Crystal form of pyridopyrazole derivative and preparation method therefor and use thereof

Abstract

Provided are a crystal form of a compound of formula (I), a preparation method therefor, and a use thereof in preparation of related drugs.

Description

A pyridopyrazole derivative crystal form, its preparation method and application Technical Field

[0001] This invention relates to multiple crystal forms of a compound, their preparation methods and applications, specifically to multiple crystal forms of a pyridopyrazole derivative, their preparation methods and applications, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Protein ubiquitination is a key protein modification that regulates multiple cellular processes. It is synergistically controlled by E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). DUBs cleave the isopeptide bonds between ubiquitin and the modified protein, removing ubiquitin from the target protein and rescuing it from degradation pathways; they also participate in the editing, maturation, and recycling of ubiquitin molecules after degradation. More than 100 deubiquitinating enzymes are currently known, and these proteins are subdivided into six subfamilies. The ubiquitin-specific protease (USP) subfamily is the largest, with 58 known members. USPs are cysteine ​​proteases containing highly conserved catalytic domains; USP1 is a member of the USP subfamily of DUBs.

[0003] The Fanconi Anemia (FA) and DNA Translesion Synthesis (TLS) pathways were among the first discovered DNA damage tolerance and repair pathways regulated by reversible ubiquitination. USP1 can regulate the deubiquitination of specific proteins in the FA and TLS pathways to participate in the regulation of DNA damage-repair pathways. USP1 plays an important role in tumor cell DNA repair; reports indicate that USP1 deficiency leads to reduced survival and replication fork degradation in BRCA1-deficient cells. UAF1 (USP1-associated factor 1), as a cofactor of USP1, USP12, and USP46, can enhance their deubiquitinase activity by forming a stable USP / UAF1 protein complex. The USP1 / UAF1 complex deubiquitinates various substrates and is involved in DNA repair processes, tumor pathogenesis, and the regulation of antiviral innate immunity. Currently, there are no marketed drugs targeting the USP1 protein, making the research on USP1 inhibitors a promising area for application.

[0004] The patent PCT / CN2023 / 076700 describes a compound of formula (I) that has good USP1 inhibitory activity.

[0005] This invention describes the crystal form of a compound of formula (I), which belongs to the category of USP1 inhibitors and is intended for the treatment of solid tumors. The preparation method of the compound is also disclosed. Summary of the Invention

[0006] The present invention provides crystal forms of compounds of formula (I), methods for their preparation, and their use in pharmaceutical compositions and in medicine.

[0007] This invention provides a crystalline form of compound of formula (I):

[0008] In some specific embodiments, the crystalline form is crystal form A, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.60°±0.2°, 9.50°±0.2°, 10.02°±0.2°, 13.27°±0.2°, and 19.98°±0.2°.

[0009] In some specific embodiments, the crystalline form is crystalline form A, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.60°±0.2°, 9.50°±0.2°, 10.02°±0.2°, 10.44°±0.2°, 11.90°±0.2°, 13.27°±0.2°, 17.19°±0.2°, 17.22°±0.2°, 19.03°±0.2°, 19.43°±0.2°, 19.98°±0.2°, and 21.54°±0.2°.

[0010] In some specific embodiments, the crystalline form is crystalline form A, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.60°±0.2°, 9.50°±0.2°, 10.02°±0.2°, 10.44°±0.2°, 11.90°±0.2°, 12.90°±0.2°, 13.27°±0.2°, and 16.22°±0. 0.2°, 17.19°±0.2°, 17.22°±0.2°, 17.55°±0.2°, 19.03°±0.2°, 19.18°±0.2°, 19.43°±0.2°, 19.71°±0.2°, 19.98°±0.2°, 20.19°±0.2°, 20.40°±0.2°, 21.54°±0.2°, 25.90°±0.2°.

[0011] In a specific implementation, the crystalline material is crystalline form A, and its X-ray powder diffraction pattern is basically as shown in Figure 2 when using Cu-Kα radiation.

[0012] In a specific implementation, the differential scanning calorimetry (DSC) curve of crystal form A shows a melting endothermic signal at around 183°C and an endothermic signal at around 203°C. Its thermogravimetric analysis (TGA) curve shows no significant weight loss during heating to 120°C and possible decomposition after 300°C, as shown in Figure 1.

[0013] In some specific embodiments, the crystalline form is crystalline form B, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 5.90°±0.2°, 6.89°±0.2°, 9.96°±0.2°, 11.89°±0.2°, 12.51°±0.2°, 13.83°±0.2°, 14.32°±0.2°, and 19.39°±0.2°.

[0014] In some specific embodiments, the crystalline form is crystalline form B, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 5.90°±0.2°, 6.89°±0.2°, 9.96°±0.2°, 11.89°±0.2°, 12.51°±0.2°, 13.83°±0.2°, 14.32°±0.2°, 14.91°±0.2°, 16.21°±0.2°, 17.92°±0.2°, and 19.39°±0.2°.

[0015] In some specific embodiments, the crystalline form is crystalline form B, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 5.90°±0.2°, 6.89°±0.2°, 8.97°±0.2°, 9.96°±0.2°, 11.89°±0.2°, 12.51°±0.2°, 12.69°±0.2°, 13.83°±0.2°, 14.32°±0.2°, 14.91°±0.2°, 16.21°±0.2°, 17.92°±0.2°, 18.74°±0.2°, 19.39°±0.2°, 20.84°±0.2°, 21.84°±0.2°, and 25.22°±0.2°.

[0016] In a specific implementation scheme, crystal form B is irradiated with Cu-Kα, and its X-ray powder diffraction pattern is basically as shown in Figure 4.

[0017] In a specific implementation, the differential scanning calorimetry (DSC) curve of crystal form B shows endothermic signals at around 146℃, 161℃, and 204℃, while the thermogravimetric analysis (TGA) curve shows a 7.3% weight loss during heating to 170℃, and possible decomposition after 300℃, as shown in Figure 3.

[0018] In some specific embodiments, the crystalline form is crystalline form C, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 12.18°±0.2°, 16.71°±0.2°, and 17.10°±0.2°.

[0019] In some specific embodiments, the crystalline form is crystalline form C, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 12.18°±0.2°, 16.71°±0.2°, 17.10°±0.2°, 17.35°±0.2°, and 19.47°±0.2°.

[0020] In some specific embodiments, the crystalline form is crystalline form C, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 12.18°±0.2°, 12.93°±0.2°, 14.91°±0.2°, 16.71°±0.2°, 17.10°±0.2°, 17.35°±0.2°, 18.01°±0.2°, 19.47°±0.2°, 19.73°±0.2°, 22.22°±0.2°, and 23.60°±0.2°.

