Polymorph of usp1 inhibitor

Abstract

Provided in the present invention are a polymorph and salt form of a compound 2-(4-cyclopropyl-6-methoxypyrimidine-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azolin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-nitrile of formula (I). The polymorph and salt form provided by the present invention have good chemical stability and physical stability, low hygroscopicity, and are less affected by heat, humidity and illumination, thereby facilitating storage and preparation into formulations.

Description

Polymorphic form of a USP1 inhibitor Technical Field

[0001] The present invention discloses multiple crystal forms of a USP1 inhibitor and a preparation method thereof, as well as applications of the same in treating cancer diseases. Background Art

[0002] Ubiquitin is a small, highly conserved protein of 76 amino acids that is post-translationally conjugated to substrate proteins, including itself, through a three-step enzymatic reaction. The initial covalent attachment occurs primarily between the C-terminal glycine of ubiquitin and the ε-amino group of a lysine residue on the target protein. 1 Additional ubiquitin molecules can be attached to one of ubiquitin’s seven internal lysines, resulting in different ubiquitin chain topologies. The biological consequences of ubiquitination are determined by the length and linkage topology. Similar to other types of post-translational modifications, ubiquitination is a reversible process that is counterregulated by enzymes called deubiquitinating enzymes (DUBs), which catalyze the removal of ubiquitin from modified proteins. Importantly, dysfunction of ubiquitin-dependent signaling pathways has been implicated in various human diseases, suggesting that inhibition of ubiquitin pathway components represents a novel therapeutic target for drug discovery.

[0003] The ubiquitin-proteasome system offers additional opportunities for therapeutic intervention, potentially increasing specificity and improving clinical efficacy. The most obvious targets include enzymes involved in ubiquitin conjugation and deconjugation (i.e., ubiquitin ligases and DUBs), upstream processes of proteasome-mediated protein degradation. Among DUBs, ubiquitin-specific protease 1 (USP1) has emerged as an attractive anticancer target due to its involvement in regulating DNA damage response pathways. USP1 associates with UAF1 (USP1-associated factor 1) to form the heterodimeric USP1 / UAF1 complex, which is required for deubiquitinase activity. The USP1 / UAF1 complex has been shown to regulate tolerance to DNA cross-linker-induced DNA damage by deubiquitinating PCNA (proliferating cell nuclear antigen) 11 and FANCD2 (Fanconi anemia complementation group D2), proteins involved in translesion synthesis and Fanconi anemia pathways, respectively. Numerous studies have investigated this mechanism of action, but no USP1 inhibitors have been marketed. Therefore, the development of effective USP1 inhibitors for clinical use is urgently needed.

[0004] Patent PCT / CN2023 / 116528 discloses a small molecule inhibitor targeting USP1, specifically the USP1 target. Its structure is shown in Formula (I), and its chemical name is 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile. This small molecule inhibitor has strong cell proliferation inhibition activity and has demonstrated good tumor suppression activity and good tolerability in in vivo efficacy studies, suggesting potential for development into a clinical drug. Summary of the Invention

[0005] The present invention discloses a polymorph of a USP1 inhibitor, a preparation method thereof, and applications thereof in treating cancer diseases.

[0006] Specifically,

[0007] The present invention provides a crystalline form A of the compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile of formula (I), characterized in that, using Cu-Kα radiation, the crystalline form A has an X-ray powder diffraction pattern with characteristic peaks at 2θ values ​​of 6.31°, 9.21°, 11.55°, 13.55°, 16.80°, and 20.06°, and the 2θ error range is ±0.2°.

[0008] In some embodiments of the present invention, the above-mentioned crystalline form A is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 6.31°, 7.68°, 9.21°, 9.93°, 11.55°, 12.44°, 13.55°, 15.43°, 16.80°, 20.06°, 21.66°, 22.01°, 24.46°, and 25.23°, and the 2θ error range is ±0.2°.

[0009] In some embodiments of the present invention, the above-mentioned crystalline form A is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 5.52°, 6.31°, 7.68°, 9.21°, 9.93°, 10.86°, 11.55°, 12.44°, 12.59°, 13.55°, 14.71°, 15.43°, 16.80°, 20.06°, 20.95°, 21.66°, 22.01°, 24.46°, 25.23°, 25.80°, 26.17°, and 27.04°, and the 2θ error range is ±0.2°.

[0010] In some embodiments of the present invention, the above-mentioned crystal form A is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1.

[0011] In some embodiments of the present invention, the above-mentioned crystal form A is characterized in that the TGA-DSC spectrum of the crystal form A is shown in Figure 2.

[0012] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form A of the compound of formula (I) are shown in Table 1.

[0013] Table 1 XRPD diffraction peak analysis data of the crystal form A of the compound of formula (I)

[0014] The present invention provides a crystalline form B of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the crystalline form B has an X-ray powder diffraction pattern with characteristic peaks at 2θ values ​​of 5.83°, 6.18°, 10.91°, 11.59°, 14.06°, and 14.48°, and the 2θ error range is ±0.2°.

[0015] In some embodiments of the present invention, the above-mentioned crystal form B is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2θ values ​​of 5.83°, 6.18°, 9.11°, 10.91°, 11.59°, 12.48°, 13.25°, 14.06°, 14.48°, 15.85°, 17.38°, 20.85°, and 23.62°, and the 2θ error range is ±0.2°.

[0016] In some embodiments of the present invention, the above-mentioned crystal form B is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2θ values ​​of 5.83°, 6.18°, 7.88°, 9.11°, 10.55°, 10.91°, 11.59°, 12.48°, 12.93°, 13.25°, 14.06°, 14.48°, 15.85°, 17.38°, 19.93°, 20.37°, 20.85°, 23.15°, 23.62°, and 26.44°, and the 2θ error range is ±0.2°.

[0017] In some embodiments of the present invention, the above-mentioned Form B is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form B is shown in Figure 3.

[0018] In some embodiments of the present invention, the above-mentioned crystal form B is characterized in that the TGA-DSC spectrum of the crystal form B is shown in Figure 4.

[0019] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form B of the compound of formula (I) are shown in Table 2.

[0020] Table 2 XRPD diffraction peak analysis data of the crystal form B of the compound of formula (I)

[0021] The present invention provides a crystalline form W of a compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form W has characteristic peaks at 2θ values ​​of 10.54°, 11.81°, 21.52°, 21.84°, and 25.94°, and the 2θ error range is ±0.2°.

[0022] In some embodiments of the present invention, the above-mentioned crystal form W is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form W has characteristic peaks at 2θ values ​​of 7.91°, 10.54°, 11.47°, 11.81°, 15.96°, 17.85°, 18.09°, 18.28°, 20.45°, 21.52°, 21.84°, 24.93°, and 25.94°, and the 2θ error range is ±0.2°.

[0023] In some embodiments of the present invention, the above-mentioned crystal form W is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form W has characteristic peaks at 2θ values ​​of 7.91°, 8.19°, 10.54°, 11.17°, 11.47°, 11.81°, 13.65°, 15.96°, 16.20°, 17.85°, 18.09°, 18.28°, 18.48°, 19.33°, 20.45°, 20.98°, 21.52°, 21.84°, 24.93°, 25.94°, and 26.57°, and the 2θ error range is ±0.2°.

[0024] In some embodiments of the present invention, the above-mentioned crystal form W is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form W is shown in Figure 5.

[0025] In some embodiments of the present invention, the above-mentioned crystal form W is characterized in that the DSC spectrum of the crystal form W has an endothermic peak at about 253.5°C.

[0026] In some embodiments of the present invention, the above-mentioned crystal form W is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 6.

[0027] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form W of the compound of formula (I) are shown in Table 3.

[0028] Table 3 XRPD diffraction peak analysis data of the crystal form W of the compound of formula (I)

[0029] The present invention also provides a crystalline form C of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ values ​​of 6.27°, 6.91°, 7.60°, 14.25°, 15.28°, and 21.16°, and the 2θ error range is ±0.2°.

[0030] In some embodiments of the present invention, the above-mentioned crystal form C is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 6.27°, 6.91°, 7.60°, 9.35°, 11.73°, 12.61°, 13.90°, 14.25°, 14.44°, 15.28°, 16.86°, 17.29°, 21.16°, and 26.36°, and the 2θ error range is ±0.2°.

[0031] In some embodiments of the present invention, the above-mentioned crystal form C is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 6.27°, 6.91°, 7.60°, 9.35°, 11.73°, 12.61°, 13.90°, 14.25°, 14.44°, 15.28°, 16.86°, 17.29°, 19.00°, 21.16°, 21.46°, 23.06°, 23.30°, 24.40°, 26.36°, and 28.07°, and the 2θ error range is ±0.2°.

[0032] In some embodiments of the present invention, the above-mentioned crystal form C is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form C is shown in Figure 7.

[0033] In some embodiments of the present invention, the above-mentioned crystal form C is characterized in that the TGA-DSC spectrum of the crystal form C is shown in Figure 8.

[0034] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form C of the compound of formula (I) are shown in Table 4.

[0035] Table 4 XRPD diffraction peak analysis data of the compound of formula (I) Form C

[0036] The present invention also provides a crystalline form H of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ values ​​of 6.08°, 8.73°, 12.89°, 15.49°, 20.03°, and 20.26°, and the 2θ error range is ±0.2°.

[0037] In some embodiments of the present invention, the above-mentioned crystal form H is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form H has characteristic peaks at 2θ values ​​of 6.08°, 8.73°, 9.45°, 10.89°, 12.89°, 13.48°, 15.49°, 15.79°, 18.39°, 19.04°, 20.03°, 20.26°, 25.11°, and 25.43°, and the 2θ error range is ±0.2°.

[0038] In some embodiments of the present invention, the above-mentioned crystalline form H is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ values ​​of 6.08°, 7.70°, 8.73°, 9.16°, 9.45°, 10.89°, 12.22°, 12.89°, 13.48°, 14.47°, 15.49°, 15.79°, 16.51°, 18.39°, 19.04°, 20.03°, 20.26°, 23.37°, 24.54°, 25.11°, and 25.43°, and the 2θ error range is ±0.2°.

[0039] In some embodiments of the present invention, the above-mentioned crystal form H is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form H is shown in Figure 9.

[0040] In some embodiments of the present invention, the above-mentioned crystal form H is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 10.

[0041] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form H of the compound of formula (I) are shown in Table 5.

[0042] Table 5 XRPD diffraction peak analysis data of the compound of formula (I) Form H

[0043] The present invention also provides a crystalline form O of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 5.90°, 9.41°, 10.88°, 11.50°, 14.46°, and 23.38°, and the 2θ error range is ±0.2°.

[0044] In some embodiments of the present invention, the above-mentioned crystal form O is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form O has characteristic peaks at 2θ values ​​of 5.90°, 6.33°, 9.41°, 10.88°, 11.50°, 12.50°, 13.34°, 14.46°, 14.99°, 17.22°, 20.57°, 21.11°, 22.15°, 23.38°, and 26.91°, and the 2θ error range is ±0.2°.

[0045] In some embodiments of the present invention, the above-mentioned crystal form O is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form O has characteristic peaks at 2θ values ​​of 5.90°, 6.33°, 7.12°, 9.41°, 10.88°, 11.50°, 12.50°, 13.34°, 14.46°, 14.99°, 15.91°, 17.22°, 18.26°, 19.24°, 19.56°, 20.02°, 20.57°, 21.11°, 22.15°, 23.38°, 24.41°, 25.16°, and 26.91°, and the 2θ error range is ±0.2°.

[0046] In some embodiments of the present invention, the above-mentioned crystal form O is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form O is shown in Figure 11.

[0047] In some embodiments of the present invention, the above-mentioned crystal form O is characterized in that the TGA-DSC spectrum of the crystal form O is shown in Figure 12.

[0048] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form O of the compound of formula (I) are shown in Table 6.

[0049] Table 6 XRPD diffraction peak analysis data of the crystal form O of the compound of formula (I)

[0050] The present invention also provides a crystalline form Y of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Y has characteristic peaks at 2θ values ​​of 6.78°, 8.26°, 9.91°, 11.60°, 13.64°, and 16.74°, and the 2θ error range is ±0.2°.

[0051] In some embodiments of the present invention, the above-mentioned crystal form Y is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form Y has characteristic peaks at 2θ values ​​of 6.78°, 7.53°, 8.26°, 8.74°, 9.91°, 10.73°, 11.60°, 12.51°, 13.64°, 14.11°, 16.74°, 20.18°, 21.83°, and 23.65°, and the 2θ error range is ±0.2°.

[0052] In some embodiments of the present invention, the above-mentioned crystal form Y is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form Y is shown in Figure 13.

[0053] In some embodiments of the present invention, the above-mentioned crystal form Y is characterized in that the TGA-DSC spectrum of the crystal form Y is shown in Figure 14.

[0054] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form Y of the compound of formula (I) are shown in Table 7.

[0055] Table 7 XRPD diffraction peak analysis data of the crystal form Y of the compound of formula (I)

[0056] The present invention also provides a crystalline form S of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form S has characteristic peaks at 2θ values ​​of 5.58°, 15.69°, 16.49°, 16.70°, 17.99°, and 24.12°, and the 2θ error range is ±0.2°.

[0057] In some embodiments of the present invention, the above-mentioned crystal form S is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form S has characteristic peaks at 2θ values ​​of 5.58°, 13.06°, 13.58°, 13.75°, 14.59°, 15.32°, 15.69°, 16.49°, 16.70°, 17.99°, 19.39°, 23.39°, 23.67°, and 24.12°, and the 2θ error range is ±0.2°.

[0058] In some embodiments of the present invention, the above-mentioned crystal form S is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form S has characteristic peaks at 2θ values ​​of 5.58°, 7.77°, 9.61°, 13.06°, 13.58°, 13.75°, 14.59°, 15.32°, 15.69°, 16.49°, 16.70°, 17.99°, 19.39°, 20.24°, 20.37°, 21.60°, 22.78°, 23.39°, 23.67°, 24.12°, and 29.70°, and the 2θ error range is ±0.2°.

