid, suspending the mixture at room temperature, then adding a third solvent thereto, continuing to suspend the mixture at room temperature, centrifuging, and drying to obtain the crystal form A of the methanesulfonate of the compound represented by formula (I);

[0144] Preferably, the second solvent is selected from ethanol, n-propanol, dimethylformamide, ethylene glycol dimethyl ether and dimethyl sulfoxide, or dichloromethane and chloroform, for example, ethanol;

[0145] Preferably, the third solvent is selected from one or more of methyl tert-butyl ether, n-heptane, isopropyl ether, methyl cyclopentyl ether, tetrahydrofuran, 1,4-dioxane, acetone, and n-hexane, for example, methyl tert-butyl ether. Preferably, the volume ratio of the second solvent to the third solvent is 1:(1-5), for example, 1:(1.2-3);

[0146] Preferably, the compound represented by formula (I) may be in the form of an amorphous or crystalline form, for example, the crystal form A of the compound represented by formula (I);

[0147] Preferably, the methanesulfonic acid is added in the form of a solution, for example, the solvent for preparing the methanesulfonic acid solution is ethanol; preferably, the concentration of the methanesulfonic acid solution is 0.9 to 1.3 mol / L;

[0148] Preferably, the compound represented by formula (I), the second solvent and methanesulfonic acid are mixed and suspended at room temperature for 1 to 4 hours;

[0149] Preferably, the suspension time at room temperature after adding the third solvent is 1 to 3 days;

[0150] Preferably, the drying is vacuum drying at room temperature.

[0151] The present invention also provides a method for preparing the crystal form B of the ethanesulfonate of the compound represented by formula (I), comprising: mixing the compound represented by formula (I), ethanesulfonic acid, and a fourth solvent, first heating and stirring, then cooling and stirring, centrifuging the suspension, and drying to obtain the crystal form B of the ethanesulfonate of the compound represented by formula (I);

[0152] The fourth solvent is selected from isopropyl acetate;

[0153] Preferably, the compound represented by formula (I) may be in the form of an amorphous or crystalline form, for example, the D crystal form of the compound represented by formula (I);

[0154] Preferably, the ethanesulfonic acid is added in the form of a solution, for example, the solvent for preparing the ethanesulfonic acid solution is ethyl acetate; preferably, the concentration of the ethanesulfonic acid solution is 0.9 to 1.3 mol / L;

[0155] Preferably, the mass volume ratio of the compound represented by formula (I) (e.g., crystal form D of the compound represented by formula (I)) to the fourth solvent is 1 g: (8-15) mL;

[0156] Preferably, the heating and stirring temperature is 40 to 60° C., and the time is 15 to 24 hours;

[0157] Preferably, the temperature of the cooling and stirring is room temperature, and the time is 2 to 6 hours;

[0158] Preferably, the drying is vacuum drying at 40-60°C.

[0159] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt or a crystal of the pharmaceutically acceptable salt of the compound represented by the above formula (I).

[0160] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0161] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0162] The present invention also provides the use of the pharmaceutically acceptable salt, crystal of the pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a drug for treating KIF18A-mediated conditions and / or diseases, such as the use in the preparation of a KIF18A inhibitor drug.

[0163] 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 the pharmaceutically acceptable salt, crystal of the pharmaceutically acceptable salt, or pharmaceutical composition.

[0164] According to an embodiment of the present invention, the disease is, for example, cancer, including bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

[0165] 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.

[0166] 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.

[0167] The term "room temperature" refers to 15 to 40°C, preferably 20 to 30°C, for example 25°C.

[0168] The term "(17.3-17.6)±0.20°" refers to X-ray powder diffraction peaks expressed in 2θ angles at any one or more positions within the range of (17.3-17.6)±0.20° (e.g., 17.3±0.20°, 17.4±0.20°, 17.5±0.20°, or 17.6±0.20°). Multiple process validation experiments have revealed that, due to differences in test conditions or crystallization processes, the peaks at 17.3±0.20° and 17.6±0.20° sometimes overlap to form a single peak at approximately 17.5±0.3°. This does not affect identification as the same crystalline form.

[0169] Those skilled in the art should know that when determining whether two crystal forms are the same, it mainly depends on the position of the diffraction peak (expressed in 2θ angles), especially the position of the low-angle diffraction peak. The intensity or order of the diffraction peak is easily affected by many factors and can easily change greatly.

[0170] Those skilled in the art also know that for the same crystal form, the crystallization conditions may not be exactly the same in different batches. Therefore, in the XRPD spectrum, for the same crystal form, two adjacent diffraction peaks may overlap into a single peak, or a derivative peak may split into two adjacent peaks. This phenomenon is also common in the drug development process. Beneficial effects

[0171] The present invention provides pharmaceutically acceptable salts of the compound represented by formula (I) and crystals of the salts, which have good hygroscopicity, solubility and / or stability and are suitable for pharmaceutical preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0172] Figure 1: XRPD pattern of the amorphous form of the compound represented by formula (I);

[0173] Figure 2: XRPD pattern of the crystalline form of compound A represented by formula (I);

[0174] Figure 3: XRPD pattern of Form A of the sodium salt of the compound represented by formula (I);

[0175] Figure 4: Overlay of DSC and TGA images of Form A of the sodium salt of the compound represented by formula (I);

[0176] Figure 5: NMR spectrum of Form A of the sodium salt of the compound represented by formula (I);

[0177] Figure 6: XRPD pattern of Form A of the potassium salt of the compound represented by formula (I);

[0178] Figure 7: Overlay of DSC and TGA images of Form A of the potassium salt of the compound represented by formula (I);

[0179] Figure 8: NMR spectrum of Form A of the potassium salt of the compound represented by formula (I)

[0180] Figure 9: XRPD pattern of Form A of the hydrochloride salt of the compound represented by formula (I);

[0181] Figure 10: Overlay of DSC and TGA images of Form A of the hydrochloride salt of the compound represented by formula (I);

[0182] Figure 11: NMR spectrum of Form A of the hydrochloride salt of the compound represented by formula (I);

[0183] Figure 12: XRPD pattern of Form B of the hydrochloride salt of the compound represented by formula (I);

[0184] Figure 13: Overlay of DSC and TGA images of Form B of the hydrochloride salt of the compound represented by formula (I);

[0185] Figure 14: NMR spectrum of Form B of the hydrochloride salt of the compound represented by formula (I);

[0186] Figure 15: XRPD pattern of Form A of p-toluenesulfonate salt of the compound represented by formula (I);

[0187] Figure 16: Overlay of DSC and TGA images of Form A of the p-toluenesulfonate salt of the compound represented by formula (I);

[0188] Figure 17: NMR spectrum of Form A of p-toluenesulfonate salt of the compound represented by formula (I);

[0189] Figure 18: XRPD pattern of Form A of the mesylate salt of the compound represented by formula (I);

[0190] Figure 19: Overlay of DSC and TGA images of Form A of the mesylate salt of the compound represented by formula (I);

[0191] Figure 20: NMR spectrum of Form A of the methanesulfonate salt of the compound represented by formula (I);

[0192] Figure 21: XRPD pattern of Form A of the maleate salt of the compound represented by formula (I);