[0021] In a specific implementation, the crystalline material is crystalline form C, and its X-ray powder diffraction pattern is basically as shown in Figure 6 using Cu-Kα radiation.

[0022] In a specific implementation, the crystalline material is crystalline form C, whose differential scanning calorimetry (DSC) curve shows a melting endothermic signal at around 202°C, and its thermogravimetric analysis (TGA) curve shows almost no weight loss during heating to 120°C, and decomposition may occur after 300°C, as shown in Figure 5.

[0023] In a specific implementation scheme, the crystal structure of the compound shown in formula (I) was successfully determined by the MicroED method. The cell parameters are shown in Table 1. The crystal structure belongs to the orthorhombic crystal system, space group Pbca, and its cell parameters are as follows: α=90°, β=90°, γ=90°, The Z' of the system is 8; in a specific implementation, the asymmetric structural unit of crystal form C contains one compound molecule as shown. In a specific implementation, the asymmetric unit in the unit cell is shown in Figure 7.

[0024] Table 1 shows the unit cell parameters of crystal form C of the compound represented by formula (I).

[0025] In some specific embodiments, the crystal form is crystal form D, and its X-ray powder diffraction pattern, when irradiated with Cu-Kα, has characteristic diffraction peaks at the following 2θ positions: 7.31°±0.2° and 7.74°±0.2°.

[0026] In some specific embodiments, the crystalline form is crystal form D, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.31°±0.2°, 7.74°±0.2°, 13.02°±0.2°, 19.60°±0.2°, and 19.74°±0.2°.

[0027] In a specific implementation, the crystal form is crystal form D, and its X-ray powder diffraction pattern is basically as shown in Figure 9 using Cu-Kα radiation.

[0028] In a specific implementation, the crystalline material is crystal form D. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 136°C and 203°C, and its thermogravimetric analysis (TGA) curve shows a 7.2% weight loss during heating to 150°C. It may decompose after 300°C, as shown in Figure 8.

[0029] In some specific embodiments, the crystalline form is E, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.95°±0.2°, 10.02°±0.2°, 13.96°±0.2°, and 14.37°±0.2°.

[0030] In some specific embodiments, the crystalline form is crystalline form E, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.94°±0.2°, 6.95°±0.2°, 10.02°±0.2°, 11.93°±0.2°, 12.60°±0.2°, 13.96°±0.2°, 14.37°±0.2°, and 19.53°±0.2°.

[0031] In some specific embodiments, the crystalline form is crystalline form E, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ positions: 5.94°±0.2°, 6.95°±0.2°, 9.00°±0.2°, 9.33°±0.2°, 10.02°±0.2°, 11.80°±0.2°, 11.93°±0.2°, 12... 0.60°±0.2°, 13.96°±0.2°, 14.37°±0.2°, 16.63°±0.2°, 17.82°±0.2°, 18.63°±0.2°, 19.53°±0.2°, 20.88°±0.2°, 21.05°±0.2°, 21.87°±0.2°, 22.73°±0.2°, 23.22°±0.2°.

[0032] In a specific implementation, the crystal form is E, and its X-ray powder diffraction pattern is basically as shown in Figure 11 when Cu-Kα radiation is used.

[0033] In a specific implementation, the crystalline form is crystal form E. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 150℃ and 203℃, and exothermic signals at around 183℃. Thermogravimetric analysis (TGA) curve shows a 5.4% weight loss during heating to 150℃, and possible decomposition after 300℃, as shown in Figure 10.

[0034] In some specific embodiments, the crystalline form is F, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 11.44°±0.2°, 18.20°±0.2°, 20.02°±0.2°, and 20.23°±0.2°.

[0035] In some specific embodiments, the crystalline form is crystalline form F, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.90°±0.2°, 8.29°±0.2°, 9.76°±0.2°, 10.68°±0.2°, 11.44°±0.2°, 12.66°±0.2°, 13.90°±0.2°, 15.87°±0.2°, 16.68°±0.2°, 18.20°±0.2°, 18.80°±0.2°, 19.15°±0.2°, 20.02°±0.2°, 20.23°±0.2°, 21.25°±0.2°, and 21.51°±0.2°.

[0036] In a specific implementation, the crystal form is crystal form F, and its X-ray powder diffraction pattern is basically as shown in Figure 13 when Cu-Kα radiation is used.

[0037] In a specific implementation, the crystalline form is crystal form F. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 136℃ and 201℃, and exothermic signals at around 159℃. Thermogravimetric analysis (TGA) curve shows a 9.5% weight loss during heating to 210℃, and possible decomposition after 300℃, as shown in Figure 12.

[0038] In some specific embodiments, the crystalline form is crystalline G, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.90°±0.2°, 10.01°±0.2°, and 13.89°±0.2°.

[0039] In some specific embodiments, the crystalline form is crystalline form G, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.90°±0.2°, 6.90°±0.2°, 10.01°±0.2°, 11.89°±0.2°, 12.59°±0.2°, 13.89°±0.2°, 14.34°±0.2°, and 20.82°±0.2°.

[0040] In a specific implementation, the crystalline material is of crystalline form G, and its X-ray powder diffraction pattern is basically as shown in Figure 15 when Cu-Kα radiation is used.

[0041] In a specific implementation, the crystalline material is crystalline form G, whose differential scanning calorimetry (DSC) curve shows endothermic signals at around 149℃ and 204℃, and its thermogravimetric analysis (TGA) curve shows a 6.4% weight loss during heating to 160℃, and possible decomposition after 300℃, as shown in Figure 14.

[0042] In some specific embodiments, the crystal form is crystal form H, and its X-ray powder diffraction pattern, when irradiated with Cu-Kα, has characteristic diffraction peaks at the following 2θ positions: 9.99°±0.2° and 13.87°±0.2°.

[0043] In some specific embodiments, the crystalline form is crystalline form H, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.90°±0.2°, 9.99°±0.2°, 12.55°±0.2°, 13.87°±0.2°, 14.33°±0.2°, 16.34°±0.2°, 19.39°±0.2°, 20.65°±0.2°, and 20.88°±0.2°.

[0044] In a specific implementation, the crystal form is H, and its X-ray powder diffraction pattern is basically as shown in Figure 17 when Cu-Kα radiation is used.

[0045] In a specific implementation, the crystalline form is crystalline form H. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 155℃ and 203℃, and its thermogravimetric analysis (TGA) curve shows a 5.2% weight loss during heating to 160℃. It may decompose after 300℃, as shown in Figure 16.

[0046] In some specific embodiments, the crystalline form is crystal form I, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 6.90°±0.2°, 10.01°±0.2°, 13.86°±0.2°, 14.27°±0.2°, and 20.90°±0.2°.