[0059] In some embodiments of the present invention, the above-mentioned crystal form S is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form S is shown in Figure 15.

[0060] In some embodiments of the present invention, the above-mentioned crystal form S is characterized in that the TGA-DSC spectrum of the crystal form S is shown in Figure 16.

[0061] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form S of the compound of formula (I) are shown in Table 8.

[0062] Table 8 XRPD diffraction peak analysis data of the crystal form S of the compound of formula (I)

[0063] The present invention also provides a crystalline form AB of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form AB has characteristic peaks at 2θ values ​​of 8.01°, 11.08°, 12.46°, 14.86°, and 16.15°, and the 2θ error range is ±0.2°.

[0064] In some embodiments of the present invention, the above-mentioned crystal form AB is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form AB has characteristic peaks at 2θ values ​​of 8.01°, 11.08°, 12.46°, 13.17°, 14.86°, 16.15°, 17.91°, 21.35°, 22.11°, 24.36°, 25.24°, 26.30°, 27.54°, 28.75°, and 36.52°, and the 2θ error range is ±0.2°.

[0065] In some embodiments of the present invention, the above-mentioned crystal form AB is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form AB is shown in Figure 17.

[0066] In some embodiments of the present invention, the above-mentioned crystal form AB is characterized in that the TGA-DSC spectrum of the crystal form AB is shown in Figure 18.

[0067] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form AB of the compound of formula (I) are shown in Table 9.

[0068] Table 9 XRPD diffraction peak analysis data of the compound of formula (I) crystalline form AB

[0069] The present invention also provides a crystalline form D of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 2θ values ​​of 5.35, 8.76, 10.78, 19.62, and 21.02, and the 2θ error range is ±0.2°.

[0070] In some embodiments of the present invention, the above-mentioned crystal form D is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values ​​of 5.35, 8.76, 10.78, 11.27, 12.34, 15.38, 16.24, 17.65, 19.62, 20.82, 21.02, and 21.75, and the 2θ error range is ±0.2°.

[0071] In some embodiments of the present invention, the above-mentioned crystal form D is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values ​​of 5.35, 8.76, 10.78, 11.27, 12.34, 13.88, 15.38, 16.24, 17.29, 17.65, 19.62, 20.82, 21.02, 21.33, 21.75, 22.30, 22.92, 25.41, 26.04, and 26.69, and the 2θ error range is ±0.2°.

[0072] In some embodiments of the present invention, the above-mentioned crystal form D is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form D is shown in Figure 19.

[0073] In some embodiments of the present invention, the above-mentioned crystal form D is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 20.

[0074] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form D of the compound of formula (I) are shown in Table 10.

[0075] Table 10 XRPD diffraction peak analysis data of the crystal form D of the compound of formula (I)

[0076] The present invention also provides a crystalline form G of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2θ values ​​of 4.88, 9.77, 14.73, 21.21, and 23.96, and the 2θ error range is ±0.2°.

[0077] In some embodiments of the present invention, the above-mentioned crystal form G is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.88, 9.77, 13.65, 14.73, 15.53, 15.92, 17.48, 19.27, 21.21, 21.76, 23.96, and 24.95, and the 2θ error range is ±0.2°.

[0078] In some embodiments of the present invention, the above-mentioned crystal form G is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.88, 6.51, 7.76, 9.77, 10.23, 13.65, 14.01, 14.73, 15.53, 15.92, 17.48, 19.27, 19.77, 20.20, 20.63, 21.21, 21.76, 23.96, 24.35, 24.95, and 27.84, and the 2θ error range is ±0.2°.

[0079] In some embodiments of the present invention, the above-mentioned crystal form G is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern is as shown in Figure 21.

[0080] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form G of the compound of formula (I) are shown in Table 11.

[0081] Table 11 XRPD diffraction peak analysis data of the compound of formula (I) Form G

[0082] The present invention also provides a crystalline form P of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the crystalline form P has an X-ray powder diffraction pattern with characteristic peaks at 2θ values ​​of 7.52, 9.54, 12.14, 13.87, 16.93, and 23.67, and the 2θ error range is ±0.2°.

[0083] In some embodiments of the present invention, the above-mentioned crystal form P is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.52, 8.56, 9.54, 10.64, 12.14, 13.87, 15.41, 16.93, 18.59, 20.59, 23.67, and 28.06, and the 2θ error range is ±0.2°.

[0084] In some embodiments of the present invention, the above-mentioned crystal form P is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 22.

[0085] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form P of the compound of formula (I) are shown in Table 12.

[0086] Table 12 XRPD diffraction peak analysis data of the crystal form P of the compound of formula (I)

[0087] The present invention also provides a crystalline form Q of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Q has characteristic peaks at 5.62, 10.34, 14.95, 17.90, 22.77, and 23.18, and the 2θ error range is ±0.2°.

[0088] In some embodiments of the present invention, the above-mentioned crystal form Q is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.62, 10.34, 12.17, 14.95, 16.83, 17.26, 17.90, 21.39, 21.77, 22.77, 23.18, and 25.52, and the 2θ error range is ±0.2°.

[0089] In some embodiments of the present invention, the above-mentioned crystal form Q is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.62, 8.38, 10.34, 10.99, 11.30, 12.17, 13.86, 14.95, 15.89, 16.83, 17.26, 17.90, 21.39, 21.77, 22.19, 22.40, 22.77, 23.18, 23.78, 25.52, 25.85, and 28.63, and the 2θ error range is ±0.2°.

[0090] In some embodiments of the present invention, the above-mentioned crystal form Q is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 23.

[0091] In some embodiments of the present invention, the above-mentioned crystal form Q is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 24.

[0092] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form Q of the compound of formula (I) are shown in Table 13.

[0093] Table 13 XRPD diffraction peak analysis data of the compound of formula (I) crystal form Q

[0094] The present invention also provides a crystalline form X of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form X has characteristic peaks at 2θ values ​​of 10.15, 10.75, 15.79, 20.99, 23.56, and 26.80, and the 2θ error range is ±0.2°.

[0095] In some embodiments of the present invention, the above-mentioned crystal form X is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.15, 10.75, 12.28, 13.80, 15.79, 16.45, 17.02, 17.97, 19.63, 20.99, 23.56, and 26.80, and the 2θ error range is ±0.2°.

[0096] In some embodiments of the present invention, the above-mentioned crystal form X is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.70, 10.15, 10.75, 11.05, 12.28, 12.90, 13.80, 14.60, 15.79, 16.45, 16.70, 17.02, 17.97, 19.63, 20.28, 20.49, 20.99, 22.71, 23.56, 24.07, 24.31, and 26.80, and the 2θ error range is ±0.2°.

[0097] In some embodiments of the present invention, the above-mentioned crystal form X is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 25.

[0098] In some embodiments of the present invention, the above-mentioned crystal form X is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 26.

[0099] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the above-mentioned crystal form X of the compound of formula (I) are shown in Table 14.

[0100] Table 14 XRPD diffraction peak analysis data of the crystal form X of the compound of formula (I)

[0101] The present invention provides a crystalline form E of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.42, 10.22, 15.52, 20.20, 20.57, and 24.97, and the 2θ error range is ±0.2°.

[0102] In some embodiments of the present invention, the above-mentioned crystal form E is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.42, 10.22, 12.13, 15.52, 18.71, 18.95, 20.20, 20.57, 22.52, 24.97, 26.24, and 27.84, and the 2θ error range is ±0.2°.

[0103] In some embodiments of the present invention, the above-mentioned crystal form E is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.42, 10.22, 12.13, 12.52, 13.63, 15.52, 15.84, 17.50, 18.01, 18.71, 18.95, 19.39, 20.20, 20.57, 21.11, 21.67, 22.52, 23.38, 24.97, 26.24, and 27.84, and the 2θ error range is ±0.2°.

[0104] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E using Cu-Kα radiation is shown in Figure 27.

[0105] In some embodiments of the present invention, the above-mentioned crystal form E is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 28.

[0106] The present invention provides a crystalline form F of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.08, 12.30, 15.50, 16.29, 19.88, and 27.07, and the 2θ error range is ±0.2°.

[0107] In some embodiments of the present invention, the above-mentioned crystal form F is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.08, 11.12, 12.30, 12.66, 15.50, 16.29, 19.88, 20.87, 22.66, 23.55, 24.48, and 27.07, and the 2θ error range is ±0.2°.

[0108] In some embodiments of the present invention, the above-mentioned crystal form F is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.08, 10.66, 11.12, 12.30, 12.66, 13.80, 15.00, 15.50, 16.29, 18.86, 19.88, 20.28, 20.87, 21.85, 21.98, 22.38, 22.66, 23.16, 23.55, 24.00, 24.48, and 27.07, and the 2θ error range is ±0.2°.

[0109] In some embodiments of the present invention, the above-mentioned crystal form F is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 29.

[0110] In some embodiments of the present invention, the above-mentioned crystal form F is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 30.

[0111] The present invention provides a crystalline form I of the compound of formula (Ⅰ) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.55, 10.23, 14.89, 16.82, 22.63, and 23.08, and the 2θ error range is ±0.2°.

[0112] In some embodiments of the present invention, the above-mentioned crystal form I is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.55, 9.64, 10.23, 10.96, 12.05, 14.89, 15.86, 16.82, 17.80, 22.09, 22.63, and 23.08, and the 2θ error range is ±0.2°.

[0113] In some embodiments of the present invention, the above-mentioned crystal form I is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.55, 8.33, 9.64, 10.23, 10.96, 12.05, 13.88, 14.89, 15.86, 16.82, 17.80, 18.59, 20.32, 21.41, 22.09, 22.63, 23.08, 25.79, 28.45, and 38.50, and the 2θ error range is ±0.2°.

[0114] In some embodiments of the present invention, the above-mentioned Form I uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 31.

[0115] The present invention provides a crystalline form J of the compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile of formula (I), characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.28, 8.96, 12.91, 21.51, 25.35, and 27.00, and the 2θ error range is ±0.2°.

[0116] In some embodiments of the present invention, the above-mentioned crystal form J is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.28, 8.96, 10.78, 12.91, 14.75, 16.42, 17.93, 20.14, 21.51, 23.36, 25.35, 27.00, and 30.72, and the 2θ error range is ±0.2°.

[0117] In some embodiments of the present invention, the above-mentioned crystal form J, using Cu-Kα radiation, has an X-ray powder diffraction pattern as shown in Figure 32.

[0118] The present invention provides a crystalline form K of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.79, 10.55, 10.82, 19.74, 22.43, and 24.05, and the 2θ error range is ±0.2°.

[0119] In some embodiments of the present invention, the above-mentioned crystal form K is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.79, 10.55, 10.82, 12.34, 17.41, 18.10, 18.43, 19.74, 22.43, 23.29, 24.05, and 25.88, and the 2θ error range is ±0.2°.

[0120] In some embodiments of the present invention, the above-mentioned crystal form K is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.79, 10.55, 10.82, 12.34, 14.41, 17.18, 17.41, 18.10, 18.43, 18.95, 19.74, 20.06, 22.43, 22.71, 23.29, 24.05, 24.58, 25.35, 25.88, 26.76, and 29.85, and the 2θ error range is ±0.2°.

[0121] In some embodiments of the present invention, the above-mentioned crystal form K is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern is as shown in Figure 33.

[0122] The present invention provides a crystalline form L of a compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.55, 11.48, 12.89, 17.44, 17.90, and 26.50, and the 2θ error range is ±0.2°.

[0123] In some embodiments of the present invention, the above-mentioned crystal form L is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.55, 11.48, 12.89, 15.19, 17.44, 17.90, 21.33, 23.23, 23.95, 25.37, 26.50, 27.75, and 29.18, and the 2θ error range is ±0.2°.

[0124] In some embodiments of the present invention, the above-mentioned crystal form L is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 34.

[0125] The present invention provides a crystalline form M of a compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 11.07, 12.46, 14.92, 16.08, 17.91, and 25.20, and the 2θ error range is ±0.2°.

[0126] In some embodiments of the present invention, the above-mentioned crystal form M is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.22, 11.07, 12.46, 13.13, 14.92, 16.08, 17.91, 20.66, 22.14, 23.58, 25.20, and 28.80, and the 2θ error range is ±0.2°.

[0127] In some embodiments of the present invention, the above-mentioned crystal form M is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.01, 10.22, 11.07, 12.46, 13.13, 14.92, 16.08, 17.91, 20.66, 22.14, 23.58, 24.35, 25.20, 27.56, 28.80, 31.44, and 36.49, and the 2θ error range is ±0.2°.

[0128] In some embodiments of the present invention, the above-mentioned crystal form M is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 35.

[0129] The present invention provides a crystalline form N of the compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile of formula (I), characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.74, 10.02, 12.96, 13.81, 14.30, and 15.66, and the 2θ error range is ±0.2°.

[0130] In some embodiments of the present invention, the above-mentioned crystal form N is characterized in that it uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.74, 10.02, 12.96, 13.81, 14.30, 15.66, 16.23, 17.70, 18.34, 19.64, 21.18, 23.11, and 23.63, and the 2θ error range is ±0.2°.

[0131] In some embodiments of the present invention, the above-mentioned crystal form N is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 36.

[0132] The present invention provides a crystalline form R of a compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.21, 15.84, 17.06, 21.11, 23.62, and 26.85, and the 2θ error range is ±0.2°.

[0133] In some embodiments of the present invention, the above-mentioned crystal form R is characterized in that it uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.21, 11.12, 12.93, 13.85, 14.66, 15.84, 17.06, 21.11, 22.79, 23.62, 24.38, and 26.85, and the 2θ error range is ±0.2°.

[0134] In some embodiments of the present invention, the above-mentioned crystal form R is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.21, 10.88, 11.12, 12.32, 12.93, 13.85, 14.37, 14.66, 15.84, 16.50, 17.06, 17.46, 19.69, 20.35, 20.55, 21.11, 22.79, 23.14, 23.62, 24.38, and 26.85, and the 2θ error range is ±0.2°.