[0193] Figure 22: Overlay of DSC and TGA images of Form A of the maleate salt of the compound represented by formula (I);

[0194] Figure 23: NMR spectrum of Form A of the maleate salt of the compound represented by formula (I);

[0195] Figure 24: DVS spectrum of Form A of the sodium salt of the compound represented by formula (I);

[0196] Figure 25: XRPD patterns of Form A of the sodium salt of the compound represented by formula (I) before and after DVS testing;

[0197] Figure 26: DVS spectrum of Form A of the hydrochloride salt of the compound represented by formula (I);

[0198] Figure 27: XRPD patterns of Form A of the hydrochloride salt of the compound represented by formula (I) before and after DVS testing;

[0199] Figure 28: DVS spectrum of Form B of the hydrochloride salt of the compound represented by formula (I);

[0200] Figure 29: XRPD patterns of Form B hydrochloride of the compound represented by formula (I) before and after DVS testing;

[0201] Figure 30: DVS spectrum of Form A of p-toluenesulfonate salt of the compound represented by formula (I);

[0202] Figure 31: XRPD patterns of Form A of the p-toluenesulfonate salt of the compound represented by formula (I) before and after DVS testing;

[0203] Figure 32: DVS spectrum of Form A of the mesylate salt of the compound represented by formula (I);

[0204] Figure 33: XRPD patterns of Form A of the mesylate salt of the compound represented by formula (I) before and after DVS testing;

[0205] Figure 34: DVS spectrum of Form A of the maleate salt of the compound represented by formula (I);

[0206] Figure 35: XRPD patterns of Form A of the maleate salt of the compound represented by formula (I) before and after DVS testing;

[0207] Figure 36: XRPD pattern of stability study of Form A of p-toluenesulfonate salt of the compound represented by formula (I);

[0208] Figure 37: XRPD pattern of stability study of Form A of the methanesulfonate salt of the compound represented by formula (I);

[0209] Figure 38: XRPD pattern of the crystalline form D of the compound represented by formula (I);

[0210] Figure 39: XRPD pattern of Form C of the hydrochloride salt of the compound represented by formula (I);

[0211] Figure 40: DSC chart of Form C of the hydrochloride salt of the compound represented by formula (I);

[0212] Figure 41: TGA chart of Form C of the hydrochloride salt of the compound represented by formula (I);

[0213] Figure 42: XRPD pattern of Form D of the hydrochloride salt of the compound represented by formula (I);

[0214] Figure 43: DSC chart of Form D of the hydrochloride salt of the compound represented by formula (I);

[0215] Figure 44: TGA chart of Form D of the hydrochloride salt of the compound represented by formula (I);

[0216] Figure 45: XRPD pattern of Form B of the methanesulfonate salt of the compound represented by formula (I);

[0217] Figure 46: DSC chart of Form B of the methanesulfonate salt of the compound represented by formula (I);

[0218] Figure 47: TGA chart of Form B of the methanesulfonate salt of the compound represented by formula (I);

[0219] Figure 48: XRPD pattern of Form A of the ethanesulfonate salt of the compound represented by formula (I);

[0220] Figure 49: DSC chart of Form A of the ethanesulfonic acid salt of the compound represented by formula (I);

[0221] Figure 50: TGA chart of Form A of the ethanesulfonic acid salt of the compound represented by formula (I);

[0222] Figure 51: XRPD pattern of Form B of the ethanesulfonate salt of the compound represented by formula (I);

[0223] Figure 52: DSC graph of Form B of the ethanesulfonic acid salt of the compound represented by formula (I);

[0224] Figure 53: TGA chart of Form B of ethanesulfonic acid salt of the compound represented by formula (I);

[0225] Figure 54: XRPD pattern of Form A of the hydrobromide salt of the compound represented by formula (I);

[0226] Figure 55: DSC chart of Form A of the hydrobromide salt of the compound represented by formula (I);

[0227] Figure 56: TGA chart of Form A of the hydrobromide salt of the compound represented by formula (I);

[0228] Figure 57: XRPD pattern of Form B of the hydrobromide salt of the compound represented by formula (I);

[0229] Figure 58: DSC chart of Form B of the hydrobromide salt of the compound represented by formula (I);

[0230] Figure 59: TGA chart of Form B of the hydrobromide salt of the compound represented by formula (I);

[0231] Figure 60: DVS spectrum of Form B of ethanesulfonic acid salt of the compound represented by formula (I). DETAILED DESCRIPTION

[0232] 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.

[0233] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0234] The following are the instruments, parameters, characterizations, and test methods used in the examples:

[0235] (1) NMR analysis 1 H NMR)

[0236] 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).

[0237] (2) X-ray powder diffraction (XRPD)

[0238] 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 Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[0239] 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°, and the total measurement time was 3 minutes and 30 seconds. The measurement method used Kα1 radiation with a Cu target, a voltage of 45 kV, a current of 40 mA, and a zero-background sample pan.

[0240] (3) Thermogravimetric analysis (TGA)

[0241] 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.

[0242] (4) Differential Scanning Calorimetry (DSC)

[0243] 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.

[0244] (5) Dynamic moisture adsorption and desorption analysis (DVS)

[0245] Dynamic moisture sorption and desorption analysis for preliminary evaluation of hygroscopicity was performed using DVS Intrinsic Plus (SMS, UK).

[0246] The test method for Figures 24-35: The test uses a gradient mode with a humidity ramp of 50%-95%-50%, with each ramp increasing by 15%. The gradient endpoint is determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum ramp duration of 60 minutes. After the test, the sample is analyzed by XRPD to confirm any change in solid form.

[0247] Test method of Figure 60: The test adopts gradient mode, the humidity changes from 50% to 95% to 0% to 95%, the humidity change of each gradient is 10% in the range of 0% to 90%, and the gradient end point is judged by dm / dt method, and the gradient end point is when dm / dt is less than 0.002% and maintained for 10 minutes.

[0248] (6) High performance liquid chromatography (HPLC)

[0249] The HPLC model was SHIMADZU LC-20A (Shimadzu, JP), and the test conditions were shown in Table 1.

[0250] Table 1 HPLC test conditions

[0251] Example 1 Preparation of the amorphous compound represented by formula (I)

[0252] Step 1 Synthesis of (1S,4R)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptane-3-imine (Compound 2c)

[0253] Under 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.

[0254] Compound 2c was characterized as follows:

[0255] 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).

[0256] MS:(ESI,m / z):345.1[M+H]+ .

[0257] 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)

[0258] 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).

[0259] Compound 2d was characterized as follows: MS: (ESI, m / z): 262.8 [M+H] + .

[0260] Step 3 Synthesis of Compound 2

[0261] 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 (20% ammonia in ethanol) were stirred at 80°C for 12 hours. The reaction was complete by HPLC. 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). Compound 2 (250 mg, 66% yield) was obtained.

[0262] Compound 2 is characterized as follows:

[0263] 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).

[0264] MS:(ESI,m / z):199.9[M+H] + .