[0047] In a specific implementation, the crystal form is crystal form I, and its X-ray powder diffraction pattern is basically as shown in Figure 19 when Cu-Kα radiation is used.

[0048] In a specific implementation, the crystalline material is crystal form I. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 172°C and 204°C, and its thermogravimetric analysis (TGA) curve shows a 7.3% weight loss during heating to 200°C. It may decompose after 300°C, as shown in Figure 18.

[0049] In some specific embodiments, the crystal form is crystal form J, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 9.96°±0.2° and 13.82°±0.2°.

[0050] In some specific embodiments, the crystalline form is crystalline form J, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.91°±0.2°, 6.87°±0.2°, 9.96°±0.2°, 11.90°±0.2°, 12.49°±0.2°, 13.82°±0.2°, 14.32°±0.2°, 14.90°±0.2°, 16.25°±0.2°, 17.90°±0.2°, 19.41°±0.2°, and 20.82°±0.2°.

[0051] In a specific implementation, the crystal form is crystal form J, and its X-ray powder diffraction pattern is basically as shown in Figure 21 when Cu-Kα radiation is used.

[0052] In a specific implementation, the crystalline form is crystal form J. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 155℃ and 204℃, and exothermic signals at around 163℃. The thermogravimetric analysis (TGA) curve shows a 6.9% weight loss during heating to 200℃, and possible decomposition after 300℃, as shown in Figure 20.

[0053] In some specific embodiments, the crystal form is K, and its X-ray powder diffraction pattern, when irradiated with Cu-Kα, has characteristic diffraction peaks at the following 2θ positions: 10.01°±0.2° and 14.33°±0.2°.

[0054] In some specific embodiments, the crystalline form is crystalline form K, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.90°±0.2°, 10.01°±0.2°, 12.64°±0.2°, 13.61°±0.2°, 13.86°±0.2°, 14.33°±0.2°, and 20.86°±0.2°.

[0055] In some specific embodiments, the crystalline form is crystalline form K, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.90°±0.2°, 10.01°±0.2°, 12.64°±0.2°, 13.61°±0.2°, 13.86°±0.2°, 14.33°±0.2°, 14.83°±0.2°, 14.99°±0.2°, 17.96°±0.2°, 18.52°±0.2°, 19.36°±0.2°, 20.86°±0.2°, 21.86°±0.2°, and 23.14°±0.2°.

[0056] In a specific implementation, the crystal form is K, and its X-ray powder diffraction pattern is basically as shown in Figure 23 when Cu-Kα radiation is used.

[0057] In a specific implementation, the crystalline form is crystal form K, and its differential scanning calorimetry (DSC) curve shows endothermic signals at around 153℃, 168℃, and 203℃. The thermogravimetric analysis (TGA) curve shows a 6.3% weight loss during heating to 180℃, and decomposition may occur after 300℃, as shown in Figure 22.

[0058] In some specific embodiments, the crystal form is L, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, has characteristic diffraction peaks at the following 2θ positions: 5.38°±0.2° and 10.84°±0.2°.

[0059] In a specific implementation, the crystal form is L, and its X-ray powder diffraction pattern is basically as shown in Figure 25 when Cu-Kα radiation is used.

[0060] In a specific implementation, the crystalline form is crystal form L. Its differential scanning calorimetry (DSC) curve shows a melting endothermic signal at around 177°C, and its thermogravimetric analysis (TGA) curve shows a weight loss of 1.3% during heating to 150°C. It may decompose after 300°C, as shown in Figure 24.

[0061] In some specific embodiments, the crystalline form is crystalline form M, and its X-ray powder diffraction pattern, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks at the following 2θ positions: 9.89°±0.2° and 13.85°±0.2°.

[0062] In some specific embodiments, the crystalline form is crystalline form M, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.90°±0.2°, 6.86°±0.2°, 9.89°±0.2°, 11.89°±0.2°, 13.85°±0.2°, 14.31°±0.2°, 14.91°±0.2°, and 19.37°±0.2°.

[0063] In some specific embodiments, the crystalline form is crystalline form M, wherein, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.90°±0.2°, 6.86°±0.2°, 9.89°±0.2°, 11.89°±0.2°, 12.43°±0.2°, 13.85°±0.2°, 14.31°±0.2°, 14.91°±0.2°, 16.01°±0.2°, 19.37°±0.2°, 19.90°±0.2°, 20.41°±0.2°, 20.84°±0.2°, and 21.91°±0.2°.

[0064] In a specific implementation, the crystalline material is of crystalline form M, and its X-ray powder diffraction pattern is basically as shown in Figure 27 when Cu-Kα radiation is used.

[0065] In a specific implementation, the crystalline form is crystalline form M. Its differential scanning calorimetry (DSC) curve shows endothermic signals at around 136℃ and 201℃, and exothermic signals at around 152℃. Thermogravimetric analysis (TGA) curve shows a 9.2% weight loss during heating to 150℃, and possible decomposition after 300℃, as shown in Figure 26.

[0066] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the aforementioned crystalline forms, and a pharmaceutically acceptable carrier and / or excipient, preferably wherein the therapeutically effective amount is 1-1500 mg. The pharmaceutical composition may be in unit dosage form (unit dosage is also referred to as a “dosage strength”).

[0067] The present invention also provides the use of the crystal form or composition described in any of the foregoing embodiments in the preparation of a medicament for treating USP1-related tumor diseases. Further, the USP1-mediated disease is a tumor.

[0068] The present invention also provides a method for treating a tumor associated with USP1, the method comprising administering to a subject a therapeutically effective amount of the crystalline form or a combination thereof shown in any of the foregoing embodiments, wherein the disease is preferably a tumor, and the therapeutically effective amount is preferably 1-1500 mg. In some embodiments, the mammals described in the present invention include humans.

[0069] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the crystalline form disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the crystalline form disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0070] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of the crystal form of the present invention.

[0071] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the crystal form described herein, along with a carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, etc. The crystalline forms of the present invention are available in mg, 230mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, and 1500mg.

[0072] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the crystal form of the present invention, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg, wherein the disease is preferably a tumor, particularly a solid tumor.

[0073] A method for treating a disease in a mammal. The method comprises administering a crystalline form of the drug of the present invention, along with a pharmaceutically acceptable carrier and / or excipient, to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, and 100-1000 mg / day. The daily doses are 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. In some embodiments, the daily doses include, but are not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0074] The present invention relates to a kit that may include a single-dose or multi-dose form of a crystal, the kit containing the crystal of the present invention in an amount identical to that in the above-described pharmaceutical composition.