[0135] In some embodiments of the present invention, the above-mentioned crystal form R is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 37.

[0136] The present invention provides a crystalline form T of the compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile of formula (I), characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 15.56, 20.33, 10.37, 20.62, 9.60, and 26.16, and the 2θ error range is ±0.2°.

[0137] In some embodiments of the present invention, the above-mentioned crystal form T is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 15.56, 20.33, 10.37, 20.62, 9.60, 26.16, 12.07, 25.16, 20.83, 16.13, 18.92, and 18.12, and the 2θ error range is ±0.2°.

[0138] In some embodiments of the present invention, the above-mentioned crystal form T is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 15.56, 20.33, 10.37, 20.62, 9.60, 26.16, 12.07, 25.16, 20.83, 16.13, 18.92, 18.12, 22.15, 23.46, 22.75, 10.90, 27.98, 21.12, 17.76, 17.30, and 18.68, and the 2θ error range is ±0.2°.

[0139] In some embodiments of the present invention, the above-mentioned crystal form T is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 38.

[0140] In some embodiments of the present invention, the above-mentioned crystal form T is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 39.

[0141] The present invention provides a crystalline form U of the compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile of formula (Ⅰ), characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.40, 10.07, 10.45, 21.03, 22.07, and 24.72, and the 2θ error range is ±0.2°.

[0142] In some embodiments of the present invention, the above-mentioned crystal form U is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.40, 10.07, 10.45, 12.17, 12.80, 14.72, 15.92, 18.70, 21.03, 22.07, 24.72, and 27.61, and the 2θ error range is ±0.2°.

[0143] In some embodiments of the present invention, the above-mentioned crystal form U is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.40, 10.07, 10.45, 12.17, 12.80, 14.40, 14.72, 15.06, 15.92, 16.58, 17.37, 18.03, 18.70, 19.51, 20.31, 21.03, 22.07, 22.84, 23.25, 24.72, and 27.61, and the 2θ error range is ±0.2°.

[0144] In some embodiments of the present invention, the above-mentioned crystal form U is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 40.

[0145] In some embodiments of the present invention, the above-mentioned crystal form U is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 41.

[0146] The present invention provides a crystalline form V of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.02, 11.59, 12.88, 13.07, 19.50, and 19.92, and the 2θ error range is ±0.2°.

[0147] In some embodiments of the present invention, the above-mentioned crystalline form V is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.02, 10.93, 11.59, 11.74, 12.18, 12.88, 13.07, 16.35, 18.23, 19.50, 19.92, and 23.45, and the 2θ error range is ±0.2°.

[0148] In some embodiments of the present invention, the above-mentioned crystalline form V is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.02, 8.12, 9.04, 9.50, 10.16, 10.51, 10.93, 11.59, 11.74, 12.18, 12.88, 13.07, 14.01, 16.35, 17.26, 18.23, 19.50, 19.92, 20.88, 23.11, 23.45, and 24.67, and the 2θ error range is ±0.2°.

[0149] In some embodiments of the present invention, the above-mentioned crystal form V is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 42.

[0150] In some embodiments of the present invention, the above-mentioned crystal form V is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 43.

[0151] The present invention provides a crystalline form Z of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.23, 15.60, 16.83, 23.48, 24.59, and 27.07, and the 2θ error range is ±0.2°.

[0152] In some embodiments of the present invention, the above-mentioned crystal form Z is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.23, 11.19, 12.79, 13.69, 14.67, 15.60, 16.83, 21.17, 22.88, 23.48, 24.59, and 27.07, and the 2θ error range is ±0.2°.

[0153] In some embodiments of the present invention, the above-mentioned crystal form Z is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.23, 10.83, 11.19, 12.18, 12.79, 13.69, 14.36, 14.67, 15.60, 16.32, 16.83, 17.51, 19.81, 20.36, 20.65, 21.17, 22.60, 22.88, 23.48, 23.88, 24.59, and 27.07, and the 2θ error range is ±0.2°.

[0154] In some embodiments of the present invention, the above-mentioned crystal form Z is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 44.

[0155] In some embodiments of the present invention, the above-mentioned crystal form Z is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 45.

[0156] The present invention provides a crystalline form AA of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.37, 9.10, 10.24, 13.04, 16.69, and 21.69, and the 2θ error range is ±0.2°.

[0157] In some embodiments of the present invention, the above-mentioned crystalline form AA is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.37, 9.10, 10.24, 10.90, 13.04, 13.75, 14.99, 16.69, 21.69, 23.69, 25.54, and 27.20, and the 2θ error range is ±0.2°.

[0158] In some embodiments of the present invention, the above-mentioned crystalline form AA is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.37, 9.10, 10.24, 10.90, 11.98, 13.04, 13.46, 13.75, 14.99, 16.69, 19.40, 20.01, 20.35, 21.69, 22.90, 23.69, 25.54, 27.20, 28.18, and 30.95, and the 2θ error range is ±0.2°.

[0159] In some embodiments of the present invention, the above-mentioned crystal form AA is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 46.

[0160] In some embodiments of the present invention, the above-mentioned crystal form AA is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 47.

[0161] The present invention provides a crystalline form AD of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.84, 10.16, 11.37, 13.51, 17.33, and 19.93, and the 2θ error range is ±0.2°.

[0162] In some embodiments of the present invention, the above-mentioned crystal form AD is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.84, 7.94, 10.16, 11.37, 12.71, 13.51, 14.47, 17.33, 19.93, 23.18, 24.00, and 26.68, and the 2θ error range is ±0.2°.

[0163] In some embodiments of the present invention, the above-mentioned crystal form AD is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.84, 7.94, 10.16, 11.37, 11.74, 12.71, 13.51, 14.47, 15.99, 17.33, 19.93, 20.73, 21.77, 22.22, 23.18, 24.00, 25.07, 25.65, 26.68, 27.94, and 34.57, and the 2θ error range is ±0.2°.

[0164] In some embodiments of the present invention, the above-mentioned crystal form AD is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 48.

[0165] The present invention provides a crystalline form AE of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.42, 11.42, 16.04, 18.10, 21.69, and 25.60, and the 2θ error range is ±0.2°.

[0166] In some embodiments of the present invention, the above-mentioned crystal form AE is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.35, 10.42, 10.79, 11.42, 12.91, 14.72, 16.04, 16.91, 18.10, 20.49, 21.69, and 25.60, and the 2θ error range is ±0.2°.

[0167] In some embodiments of the present invention, the above-mentioned crystal form AE is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.35, 5.52, 10.42, 10.79, 11.42, 12.02, 12.91, 14.72, 16.04, 16.91, 17.46, 18.10, 19.02, 20.49, 21.69, 22.57, 25.09, 25.60, and 30.92, and the 2θ error range is ±0.2°.

[0168] In some embodiments of the present invention, the above-mentioned crystal form AE is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 49.

[0169] The present invention provides a crystalline form AF of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.69, 9.39, 13.45, 22.03, 23.43, and 23.67, and the 2θ error range is ±0.2°.

[0170] In some embodiments of the present invention, the above-mentioned crystal form AF is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.69, 9.39, 12.42, 13.45, 15.57, 17.77, 19.84, 20.28, 22.03, 23.43, 23.67, and 28.84, and the 2θ error range is ±0.2°.

[0171] In some embodiments of the present invention, the above-mentioned crystal form AF is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.69, 9.39, 11.31, 12.42, 12.69, 13.45, 14.69, 14.88, 15.57, 17.54, 17.77, 18.28, 19.84, 20.28, 22.03, 22.83, 23.43, 23.67, 24.20, 28.22, and 28.84, and the 2θ error range is ±0.2°.

[0172] In some embodiments of the present invention, the above-mentioned crystal form AF is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 50.

[0173] Specifically, the present disclosure provides a p-toluenesulfonate salt of a compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to the p-toluenesulfonic acid is 1:1.

[0174] In some embodiments of the present disclosure, the above-mentioned p-toluenesulfonate is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate has characteristic peaks at 2θ values ​​of 15.41, 19.65, 19.92, 21.30, and 22.75, and the 2θ error range is ±0.2°.

[0175] In some embodiments of the present disclosure, the above-mentioned p-toluenesulfonate is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate has characteristic peaks at 2θ values ​​of 8.53, 8.82, 13.16, 13.46, 14.19, 15.41, 19.65, 19.92, 21.30, 22.15, 22.75, and 26.37, and the 2θ error range is ±0.2°.

[0176] In some embodiments of the present disclosure, the above-mentioned p-toluenesulfonate is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate has characteristic peaks at 2θ values ​​of 6.18, 8.53, 8.82, 13.16, 13.46, 14.19, 15.41, 17.25, 18.41, 18.85, 19.65, 19.92, 20.94, 21.30, 21.62, 22.15, 22.75, 25.76, 26.37, and 30.14, and the 2θ error range is ±0.2°.

[0177] In some embodiments of the present disclosure, the p-toluenesulfonate is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate is as shown in FIG1 .

[0178] In some embodiments of the present disclosure, the XRPD diffraction peak analysis data of the p-toluenesulfonate salt of the compound of formula (I) are shown in Table 15.

[0179] Table 15 XRPD diffraction peak analysis data of p-toluenesulfonate salt of compound of formula (I)

[0180] The present disclosure provides a maleate salt of the compound of formula (I), 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to p-maleic acid is 1:1.

[0181] In some embodiments of the present disclosure, the maleate salt is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the maleate salt has characteristic peaks at 2θ values ​​of 5.93, 7.65, 14.67, 17.05, and 19.79, and the 2θ error range is ±0.2°.

[0182] In some embodiments of the present disclosure, the maleate salt is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.93, 7.65, 10.58, 13.50, 14.67, 17.05, 18.94, 19.79, 20.92, 23.38, 23.63, and 23.98, and the 2θ error range is ±0.2°.

[0183] In some embodiments of the present disclosure, the maleate salt is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 3.28, 3.56, 3.71, 3.76, 3.80, 4.12, 4.24, 4.48, 4.68, 5.06, 5.20, 5.39, 5.75, 6.03, 6.31, 6.55, 7.54, 8.35, 11.54, and 14.88, and the 2θ error range is ±0.2°.

[0184] In some embodiments of the present disclosure, the maleate salt is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in FIG3 .

[0185] In some embodiments of the present disclosure, the XRPD diffraction peak analysis data of the maleate salt of the compound of formula (I) are shown in Table 16.

[0186] Table 16 XRPD diffraction peak analysis data of maleate salt of compound of formula (I)

[0187] The present disclosure also provides a fumarate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to the fumaric acid is 1:1.

[0188] In some embodiments of the present disclosure, the above-mentioned fumarate is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the fumarate has characteristic peaks at 2θ values ​​of 6.76, 9.74, 10.98, 16.58, and 22.20, and the 2θ error range is ±0.2°.

[0189] In some embodiments of the present disclosure, the above-mentioned fumarate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.40, 6.76, 9.74, 10.98, 11.71, 12.99, 14.36, 16.58, 19.69, 21.45, 22.20, and 23.36, and the 2θ error range is ±0.2°.

[0190] In some embodiments of the present disclosure, the above-mentioned fumarate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.40, 6.76, 9.74, 10.98, 11.71, 12.99, 13.28, 14.36, 14.90, 16.58, 17.16, 17.89, 19.69, 21.45, 22.20, 23.36, 24.50, 25.21, 27.30, and 28.62, and the 2θ error range is ±0.2°.

[0191] In some embodiments of the present disclosure, the fumarate salt is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in FIG4 .

[0192] In some embodiments of the present disclosure, the XRPD diffraction peak analysis data of the fumarate salt of the compound of formula (I) are shown in Table 17.

[0193] Table 17 XRPD diffraction peak analysis data of the fumarate salt of the compound of formula (I)

[0194] The present disclosure provides a citrate salt of a compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to citric acid is 1:1.

[0195] In some embodiments of the present disclosure, the above-mentioned citrate is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the citrate has characteristic peaks at 2θ values ​​of 6.85, 10.84, 13.83, 19.51, and 25.48, and the 2θ error range is ±0.2°.

[0196] In some embodiments of the present disclosure, the above-mentioned citrate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.85, 10.84, 11.64, 13.83, 16.29, 17.97, 19.15, 19.51, 24.70, 25.48, 25.91, and 27.19, and the 2θ error range is ±0.2°.

[0197] In some embodiments of the present disclosure, the above-mentioned citrate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.85, 10.84, 11.64, 13.83, 14.18, 15.39, 16.29, 16.55, 17.97, 19.15, 19.51, 20.30, 21.06, 24.06, 24.70, 25.48, 25.91, 27.19, 27.58, and 27.95, and the 2θ error range is ±0.2°.

[0198] In some embodiments of the present disclosure, the citrate salt is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in FIG4 .

[0199] In some embodiments of the present disclosure, the XRPD diffraction peak analysis data of the citrate salt of the compound of formula (I) are shown in Table 18.

[0200] Table 18 XRPD diffraction peak analysis data of the citrate salt of the compound of formula (I)

[0201] The present disclosure also provides a succinate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to succinic acid is 1:1.

[0202] In some embodiments of the present disclosure, the above-mentioned succinate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.74, 17.20, 19.05, 20.01, and 21.11, and the 2θ error range is ±0.2°.

[0203] In some embodiments of the present disclosure, the above-mentioned succinate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.74, 10.60, 13.63, 14.11, 14.85, 16.64, 17.20, 19.05, 20.01, 21.11, 23.91, and 24.28, and the 2θ error range is ±0.2°.

[0204] In some embodiments of the present disclosure, the above-mentioned succinate is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.74, 10.60, 13.63, 14.11, 14.63, 14.85, 16.47, 16.64, 17.20, 17.45, 18.39, 18.80, 19.05, 20.01, 21.11, 21.72, 23.26, 23.91, 24.28, and 26.94, and the 2θ error range is ±0.2°.