[0265] 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)

[0266] Under nitrogen protection, 4-bromo-2-(6-azaspiro[2.5]octane-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 the reactor. The temperature was controlled at 25±5°C, and DIEA (5.42 g, 47 mmol, 2.2 eq.) was added dropwise to the system. 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 system. 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 autoclave was controlled at 25±5°C, and H₂O (40.2 mL) was added dropwise to the system. The mixture was stirred for at least 1 hour, centrifuged, and the filter cake was rinsed with H₂O (13.4 mL) and collected. The wet filter cake and H₂O (33.5 mL) were added to the autoclave. The temperature in the autoclave was controlled at 25±5°C, and the mixture was stirred for at least 1 hour. The mixture was centrifuged, and the filter cake was rinsed with H₂O (13.4 mL) and collected. The filter cake was dried in vacuo at 45±5°C to obtain 3a (9.88 g, 93% yield) as a brown solid.

[0267] Compound 3a was characterized as follows:

[0268] 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).

[0269] MS (EI, m / z): 492.5 [M+H] + .

[0270] Step 5: Synthesis of the compound represented by formula (I)

[0271] 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), trans-NN-dimethyl-1,2-cyclohexanediamine (2.75 g, 1.9 mmol, 1.0 eq.) were added to the reactor. The nitrogen atmosphere was replaced 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 and stirred 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 represented by formula (I) (7.55 g, purity 99.0%, ee value 99.5%, yield 73%).

[0272] The compound represented by formula (I) is characterized as follows:

[0273] 1 H NMR(400MHz,Methanol-d4)δ12.28(s,1H),10.16(s,1H),8.20(d,1H),8.00(d,1H),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).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 time 9.4 min and 12.0 min (main peak).

[0274] MS (EI, m / z): 536.6 [M+H] + .

[0275] 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 , indicating that the white solid was amorphous.

[0276] Example 2 Preparation of the Crystalline Form of Compound A Represented by Formula (I)

[0277] 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 added dropwise to 10 volumes of methyl tert-butyl ether. After stirring for about 30 min, the system with solid precipitation was centrifuged and the solid was vacuum dried at room temperature to obtain Form A. The XRPD pattern is shown in Figure 2.

[0278] Example 3 Preparation and Characterization of Form A of the Sodium Salt of the Compound Represented by Formula (I)

[0279] 53.5 mg of Form A of the compound represented by Formula (I) obtained in Example 2 was added to 6.0 mL of acetonitrile and 0.2 mL of a 1 M sodium hydroxide aqueous solution, and the mixture was suspended at room temperature for 2 days. The mixture was centrifuged and the solid was dried under vacuum at room temperature overnight to obtain Form A of the sodium salt. The XRPD pattern is shown in Figure 3, and the analytical data are shown in Table 2 below.

[0280] Table 2

[0281] The obtained crystal form A of the sodium salt of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the spectra are shown in Figures 4 and 5. 1 The HNMR results showed that the integration results were basically consistent with the free state; an acetonitrile solvent peak was visible at 2.03 ppm, suggesting that the sample contained a small amount of residual solvent.

[0282] Example 4 Preparation and Characterization of Form A of the Potassium Salt of the Compound Represented by Formula (I)

[0283] 26.8 mg of Form A of Compound (I) obtained in Example 2 and 2 equivalents of a 1M aqueous potassium hydroxide solution were added to 3 mL of acetonitrile and suspended at room temperature for 2 days. The solution was then switched to solidification conditions. The suspension was centrifuged, and the solid was dried under vacuum at room temperature. Form A of the potassium salt was obtained. The XRPD pattern is shown in Figure 6, and the analytical data are shown in Table 3 below.

[0284] Table 3

[0285] The obtained A crystal form of potassium salt of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the spectra are shown in Figures 7 and 8. 1 HNMR results showed that the integration results were basically consistent with the free state; there was no obvious solvent peak and displacement change.

[0286] Example 5 Preparation and Characterization of Form A of the Hydrochloride Salt of the Compound Represented by Formula (I)

[0287] 214.5 mg of Form A of the compound represented by formula (I) obtained in Example 2 was added to 12.0 mL of acetonitrile and 0.8 mL of 1 M hydrochloric acid ethanol solution. The mixture was suspended at room temperature for 1 day, then inverted to 10° C. and continued to be suspended for 1 day. The mixture was centrifuged and the solid was vacuum dried at room temperature overnight to obtain Form A of the hydrochloride salt. The XRPD pattern is shown in Figure 9, and the analytical data are shown in Table 4 below.

[0288] Table 4

[0289] The obtained A-type hydrochloride of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the spectra are shown in Figures 10 and 11. 1 The H NMR results showed that the integration results were basically consistent with the free state; solvent peaks of ethanol were visible at 3.60 ppm and 1.18 ppm; according to the integration results, the ratio of compound to ethanol was 1:0.2, suggesting that the sample contained a small amount of residual solvent.

[0290] Example 6 Preparation and Characterization of Form B of the Hydrochloride Salt of the Compound Represented by Formula (I)

[0291] 26.8 mg of the crystalline form A of the compound represented by formula (I) obtained in Example 2 was taken, 1.5 mL of acetonitrile and 0.1 mL of ethanolic hydrochloric acid solution (1 M) were added, and the mixture was suspended at room temperature for 2 days, then transferred to 10°C and continued to be suspended for 1 day. The mixture was centrifuged and the solid was vacuum dried at room temperature for 3 days to obtain the crystalline form B of the hydrochloride salt. The XRPD spectrum is shown in Figure 12, and the analytical data are shown in Table 5 below.

[0292] Table 5

[0293] The obtained B crystal form of the hydrochloride of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the spectra are shown in Figures 13 and 14. 1 The H NMR results showed that the integration results were basically consistent with those of the free raw material, with no obvious solvent peak.

[0294] Example 7 Preparation and Characterization of Form A of the p-Toluenesulfonate Salt of the Compound Represented by Formula (I)

[0295] 134.0 mg of Form A of the compound represented by formula (I) obtained in Example 2 was taken, 10.0 mL of ethyl acetate and 104.6 mg of p-toluenesulfonic acid were added, and the mixture was suspended at room temperature for 2 days, centrifuged, and the solid was vacuum-dried at room temperature overnight to obtain Form A of the p-toluenesulfonate salt. The XRPD pattern is shown in Figure 15, and the analytical data are shown in Table 6 below.

[0296] Table 6

[0297] The obtained p-toluenesulfonate of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the spectra are shown in Figures 16 and 17. 1 The H NMR results showed that the integration results were basically consistent with the free state, with no obvious solvent peak; peaks of p-toluenesulfonic acid were visible at 2.36 ppm, 7.61 ppm, and 7.19 ppm, and the salt formation ratio was 1:2.

[0298] Example 8 Preparation and Characterization of Crystal Form A of the Methanesulfonate of the Compound Represented by Formula (I)

[0299] 268.2 mg of Form A of the compound represented by Formula (I) obtained in Example 2 was weighed, 15.0 mL of ethanol and 1.0 mL of 1 M methanesulfonic acid ethanol solution were added, and the mixture was suspended at room temperature for 2 h without solid precipitation. 30 mL of MTBE was added dropwise and the mixture was suspended at room temperature for 2 days. The mixture was centrifuged and the solid was vacuum dried at room temperature overnight to obtain Form A of the mesylate salt. The XRPD pattern is shown in Figure 18, and the analytical data are shown in Table 7 below.