[0075] In this invention, the amount of the crystal form of the invention is converted in the form of free alkali in each case.

[0076] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0077] The crystalline form of the present invention is present in the form of about 5% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 10% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 15% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 20% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 25% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 30% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 35% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 40% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 45% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 50% by weight to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present in the form of about 55% by weight to about 100% by weight of the active pharmaceutical ingredient. In some embodiments, it is present at about 60% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 65% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 70% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 75% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 80% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 85% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 90% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 95% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 98% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, it is present at about 99% to about 100% by weight of the active pharmaceutical ingredient; in some embodiments, substantially all of the active pharmaceutical ingredient is substantially pure crystal.

[0078] The crystalline form of the present invention can be prepared by the following method:

[0079] 1. Volatilization experiment: Add the compound of formula I to the selected single solvent or binary solvent to form a clear solution of the sample, and volatilize it in an open container at different temperatures until the solvent is dry.

[0080] 2. Suspension method: Add the compound of formula I to the selected single solvent or binary solvent until a suspension is formed. After suspending and stirring at room temperature to 50°C for a certain period of time (e.g., 1h to 3 days, or 2h to 24h, or 2h to 12h, or 3 to 5h), centrifuge the suspension and dry it to obtain the product.

[0081] 3. Dissolution and crystallization method: Dissolve the compound of formula I in a good solvent, take a certain amount of the solution and add it dropwise to a poor solvent, or add the poor solvent dropwise to the solution, stir to precipitate the solid, separate and dry to obtain the product.

[0082] 4. Cooling method: Dissolve a certain amount of sample in the corresponding solvent at high temperature, transfer the solution to room temperature to cool, let it stand or stir to crystallize, separate, and dry to obtain the final product.

[0083] 5. Thermal method experiment: Take a certain amount of sample, place it on a glass slide and put it on a hot stage. Heat it to the target temperature at a certain rate (e.g., 5-20℃ / min, or 10-15℃ / min) and keep it at the temperature for a period of time (e.g., 0.5-5min, or 1-3min, or 1-2min). Then let it cool naturally to room temperature to obtain a solid.

[0084] 6. Gas-phase diffusion experiment: Add a certain amount of compound I at room temperature to a suitable amount of good solvent to completely dissolve the sample or prepare a saturated solution of good solvent; take a certain amount of solution, place the clear solution in a poor solvent atmosphere and let it stand at room temperature until a solid precipitates, then separate it to obtain the product. Alternatively, place the solid of compound I in a solvent atmosphere and let it stand at room temperature for 1 to 7 days to obtain the product.

[0085] The terms "good solvent" and "bad solvent" in this invention are relative. In a pair of solvents, the one with higher solubility is considered a good solvent, and the one with lower solubility is considered a bad solvent. In some embodiments, the good solvent is selected from those with higher solubility among ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, methanol, ethanol, n-propanol, butyl formate, 4-methyl-2-pentanone, tetrahydrofuran, isopropanol, ethyl acetate, n-heptane, diethyl ether, water, acetonitrile, toluene, chloroform, acetone, butyl formate, MTBE, and cyclohexane, while the bad solvent is selected from those with lower solubility among the aforementioned solvents. In some embodiments, the good solvent is selected from ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, methanol, ethanol, n-propanol, butyl formate, 4-methyl-2-pentanone, tetrahydrofuran, or mixtures thereof. In some embodiments, the undesirable solvent is selected from isopropanol, ethyl acetate, n-heptane, diethyl ether, water, acetonitrile, toluene, chloroform, acetone, butyl formate, MTBE, cyclohexane, or mixtures thereof.

[0086] In some implementations, the solvents for the evaporation method are water and acetone.

[0087] In some embodiments, the solvent used in the solution-crystallization method is dichloromethane and n-heptane; in some embodiments, the solvent used in the solution-crystallization method is dichloromethane and isopropyl ether; in some embodiments, the solvent used in the solution-crystallization method is ethyl acetate and n-heptane; in some embodiments, the solvent used in the solution-crystallization method is 4-methyl-2-pentanone and n-heptane; in some embodiments, the solvent used in the solution-crystallization method is dioxane and n-heptane.

[0088] In some embodiments, the solvent used in the cooling method is ethylene glycol dimethyl ether and cyclohexane; in some embodiments, the solvent used in the cooling method is toluene and cyclohexane; in some embodiments, the solvent used in the cooling method is isopropyl acetate and cyclohexane; in some embodiments, the solvent used in the cooling method is dioxane and cyclohexane; in some embodiments, the solvent used in the cooling method is dioxane and water; in some embodiments, the solvent used in the cooling method is DMSO and water.

[0089] In some implementations, the gas phase diffusion method employs gas phase diffusion in ethyl acetate.

[0090] The terms "good solvent" and "bad solvent" in this invention are relative. In a pair of solvents, the one with higher solubility is a good solvent, and the one with lower solubility is a bad solvent.

[0091] Unless otherwise specified, the solvent used in the above preparation method may be a single solvent or a combination of two or more solvents.

[0092] The X-ray powder diffraction or DSC pattern and TGA pattern disclosed in this invention, which are substantially the same, also fall within the scope of this invention.

[0093] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0094] IC 50 "Half-inhibition concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0095] As used in this invention, "crystal of the present invention", "crystal form of the present invention", "crystal form of the present invention" and the like are interchangeable.

[0096] The "room temperature" mentioned in this invention generally refers to 4-30℃, and preferably to 20±5℃.

[0097] The crystal structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0098] The "2θ or 2θ angle" mentioned in this invention refers to the peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is typically the horizontal axis unit in a diffraction pattern. If the reflected beam is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup needs to record the reflected beam at a 2θ angle. It should be understood that the specific 2θ value for a particular crystal form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of the 2θ may be ±0.3, ±0.2, or ±0.1.

[0099] It is understood that the numerical values ​​described and protected in this invention are approximate. Variations within these values ​​may be attributed to equipment calibration, equipment errors, crystal purity, crystal size, sample size, and other factors.

[0100] It is understood that the crystal forms of the present invention are not limited to those that are exactly the same as the characteristic spectra described in the accompanying drawings, such as XRD, DSC, TGA, and DVS. Any crystal form having a characteristic spectra that are substantially the same or essentially the same as those described in the accompanying drawings falls within the scope of the present invention.

[0101] It is understood that, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of the present invention are characterized by DSC plots with characteristic peak positions, possessing substantially the same properties as the DSC plots provided in the accompanying drawings, with a measurement error tolerance of ±5°C, generally required to be ±3°C.