[0205] In some embodiments of the present disclosure, the succinate salt is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is as shown in FIG5 .

[0206] In some embodiments of the present disclosure, the XRPD diffraction peak analysis data of the succinate salt of the compound of formula (I) are shown in Table 19.

[0207] Table 19 XRPD diffraction peak analysis data of succinate salt of compound of formula (I)

[0208] The present invention also provides a pharmaceutical composition comprising any of the above crystal forms and a pharmaceutically acceptable carrier.

[0209] The present invention also provides use of any of the above-mentioned crystal forms and pharmaceutical compositions in the preparation of drugs for treating USP1-mediated cancers.

[0210] The present invention also provides use of any of the above-mentioned crystal forms and pharmaceutical compositions for treating USP1-mediated cancers.

[0211] In some embodiments of the present invention, the above-mentioned cancers include ovarian cancer and breast cancer.

[0212] The present invention also provides a method for preparing the crystal form W, comprising the following steps:

[0213] (a) dissolving the compound of formula (I) in a first solvent;

[0214] (b) adding a second solvent to the solution of step (a) and stirring for a certain period of time;

[0215] (c) After the solid precipitates, it is collected by filtration and dried.

[0216] In some embodiments of the present invention, the first solvent in the above preparation method is selected from one or more mixtures of acetone, butanone, methyl isobutyl ketone, methanol, ethanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, and dimethyl sulfoxide.

[0217] In some embodiments of the present invention, the first solvent in the above preparation method is selected from one or more mixtures of acetone, butanone, ethyl formate, methyl acetate, ethyl acetate, and 2-methyltetrahydrofuran.

[0218] In some embodiments of the present invention, the first solvent in the above preparation method is selected from one or more mixtures of tetrahydrofuran, 1,4-dioxane, dichloromethane, and dimethyl sulfoxide.

[0219] In some embodiments of the present invention, the second solvent in the above preparation method is selected from one or more mixtures of water, n-heptane, acetonitrile, and methyl tert-butyl ether.

[0220] In some embodiments of the present invention, the second solvent in the above preparation method is selected from one or more mixtures of n-heptane, cyclohexane, and n-pentane.

[0221] In some embodiments of the present invention, the second solvent in the above preparation method is selected from one or more mixtures of methyl tert-butyl ether and methylcyclohexane.

[0222] Technical Effects

[0223] The crystal form in the present application has good chemical stability, physical stability and low hygroscopicity, is less affected by temperature, humidity and light, and is convenient for storage and formulation development.

[0224] Definition and Description

[0225] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0226] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

[0227] It is well known in the art that X-ray powder diffraction patterns have one or more measurement errors depending on slight changes in measurement conditions. The structures of the crystals, crystals or crystal forms disclosed or claimed in the present invention may exhibit similar but not identical analytical characteristics within a reasonable error range depending on the experimental conditions, purity, equipment and other constant variables known to those skilled in the art. For example, the diffraction angle (2θ) in powder X-ray powder diffraction generally produces an error within the range of ±0.20°. Therefore, the present invention not only includes crystals with completely consistent diffraction angles in powder X-ray powder diffraction, but also includes crystals with consistent diffraction angles within the error range of ±0.20°. The crystalline form of the compound of formula (I) of the present invention is not limited to crystals having an X-ray powder diffraction pattern identical to the X-ray powder diffraction pattern shown in the accompanying drawings. Any crystal having an X-ray powder diffraction pattern substantially identical to that shown in the accompanying drawings falls within the scope of the present invention.

[0228] The “X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in the accompanying drawings” appearing herein. It should be understood that the term “substantially identical” as used in this context is also intended to indicate that the 2θ angle values ​​of the X-ray powder diffraction pattern may have slight variations due to the inherent experimental variations associated with such measurements, and both are of the same crystalline form.

[0229] It should be understood that using different types of equipment or different testing conditions may produce slightly different DSC patterns and endothermic transition temperature readings. DSC data can reflect changes in the form of a substance. Strong endothermic peaks can indicate dehydration or desolvation, crystallization, or melting. When reflecting a molten state, the corresponding temperature is generally understood to be the melting point. This value will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the testing equipment. Those skilled in the art will understand that the temperature at which a substance transitions from a solid state to a liquid state typically falls within a temperature range, not a fixed point. Therefore, the temperature corresponding to the endothermic peak or the melting point can be represented by the onset value, peak value, or other reasonable value. The maximum endothermic transition temperature of a crystalline form can be within ±5.0°C, preferably ±2.0°C, of ​​the specific values ​​disclosed above. For example, if a DSC spectrum has an endothermic peak around 253.5°C, it means that the endothermic peak is at 253.5°C + 5.0°C, preferably 253.5°C + 2.0°C.

[0230] The present invention also uses thermogravimetric analysis (TGA) to analyze the relationship between the degree of decomposition, sublimation, and evaporation (weight loss) of the crystal form and temperature. It should be understood that the values ​​obtained for the same crystal form may be affected by factors such as sample purity, particle size, different equipment types, and different testing methods, resulting in certain errors. The temperature at which the crystal form decomposes, sublimates, or evaporates can be within the range of ±3.0°C, for example, ±2.0°C, of ​​the specific values ​​disclosed above.

[0231] The "stability" of a crystal form includes "chemical stability" and / or "physical stability." "Chemical stability" refers to the degree to which a crystal form degrades under certain conditions of temperature, humidity, and light. "Chemical stability" reflects the stability of a crystal form under storage conditions. "Physical stability" refers to the degree to which a crystal form undergoes solid-state transformation under certain conditions, such as conversion to another crystal form under conditions of high temperature, high humidity, grinding, tableting, desolvation, or solvent adsorption. Therefore, "physical stability" can, to a certain extent, reflect the stability of a crystal form during use, such as during formulation.

[0232] The crystalline structures of the present invention can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing the crystalline structure from a solvent mixture include evaporation of the solvent, lowering the temperature of the solvent mixture, seeding of a supersaturated solvent mixture of the molecule and / or salt, lyophilization of the solvent mixture, addition of an antisolvent to the solvent mixture, and the like.

[0233] The term "drying" refers to the process of removing the solvent from the obtained solid, including but not limited to natural drying at room temperature, high temperature drying, vacuum drying, etc.

[0234] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0235] In the examples of this invention, the title compound names were derived from the compound structures using ChemDraw. If the compound name and structure are inconsistent, the structure can be determined by integrating relevant information and reaction routes. If other methods are unavailable for confirmation, the given compound structure will prevail.

[0236] The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0237] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0238] Instruments and analytical methods:

[0239] 1. X-ray powder diffraction (XRPD)

[0240] Solid samples were analyzed using an X-ray powder diffractometer (Aeris). An appropriate amount of sample powder was placed in the groove of the sample holder and pressed into a flat and dense surface using a glass sheet. The XRPD measurement parameters are shown in Table 20.

[0241] Table 20 XRPD test parameters

[0242] 2. Simultaneous thermal analysis (TGA-DSC)

[0243] Alternatively, use a Mettler Toledo simultaneous thermal analyzer for thermogravimetric and differential scanning calorimetry analysis of solids. Use a small spoon to place an appropriate amount of the sample into a crucible, ensuring it is evenly spread. Weigh the crucible, heat the sample according to the parameters listed in Table 21, and analyze the data using STARe.

[0244] Table 21 TGA-DSC analysis method parameters

[0245] 3. H NMR spectroscopy ( 1 H-NMR)

[0246] 1 H-NMR measurements were performed using a Bruker AVANCE NEO 400 nuclear magnetic resonance instrument, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d6).

[0247] 4. Dynamic moisture adsorption and desorption analysis (DVS)

[0248] The hygroscopicity of the samples was measured using a DVS Intrinsic dynamic moisture sorption instrument. The samples were placed in a tared sample basket and automatically weighed. The samples were analyzed according to the parameters in Table 22.

[0249] Table 22 DVS analysis method parameters

[0250] 5. Dissolution

[0251] The dissolution rate was determined according to the dissolution and release rate determination method in the Chinese Pharmacopoeia 2020 edition 0931. The test conditions are as follows: Description of the drawings:

[0252] Figure 1 is the XRPD spectrum of Form A of the compound of formula (I).

[0253] Figure 2 is a TGA-DSC spectrum of Form A of the compound of formula (I).

[0254] Figure 3 is the XRPD spectrum of Form B of the compound of formula (I).

[0255] Figure 4 is a TGA-DSC spectrum of Form B of the compound of formula (I).

[0256] Figure 5 is the XRPD spectrum of Form W of the compound of formula (I).

[0257] Figure 6 is a TGA-DSC spectrum of Form W of the compound of formula (I).

[0258] Figure 7 is an XRPD spectrum of Form C of the compound of formula (I).

[0259] FIG8 is a TGA-DSC spectrum of Form C of the compound of formula (I).

[0260] Figure 9 is an XRPD spectrum of Form H of the compound of formula (I).

[0261] Figure 10 is a TGA-DSC spectrum of Form H of the compound of formula (I).

[0262] Figure 11 is the XRPD spectrum of Form O of the compound of formula (I).

[0263] FIG12 is a TGA-DSC spectrum of Form O of the compound of formula (I).

[0264] Figure 13 is the XRPD spectrum of Form Y of the compound of formula (I).

[0265] FIG14 is a TGA-DSC spectrum of Form Y of the compound of formula (I).

[0266] Figure 15 is an XRPD spectrum of Form S of the compound of formula (I).

[0267] Figure 16 is a TGA-DSC spectrum of Form S of the compound of formula (I).

[0268] Figure 17 is an XRPD spectrum of Form AB of the compound of formula (I).

[0269] Figure 18 is a TGA-DSC spectrum of Form AB of the compound of formula (I).

[0270] Figure 19 is the XRPD spectrum of Form D of the compound of formula (I).

[0271] Figure 20 is a TGA-DSC spectrum of Form D of the compound of formula (I).

[0272] Figure 21 is the XRPD spectrum of Form G of the compound of formula (I).

[0273] Figure 22 is the XRPD spectrum of Form P of the compound of formula (I).

[0274] Figure 23 is the XRPD spectrum of Form Q of the compound of formula (I).

[0275] Figure 24 is a TGA-DSC spectrum of Form Q of the compound of formula (I).

[0276] Figure 25 is the XRPD spectrum of Form X of the compound of formula (I).

[0277] Figure 26 is a TGA-DSC spectrum of Form X of the compound of formula (I).

[0278] Figure 27 is the XRPD spectrum of Form E of the compound of formula (I).

[0279] Figure 28 is a TGA-DSC spectrum of Form E of the compound of formula (I).

[0280] Figure 29 is an XRPD spectrum of Form F of the compound of formula (I).

[0281] Figure 30 is a TGA-DSC spectrum of Form F of the compound of formula (I).

[0282] Figure 31 is the XRPD spectrum of Form I of the compound of formula (I).

[0283] Figure 32 is the XRPD spectrum of Form J of the compound of formula (I).

[0284] Figure 33 is the XRPD spectrum of Form K of the compound of formula (I).

[0285] Figure 34 is the XRPD spectrum of Form L of the compound of formula (I).

[0286] Figure 35 is the XRPD spectrum of Form M of the compound of formula (I).

[0287] Figure 36 is the XRPD spectrum of Form N of the compound of formula (I).

[0288] Figure 37 is the XRPD spectrum of Form R of the compound of formula (I).

[0289] Figure 38 is the XRPD spectrum of Form T of the compound of formula (I).

[0290] Figure 39 is a TGA-DSC spectrum of Form T of the compound of formula (I).

[0291] Figure 40 is the XRPD spectrum of Form U of the compound of formula (I).

[0292] Figure 41 is a TGA-DSC spectrum of Form U of the compound of formula (I).

[0293] Figure 42 is the XRPD spectrum of Form V of the compound of formula (I).

[0294] Figure 43 is a TGA-DSC spectrum of Form V of the compound of formula (I).

[0295] Figure 44 is the XRPD spectrum of Form Z of the compound of formula (I).

[0296] Figure 45 is a TGA-DSC spectrum of Form Z of the compound of formula (I).

[0297] Figure 46 is the XRPD spectrum of the crystalline form AA of the compound of formula (I).

[0298] Figure 47 is a TGA-DSC spectrum of Form AA of the compound of formula (I).

[0299] Figure 48 is the XRPD spectrum of Form AD of the compound of formula (I).

[0300] Figure 49 is the XRPD spectrum of Form AE of the compound of formula (I).

[0301] Figure 50 is the XRPD spectrum of Form AF of the compound of formula (I).

[0302] Figure 51 is the XRPD spectrum of the p-toluenesulfonate salt of the compound of formula (I).

[0303] Figure 52 is the XRPD spectrum of the maleate salt of the compound of formula (I).

[0304] Figure 53 is the XRPD spectrum of the fumarate salt of the compound of formula (I).

[0305] Figure 54 is the XRPD spectrum of the citrate salt of the compound of formula (I).

[0306] Figure 55 is the XRPD spectrum of the succinate salt of the compound of formula (I).

[0307] Figure 56 shows the tumor growth of mice in groups G1 to G4 in Test Example 4 of Example 2 of the present application;

[0308] Figure 57 shows the changes in body weight of mice in groups G1 to G4 in Test Example 4 of Example 2 of the present application.

[0309] Figure 58 shows the DVS spectrum of Form W

[0310] Figure 59 shows the DVS spectrum of Form D

[0311] Figure 60 shows the dissolution data of Form D and Form W DETAILED DESCRIPTION

[0312] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any way. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0313] Example 1: Preparation of the compound of formula (I)

[0314] Step A: Dissolve 5-bromo-2-chloropyrimidin-4-amine (108 g, 518 mmol) in 1,4-dioxane / water (2119 mL / 235 mL) at room temperature under nitrogen. Then, add 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (150 g, 570 mmol), sodium carbonate (110 g, 1036 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38 g, 46.6 mmol) sequentially to the solution. The reaction mixture is stirred at 90°C for 16 hours.