[0300] Table 7

[0301] The obtained crystal form A of the methanesulfonate of the compound represented by formula (I) was subjected to TGA, DSC, 1 H NMR detection, the spectra are shown in Figures 19 and 20. 1 H NMR results showed that the integration results were basically consistent with the free form; ethanol signal peaks were visible at 1.18 ppm and 3.60 ppm, suggesting a small amount of residual solvent in the sample. A methanesulfonic acid peak was observed at 2.65 ppm, suggesting a possible salt ratio of 1:2.

[0302] Example 9 Preparation and Characterization of Crystal Form A of the Maleate Salt of the Compound Represented by Formula (I)

[0303] 134.1 mg of the crystalline form A of the compound represented by formula (I) obtained in Example 2 was taken, 10.0 mL of ethyl acetate and 63.6 mg of maleic acid were added, and the mixture was suspended at room temperature for 2 days, centrifuged, and the solid was vacuum dried at room temperature overnight to obtain the crystalline form A of the maleate salt of the compound represented by formula (I). The XRPD spectrum is shown in Figure 21, and the analytical data are shown in Table 8 below.

[0304] Table 8

[0305] The obtained maleate crystal form A of the compound represented by formula (I) was subjected to TGA, DSC, 1H NMR detection, the spectra are shown in Figures 22 and 23. 1 H NMR results showed that the integration results were basically consistent with the free state, with no obvious solvent signal peak. A peak of maleic acid was visible at 6.29 ppm, and the salt ratio was approximately 1:1.

[0306] Example 10 Preparation and Characterization of Crystal Form D of the Compound Represented by Formula (I)

[0307] 20.4 mg of Form A of the compound represented by formula (I) was weighed, 1.3 mL of ethanol was added to completely dissolve the sample, and after suspending at room temperature for 20 minutes, a sufficient amount of white solid precipitated. The suspension was centrifuged, and the solid was vacuum dried at room temperature for characterization to obtain Form D of the compound represented by formula (I). The XRPD spectrum is shown in Figure 38, and the analytical data are shown in Table 9 below.

[0308] Table 9

[0309] Example 11 Preparation and Characterization of Form C of the Hydrochloride Salt of the Compound Represented by Formula (I)

[0310] Weigh 50 mg of the crystalline form D of the compound represented by formula (I) obtained in Example 10, add 1.2 eq of hydrochloric acid (4 M hydrochloric acid isopropanol solution), add 0.6 mL of isopropanol, stir at 50°C for 2 hours, cool to room temperature and stir for 2 days, centrifuge the suspension, and dry the obtained solid in vacuo at 50°C to obtain the crystalline form C of the hydrochloride salt of the compound represented by formula (I), whose XRPD pattern is shown in Figure 39, and its analytical data are shown in Table 10 below.

[0311] Table 10

[0312] The obtained Form C of the hydrochloride salt of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 40 and 41.

[0313] The C crystal form of the hydrochloride of the compound represented by formula (I) 1 The H NMR results are as follows:

[0314] 1H NMR (400MHz, DMSO-d6) δ12.07(s,1H),10.22(s,1H),7.93(t,J=13.0Hz,2H),7.53( s,1H),7.38(s,1H),7.24(d,J=2.1Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),5.40(s,1H ),3.88(s,2H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),2.39(d,J=9.6Hz,1H) ,2.22(s,1H),2.16–1.88(m,3H),1.59(s,3H),1.26(d,J=22.7Hz,5H),0.30(s,4H).

[0315] According to the ion chromatography results, the salt formation ratio of the compound represented by formula (I) and hydrochloric acid was calculated to be 1:1.5.

[0316] Example 12 Preparation and Characterization of Form D of the Hydrochloride Salt of the Compound Represented by Formula (I)

[0317] Weigh 50 mg of the crystal form D of the compound represented by formula (I) obtained in Example 10, add 1.2 eq of hydrochloric acid (2M hydrochloric acid ethyl acetate solution), 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 the suspension is centrifuged, the obtained solid is vacuum-dried at 50°C to obtain the crystal form D of the hydrochloride salt of the compound represented by formula (I), whose XRPD spectrum is shown in Figure 42, and its analytical data are shown in Table 11 below.

[0318] Table 11

[0319] The obtained crystal form D of the hydrochloride salt of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 43 and 44.

[0320] The D crystal form of the hydrochloride of the compound represented by formula (I) 1 The H NMR results are as follows:

[0321] 1H NMR (400MHz, DMSO-d6) δ12.17(s,1H),10.19(s,1H),7.97(d,J=8.5Hz,2H),7.42(s,1H),7.37–7.15(m,2H),7.08(dd,J=8.6,2.1Hz,1H),5. 31(d,J=7.7Hz,2H),3.36(t,J=6.5Hz,3H),2.33(d,J=10.7Hz,2H),2.18(s,1H),2.12–1.93(m,3H),1.64(s,4H),1.23(s,5H),0.30(s,4H).

[0322] According to the ion chromatography results, the salt formation ratio of the compound represented by formula (I) and hydrochloric acid was calculated to be 1:0.7.

[0323] Example 13 Preparation and Characterization of Crystal Form B of the Methanesulfonate of the Compound Represented by Formula (I)

[0324] 50 mg of the crystalline form D of the compound represented by formula (I) obtained in Example 10 was weighed, 1.2 eq of methanesulfonic acid (4 M methanesulfonic acid acetone / methyl tert-butyl ether, 1 v / 2 v solution) was added, 0.4 mL of acetone / methyl tert-butyl ether (1 v / 2 v) was added, and the mixture was stirred at 50° C. for 2 hours, then cooled to room temperature and stirred for 2 days. After the suspension was centrifuged, the obtained solid was vacuum-dried at 50° C. to obtain the crystalline form B of the methanesulfonate salt of the compound represented by formula (I), whose XRPD spectrum is shown in FIG45 , and its analytical data are shown in Table 12 below.

[0325] Table 12

[0326] The obtained Form B of the methanesulfonate of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 46 and 47.

[0327] The B crystal form of the methanesulfonate of the compound represented by formula (I) 1 The H NMR results are as follows:

[0328] 1H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 10.18 (s, 1H), 7.95 (d, J = 8.5Hz, 2H), 7.52 (s, 1H) ),7.37(s,1H),7.23(d,J=2.1Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),5.49–5.28(m,2H), 3.86(s,2H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),2.38(d,J=9.9Hz,1H),2.31 (s,3H),2.22(s,1H),2.14–1.93(m,3H),1.60(s,3H),1.37–1.17(m,4H),0.30(s,4H).

[0329] According to the NMR integration results, the salt ratio of the compound represented by formula (I) and methanesulfonic acid was calculated to be 1:1.1.

[0330] Example 14 Preparation and Characterization of Form A of the Ethysulfonate Salt of the Compound Represented by Formula (I)

[0331] Weigh 50 mg of the crystalline form D of the compound represented by formula (I) obtained in Example 10, add 1.2 eq of ethanesulfonic acid (1 M ethyl acetate solution of ethanesulfonic acid), add 0.2 mL of isopropyl acetate, and stir at 50°C for 2 hours, then cool to room temperature and stir for 2 days. After the suspension is centrifuged, the resulting solid is vacuum-dried at 50°C to obtain the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I), whose XRPD pattern is shown in Figure 48, and its analytical data are shown in Table 13 below.