[0102] "Carrier" refers to a system that does not cause significant stimulation to the organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0103] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter. (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyesters, polycarbonates and / or polyanhydrides; and (22) Other non-toxic compatible substances used in pharmaceutical preparations. Attached Figure Description

[0104] Figure 1 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form A of the compound shown in formula (I).

[0105] Figure 2 shows the X-ray powder diffraction pattern of crystal form A of the compound shown in formula (I).

[0106] Figure 3 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form B of the compound shown in formula (I).

[0107] Figure 4 shows the X-ray powder diffraction pattern of crystal form B of the compound shown in formula (I).

[0108] Figure 5 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form C of the compound shown in formula (I).

[0109] Figure 6 shows the X-ray powder diffraction pattern of crystal form C of the compound shown in formula (I).

[0110] Figure 7 shows the single crystal structure of crystal form C of the compound shown in formula (I).

[0111] Figure 8 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form D of the compound shown in formula (I).

[0112] Figure 9 shows the X-ray powder diffraction pattern of crystal form D of the compound shown in formula (I).

[0113] Figure 10 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form E of the compound shown in formula (I).

[0114] Figure 11 shows the X-ray powder diffraction pattern of crystal form E of the compound shown in formula (I).

[0115] Figure 12 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form F of the compound shown in formula (I).

[0116] Figure 13 shows the X-ray powder diffraction pattern of crystal form F of the compound shown in formula (I).

[0117] Figure 14 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form G of the compound shown in formula (I).

[0118] Figure 15 shows the X-ray powder diffraction pattern of crystal form G of the compound shown in formula (I).

[0119] Figure 16 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form H of the compound shown in formula (I).

[0120] Figure 17 shows the X-ray powder diffraction pattern of crystal form H of the compound shown in formula (I).

[0121] Figure 18 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form I of the compound shown in formula (I).

[0122] Figure 19 shows the X-ray powder diffraction pattern of crystal form I of the compound shown in formula (I).

[0123] Figure 20 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form J of the compound shown in formula (I).

[0124] Figure 21 shows the X-ray powder diffraction pattern of crystal form J of the compound shown in formula (I).

[0125] Figure 22 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form K of the compound shown in formula (I).

[0126] Figure 23 shows the X-ray powder diffraction pattern of crystal form K of the compound shown in formula (I).

[0127] Figure 24 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form L of the compound shown in formula (I).

[0128] Figure 25 shows the X-ray powder diffraction pattern of crystal form L of the compound shown in formula (I).

[0129] Figure 26 shows the differential scanning calorimetry curve and thermogravimetric analysis spectrum of crystal form M of the compound shown in formula (I).

[0130] Figure 27 shows the X-ray powder diffraction pattern of crystal form M of the compound shown in formula (I). Detailed Implementation

[0131] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0132] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0133] HPLC determination was performed using an LC-20AT (Shimadzu) high-performance liquid chromatograph (Shim-pack GIST C18, 4.6 × 250 mm (HSS), 5 μm).

[0134] XRD measurements were performed using a Bruker D8 Advance Diffractometer. The 2θ scan angle ranged from 3° to 45°, with a scan step of 0.013° and an exposure time of 0.08 seconds. The phototube voltage and current for the test samples were 45 kV and 40 mA, respectively, and the sample disk was a zero-background sample disk.

[0135] TGA testing conditions: The thermogravimetric analyzer was a TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a pre-equilibrated sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at the sample location at 60 mL / min and at the balance at 40 mL / min.

[0136] DSC testing conditions: The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a standard pan or a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0137] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0138] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0139] Unless otherwise specified in the examples, the room temperature is 20℃~30℃.

[0140] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0141] Example 1: Preparation of compound (I)

[0142] Step 1: Preparation of 2A

[0143] 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (5 g, 23.58 mmol) was dissolved in THF (60 mL), and boranetetrahydrofuran solution (47 mL, 1 M) was slowly added dropwise at 0 °C, with stirring overnight at room temperature. The solution was quenched with methanol at 0 °C, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20-1 / 2) to give 2A (3.8 g, yield: 81%).

[0144] LCMS m / z = 199.2 [M+H] +

[0145] Step 2: Preparation of 2B

[0146] 2A (3.8 g, 19.16 mmol) was dissolved in DCM (100 mL), and Dysmartin oxidant (16.25 g, 38.32 mmol) was added in portions at 0 °C. The reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20-1 / 2) to give 2B (3.02 g, yield: 80%).

[0147] LCMS m / z = 197.1 [M+H] +

[0148] Step 3: Preparation of 2C

[0149] 1,1-Dibromo-3,3,3-trifluoroacetone (4.98 g, 18.49 mmol, CAS: 431-67-4) was placed in a 250 mL single-necked flask, and 30 mL of water and sodium acetate (1.89 g, 23.09 mmol) were added. The mixture was reacted at 90 °C for 1 h. After cooling to room temperature, 60 mL of methanol, 2B (3.02 g, 15.39 mmol), and concentrated ammonia (15 mL) were added sequentially, and the mixture was reacted at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into 200 mL of water, filtered, and the filter cake was washed with water (2 x 10 mL). The filter cake was dried under reduced pressure to give 2C (2.9 g, yield: 62%).

[0150] LCMS m / z = 303.1 [M+H] +

[0151] 1 H NMR (400MHz, DMSO-d6) δ12.36–12.16(m,1H),7.68–7.55(m,1H),3.59(s,3H),1.90-1.72(m,12H).

[0152] Step 4: 2D fabrication

[0153] 2C (2.0 g, 6.62 mmol) was dissolved in 30 mL of DMF at room temperature, followed by the addition of isopropyl iodine (4.50 g, 26.48 mmol) and cesium carbonate (6.47 g, 19.86 mmol). The reaction was carried out overnight at 90 °C. After cooling to room temperature, the mixture was extracted with water and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20-1 / 1) to give 2D (1.2 g, yield: 52%).

[0154] LCMS m / z = 345.2 [M+H] +

[0155] Step 5: Preparation of 2E

[0156] 2D (1.2 g, 3.48 mmol) was dissolved in 20 mL of THF, and lithium borohydride (0.38 g, 17.40 mmol) was added. The mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2E (0.9 g, yield: 81%).

[0157] LCMS m / z = 317.2[M+H] +

[0158] Step 6: Preparation of 2F

[0159] At 0 °C, methanesulfonyl chloride (64 mg, 0.56 mmol) was added to a solution of 2E (0.12 g, 0.37 mmol) and triethylamine (0.11 g, 1.09 mmol) in dichloromethane (15 mL), and stirred at room temperature for 1 h. The mixture was quenched with 20 mL of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 100–1 / 20) to give 2F (0.11 g, 74% yield).