[0315] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure. The resulting residue was slurried with ethyl acetate / petroleum ether, and the resulting filter cake was slurried again with acetonitrile / water to obtain 94.6 g of a crude product of 4-(4-amino-2-chloropyrimidin-5-yl)-3-chlorobenzonitrile.

[0316] MS (ESI) M / Z: 265.0 [M+H] + .

[0317] Step B: 4-(4-amino-2-chloropyrimidin-5-yl)-3-chlorobenzonitrile (94.6 g, 358 mmol) was dissolved in 1,4-dioxane / water (1394 mL / 232 mL) at room temperature under nitrogen. (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (69.5 g, 358 mmol), cesium carbonate (233 g, 716 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (36.5 g, 46.5 mmol) were then added to the solution. The reaction was stirred at 90°C for 16 hours.

[0318] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and concentrated under reduced pressure. The resulting residue was slurried with ethyl acetate / petroleum ether, and the filter cake was rinsed with water and dried to obtain 118 g of crude 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indole-7-carbonitrile.

[0319] MS (ESI) M / Z: 343.2 [M+H] + .

[0320] Step C: Dissolve 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9H-pyrimido[4,5-b]indole-7-carbonitrile (53.8 g, 157.2 mmol) in N,N-dimethylformamide (436 mL) at room temperature. Cesium carbonate (114 g, 349.2 mmol) and 9-(chloromethyl)-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine (26.2 g, 87.3 mmol) were then added to the reaction. The reaction was stirred at 45°C for 16 hours.

[0321] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to water (900 mL) to precipitate a solid, which was purified by silica gel column chromatography to give 20.42 g of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile.

[0322] MS (ESI) M / Z: 607.2 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ9.82 (s, 1H), 8.72 (s, 1H), 8.59 (d, J = 8.4Hz, 1H), 8.50 (s, 1H), 7.9 6(d,J=0.8Hz,1H),7.86(dd,J=8.0,1.2Hz,1H),7.62(d,J=8.0Hz,1H),7.41(d,J=0.8Hz,1 H),7.33(dd,J=8.0,1.6Hz,1H),5.81(s,2H),3.95(t,J=6.8Hz,2H),3.87(s,3H),2.60(t, J=7.0Hz,2H),2.27-2.15(m,2H),1.77-1.67(m,1H),1.10-1.02(m,2H),0.88-0.77(m,2H).

[0324] Example 2 Biological Test Evaluation:

[0325] Test Example 1 USP1 enzyme activity test method

[0326] 1. Experimental plan:

[0327] USP1 enzyme activity assay was used to screen USP1i compounds.

[0328] 1.1 Experimental Materials: Recombinant human His6-USP1 / His6-UAF1 complex protein (R&D, catalog number E-568-050); Ubiquitin Rhodamine 110 (Ub-Rho) (R&D, catalog number U-555-050); Fluorescence 384-well plate (Perkin Elmer, catalog number 6007279).

[0329] 1.2 Test sample: Compound of formula (I), whose structural formula and preparation method are shown in the above examples.

[0330] 1.3 Experimental process:

[0331] (1) Prepare 1× assay buffer (modified Tris buffer, components: 50 mM Tris-HCl (pH 7.8) (Sigma, Catalog No.: T2569-1L), 0.01% Tween-20 (Sigma, Catalog No.: P2287-100ML), 1 mM DTT (Sigma, Catalog No.: D0632-10G), 0.01% BSA (Sigma, Catalog No.: B2064-100G), 0.5 mM EDTA (Invitrogen, Catalog No.: 15575020)).

[0332] (2) Compound dilution: Use dimethyl sulfoxide (DMSO, 100% purity) to prepare a 10 mM (mol / L) solution of the test compound; dilute the test compound solution 3-fold to 10 concentrations, with the highest concentration being 10 mM; transfer the diluted test compound solution to a fluorescent 384-well plate using an Echo acoustic pipetting system, with two replicate wells set for each concentration, and the final DMSO concentration is 1 vol%; the final concentrations of the test compound solution are 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM, and 0.5 nM.

[0333] (3) Prepare enzyme solution: Prepare enzyme solution in 1× assay buffer.

[0334] (4) Prepare substrate solution: Add ubiquitin rhodamine 110 (Ub-Rho) to 1× detection buffer to form a substrate solution.

[0335] (5) Transfer 10 μL of the enzyme solution prepared in step (3) to a fluorescent 384-well plate.

[0336] (6) Incubate at room temperature for 1 hour.

[0337] (7) Add 10 μL of the substrate solution prepared in step (4) to each well to start the reaction. The final reaction system is 200 nL of the test compound + 10 uL of the enzyme solution + 10 uL of the substrate solution. The final concentration of the enzyme is 0.05 nM, and the final concentration of the substrate solution is 300 nM. Centrifuge for 30 s and shake for 30 s.

[0338] (8) The plate was read on a SpectraMax Paradigm multifunctional microplate reader for 30 minutes with an excitation wavelength of 480 nm and an emission wavelength of 540 nm.

[0339] (9) Collect data on SpectraMax Paradigm.

[0340] (10) Curve fitting:

[0341] The data were fitted in Excel using equation (I) to obtain inhibition values;

[0342] Equation (I): Inhibition rate % = (maximum signal value - target signal value) / (maximum signal value - minimum signal value) × 100;

[0343] Among them, the maximum signal value represents the luminescent signal intensity of the positive control well without the compound of the present application; the minimum signal value represents the luminescent signal intensity of the negative control well without the enzyme; and the target signal value represents the luminescent signal intensity of the test compound.

[0344] Fit the data in XL-Fit using equation (II) to obtain IC 50 value;

[0345] Equation (II): Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)×HillSlope)

[0346] Where Y is the inhibition percentage, X is the compound concentration; Bottom is the lowest inhibition rate; Top is the highest inhibition rate; HillSlope is the slope.

[0347] 2. Experimental results:

[0348] The results show that the compound of formula (I) has a good inhibitory effect on USP1. The results are shown in Table 23.

[0349] Table 23 Enzyme inhibition results

[0350] 3. Conclusion:

[0351] It can be seen from the above experimental results that the compound of formula (I) has a good inhibitory effect on USP1 and is an effective USP1 inhibitor.

[0352] Test Example 2 USP1 CTG Test Method

[0353] 1. Experimental Plan

[0354] The in vitro biological activity of USP1i compounds was verified using the NCI-H1693 cell killing assay.

[0355] 1.1 Experimental Materials:

[0356] NCI-H1693 cells were purchased from ATCC (Cat. No. CRL-5866) and cultured in a 37°C, 5% CO2 (containing 5% CO2 and 95% air) cell culture incubator; 1640 complete medium: 94wt% RPMI-1640 liquid medium (Gibco Cat. No. 11875-093), 5wt% FBS (Gibco Cat. No. 10099-141), 1wt% Pen Strep (Gibco Cat. No. 15070-063); fluorescent 384-well plates (Perkin Elmer, Cat. No. 6007279); trypsin (Gibco Cat. No. 25200056); CTG buffer ( 2.0 Cell Viability Assay, Promega, Catalog No.: G9241).

[0357] 1.2 Test sample:

[0358] The compound of formula (I), its structural formula and preparation method are shown in the above examples;

[0359] The structural formula of comparative compound 1 is:

[0360] The structural formula of comparative compound 2 is:

[0361] 1.3 Experimental process:

[0362] (1) 75cm 2 NCI-H1693 cells in a culture flask were digested with 2 mL of trypsin for 2-3 minutes, then neutralized with 2 mL of 1640 complete medium. Centrifuged at 1200 rpm for 5 minutes. The supernatant was removed and the cell pellet was resuspended in 4 mL of 1640 complete medium. 500 μL of the cell suspension was collected and counted using a Vi-CELL-XR cell counter.

[0363] (2) Using a Multidrop instrument, 500 NCI-H1693 cells were seeded per well in a fluorescent 384-well plate (each well contained 40 μL of 1640 complete medium), and drugs were added after 24 hours.

[0364] (3) Using an ultra-micropipette, the test sample (concentration: 3.33 mM, dissolved in DMSO) was diluted with 10 uM as the highest starting concentration, and then diluted with 9 gradients (10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM) in a 1:3 ratio, and the drug was added. Two replicate wells were set for each concentration; 9 wells were set for positive control and blank control, with the positive control being the replicate wells of 10 μM positive compound and the blank control being the replicate wells of DMSO.

[0365] (4) After drug addition, the cells were placed in a 37°C, 5% CO2 (containing 5% CO2 by volume and the rest being air) incubator and cultured for 6 days. After 6 days, 25 μL of CTG buffer was added to each well for CTG detection, and the plate was read and analyzed using a microplate reader.

[0366] (5) Analyze the CTG readings:

[0367] The average inhibition rate of the positive control replicates was set as 100%;

[0368] The average value of negative control replicates was set as the relative inhibition rate of 0%.

[0369] The CTG readings were converted into relative inhibition rates, and the inhibition rates (inhibition %) of the compounds at various concentrations on cells were calculated according to the following formula.

[0370] Inhibition%=(bx) / (ba×100%;

[0371] a=CTG value (highest concentration well)

[0372] b=CTG value (blank control well)

[0373] x=CTG value(x nM)

[0374] (6) Using GraphPad PRISM 8 to analyze IC 50 Perform calculations.

[0375] The concentrations and inhibition rates corresponding to 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, and 1.5 nM were statistically analyzed and calculated using Log10 (compound concentration).

[0376] Enter the data into GraphPad PRISM 8, select "Analysis", select "Nonlinear regression (curve fit)", select "Log (inhibitor) vs. response-Variable slope", select the calculation formula, and calculate it according to the following formula:

[0377] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0378] X:Log10(compound concentration)

[0379] Y: corresponding response

[0380] Top and Bottom: corresponding responses with the same units as Y

[0381] Notice:

[0382] - If X is not already the logarithm of dose, go back and transform the data.

[0383] - If any base response is subtracted, clamp Bottom to a constant value of 0.0.

[0384] Fit the data to obtain IC 50 value.

[0385] Adjust the fitting conditions according to the specific data conditions. Make appropriate constraint adjustments to Bottom, Top, and HillSlope to achieve the curve that best fits the actual situation.

[0386] 2. Experimental results:

[0387] The inhibition results of the compounds in the examples of the present application on NCI-H1693 cells are shown in Table 24.

[0388] Table 24 NCI-H1693 cell inhibition results

[0389] 3. Conclusion:

[0390] It can be seen from the above experimental results that the compound of formula (I) of the present application has obvious cell inhibitory activity.

[0391] Test Example 3 Pharmacokinetic Determination of the Compound of the Application in Male Beagle Dogs

[0392] 1. Experimental plan:

[0393] Male Beagle dogs were used as test animals to study the pharmacokinetic characteristics of the compound of the present application in dog plasma after intravenous and oral administration. Plasma samples were collected at specific time points, and the compound concentration in plasma was detected by LC-MS / MS. DMPK parameters were calculated and the pharmacokinetic characteristics of the compound of the present application in dog plasma were evaluated.

[0394] 1.1 Experimental drugs:

[0395] The compound of formula (I), its structural formula and preparation method are shown in the above examples;

[0396] The structural formula of KSQ-4279 is:

[0397] 1.2 Experimental Animals

[0398] Male Beagle dogs, weighing 9-13kg, supplied by Beijing Mas Biotechnology Co., Ltd.

[0399] 1.3 Administration:

[0400] Dosing information for the compound of this application: 3 dogs each received IV injection (0.2 mg / kg in a 0.5 mL / kg volume) and PO administration (3 mg / kg in a 3 mL / kg volume). The dosing vehicle consisted of 5 vol% DMSO, 10 vol% Solutol (Kolliphor HS15), and 85 vol% saline.

[0401] 1.4 Sample collection:

[0402] After administration to the dogs, 0.5 mL of blood was collected from the cephalic vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the IV group and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the PO group. The blood was placed in EDTA-K2 tubes and centrifuged at 2000 g for 10 minutes at 2-8°C to separate plasma. The plasma was then stored at -80°C until sample analysis.

[0403] 1.5 Sample processing:

[0404] Canine plasma sample processing:

[0405] 1) 50 μL of plasma sample was added to 200 μL of acetonitrile for precipitation, vortexed for 30 seconds, and centrifuged at 3900 rpm at 4°C for 15 minutes.

[0406] 2) The supernatant after treatment was diluted 3-fold with water, and the concentration of the test compound was analyzed by LC / MS / MS.

[0407] 2. Experimental results:

[0408] Table 25

[0409] Note: In Table 25, “CL” is total clearance; “AUC last ” is the area under the plasma drug concentration-time curve from time 0 to the final quantifiable time point.

[0410] 3. Conclusion:

[0411] It can be seen from the above experimental results that the compound of formula (I) of the present application has obvious advantages in clearance rate level and drug exposure compared with the control compound.

[0412] Test Example 4: OV0589 transplant tumor model (PDX) efficacy experiment

[0413] 1. Experimental plan:

[0414] Female BALB / c nude mice were used as test animals. After oral administration of the compounds of the present application, tumors were measured and weighed regularly to investigate tumor growth inhibition and tolerance in different dosing groups. Plasma and tumor samples were collected at specific time points after the study for pharmacokinetic / pharmacodynamic (PK / PD) analysis.

[0415] 1.1 Experimental drugs:

[0416] The compound of formula (I), its structural formula and preparation method are shown in the above examples;

[0417] Compound KSQ4279 has the structural formula:

[0418] 1.2 Experimental Materials:

[0419] Tumor-bearing mouse tumor (R10P8) was purchased from Sino-US Crown Biotechnology (Beijing) Co., Ltd.; Ubiquityl-PCNA (Lys164) (D5C7P) mAb antibody was purchased from Cell Signaling, catalog number: 13439S; PCNA (PC10) antibody was purchased from Santa Cruz, catalog number: sc-56.