[0332] Table 13

[0333] The obtained crystal form A of the ethanesulfonate of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 49 and 50.

[0334] A crystal form of the ethanesulfonate of the compound represented by formula (I) 1 The H NMR results are as follows:

[0335] 1H NMR (400MHz, DMSO-d6) δ12.13(s,1H),10.18(s,1H),7.96(d,J=8.5Hz,2H),7.47( s,1H),7.33(s,1H),7.23(d,J=2.1Hz,1H),7.07(dd,J=8.5,2.1Hz,1H),5.34(s,1H ),3.76(t,J=6.5Hz,4H),3.36(t,J=6.5Hz,2H),2.38(q,J=7.4Hz,3H),2.20(s,1H) ,2.14–1.94(m,3H),1.62(s,3H),1.23(s,4H),1.05(t,J=7.4Hz,3H),0.30(s,4H).

[0336] According to the NMR integration results, the salt ratio of the compound represented by formula (I) and ethanesulfonic acid was calculated to be 1:1.0.

[0337] Example 15 Preparation and Characterization of Form B of the Ethysulfonate Salt of the Compound Represented by Formula (I)

[0338] 1 g of the crystal form D of the compound represented by formula (I) obtained in Example 10 was weighed, 1.0 eq of ethanesulfonic acid (1 M ethanesulfonic acid ethyl acetate solution) was added, 10 mL of isopropyl acetate was added, and the mixture was stirred at 50° C. for 18 hours, then cooled to room temperature and stirred for 4 hours. After the suspension was centrifuged, the obtained solid was vacuum-dried at 50° C. to obtain the crystal form B of the ethanesulfonic acid salt of the compound represented by formula (I), whose XRPD spectrum is shown in FIG51 , and its analytical data are shown in Table 14 below.

[0339] Table 14

[0340] The obtained Form B of the ethanesulfonic acid salt of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 52 and 53.

[0341] The B crystal form of the ethanesulfonate of the compound represented by formula (I) 1 The H NMR results are as follows:

[0342] 1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.19(s,1H),8.02–7.78(m,2H),7.55(s,1H),7.39(s, 1H),7.24(d,J=2.1Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),5.41(s,1H),3.89(s,2H),3.77(t,J= 6.5Hz,2H),3.36(d,J=13.0Hz,2H),3.02(t,J=5.6Hz,4H),2.39(q,J=7.4Hz,3H),2.23(s,1H) ,2.07(d,J=10.0Hz,2H),1.59(s,3H),1.37–1.21(m,3H),1.06(t,J=7.4Hz,3H),0.31(s,4H).

[0343] According to the NMR integration results, the salt ratio of the compound represented by formula (I) and ethanesulfonic acid was calculated to be 1:1.0.

[0344] Example 16 Preparation and Characterization of Crystal Form A of the Hydrobromide Salt of the Compound Represented by Formula (I)

[0345] 50 mg of the crystalline form D of the compound represented by formula (I) obtained in Example 10 was weighed, 1.2 eq of hydrobromic acid (1 M hydrobromic acid ethyl ethyl solution) was added, 0.2 mL of isopropyl acetate was added, and the mixture was stirred at 50°C for 2 hours, then cooled to room temperature and stirred for 2 days. After the suspension was centrifuged, the obtained solid was vacuum-dried at 50°C to obtain the crystalline form A of the hydrobromide salt of the compound represented by formula (I), whose XRPD pattern is shown in Figure 54, and its analytical data are shown in Table 15 below.

[0346] Table 15

[0347] The obtained Form A of the hydrobromide salt of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 55 and 56.

[0348] A crystal form of the hydrobromide salt of the compound represented by formula (I) 1 The H NMR results are as follows:

[0349] 1H NMR (400MHz, DMSO-d6) δ12.09(s,1H),10.18(s,1H),7.93(t,J=13.0Hz,2H),7.53(s ,1H),7.38(s,1H),7.23(d,J=2.1Hz,1H),7.08(dd,J=8.5,2.0Hz,1H),5.39(s,1H), 3.87(s,2H),3.77(t,J=6.5Hz,3H),3.36(t,J=6.5Hz,2H),2.39(d,J=9.7Hz,1H),2. 22(s,1H),2.06(q,J=10.1,9.3Hz,2H),1.59(s,3H),1.37–1.20(m,4H),0.30(s,4H).

[0350] According to the ion chromatography results, the salt formation ratio of the compound represented by formula (I) and hydrobromic acid was calculated to be 1:1.1.

[0351] Example 17 Preparation and Characterization of Form B of the Hydrobromide Salt of the Compound Represented by Formula (I)

[0352] 50 mg of the crystalline form D of the compound represented by formula (I) obtained in Example 10 was weighed, 2.2 eq of hydrobromic acid (1 M hydrobromic acid ethyl ethyl solution) was added, 0.2 mL of isopropyl acetate was added, and the mixture was stirred at 50°C for 2 hours, then cooled to room temperature and stirred for 2 days. After the suspension was centrifuged, the resulting solid was vacuum-dried at 50°C to obtain the crystalline form B of the hydrobromide salt of the compound represented by formula I. Its XRPD pattern is shown in Figure 57, and its analytical data are shown in Table 16 below.

[0353] Table 16

[0354] The obtained Form B of the hydrobromide salt of the compound represented by formula (I) was subjected to DSC and TGA tests, and the spectra are shown in Figures 58 and 59.

[0355] The B crystal form of the hydrobromide salt of the compound represented by formula (I) 1 The H NMR results are as follows:

[0356] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.21(s,1H),7.94(d,J=8.5Hz,1H),7.82–7.60(m, 2H),7.48(t,J=7.8Hz,1H),7.24(d,J=2.2Hz,1H),7.09(dd,J=8.5,2.1Hz,1H),5.50(s,1H) ,4.00(s,1H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),2.45(d,J=9.2Hz,1H),2.28(d, J=13.3Hz,1H),2.12(dd,J=14.1,9.8Hz,2H),1.54(s,4H),1.38–1.11(m,3H),0.31(s,4H).

[0357] According to the ion chromatography results, the salt formation ratio of the compound represented by formula (I) and hydrobromic acid was calculated to be 1:2.1.

[0358] Summary of properties of different salt types

[0359] Table 17

[0360] Example 18 Biological Evaluation

[0361] (1) Test name: KIF18A enzyme activity assay

[0362] (2) Operation steps:

[0363] 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.

[0364] 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%.

[0365] 3) Seal the reaction plate with sealing film and centrifuge at 1000g for 1 minute.

[0366] 4) Prepare 2× enzyme solution using 1× reaction buffer.

[0367] 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.

[0368] 6) Prepare 2× ATP solution using 1× reaction buffer.

[0369] 7) Add 5 μL of 2× ATP solution to the reaction plate and centrifuge at 1000 g for 1 minute to start the reaction.

[0370] 8) React at room temperature for 60 minutes.

[0371] 9) Add 10 μL of ADP Glo reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

[0372] 10) Add 20 μL of kinase assay reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

[0373] 11) Centrifuge at 1000g for 1 minute.