[0160] LCMS m / z = 395.1 [M+H] +

[0161] Step 7: Preparation of 2G

[0162] 1F (0.1 g, 0.58 mmol) and 2F (0.23 g, 0.58 mmol) were dissolved in DMF (5 mL), and cesium carbonate (0.38 g, 1.17 mmol) and sodium iodide (0.087 g, 0.58 mmol) were added. The mixture was reacted at 140 °C for 2 h. After cooling to room temperature, 20 mL of water and 20 mL of ethyl acetate were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to give 2G (0.060 g, yield: 22%).

[0163] LCMS m / z = 470.2[M+H] +

[0164] Step 8: Preparation of compound (I)

[0165] 2g (0.06g, 0.13mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (0.050g, 0.26mmol), XPhos G3 (0.011g, 0.013mmol, CAS: 1445085-55-1) and potassium phosphate (0.056g, 0.27mmol) were placed in a 50mL single-necked flask, 1,4-dioxane (4mL) and water (1mL) were added, the mixture was purged with nitrogen three times, and the mixture was heated to 90℃ and stirred overnight. Cool to room temperature, add 20 mL of water and 20 mL of ethyl acetate for extraction, dry the organic layer with anhydrous sodium sulfate and concentrate under reduced pressure, purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 1), purify the concentrated residue by silica gel column chromatography again (dichloromethane / methanol (V / V) = 100 / 0-100 / 3) to give compound (I) (30 mg, yield: 39%).

[0166] LCMS m / z = 584.2 [M+H] +

[0167] 1 H NMR(400MHz,CD3OD)δ8.97(d,1H),8.64(s,1H),8.38(d,1H),7.65–7.58(m,1H),4.93–4.84(m,1H),4.39(s,2H),3.93 (s,3H),2.06–1.94(m,6H),1.74–1.59(m,7H),1.41(d,6H),1.27–1.20(m,1H),1.16–1.09(m,1H),0.99–0.86(m,2H).

[0168] Preparation of crystal form

[0169] Example 2: Preparation of crystal form A of compound (I)

[0170] Weigh 40.1 mg of the compound shown in formula (I), add it to 0.2 mL of dichloromethane to dissolve, take 0.1 mL of the solution, add it dropwise to 2.0 mL of n-heptane solution, stir for 1 h, centrifuge to obtain crystal form A of compound (I).

[0171] Example 3: Preparation of crystal form B of compound (I)

[0172] Weigh 40.1 mg of the compound shown in formula (I), dissolve it in 0.2 mL of dichloromethane, take 0.1 mL of the solution, add it dropwise to 2.0 mL of isopropyl ether solution, stir for 1 h, centrifuge to obtain crystal form B of compound (I).

[0173] Example 4: Preparation of crystal form C of compound (I)

[0174] Take 40.8 mg of the compound shown in formula (I) and dissolve it in 0.4 mL of ethyl acetate. Take 0.2 mL of the solution and add it dropwise to 2.0 mL of n-heptane solution. Stir for 1 h and centrifuge to obtain crystal form C of compound (I).

[0175] Example 5: Preparation of crystal form D of compound (I)

[0176] Take 40.2 mg of the compound shown in formula (I) and dissolve it in 0.2 mL of 4-methyl-2-pentanone. Take 0.1 mL of the solution and add it dropwise to 2.0 mL of n-heptane solution. Stir for 1 h and centrifuge to obtain crystal form D of compound (I).

[0177] Example 6: Preparation of crystal form E of compound (I)

[0178] Take 20.2 mg of the compound shown in formula (I) and add it to a mixed solution of 0.5 mL water and 0.5 mL acetone. Let it stand at room temperature with the container open until the solvent has completely evaporated to obtain the crystal form E of the compound of formula (I).

[0179] Example 7: Preparation of crystal form F of compound (I)

[0180] Take 20.3 mg of the compound shown in formula (I) and dissolve it in 0.1 mL of dioxane. Take 0.1 mL of the solution and add it dropwise to 2.0 mL of n-heptane solution. Stir for 1 h and centrifuge to obtain the crystal form F of the compound of formula (I).

[0181] Example 8: Preparation of crystal form G of compound (I)

[0182] Take 20.0 mg of the amorphous sample of the compound shown in formula (I), place it in an ethyl acetate solvent atmosphere, let it stand at room temperature, and perform a gas phase diffusion experiment to obtain the crystal form G of the compound of formula (I).

[0183] Example 9: Preparation of crystal form H of compound (I)

[0184] Take 20.6 mg of the compound shown in formula (I), add 0.2 mL of ethylene glycol dimethyl ether and 0.5 mL of cyclohexane, filter and take the clear solution, and carry out a cooling crystallization experiment at 50℃→25℃→4℃→-15℃ to obtain the crystal form H of the compound of formula (I).

[0185] Example 10: Preparation of Crystal Form I of Compound (I)

[0186] Take 20.2 mg of the compound shown in formula (I), add 0.2 mL of toluene and 0.5 mL of cyclohexane, filter and take the clear solution, and carry out a cooling crystallization experiment at 50℃→25℃→4℃→-15℃. No solid precipitates. Then let it evaporate at room temperature to obtain crystal form I of compound (I).

[0187] Example 11: Preparation of crystal form J of compound (I)

[0188] Take 19.7 mg of the compound shown in formula (I), add 0.2 mL of isopropyl acetate and 0.5 mL of cyclohexane, filter and take the clear solution, and carry out a cooling crystallization experiment at 50℃→25℃→4℃→-15℃ to obtain the crystal form J of the compound of formula (I).

[0189] Example 12: Preparation of crystal form K of compound (I)

[0190] Take 19.9 mg of the compound shown in formula (I), add 0.1 mL of dioxane and 0.5 mL of cyclohexane, filter and take the clear solution, and carry out a cooling crystallization experiment at 50℃→25℃→4℃ to obtain the crystal form K of the compound of formula (I).

[0191] Example 13: Preparation of crystal form L of compound (I)

[0192] Take 20.3 mg of the compound shown in formula (I), add 0.8 mL of dioxane and 0.5 mL of water, filter and take the clear solution, and carry out a cooling crystallization experiment at 50℃→25℃→4℃ to obtain the crystal form L of the compound of formula (I).

[0193] Example 14: Preparation of crystal form M of compound (I)

[0194] Take 20.3 mg of the compound shown in formula (I), add 2.9 mL of DMSO and 0.5 mL of water, filter and take the clear solution, and carry out a cooling crystallization experiment at 50℃→25℃→4℃→15℃→4℃ to obtain the crystal form M of the compound of formula (I).