[0420] 1.3 Experimental Animals

[0421] Female BALB / c nude mice, weighing 21-25 g, supplier: Beijing Ankai Yibo Biotechnology Co., Ltd.

[0422] 2. Experimental steps:

[0423] Under the conditions of temperature 20-26℃, humidity 30-70%, and alternating light and day, the tumor (R10P8) of the tumor-bearing mice grew to a diameter of about 1 cm (the tumor size reached 50-800 mm). 3 ) when the tumor was collected and cut into pieces of about 2 to 3 mm 3 The tumor mass (R10P8) was inoculated subcutaneously in the right anterior scapula of female BALB / c nude mice. The tumor growth in the mice was regularly observed. 35 days after inoculation, when the tumor (R10P9) grew to an average volume of approximately 150 mm 3 (Inclusion range 86.54mm 3 ~262.96mm 3 ) According to the tumor size and mouse body weight, the mice were randomly divided into groups using StudyDirector™ (version 3.1.399.19, supplier: Studylog System, Inc., S. San Francisco, CA, USA), and the drugs were administered on the next day after grouping.

[0424] Twelve mice were randomly divided into four groups, namely G1 to G4. Group G1 was the vehicle control group, with the vehicle consisting of 10 vol% DMSO + 20 vol% Solutol + 70 vol% Water + 5 vol% DMSO + 10 vol% Solutol + 85 vol% Saline; Group G2 was orally administered with KSQ4279 at a dose of 100 mg / kg (mpk) in a vehicle consisting of 5 vol% DMSO + 10 vol% Solutol + 85 vol% Saline; Group G3 was orally administered with the compound of formula (I) at a dose of 30 mg / kg in a vehicle consisting of 10 vol% DMSO + 20 vol% Solutol + 70 vol% Water; and Group G4 was orally administered with the compound of formula (I) at a dose of 100 mg / kg in a vehicle consisting of 10 vol% DMSO + 20 vol% Solutol + 70 vol% Water.

[0425] The growth of tumors in mice was observed regularly, and the tumor volume was measured (see Figure 56 for the results). The weight changes of mice were also observed regularly (see Figure 57 for the results). After 36 days of administration, plasma and tumor samples were collected for PK / PD analysis.

[0426] PK assay The pharmacokinetic assay in mice was performed as described in the previous test example 3.

[0427] PD detection: Tumor samples were collected 8 hours after the last administration and divided into tumor samples weighing 50-100 mg. 1× tissue lysis buffer was prepared using ddH2O, and then 20uL of tissue lysis buffer (Cell Signaling Cell Lysis Buffer (10×) Catalog Number: #9803) was added per mg of sample. The tumor samples were ground using a tissue grinder. The ground tumor sample lysate was placed on ice for 30 minutes. Subsequently, centrifuged at 12000rpm and 4°C for 15 minutes. The sample supernatant was retained. The PD marker (Ubiquityl-PCNA / PCNA) in the sample was detected using a protein blotting assay.

[0428] 3. Experimental results:

[0429] Figure 56 shows the tumor growth of mice in groups G1 to G4. As can be seen from Figure 56, the best inhibitory effect on tumor growth was achieved with the compound of formula (I) (dosage: 100 mg / kg), followed by the compound of formula (I) (dosage: 30 mg / kg). The inhibitory effect of KSQ4279 (dosage: 100 mg / kg) on ​​tumor growth was significantly less than that achieved with the compound of formula (I) (dosage: 100 mg / kg) and the compound of formula (I) (dosage: 30 mg / kg). Figure 57 shows the weight changes of mice in groups G1 to G4. As can be seen from Figure 57, the weight changes of mice in groups G1 to G4 were all within the normal range and were well tolerated.

[0430] Table 26 shows the statistical results of tumor growth inhibition rate of mice in groups G2 to G4. It can be seen from Table 26 that the administration of compound of formula (I) (dosage of 100 mg / kg) has the best inhibitory effect on tumor growth, followed by the administration of compound of formula (I) (dosage of 30 mg / kg). The inhibitory effect of administration of KSQ4279 (dosage of 100 mg / kg) on ​​tumor growth is significantly inferior to that of administration of compound of formula (I) (dosage of 100 mg / kg) and administration of compound of formula (I) (dosage of 30 mg / kg).

[0431] Table 26 Statistical results of tumor growth inhibition rate

[0432] Note: "TGI%" is tumor growth inhibition rate; TGI% = [1-ΔT / C] × 100%, ΔT / C = (mean(T)-mean(T0)) / (mean(C)-mean(C0)), T and C are the average tumor volumes of the drug-treated group and the vehicle control group on the 38th day, respectively, and T0 and C0 are the average tumor volumes of the drug-treated group and the vehicle control group on the 0th day, respectively.

[0433] 4. Conclusion:

[0434] From the above data, it can be seen that compared with the control compound, the compound of the present application has obvious advantages in inhibiting tumor growth, and the dosage is significantly lower than that of the control compound.

[0435] Example 3 Preparation of Form A

[0436] To 1.032 g of the compound of formula (I) was added 4 mL of ethanol, the temperature was raised to 80°C, stirred for 1 h, cooled to room temperature, filtered, and dried under vacuum at 60°C for 14 h.

[0437] The obtained solid was subjected to XRPD and TGA-DSC test characterization, and the solid was Form A.

[0438] The XRPD spectrum is shown in Figure 1.

[0439] The TGA-DSC spectrum is shown in Figure 2.

[0440] Example 4 Preparation of Form B

[0441] 5 mL of methanol was added to 0.4942 g of the compound of formula (I) and the mixture was slurried at room temperature for 1 day. A sample was taken and dried under vacuum at 50° C. for 3 h.

[0442] The obtained solid was subjected to XRPD and TGA-DSC test characterization, and the solid was Form B.

[0443] The XRPD spectrum is shown in Figure 3.

[0444] The TGA-DSC spectrum is shown in Figure 4.

[0445] Example 5 Preparation of Form W:

[0446] To 0.0414 g of the compound of formula (I) was added 0.5 mL of butanone to dissolve the mixture. After filtration, 2 mL of n-heptane was slowly added dropwise to precipitate a solid, which was then dried under vacuum at 50° C. for 4 h.

[0447] The XRPD spectrum is shown in Figure 5.

[0448] The TGA-DSC spectrum is shown in Figure 6, which has an obvious endothermic peak at around 253.5°C.

[0449] Example 6 Preparation of Form C:

[0450] Weigh 0.4046 g of the compound of formula (I) into a vial, add 6 mL of ethyl acetate, and heat to 85°C to dissolve. Filter into a new vial, add 2 mL of n-heptane dropwise, and slurry at room temperature for 16 h. Filter and dry under vacuum at 50°C.

[0451] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form C.

[0452] The XRPD spectrum is shown in Figure 7.

[0453] The TGA-DSC spectrum is shown in Figure 8.

[0454] Example 7 Preparation of Form H:

[0455] 0.5 mL of purified water was added to 0.0106 g of Form A, and the mixture was slurried at room temperature for 17 h. Samples were taken for characterization.

[0456] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be Form H.

[0457] The XRPD spectrum is shown in Figure 9.

[0458] The TGA-DSC spectrum is shown in Figure 10.

[0459] Example 7 Preparation of Form O:

[0460] The wet product of Form C was vacuum dried at 50°C for 4 h and placed at room temperature for 2 days before sampling.

[0461] The obtained solid was subjected to XRPD and TGA-DSC test characterization, and the solid was crystal form O.

[0462] The XRPD spectrum is shown in Figure 11.

[0463] The TGA-DSC spectrum is shown in Figure 12.

[0464] Example 8 Preparation of Form Y:

[0465] Method 1:

[0466] To 0.0984 g of the compound of formula (I) was added 0.5 mL of acetone to dissolve the mixture. After filtration, 1 mL of purified water was slowly added dropwise to precipitate a solid, which was then dried under vacuum at 50° C. for 4 h.

[0467] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be Form Y.

[0468] The XRPD spectrum is shown in Figure 13.

[0469] The TGA-DSC spectrum is shown in Figure 14.

[0470] Method 2:

[0471] To 100 mg of the compound of formula (I) was added 1 mL of acetone, the solution was dissolved and filtered into a new vial, and water was slowly added dropwise. When solids were precipitated, samples were taken for testing.

[0472] The obtained solid was subjected to XRPD test and characterization, and the solid was crystal form Y.

[0473] Example 9 Preparation of Form S:

[0474] 0.0793 g of the compound of formula (I) was added to a mixed solvent of 2.6 mL of n-heptane and 1.4 mL of butanone, and the mixture was slurried at room temperature for 2 days. After centrifugation, the mixture was dried in vacuum at 50° C. for 6 h.

[0475] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form S.

[0476] The XRPD spectrum is shown in Figure 15.

[0477] The TGA-DSC spectrum is shown in Figure 16.

[0478] Example 10 Preparation of Form AB:

[0479] 1.5 mL of dichloromethane was added to 0.0997 g of the compound of formula (I) to dissolve it. After filtering, 1.5 mL of n-heptane was slowly added dropwise to precipitate a solid, which was dried under vacuum at 50°C for 4 h.

[0480] The obtained solid was subjected to XRPD and TGA-DSC test characterization, and the solid was crystal form AB.

[0481] The XRPD spectrum is shown in Figure 17.

[0482] The TGA-DSC spectrum is shown in Figure 18.

[0483] Example 11 Preparation of Form D

[0484] To 0.0306 g of Form A, 1 mL of ethyl acetate / n-heptane (1:1, v / v) and 11.2 L of choline aqueous solution (40% by mass) were added, and the mixture was stirred at room temperature for 1 day. XRD analysis of the sample indicated Form D.

[0485] Example 12 Preparation of Form E

[0486] 0.5 mL of methyl isobutyl ketone was added to 0.0130 g of Form A and the mixture was slurried at room temperature for one day. A sample was taken for XRD analysis and identified as Form E. H-NMR results showed the presence of 1.02 equivalents of methyl isobutyl ketone (14.4% by mass). TGA analysis revealed two weight loss periods of 5.6% and 12.4%, respectively. Form E is presumed to be a methyl isobutyl ketone solvate.

[0487] Example 13 Preparation of Form F

[0488] 0.0223 g of Form A was slurried in 0.5 mL of tetrahydrofuran / n-heptane (1:1, v / v) at room temperature for 4 days. A sample was taken for XRD analysis and identified as Form F. H-NMR analysis revealed the presence of 0.97 equivalents of tetrahydrofuran (10.3% by mass). TGA analysis revealed two weight loss periods of 8.1% and 4.5%, respectively, suggesting that Form F is a tetrahydrofuran solvate.

[0489] Example 14 Preparation of Form G

[0490] 1 mL of methyl isobutyl ketone was added to 0.0389 g of Form A and 13.7 mg of p-toluenesulfonic acid, and the mixture was stirred at room temperature for one day. A sample was taken for XRD analysis, which confirmed Form G. H-NMR results showed the presence of 0.13 equivalents of methyl isobutyl ketone (2.1% by mass), suggesting that Form G is an anhydrate or hydrate.

[0491] Example 15 Preparation of Form I

[0492] 0.0104 g of Form A was dissolved in 3 mL of isopropanol, filtered, and slowly evaporated for 14 days to obtain a solid. XRD analysis of the sample confirmed Form I. H-NMR analysis revealed the presence of 0.36 equivalents of isopropanol (2.1% by mass), suggesting that Form G is an anhydrate or hydrate.

[0493] Example 16 Preparation of Form J

[0494] 1 mL of methyl tert-butyl ether / n-heptane (1:1, v / v) was added to 0.0194 g of Form A and the mixture was slurried at room temperature for 4 days. A sample was taken for XRD analysis and was identified as Form J. H-NMR results showed the presence of 0.91 equivalents of methyl tert-butyl ether, suggesting that Form J is a methyl tert-butyl ether solvate.

[0495] Example 17 Preparation of Form K

[0496] To 0.0105 g of Form A, 0.1 mL of 1,4-dioxane was added to dissolve the mixture. After filtration, the mixture was slowly evaporated for 14 days to yield a solid. XRD analysis of the sample confirmed Form K. H-NMR analysis revealed the presence of 0.55 equivalents of 1,4-dioxane, suggesting that Form K is a semi-1,4-dioxane solvate.

[0497] Example 18 Preparation of Form L

[0498] 0.5 mL of acetonitrile was added to 0.0108 g of Form A and the mixture was slurried at room temperature for 1 day. A sample was taken for XRD characterization, which showed that the sample was Form L.

[0499] Example 19 Preparation of Form M

[0500] 1 mL of dichloromethane / n-heptane (1:2, v / v) was added to 0.0135 g of Form A and the mixture was slurried at room temperature for 1 day. A sample was taken for XRD characterization and the result was Form M.

[0501] Example 20 Preparation of Form N

[0502] 1 mL of dimethyl sulfoxide / purified water (1:3, v / v) was added to 0.0114 g of Form A and the mixture was slurried at room temperature for 1 day. The sample was taken for XRD characterization and was Form N.

[0503] Example 20 Preparation of Form P

[0504] 0.5 mL of dimethyl sulfoxide was added to 0.1157 g of Form A to dissolve the mixture, and the mixture was filtered into a new vial. 1.5 mL of purified water was added dropwise and the mixture was slurried at room temperature for 1 day. The sample was taken for XRD characterization and the result was Form P.

[0505] Example 21 Preparation of Form Q

[0506] 1 mL of ethanol was added to 0.0209 g of Form A and the mixture was slurried at room temperature for 4 days. A sample was taken for XRD characterization, which showed that the sample was Form Q.

[0507] Example 22 Preparation of Form R

[0508] 1 mL of acetone / n-heptane (1:2, v / v) was added to 0.0200 g of Form A and the mixture was slurried at room temperature for 4 days. A sample was taken for XRD characterization and the result was Form R.