[0374] 12) Read the luminescence signal on Envision 2104.

[0375] (3) Data analysis:

[0376] The percentage inhibition was calculated as follows:

[0377] %inhibition=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100

[0378] Signalcmpd: Average value of test compounds on the reaction plate.

[0379] SignalAve_PC: Average value of positive control (AM-5308) on the reaction plate.

[0380] SignalAve_VC: Average value of negative control (DMSO) on the reaction plate.

[0381] (4) Calculate IC 50 And fitting compound dose-effect curve:

[0382] GraphPad 8.0 was used to obtain the IC values ​​of the compounds using a nonlinear fitting formula. 50 .

[0383] Quality control: Z factor>0.5; S / B>2.

[0384] (5) Experimental results: IC of the compound KIF18A represented by formula (I) 50 is 5.35nM.

[0385] Example 19 Evaluation of Moisture Absorption

[0386] DVS tests were performed on the sodium salt of the compound represented by Formula (I), Form A, hydrochloride, Form B, hydrochloride, Form A, methanesulfonate, p-toluenesulfonate, maleate, and ethanesulfonate, Form A, to evaluate their hygroscopicity. The results are shown in Figures 24-35 and 60. The results show:

[0387] During adsorption, Form A of the sodium salt gained approximately 13.87% at 80% humidity. During desorption, Form A gained approximately 27.30% at 80% humidity and approximately 0.42% at 50% humidity. DVS testing revealed no change in the crystal form of Form A.

[0388] During adsorption, Form A of the hydrochloride salt gained approximately 1.12% weight at 80% humidity. During desorption, Form A lost approximately 3.31% weight at 80% humidity and approximately 3.55% weight at 50% humidity. DVS testing revealed that Form A of the hydrochloride salt transformed into Form B of the hydrochloride salt.

[0389] During adsorption, Form B of the hydrochloride salt gained approximately 4.16% weight at 80% humidity. During desorption, Form B gained approximately 4.67% weight at 80% humidity and approximately 0.01% weight at 50% humidity. DVS testing revealed no change in the hydrochloride salt's Form B crystalline form.

[0390] During adsorption, Form A of the p-toluenesulfonate salt gained approximately 0.87% weight at 80% humidity. During desorption, Form A gained approximately 0.85% weight at 80% humidity and lost approximately 0.06% weight at 50% humidity. DVS testing revealed no change in the crystal form of Form A.

[0391] During adsorption, Form A of the mesylate salt gained approximately 0.50% weight at 80% humidity. During desorption, Form A gained approximately 6.39% weight at 80% humidity and lost approximately 0.44% weight at 50% humidity. DVS testing revealed no change in the crystalline form of Form A.

[0392] During adsorption, Form A of the maleate salt gained approximately 0.86% weight at 80% humidity. During desorption, Form A gained approximately 2.17% weight at 80% humidity and approximately 1.39% weight at 50% humidity. DVS testing of Form A of the maleate salt revealed changes in its crystalline form.

[0393] The weight of Form B of the ethanesulfonate salt increased by about 3.3% at 80% humidity during the adsorption process; and by about 3.4% at 80% humidity and by about 2.1% at 50% humidity during the desorption process.

[0394] Example 20 Solubility Test in Biological Media and Water

[0395] The dynamic solubility of the compound represented by formula (I) as p-toluenesulfonate crystal A, methanesulfonate crystal A and ethanesulfonate crystal B was determined in three biological media (FaSSIF, FeSSIF and FaSSGF) and water. The preparation process of the biological medium is shown in Table 18 below. Samples of different salt forms were added to the biological medium and water and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5h, 2h and 24h, respectively. The sampled solutions were filtered with a 0.22μm water filter membrane. Some samples with higher concentrations were appropriately diluted with diluents, and 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 24h supernatant was taken to test its pH value.

[0396] Table 18 Preparation process of biological medium

[0397] The results in Table 19 show that the 24-hour solubility of Form A of the p-toluenesulfonate salt in biological media and water is as follows: FaSSGF > water > FeSSIF > FaSSIF. The 24-hour solubility of Form A of the methanesulfonate salt in biological media and water is as follows: FaSSGF > water > FeSSIF ≈ FaSSIF.

[0398] Table 19

[0399] Example 21 Stability Test

[0400] The stability of Form A of the p-toluenesulfonate salt and Form A of the methanesulfonate salt of the compound represented by Formula (I) was studied under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated (40°C / 75% RH) conditions. Samples were taken for XRPD and HPLC characterization after 7 days and 15 days, respectively. The results are shown in Table 20, and the XRPD patterns are shown in Figures 36 and 37.

[0401] The stability of Form B of the ethanesulfonate salt of the compound represented by Formula (I) was studied under conditions of high temperature (60°C), high humidity (25°C / 92.5% RH), and light (25°C / 4500 Lux). Samples were taken for XRPD and HPLC characterization at 7 days and 14 days, respectively. The results are shown in Table 20.

[0402] The results showed that Form A of the p-toluenesulfonate salt did not undergo a phase transition under high temperature and accelerated conditions for 15 days, and its purity may have slightly increased due to the degradation of some impurities. Form A of the methanesulfonate salt did not undergo a phase transition under high temperature, accelerated conditions for 15 days, and its chemical purity did not change significantly. Form A of the ethanesulfonate salt did not undergo a phase transition under high temperature, accelerated conditions for 15 days, and its chemical purity did not change significantly. Form B of the ethanesulfonate salt did not undergo a phase transition under high temperature, high humidity, and accelerated conditions for 14 days, and its chemical purity did not change significantly.

[0403] Table 20

[0404] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A pharmaceutically acceptable salt of a compound represented by formula (I), wherein The pharmaceutically acceptable salt is one or more selected from the group consisting of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate, methanesulfonate, ethanesulfonate and hydrobromide of the compound represented by formula (I); 2. The pharmaceutically acceptable salt according to claim 1, wherein In the p-toluenesulfonate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the p-toluenesulfonic acid molecule is 1:1.8 to 1:2.5, for example, 1:1.9, 1:2, 1:2.1 or 1:2.2; In the hydrochloride of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrogen chloride is 1:0.4 to 1:2.5, for example, 1:0.7, 1:1.5 or 1:1.7; In the maleate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to maleic acid is 1:0.9 to 1:1.3, for example, 1:1; In the sodium salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to sodium ions is 1:1.8 to 1:2.5, for example, 1:1.9; In the methanesulfonate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to the methanesulfonic acid molecule is 1:0.9 to 1:2.5, for example, 1:1.1 or 1:2; In the ethanesulfonate salt of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to ethanesulfonic acid is 1:0.9 to 1:1.3, for example, 1:1, 1:1.1 or 1:1.2; In the hydrobromide of the compound represented by formula (I), the molar ratio of the compound represented by formula (I) to hydrogen bromide is 1:0.9 to 1:2.5, for example, 1:1.1 or 1:2.

1.