[0195] Crystal form test example

[0196] 1. Instrument Information and Testing Method Parameter Table

[0197] Table 2

[0198] 2. Specific peak value characterization results of XRD tests for each crystal form obtained in the above embodiments.

[0199] The X-ray powder diffraction (XRD) pattern of crystal form A of compound (I) is shown in Figure 2. The specific peak values ​​are shown in Table 3.

[0200] Table 3

[0201] The X-ray powder diffraction (XRD) pattern of crystal form B of compound (I) is shown in Figure 4. The specific peak values ​​are shown in Table 4.

[0202] Table 4

[0203] The X-ray powder diffraction (XRD) pattern of crystal form C of compound (I) is shown in Figure 6. The specific peak values ​​are shown in Table 5.

[0204] Table 5

[0205] The X-ray powder diffraction (XRD) pattern of crystal form D of compound (I) is shown in Figure 9. The specific peak values ​​are shown in Table 6.

[0206] Table 6

[0207] The X-ray powder diffraction (XRD) pattern of crystal form E of compound (I) is shown in Figure 11. The specific peak values ​​are shown in Table 7.

[0208] Table 7

[0209] The X-ray powder diffraction (XRD) pattern of crystal form F of compound (I) is shown in Figure 13. The specific peak values ​​are shown in Table 8.

[0210] Table 8

[0211] The X-ray powder diffraction (XRD) pattern of crystal form G of compound (I) is shown in Figure 15. The specific peak values ​​are shown in Table 9.

[0212] Table 9

[0213] The X-ray powder diffraction (XRD) pattern of crystal form H of compound (I) is shown in Figure 17. The specific peak values ​​are shown in Table 10.

[0214] Table 10

[0215] The X-ray powder diffraction (XRD) pattern of crystal form I of compound (I) is shown in Figure 19. The specific peak values ​​are shown in Table 11.

[0216] Table 11

[0217] The X-ray powder diffraction (XRD) pattern of crystal form J of compound (I) is shown in Figure 21. The specific peak values ​​are shown in Table 12.

[0218] Table 12

[0219] The X-ray powder diffraction (XRD) pattern of crystal form K of compound (I) is shown in Figure 23. The specific peak values ​​are shown in Table 13.

[0220] Table 13

[0221] The X-ray powder diffraction (XRD) pattern of crystal form L of compound (I) is shown in Figure 25. The specific peak values ​​are shown in Table 14.

[0222] Table 14

[0223] The X-ray powder diffraction (XRD) pattern of crystal form M of compound (I) is shown in Figure 27. The specific peak values ​​are shown in Table 15.

[0224] Table 15

[0225] 3. DSC (Differential Scanning Calorimetry) and TGA (Thermogravimetric Analysis) test results of each crystal form obtained in the above embodiments.

[0226] As shown in Figure 1, the differential scanning calorimetry (DSC) curve of crystal form A of compound (I) shows that there is a melting endothermic signal at around 183℃ and an endothermic signal at around 203℃. Its thermogravimetric analysis (TGA) curve shows that there is no significant weight loss during heating to 120℃, and decomposition may occur after 300℃.

[0227] As shown in Figure 3, the differential scanning calorimetry (DSC) curve of crystal form B of compound (I) shows endothermic signals around 146℃, 161℃, and 204℃, and the thermogravimetric analysis (TGA) curve shows a weight loss of 7.3% during heating to 170℃, and decomposition may occur after 300℃.

[0228] As shown in Figure 5, the differential scanning calorimetry (DSC) curve of the crystal form C of compound (I) shows that a melting endothermic signal appears at around 202℃, and the thermogravimetric analysis (TGA) curve shows that there is almost no weight loss during heating to 120℃, and decomposition may occur after 300℃.

[0229] As shown in Figure 8, the differential scanning calorimetry (DSC) curve of crystal form D of compound (I) shows endothermic signals around 136℃ and 203℃, and the thermogravimetric analysis (TGA) curve shows a 7.2% weight loss during heating to 150℃, and possible decomposition after 300℃.

[0230] As shown in Figure 10, the differential scanning calorimetry (DSC) curve of crystal form E of compound (I) shows that there are endothermic signals at around 150℃ and 203℃, and exothermic signals at around 183℃. The thermogravimetric analysis (TGA) curve shows that there is a 5.4% weight loss during heating to 150℃, and decomposition may occur after 300℃.

[0231] As shown in Figure 12, the differential scanning calorimetry (DSC) curve of the crystal form F of compound (I) shows that there are endothermic signals at around 136℃ and 201℃, and exothermic signals at around 159℃. The thermogravimetric analysis (TGA) curve shows that there is a 9.5% weight loss during heating to 210℃, and decomposition may occur after 300℃.

[0232] As shown in Figure 14, the differential scanning calorimetry (DSC) curve of the crystal form G of compound (I) shows endothermic signals at around 149℃ and 204℃, and the thermogravimetric analysis (TGA) curve shows a weight loss of 6.4% during heating to 160℃, and possible decomposition after 300℃.

[0233] As shown in Figure 16, the differential scanning calorimetry (DSC) curve of the crystal form H of compound (I) shows endothermic signals at around 155℃ and 203℃, and the thermogravimetric analysis (TGA) curve shows a weight loss of 5.2% during heating to 160℃, and decomposition may occur after 300℃.

[0234] As shown in Figure 18, the differential scanning calorimetry (DSC) curve of crystal form I of compound (I) shows endothermic signals at around 172℃ and 204℃, and the thermogravimetric analysis (TGA) curve shows a weight loss of 7.3% during heating to 200℃, and decomposition may occur after 300℃.

[0235] As shown in Figure 20, the differential scanning calorimetry (DSC) curve of the crystal form J of compound (I) shows that there are endothermic signals at around 155℃ and 204℃, and an exothermic signal at around 163℃. The thermogravimetric analysis (TGA) curve shows that there is a 6.9% weight loss during heating to 200℃, and decomposition may occur after 300℃.

[0236] As shown in Figure 22, the differential scanning calorimetry (DSC) curves of the crystal form K of compound (I) show endothermic signals at around 153℃, 168℃, and 203℃, while the thermogravimetric analysis (TGA) curves show a 6.3% weight loss during heating to 180℃, and possible decomposition after 300℃.

[0237] As shown in Figure 24, the differential scanning calorimetry (DSC) curve of the crystal form L of compound (I) shows that a melting endothermic signal appears at around 177℃, and the thermogravimetric analysis (TGA) curve shows that there is a 1.3% weight loss during heating to 150℃, and decomposition may occur after 300℃.