[0509] Example 23 Preparation of Form T

[0510] 1 mL of isopropyl acetate / n-heptane (1:1, v / v) was added to 0.0211 g of Form A and the mixture was slurried at room temperature for 4 days. A sample was taken for XRD characterization and the result was Form T.

[0511] Example 24 Preparation of Form U

[0512] 1 mL of 1,4-dioxane / n-heptane (1:2, v / v) was added to 0.0198 g of Form A and the mixture was slurried at room temperature for 4 days. A sample was taken for XRD characterization and it was Form U.

[0513] Example 25 Preparation of Form V

[0514] 1 mL of methanol was added to 0.0218 g of Form A and beaten at 50 °C for 1 day. The sample was taken and XRD analysis showed Form V.

[0515] Example 26 Preparation of Form X

[0516] To 0.0984 g of Form A, 0.5 mL of acetone was added, stirred, and dissolved. The mixture was filtered into a new vial, and 1 mL of n-heptane was slowly added dropwise. Solid precipitated. Samples were taken for characterization, and XRD results showed Form X.

[0517] Example 27 Preparation of Form Z

[0518] 1 mL of ethyl formate was added to 0.0965 g of Form A and the mixture was beaten for 1 day. A sample was taken and characterized by XRD, which showed that the sample was Form Z.

[0519] Example 28 Preparation of Form AA

[0520] To 0.0997 g of Form A, 0.5 mL of 2-methyltetrahydrofuran was added and stirred to dissolve. The mixture was filtered into a new vial and 1 mL of n-heptane was slowly added dropwise. Solid precipitated. XRD analysis of the sample showed Form AA.

[0521] Example 29 Preparation of Form AD

[0522] 4 mL of ethanol was added to 0.4049 g of Form A and the mixture was slurried at room temperature for 1 day. The sample was characterized by XRD and the result was Form AD.

[0523] Example 30 Preparation of Form AE

[0524] Form Q was vacuum dried at 60°C for 8 h, and a sample was taken for XRD characterization, which showed that it was Form AE.

[0525] Example 31 Preparation of Form AF

[0526] 2.6 mL of n-heptane and 1.4 mL of butanone were added to 0.0793 g of Form A and the mixture was slurried at room temperature for 1 day. A sample was taken for XRD characterization and the result was Form AF.

[0527] Example 32 Preparation of p-toluenesulfonate crystalline form

[0528] 38.9 mg of the compound of formula (I) and 15.0 mg of p-toluenesulfonic acid were weighed separately into a 3 mL vial, 1 mL of a 3:1, v / v ethyl acetate / n-heptane mixture was added, and the vial was sealed. The mixture was stirred at room temperature for 24 h, centrifuged, and dried at room temperature for 2 days.

[0529] The obtained solid was characterized by XRPD and H-NMR tests.

[0530] The XRPD characterization results are shown in Figure 51.

[0531] 1H-NMR (400MHz, DMSO-d6): δ (ppm) 9.83 (s, 1H), 8.72 (s, 1H), 8.61-8.59 (d, J = 8.4Hz, 1H), 8.51 (s, 1H), 7.96 (d, J = 1.2Hz, 1H),7.88-7.86(dd,J=8.0Hz,1.2Hz,1H),7.62-7.60(d,J=8.0Hz,1H),7.49-7.47(d,J=8.4Hz,2H),7.40(d,J=1.2Hz,1H) ,7.33-7.31(dd,J=8.0Hz,1.2Hz,1H),7.13-7.11(d,J=8.4Hz,2H),5.81(s,2H),3.97-3.94(t,J=6.8Hz,2H),3.87(s,3H ), 2.62-2.58(t,J=7.2Hz,2H),2.29(s,3H),2.22-2.19(m,2H),1.76-1.70(m,1H),1.07-1.05(m,2H),0.84-0.81(m,2H).

[0532] Example 33 Preparation of maleate

[0533] Weigh 39.9 mg of the compound of formula (I) and 8.4 mg of maleic acid into a 3 mL vial. Add 1 mL of a 3:1, v / v, ethyl acetate / n-heptane mixture and seal. Stir at room temperature for 16 h until the solution becomes clear. Slowly add 2 mL of n-heptane dropwise, resulting in the precipitation of solids. Stir for 4 h, centrifuge, and dry at room temperature for 2 days.

[0534] The obtained solid was characterized by XRPD and H-NMR tests.

[0535] The XRPD characterization results are shown in Figure 52.

[0536] 1H-NMR (400MHz, DMSO-d6): δ (ppm) 9.82 (s, 1H), 8.72 (s, 1H), 8.60-8.58 (d, J = 8.4Hz, 1H), 8.50 (s, 1H), 7.9 6(d,J=1.2Hz,1H),7.88-7.86(dd,J=8.0Hz,1.2Hz,1H),7.62-7.60(d,J=8.0Hz,1H),7.40(d,J=1.2Hz,1H) ,7.33-7.31(dd,J=8.0Hz,1.2Hz,1H),6.26(s,2H),5.80(s,2H),3.97-3.94(t,J=6.8Hz,2H),3.87(s,3H) ,2.62-2.58(t,J=7.2Hz,2H),2.22-2.19(m,2H),1.76-1.70(m,1H),1.07-1.05(m,2H),0.84-0.81(m,2H).

[0537] Example 34 Preparation of Fumarate

[0538] 37.3 mg of the compound of formula (I) and 8.5 mg of fumaric acid were weighed separately into a 3 mL vial, 1 mL of a 3:1, v / v, ethyl acetate / n-heptane mixture was added, and the vial was sealed. The mixture was stirred at room temperature for 24 h, centrifuged, and dried at room temperature for 2 days.

[0539] The obtained solid was characterized by XRPD and H-NMR tests.

[0540] The XRPD characterization results are shown in Figure 53.

[0541] 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 9.82 (s, 1H), 8.72 (s, 1H), 8.60-8.58 (d, J = 8.4Hz, 1H), 8.50 (s, 1H), 7.9 6(d,J=1.2Hz,1H),7.87-7.85(dd,J=8.0Hz,1.2Hz,1H),7.62-7.60(d,J=8.0Hz,1H),7.40(d,J=1.2Hz,1H) ,7.33-7.31(dd,J=8.0Hz,1.2Hz,1H),6.63(s,2H),5.80(s,2H),3.97-3.93(t,J=6.8Hz,2H),3.86(s,3H) ,2.62-2.58(t,J=7.2Hz,2H),2.24-2.19(m,2H),1.74-1.70(m,1H),1.08-1.04(m,2H),0.85-0.80(m,2H).

[0542] Example 35 Preparation of Citrate

[0543] 39.7 mg of the compound of formula (I) and 13.9 mg of citric acid were weighed separately into a 3 mL vial, 1 mL of a 3:1, v / v, ethyl acetate / n-heptane mixture was added, and the vial was sealed. The mixture was stirred at room temperature for 24 h, centrifuged, and dried at room temperature for 2 days.

[0544] The obtained solid was characterized by XRPD and H-NMR tests.

[0545] The XRPD characterization results are shown in Figure 54.

[0546] 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 9.82 (s, 1H), 8.72 (s, 1H), 8.60-8.58 (d, J = 8.4Hz, 1H), 8.50 (s, 1H), 7.96 (d, J =1.2Hz,1H),7.87-7.85(dd,J=8.0Hz,1.2Hz,1H),7.62-7.60(d,J=8.0Hz,1H),7.40(d,J=1.2Hz,1H),7.33-7.3 1(dd,J=8.0Hz,1.2Hz,1H),5.80(s,2H),5.18(brs,1H),3.97-3.93(t,J=6.8Hz,2H),3.86(s,3H),2.78-2.64(q ,4H),2.62-2.58(t,J=7.2Hz,2H),2.22-2.19(m,2H),1.74-1.70(m,1H),1.08-1.04(m,2H),0.85-0.81(m,2H).

[0547] Example 36 Preparation of succinate:

[0548] Weigh 41.2 mg of the compound of formula (I) and 8.8 mg of succinic acid into a 3 mL vial. Add 1 mL of a 3:1, v / v, ethyl acetate / n-heptane mixture and seal. Stir at room temperature for 16 h. After the solution becomes clear, slowly add 2 mL of n-heptane dropwise. Solid precipitates. Stir for 4 h, centrifuge, and dry at room temperature for 2 days.

[0549] The obtained solid was characterized by XRPD and H-NMR tests.

[0550] The XRPD characterization results are shown in Figure 55.

[0551] 1H-NMR (400MHz, DMSO-d6): δ (ppm) 9.82 (s, 1H), 8.72 (s, 1H), 8.60-8.58 (d, J = 8.4Hz, 1H), 8.50 (s, 1H), 7.9 6(d,J=1.2Hz,1H),7.87-7.85(dd,J=8.0Hz,1.2Hz,1H),7.62-7.60(d,J=8.0Hz,1H),7.40(d,J=1.2Hz,1H) ,7.33-7.31(dd,J=8.0Hz,1.2Hz,1H),5.80(s,2H),3.97-3.93(t,J=6.8Hz,2H),3.86(s,3H),2.62-2.58( t,J=7.2Hz,2H),2.42(s,4H),2.24-2.17(m,2H),1.74-1.69(m,1H),1.08-1.04(m,2H),0.85-0.80(m,2H).

[0552] Example 37 Hygroscopicity Experiment:

[0553] Referring to the "Guidelines for Hygroscopicity Tests of Drugs" in the Chinese Pharmacopoeia, the moisture adsorption / desorption data of crystal forms W and D were tested.

[0554] Figure 58 shows the DVS curve of Form W. The DVS results show that Form W absorbs moisture and gains weight by 0.156% at 80% RH, indicating that this form is almost non-hygroscopic. XRD analysis of the solid remaining after the DVS experiment shows no change in the form.

[0555] Figure 59 shows the DVS curve of Form D. Form W absorbs moisture at 80% RH and gains 0.26% in weight, indicating that this form is almost non-hygroscopic. XRD analysis of the solid remaining after the DVS experiment shows no change in the form.

[0556] Example 38 Stability Experiment:

[0557] The stability of Forms W, C, and H at various temperatures and humidities was investigated with reference to the "Guidelines for Stability Testing of Drug Substances and Drug Products" in the Chinese Pharmacopoeia. Purity was tested using HPLC on days 0 and 10, and the crystal form was tested using XRPD.

[0558] The experimental results are shown in Table 27. The physical properties of crystal forms W, C, and H are stable under high temperature and high humidity conditions. Their crystal forms do not change, and their chemical purity does not decrease significantly.

[0559] Table 27 Crystal stability test results

[0560] Table 28 Crystal stability test results

[0561] Example 39 Dissolution experiment:

[0562] Form D and Form W were tested for in vitro dissolution, and the dissolution rate was determined according to the dissolution and release rate determination method in accordance with the Chinese Pharmacopoeia 2020 edition 0931. The dissolution results are shown in Figure 60.

[0563] Conclusion: The cumulative dissolution rate of Form D in FaSSIF is generally higher than that of Form W. At 120 min, the dissolution rate of Form D is approximately 1.6 times that of Form W.

[0564] Example 40 Suspension competition experiment:

[0565] To further investigate the stability of the crystal form, a suspension competition method was used in the experiment. The test results are shown in Table 29 below:

[0566] Table 29 Suspension competition experiment results

[0567] Conclusion: Crystal W was converted into crystal D in butanone / heptane (1:2, v / v) at room temperature to 60°C.

[0568] Example 41 Saturation Solubility Experiment:

[0569] Samples of different crystalline forms were dispersed in dichloromethane / methanol (10:1, v / v), slurried at room temperature for 2 hours, and then filtered to obtain saturated solutions. The content of Compound I in the saturated solutions was determined by HPLC. The test results are shown in Table 30 below:

[0570] Table 30 Saturation solubility experimental results

[0571] At room temperature, the saturated solubility of Form D in dichloromethane / methanol (10:1, v / v) is higher than that of Form W. In the formulation process of preparing solid dispersions by spray drying, the use of Form D can use less organic solvent, which helps to reduce costs and reduce environmental pollution.

Claims

1. Form A of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 6.31°, 9.21°, 11.55°, 13.55°, 16.80°, and 20.06°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 6.31°, 7.68°, 9.21°, 9.93°, 11.55°, 12.44°, 13.55°, 15.43°, 16.80°, 20.06°, 21.66°, 22.01°, 24.46°, and 25.23°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 5.52°, 6.31°, 7.68°, 9.21°, 9.93°, 10.86°, 11.55°, 12.44°, 12.59°, 13.55°, 14.71°, 15.43°, 16.80°, 20.06°, 20.95°, 21.66°, 22.01°, 24.46°, 25.23°, 25.80°, 26.17°, and 27.04°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A is shown in Figure 1; further preferably, it is characterized in that the TGA-DSC spectrum of the crystalline form is shown in Figure 2.

2. Form B of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2θ values ​​of 5.83°, 6.18°, 10.91°, 11.59°, 14.06°, and 14.48°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2θ values ​​of 5.83°, 6.18°, 9.11°, 10.91°, 11.59°, 12.48°, 13.25°, 14.06°, 14.48°, 15.85°, 17.38°, 20.85°, and 23.62°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu -Kα radiation, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2θ values ​​of 5.83°, 6.18°, 7.88°, 9.11°, 10.55°, 10.91°, 11.59°, 12.48°, 12.93°, 13.25°, 14.06°, 14.48°, 15.85°, 17.38°, 19.93°, 20.37°, 20.85°, 23.15°, 23.62°, and 26.44°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern is shown in Figure 3; further preferably, it is characterized in that the TGA-DSC spectrum of the crystalline form is shown in Figure 4.