3. A crystal of a pharmaceutically acceptable salt of the compound represented by formula (I) according to claim 1-2, wherein The crystals include the crystal form A of the sodium salt of the compound represented by formula (I), the crystal form A of the potassium salt of the compound represented by formula (I), the crystal form A of the hydrochloride of the compound represented by formula (I), the crystal form B of the hydrochloride of the compound represented by formula (I), the crystal form C of the hydrochloride of the compound represented by formula (I), the crystal form D of the hydrochloride of the compound represented by formula (I), the crystal form A of the p-toluenesulfonate of the compound represented by formula (I), the crystal form A of the methanesulfonate of the compound represented by formula (I), the crystal form B of the methanesulfonate of the compound represented by formula (I), the crystal form A of the maleate of the compound represented by formula (I), the crystal form A of the ethanesulfonate of the compound represented by formula (I), the crystal form B of the ethanesulfonate of the compound represented by formula (I), the crystal form A of the hydrobromide of the compound represented by formula (I), and the crystal form B of the hydrobromide of the compound represented by formula (I).

4. The crystal according to claim 3, wherein The crystal form A of the sodium salt of the compound represented by formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.0±0.20°, 5.3±0.20°, 6.2±0.20°, 7.0±0.20°, 16.1±0.20°, 18.3±0.20°, 18.7±0.20°, and 20.0±0.20°; further, it also has characteristic peaks at 10.0±0.20°, 12.1±0.20°, 13.5±0.20°, 13.9±0.20°, 16.9±0.20°, 17.8±0.20°, 18.0±0.20° and / or 19.4±0.20°; Preferably, the Form A of the sodium salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG3 ; The A crystal form of the potassium salt of the compound represented by the formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.0±0.20°, 5.4±0.20°, 6.1±0.20°, 6.6±0.20°, 10.0±0.20°, 16.0±0.20°, and 18.8±0.20°; further, the X-ray powder diffraction pattern of the potassium salt of the compound represented by the formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 12.1±0.20°, 14.0±0.20°, 16.5±0.20°, 16.9±0.20°, 17.2±0.20°, 17.9±0.20°, 18.3±0.20° and / or 20.0±0.20° having characteristic peaks; further, also having characteristic peaks at 7.0±0.20°, 8.5±0.20°, 9.2±0.20°, 11.0±0.20°, 13.6±0.20°, 14.6±0.20°, 14.9±0.20°, 15.3±0.20°, 19.5±0.20° and / or 21.3±0.20°; Preferably, the Form A of the potassium salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG6 ; The crystal form A of the hydrochloride of the compound represented by formula (I) has characteristic peaks at 6.3±0.20°, 12.6±0.20°, 19.0±0.20°, and 19.5±0.20° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; further, characteristic peaks may also be present at 14.1±0.20°, 16.3±0.20°, and / or 28.4±0.20°; Preferably, the crystalline form A of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG9 ; The B crystal form of the hydrochloride of the compound represented by the formula (I) has characteristic peaks at 17.7±0.20°, 18.4±0.20°, 20.4±0.20°, 21.1±0.20° and 23.2±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles; further, the characteristic peaks are at 15.1±0.20°, 16.1±0.20°, 27.6±0.20° and / or 32 .7±0.20°; further, there are characteristic peaks at 10.4±0.20°, 12.8±0.20°, 24.6±0.20°, 25.7±0.20°, 30.2±0.20°, 32.1±0.20°, 33.1±0.20°, 35.6±0.20°, 37.1±0.20°, 38.3±0.20° and / or 43.6±0.20°; Preferably, the Form B of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG12 ; The C crystal form of the hydrochloride of the compound represented by the formula (I) has characteristic peaks at 16.6±0.20°, 18.8±0.20°, 20.7±0.20°, 22.2±0.20°, 23.0±0.20° and 24.8±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles; further, the C crystal form of the hydrochloride of the compound represented by the formula (I) has characteristic peaks at 3.1±0.20°, 8.3±0.20°, 12.2±0.20°, 15.2 ± 0.20°, 17.5 ± 0.20°, 19.4 ± 0.20°, 22.7 ± 0.20° and / or 29.9 ± 0.20°; further, characteristic peaks are also present at 2.3 ± 0.20°, 5.2 ± 0.20°, 7.3 ± 0.20°, 10.4 ± 0.20°, 21.5 ± 0.20°, 25.5 ± 0.20°, 27.8 ± 0.20° and / or 31.6 ± 0.20°; Preferably, the Form C of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 39; The D crystal form of the hydrochloride of the compound represented by the formula (I) has characteristic peaks at 8.2±0.20°, 16.3±0.20°, 19.3±0.20°, 20.1±0.20°, 20.9±0.20° and 27.0±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles; further, the D crystal form of the hydrochloride of the compound represented by the formula (I) has characteristic peaks at 13.3±0.20°, 15.1±0.20°, 18.2±0.20°, 2 2.5 ± 0.20°, 23.2 ± 0.20°, 24.8 ± 0.20° and / or 28.2 ± 0.20° have characteristic peaks; further, also have characteristic peaks at 5.7 ± 0.20°, 8.8 ± 0.20°, 9.6 ± 0.20°, 10 ± 0.20°, 10.5 ± 0.20°, 11.2 ± 0.20°, 12.4 ± 0.20°, 24 ± 0.20° and / or 26.1 ± 0.20°; Preferably, the D crystalline form of the hydrochloride salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 42; The crystalline form A of the maleate salt of the compound represented by formula (I) has characteristic peaks at 7.7±0.20°, 18.6±0.20°, 19.4±0.20°, 19.9±0.20° and 20.2±0.20° using Cu-Kα radiation; further, the crystalline form A has characteristic peaks at 11.4±0.20°, 13.8±0.20°, 14.9±0.20°, 15.4±0.20°, 15.6±0.20°, 21.1±0.20°, 25.4±0.20° and / or 27.9±0.20°; Preferably, the crystalline form A of the maleate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG21 .

5. The crystal according to claim 3, wherein The crystal form A of the p-toluenesulfonate salt of the compound represented by formula (I) has characteristic peaks at 7.7±0.20°, 8.3±0.20°, 15.8±0.20°, (17.3-17.6)±0.20°, 20.0±0.20°, 20.6±0.20° and 21.8±0.20° using Cu-Kα radiation and expressed in 2θ angles; For example, the crystalline form A of the p-toluenesulfonate salt of the compound represented by the formula (I) uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.7±0.20°, 8.3±0.20°, 15.8±0.20°, 17.3±0.20°, 20.0±0.20°, 20.6±0.20° and 21.8±0.20°; further, it also has characteristic peaks at 15.5±0.20°, 17.6±0.20° and / or 18.7±0.20°; further, it also has characteristic peaks at 6.2±0.20°, 7.1±0.20° and 8. , 12.0±0.20°, 12.4±0.20°, 14.1±0.20°, 14.7±0.20°, 15.3±0.20°, 16.7±0.20°, 18.3±0.20°, 18.9±0.20°, 19.2±0.20°, 19.7±0.20°, 21.2±0.20°, 21.5±0.20°, 22.1±0.20°, 23.1±0.20°, 23.5±0.20°, 24.3±0.20°, 26.9±0.20° and / or 28.7±0.20° have characteristic peaks; Preferably, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG15 ; Preferably, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 6; Preferably, the weight loss of the p-toluenesulfonate salt of the compound represented by formula (I) in the crystal form A at room temperature to 140° C. is 0.5 to 5%; Preferably, the p-toluenesulfonate salt of the compound represented by formula (I) in form A has an endothermic peak with an onset temperature of 205-210°C and a peak temperature of 210.5-215°C; Preferably, the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) has a DSC and TGA overlay diagram substantially as shown in FIG16 .

6. The crystal according to claim 3, wherein The crystal form A of the methanesulfonate of the compound represented by the formula (I) has characteristic peaks at 14.3±0.20°, 18.5±0.20°, 18.6±0.20°, 20.4±0.20°, 21.5±0.20° and 21.6±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles; further, the crystal form A also has characteristic peaks at 18.7±0.20°, 18.9±0.20°, 20.0±0.20°, 21.0±0.20°, 2 °, 22.0±0.20° and / or 23.0±0.20° have characteristic peaks; further, there are characteristic peaks at 7.1±0.20°, 10.8±0.20°, 11.4±0.20°, 14.0±0.20°, 14.8±0.20°, 16.2±0.20°, 17.9±0.20°, 22.3±0.20°, 22.8±0.20°, 24.0±0.20° and / or 27.8±0.20°; Preferably, the crystalline form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG18 ; Preferably, the crystalline form A of the methanesulfonate salt of the compound represented by formula (I) has an XRPD analysis pattern substantially as shown in Table 7; Preferably, the weight loss of Form A of the methanesulfonate of the compound represented by formula (I) at room temperature to 145° C. does not exceed 0.3%, for example, does not exceed 0.1%; Preferably, the crystal form A of the methanesulfonate of the compound represented by formula (I) has an endothermic peak with an onset temperature of 210-213°C and a peak temperature of 213.5-216°C; for example, the onset temperature is 212.7°C and the peak temperature is 214.3°C; Preferably, the crystalline form A of the methanesulfonate salt of the compound represented by formula (I) has a DSC and TGA overlay substantially as shown in FIG19 ; The crystalline form B of the methanesulfonate of the compound represented by formula (I) has characteristic peaks at 16.9±0.20°, 20.3±0.20°, 21±0.20° and 28.5±0.20° using Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles; further, it also has characteristic peaks at 8.5±0.20°, 15.4±0.20°, 17.4±0.20° and / or 18.6±0.20°; further, it also has characteristic peaks at 10.4±0.20°, 11.4±0.20°, 12.7±0.20°, 14.5±0.20°, 23.1±0.20°, 24.3±0.20°, 25.6±0.20°, 30.1±0.20° and / or 31.1±0.20°; Preferably, the Form B of the methanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in FIG. 45 .

7. The crystal according to claim 3, wherein The crystalline form A of the ethanesulfonate salt of the compound represented by the formula (I) has characteristic peaks at 15.1±0.20°, 16.8±0.20°, 19.8±0.20° and 20.5±0.20° using Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles further has characteristic peaks at 8.3±0.20°, 22.6±0.20°, 23.6±0.20°, 27.2±0.20° and / or 28.2±0.20°; further, the crystalline form A has characteristic peaks at 10.3±0.20°, 12.4±0.20°, 18.1±0.20°, 25.0±0.20°, 29.7±0.20° and / or 30.5±0.20°; Preferably, the crystalline form A of the ethanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 48; The crystalline form B of the ethanesulfonate salt of the compound represented by formula (I) has characteristic peaks at 8.5±0.20°, 15.2±0.20° and 17.5±0.20° using Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles; further, it also has characteristic peaks at 20.8±0.20°, 22.8±0.20° and / or 23.6±0.20°; further, it also has characteristic peaks at 9.9±0.20°, 10.8±0.20°, 14.7±0.20°, 19.0±0.20°, 19.5±0.20°, 21.4±0.20°, 22.1±0.20°, 24.9±0.20° and / or 26.8±0.20°; Preferably, the crystalline form B of the ethanesulfonate salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 51; Preferably, the weight loss of the ethanesulfonic acid salt of the compound represented by formula (I) in form B at room temperature to 160° C. is 1.3 to 2.3%; Preferably, the ethylsulfonate salt of the compound represented by formula (I) in Form B has one or two of the following endothermic peaks: Endothermic peak 1: The onset temperature is 15-20°C and the peak temperature is 50-55°C; for example, the onset temperature is 17.23°C and the peak temperature is 52.50°C; Endothermic peak 2: the onset temperature is 215-220°C, and the peak temperature is 221-225°C; for example, the onset temperature is 218.89°C and the peak temperature is 222.29°C; 8. The crystal according to claim 3, wherein The A-type hydrobromide salt of the compound represented by the formula (I) has characteristic peaks at 15.6±0.20°, 20.9±0.20°, 25.5±0.20° and 28.2±0.20° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angles; further, the X-ray powder diffraction at 8.0±0.20°, 11.4±0.20°, 17.0±0.20°, 17.6 ± 0.20°, 24.5 ± 0.20°, 26.4 ± 0.20° and / or 29.9 ± 0.20°; further, characteristic peaks are also present at 6.9 ± 0.20°, 10.5 ± 0.20°, 14.2 ± 0.20°, 18.6 ± 0.20°, 22.8 ± 0.20°, 23.5 ± 0.20° and / or 31.6 ± 0.20°; Preferably, the crystalline form A of the hydrobromide salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 54; The B crystal form of the hydrobromide salt of the compound represented by the formula (I) has characteristic peaks at 4.5±0.20°, 6.4±0.20°, 11.9±0.20°, 17.4±0.20°, 18.3±0.20°, 22.0±0.20° and 23.8±0.20° using Cu-Kα radiation and X-ray powder diffraction expressed in 2θ angles; further, the X-ray powder diffraction pattern of the compound represented by the formula (I) has characteristic peaks at 5.2±0.20°, 17.7±0.20°, 19.3±0.20°, 20.8±0.20° and / or 28.2±0.2 0° has a characteristic peak; further, also has a characteristic peak at 6.8±0.20°, 13.0±0.20°, 13.8±0.20°, 14.9±0.20°, 15.9±0.20°, 20.0±0.20°, 22.9±0.20°, 24.3±0.20°, 24.8±0.20°, 25.5±0.20°, 26.3±0.20°, 26.7±0.20°, 27.3±0.20°, 29.1±0.20° and / or 29.8±0.20°; Preferably, the Form B of the hydrobromide salt of the compound represented by formula (I) has an XRPD pattern substantially as shown in Figure 57.

9. A pharmaceutical composition, wherein The pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound represented by formula (I) according to any one of claims 1 to 2 or a crystal of the pharmaceutically acceptable salt according to any one of claims 3 to 8.

10. Use of the pharmaceutically acceptable salt according to any one of claims 1 to 2, the crystal of the pharmaceutically acceptable salt according to any one of claims 3 to 8, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating KIF18A-mediated disorders and / or diseases; Preferably, the drug is a KIF18A inhibitor; Preferably, the disease is cancer, including 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 the pharmaceutically acceptable salt of any one of claims 1 to 2, the pharmaceutically acceptable salt crystal of any one of claims 3 to 8, or the pharmaceutical composition of claim 9; Preferably, the disease is cancer, including bowel cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer or ovarian cancer.

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