3. Form W of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form W has characteristic peaks at 2θ values ​​of 10.54°, 11.81°, 21.52°, 21.84°, and 25.94°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form W has characteristic peaks at 2θ values ​​of 7.91°, 10.54°, 11.47°, 11.81°, 15.96°, 17.85°, 18.09°, 18.28°, 20.45°, 21.52°, 21.84°, 24.93°, and 25.94°, and the 2θ error range is ±0.2°. ; Further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form W has characteristic peaks at 2θ values ​​of 7.91°, 8.19°, 10.54°, 11.17°, 11.47°, 11.81°, 13.65°, 15.96°, 16.20°, 17.85°, 18.09°, 18.28°, 18.48°, 19.33°, 20.45°, 20.98°, 21.52°, 21.84°, 24.93°, 25.94°, and 26.57°, and the 2θ error range is ±0.2°. ; Further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form W is shown in Figure 5; further preferably, it is characterized in that the DSC spectrum of the crystal form has an endothermic peak at around 253.5°C; further preferably, it is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 6.

4. Form C of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ values ​​of 6.27°, 6.91°, 7.60°, 14.25°, 15.28°, and 21.16°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ values ​​of 6.27°, 6.91°, 7.60°, 9.35°, 11.73°, 12.61°, 13.90°, 14.25°, 14.44°, 15.28°, 16.86°, 17.29°, 21.16°, and 26.36°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using C u-Kα radiation, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ values ​​of 6.27°, 6.91°, 7.60°, 9.35°, 11.73°, 12.61°, 13.90°, 14.25°, 14.44°, 15.28°, 16.86°, 17.29°, 19.00°, 21.16°, 21.46°, 23.06°, 23.30°, 24.40°, 26.36°, and 28.07°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form C is shown in Figure 7; further, it is characterized in that the TGA-DSC spectrum of the crystalline form is shown in Figure 8.

5. Form H of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ values ​​of 6.08°, 8.73°, 12.89°, 15.49°, 20.03°, and 20.26°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ values ​​of 6.08°, 8.73°, 9.45°, 10.89°, 12.89°, 13.48°, 15.49°, 15.79°, 18.39°, 19.04°, 20.03°, 20.26°, 25.11°, and 25.43°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα Radiation, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ values ​​of 6.08°, 7.70°, 8.73°, 9.16°, 9.45°, 10.89°, 12.22°, 12.89°, 13.48°, 14.47°, 15.49°, 15.79°, 16.51°, 18.39°, 19.04°, 20.03°, 20.26°, 23.37°, 24.54°, 25.11°, and 25.43°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form H is shown in Figure 9; further preferably, it is characterized in that the TGA-DSC spectrum of the crystalline form is shown in Figure 10.

6. Form O of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 5.90°, 9.41°, 10.88°, 11.50°, 14.46°, and 23.38°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 5.90°, 6.33°, 9.41°, 10.88°, 11.50°, 12.50°, 13.34°, 14.46°, 14.99°, 17.22°, 20.57°, 21.11°, 22.15°, 23.38°, and 26.91°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the The X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ values ​​of 5.90°, 6.33°, 7.12°, 9.41°, 10.88°, 11.50°, 12.50°, 13.34°, 14.46°, 14.99°, 15.91°, 17.22°, 18.26°, 19.24°, 19.56°, 20.02°, 20.57°, 21.11°, 22.15°, 23.38°, 24.41°, 25.16°, and 26.91°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form O is shown in Figure 11; further preferably, it is characterized in that the TGA-DSC spectrum of the crystalline form is shown in Figure 12.

7. Form Y of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form Y has characteristic peaks at 2θ values ​​of 6.78°, 8.26°, 9.91°, 11.60°, 13.64°, and 16.74°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form Y has characteristic peaks at 2θ values ​​of 6.78°, 7.53°, 8.26°, 8.74°, 9.91°, 1 There are characteristic peaks at 0.73°, 11.60°, 12.51°, 13.64°, 14.11°, 16.74°, 20.18°, 21.83°, and 23.65°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form Y is shown in Figure 13; further preferably, it is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 14.

8. Form S of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form S has characteristic peaks at 2θ values ​​of 5.58°, 15.69°, 16.49°, 16.70°, 17.99°, and 24.12°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form S has characteristic peaks at 2θ values ​​of 5.58°, 13.06°, 13.58°, 13.75°, 14.59°, 15.32°, 15.69°, 16.49°, 16.70°, 17.99°, 19.39°, 23.39°, 23.67°, and 24.12°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα Radiation, the X-ray powder diffraction pattern of the crystalline form S has characteristic peaks at 2θ values ​​of 5.58°, 7.77°, 9.61°, 13.06°, 13.58°, 13.75°, 14.59°, 15.32°, 15.69°, 16.49°, 16.70°, 17.99°, 19.39°, 20.24°, 20.37°, 21.60°, 22.78°, 23.39°, 23.67°, 24.12°, and 29.70°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form S is shown in Figure 15; further preferably, it is characterized in that the TGA-DSC spectrum of the crystalline form is shown in Figure 16.

9. Form AB of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form AB has characteristic peaks at 2θ values ​​of 8.01°, 11.08°, 12.46°, 14.86°, and 16.15°, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form AB has characteristic peaks at 2θ values ​​of 8.01°, 11.08°, 12.46°, 13.17°, 14.86°, 16.1 There are characteristic peaks at 5°, 17.91°, 21.35°, 22.11°, 24.36°, 25.24°, 26.30°, 27.54°, 28.75°, and 36.52°, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form AB is shown in Figure 17; further preferably, it is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 18.

10. Form D of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 2θ values ​​of 5.35, 8.76, 10.78, 19.62, and 21.02, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 2θ values ​​of 5.35, 8.76, 10.78, 11.27, 12.34, 15.38, 16.24, 17.65, 19.62, 20.82, 21.02, and 21.75, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the crystalline form D The X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values ​​of 5.35, 8.76, 10.78, 11.27, 12.34, 13.88, 15.38, 16.24, 17.29, 17.65, 19.62, 20.82, 21.02, 21.33, 21.75, 22.30, 22.92, 25.41, 26.04, and 26.69, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form D is shown in Figure 19; further preferably, it is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 20.

11. Form G of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2θ values ​​of 4.88, 9.77, 14.73, 21.21, and 23.96, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2θ values ​​of 4.88, 9.77, 13.65, 14.73, 15.53, 15.92, 17.48, 19.27, 21.21, 21.76, 23.96, and 24.95, and the 2θ error range is ±0.2°; further preferably, it is characterized in that , using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2θ values ​​of 4.88, 6.51, 7.76, 9.77, 10.23, 13.65, 14.01, 14.73, 15.53, 15.92, 17.48, 19.27, 19.77, 20.20, 20.63, 21.21, 21.76, 23.96, 24.35, 24.95, and 27.84, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form G is shown in Figure 21.

12. Form P of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form P has characteristic peaks at 2θ values ​​of 7.52, 9.54, 12.14, 13.87, 16.93, and 23.67, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form P has characteristic peaks at 2θ values ​​of 7.52, 8.56, 9.54, 10.64, 12.14, 13.87, 15.41, 16.93, 18.59, 20.59, 23.67, and 28.06, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form P is shown in Figure 22.

13. Form Q of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Q has characteristic peaks at 5.62, 10.34, 14.95, 17.90, 22.77, and 23.18, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Q has characteristic peaks at 2θ values ​​of 5.62, 10.34, 12.17, 14.95, 16.83, 17.26, 17.90, 21.39, 21.77, 22.77, 23.18, and 25.52, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Q has characteristic peaks at 2θ values ​​of 5.62, 10.34, 12.17, 14.95, 16.83, The X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.62, 8.38, 10.34, 10.99, 11.30, 12.17, 13.86, 14.95, 15.89, 16.83, 17.26, 17.90, 21.39, 21.77, 22.19, 22.40, 22.77, 23.18, 23.78, 25.52, 25.85, and 28.63, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form Q is shown in Figure 23; further preferably, it is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 24.

14. Form X of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form X has characteristic peaks at 2θ values ​​of 10.15, 10.75, 15.79, 20.99, 23.56, and 26.80, and the 2θ error range is ±0.2°; preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form X has characteristic peaks at 2θ values ​​of 10.15, 10.75, 12.28, 13.80, 15.79, 16.45, 17.02, 17.97, 19.63, 20.99, 23.56, and 26.80, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the crystalline form X The X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.70, 10.15, 10.75, 11.05, 12.28, 12.90, 13.80, 14.60, 15.79, 16.45, 16.70, 17.02, 17.97, 19.63, 20.28, 20.49, 20.99, 22.71, 23.56, 24.07, 24.31, and 26.80, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form X is shown in Figure 25; further preferably, it is characterized in that the TGA-DSC spectrum of the crystal form is shown in Figure 26.

15. The p-toluenesulfonate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to the p-toluenesulfonic acid is 1:1; preferably, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate has characteristic peaks at 2θ values ​​of 15.41, 19.65, 19.92, 21.30, and 22.75, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate has characteristic peaks at 2θ values ​​of 8.53, 8.82, 13.16, 13.46, 14.19, 15.41, 19.65, 19.92, 21.30, 22.15, 22.75, and 26.37, and the 2θ error range is ±0.2°; further preferably, It is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate has characteristic peaks at 2θ values ​​of 6.18, 8.53, 8.82, 13.16, 13.46, 14.19, 15.41, 17.25, 18.41, 18.85, 19.65, 19.92, 20.94, 21.30, 21.62, 22.15, 22.75, 25.76, 26.37, and 30.14, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the p-toluenesulfonate is shown in Figure 51.

16. The maleate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to p-maleic acid is 1:1; preferably, characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the maleate salt has characteristic peaks at 2θ values ​​of 5.93, 7.65, 14.67, 17.05, and 19.79, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the maleate salt has characteristic peaks at 2θ values ​​of 5.93, 7.65, 10.58, 13.50, 14.67, 17.05, 18.94, 19.79, 20.92, 23.38, 23.63, and 23.98, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the maleate salt has characteristic peaks at 2θ values ​​of 5.93, 7.65, 10.58, 13.50, 14.67, 17.05, 18.94, 19.79, 20.92, 23.38, 23.63, and 23.98, and the 2θ error range is ±0.2°; One preferred step is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the maleate salt has characteristic peaks at 2θ values ​​of 3.28, 3.56, 3.71, 3.76, 3.80, 4.12, 4.24, 4.48, 4.68, 5.06, 5.20, 5.39, 5.75, 6.03, 6.31, 6.55, 7.54, 8.35, 11.54, and 14.88, and the 2θ error range is ±0.2°; further preferred, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the maleate salt is shown in Figure 52.

17. A fumarate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to the fumaric acid is 1:1; preferably, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the fumarate has characteristic peaks at 2θ values ​​of 6.76, 9.74, 10.98, 16.58, and 22.20, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the fumarate has characteristic peaks at 2θ values ​​of 5.40, 6.76, 9.74, 10.98, 11.71, 12.99, 14.36, 16.58, 19.69, 21.45, 22.20, and 23.36, and the 2θ error range is ±0.2°; further preferably, it is characterized in that The characteristic is that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the fumarate has characteristic peaks at 2θ values ​​of 5.40, 6.76, 9.74, 10.98, 11.71, 12.99, 13.28, 14.36, 14.90, 16.58, 17.16, 17.89, 19.69, 21.45, 22.20, 23.36, 24.50, 25.21, 27.30, and 28.62, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the fumarate is shown in Figure 53.

18. The citrate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to citric acid is 1:1; preferably, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the citrate has characteristic peaks at 2θ values ​​of 6.85, 10.84, 13.83, 19.51, and 25.48, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the citrate has characteristic peaks at 2θ values ​​of 6.85, 10.84, 11.64, 13.83, 16.29, 17.97, 19.15, 19.51, 24.70, 25.48, 25.91, and 27.19, and the 2θ error range is ±0.2°; further preferably, It is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the citrate salt has characteristic peaks at 2θ values ​​of 6.85, 10.84, 11.64, 13.83, 14.18, 15.39, 16.29, 16.55, 17.97, 19.15, 19.51, 20.30, 21.06, 24.06, 24.70, 25.48, 25.91, 27.19, 27.58, and 27.95, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the citrate salt is shown in Figure 54.

19. The succinate salt of the compound of formula (I) 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-9-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-9H-pyrimido[4,5-b]indole-7-carbonitrile, wherein the molar ratio of the free base to the succinic acid is 1:1; preferably, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the succinate has characteristic peaks at 2θ values ​​of 7.74, 17.20, 19.05, 20.01, and 21.11, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the succinate has characteristic peaks at 2θ values ​​of 7.74, 10.60, 13.63, 14.11, 14.85, 16.64, 17.20, 19.05, 20.01, 21.11, 23.91, and 24.28, and the 2θ error range is ±0.2°; further preferably, It is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the succinate has characteristic peaks at 2θ values ​​of 7.74, 10.60, 13.63, 14.11, 14.63, 14.85, 16.47, 16.64, 17.20, 17.45, 18.39, 18.80, 19.05, 20.01, 21.11, 21.72, 23.26, 23.91, 24.28, and 26.94, and the 2θ error range is ±0.2°; further preferably, it is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the succinate is shown in Figure 55.

20. A pharmaceutical composition comprising the crystal form or salt form according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier.

21. Use of the crystal form or salt form according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20 in the preparation of a drug for treating USP1-mediated cancer.

22. Use of the crystal form or salt form of any one of claims 1 to 19 or the pharmaceutical composition of claim 20 for treating USP1-mediated cancer.

23. The use according to claim 21 or 22, wherein the cancer comprises ovarian cancer or breast cancer.

24. The method for preparing the crystal form W according to claim 3, characterized in that: The following steps are involved: (a) dissolving the compound of formula (I) in a first solvent; (b) adding a second solvent to the solution of step (a) and stirring for a certain period of time; (c) After the solid precipitates, it is collected by filtration and dried.

25. The preparation method according to claim 24, wherein the first solvent is selected from one or more mixtures of acetone, butanone, methyl isobutyl ketone, methanol, ethanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, and dimethyl sulfoxide.

26. The preparation method according to claim 24, wherein the second solvent is selected from one or more mixtures of water, n-heptane, acetonitrile, and methyl tert-butyl ether.

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