[0238] As shown in Figure 26, the differential scanning calorimetry (DSC) curve of the crystal form M of compound (I) shows endothermic signals at around 136℃ and 201℃, and exothermic signals at around 152℃. The thermogravimetric analysis (TGA) curve shows a weight loss of 9.2% during heating to 150℃, and possible decomposition after 300℃.

[0239] 4. Studies on the stability of related crystal forms

[0240] Take a sample of compound (I) in crystal form C, place it in a simulating commercially available package at 40℃±2℃ and 75%±5% relative humidity for 6 months, and take samples in the 1st, 2nd, 3rd and 6th months to test various indicators.

[0241] Table 16 Accelerated Test Results (40℃±2℃ / 75%RH±5%RH)

[0242] Conclusion: The solid-state stability of the compound of formula (I) crystal form C is good under the above conditions.

[0243] Take a sample of compound (I) in crystal form C, place it in a simulating commercial packaging at 30℃±2℃ and relative humidity of 65%±5% for 6 months, and take samples at 0, 3 and 6 months to test various indicators.

[0244] Table 17 Long-term test results (30℃±2℃ / 65%RH±5%RH)

[0245] Conclusion: The solid-state stability of the compound of formula (I) crystal form C is good under the above conditions.

[0246] Take a sample of compound (I) in crystal form C, simulate commercial packaging, and place it under conditions of 40℃±2℃, 60℃±2℃, light, and high humidity for 30 days. Samples were taken on days 0, 5, 10, and 30 to test various indicators.

[0247] Table 18 Results of Factors Affecting High Temperature (40℃)

[0248] Table 19 Results of Factors Affecting High Temperature (60℃)

[0249] Table 20 Illumination (5000 lx, 90 μw / cm²) 2 Influencing factors results

[0250] Table 21 Results of Factors Affecting High Humidity (25℃±2℃, RH 92.5%)

[0251] Conclusion: According to Tables 18 to 21, the solid-state stability of compound (I) crystal form C is good under the above conditions.

[0252] 5. Competition and interconversion of crystal forms

[0253] 5-1 Competitive Suspension Experiment

[0254] Competitive suspension experiments of the anhydrous system were conducted at different temperatures (room temperature, 10 and 50 °C). The results are shown in Table 22. In the range of 10 °C to 50 °C, the anhydrous crystal form C is thermodynamically more stable than the crystal form A.

[0255] Table 22 Competitive Suspension Results

[0256] 5-2 Offline Thermal Transfer Crystallization Method

[0257] Offline thermal crystallization experiments were conducted using different crystal forms as raw materials. The materials were heated to the target temperature and kept at that temperature for a period of time. After cooling to room temperature, solids were obtained for XRPD testing. The results are shown in Table 23.

[0258] Table 23 Results of Offline Thermal Conversion

[0259] As shown in Table 23, crystal forms D, E, F, G, H, I, and J all transform into crystal form C.

[0260] 5-3 Online Variable Temperature XRPD Experiment

[0261] In the online variable-temperature XRPD experiment, the sample was tested at room temperature, then heated to the selected temperature at 20℃ / min, held at that temperature for 10 min, and then tested again at that temperature. The sample was then cooled to room temperature and tested again. The results are shown in Table 24.

[0262] Table 24 Results of Online Variable Temperature XRPD

[0263] Crystal form A will transform into crystal form C when heated to 185℃.

[0264] 6. Biological Test Examples

[0265] Test Example 1: USP1 / UAF1 Enzymatic Inhibitory Activity

[0266] Using rhodamine 110 ubiquitin as a substrate, the activity of the deubiquitinating enzyme USP1 / UAF1 after drug treatment was detected. The total experimental volume was 20 μL, and the test buffer consisted of 50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Bovine Serum Albumin, 1 mM DTT, and 0.01% Tween-20. At the start of the experiment, 0.5 nM of USP1 / UAF1 (Bio-Techne, E-568-050) protein was added to a 384-well plate (PerkinElmer, 6008269), followed by serially diluted test compounds. The plate was incubated at room temperature for 10 min, then 500 nM of rhodamine 110 (Bio-Techne, U-555-050) was added, and the plate was incubated at room temperature for 20 min. Enspire was used. TM The PerkinElmer multilabel reader was used for detection at 485 nM excitation light / 535 nM emission light. The IC50 was calculated using GraphPad Prism software. 50 value.

[0267] Table 25 Results of the test compounds' inhibitory activity against USP1 / UAF1 enzymes.

[0268] Note: A < 20nM

[0269] Conclusion: The compound of formula (I) of the present invention has a good inhibitory effect on the enzymatic activity of USP1 / UAF1.

[0270] Test Example 2: Pharmacokinetic Test in Beagle Dogs

[0271] Experimental objective: To evaluate the pharmacokinetic characteristics of the test substance in beagle dogs by administering a single dose intravenously and by gavage to beagle dogs, determining the concentration of the test substance in beagle plasma, and administering the test substance in beagle dogs with a single dose.

[0272] Experimental animals: Male beagle dogs, weighing approximately 8–11 kg, purchased from Beijing Mars Biotechnology Co., Ltd.

[0273] Experimental Methods: On the day of the experiment, beagles were randomly grouped according to body weight. They were fasted for 14–18 hours prior to administration but allowed free access to water. Food was given 4 hours after administration. Administration was performed according to the information in the table below.

[0274] Table 26 Drug Administration Information Table

[0275] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC

[0276] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose solution;)

[0277] Sampling: Blood was collected via the jugular vein or limb vein before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min.

[0278] Blood collection time points: 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h. All samples were stored below -60℃ before analysis. Quantitative analysis of samples was performed using LC-MS / MS.

[0279] Table 27 Pharmacokinetic parameters of the tested compounds in beagle plasma

[0280] *Note: The compound was administered via gavage (ig).

[0281] Conclusion: The compound of formula (I) of this invention exhibits good oral absorption in beagle dogs, and its oral absorption performance is superior to that of control compound A, wherein control compound A is... The preparation method is described in WO2020132269.

[0282] Test Example 3: MDA-MB-436 Cell Clonal Formation Assay

[0283] This experiment used MDA-MB-436 cells, treated with the test compound, to detect their colony-forming ability. At the start of the experiment, 500 MDA-MB-436 cells (ATCC, HTB-130) were added to each well of a 96-well plate (Corning, 3599) and incubated overnight. The next day, serially diluted compounds were added, and the plates were incubated at 37°C in a CO2-free incubator. On day 7, the old culture medium was discarded, and the serially diluted test compound was added again. On day 14, the 96-well plates were removed, the culture medium was discarded, and cell colonies were detected using a Crystal Violet Assay Kit. A Pherastar FSX microplate reader (BMG LABTECH) was used to analyze the cell colonies at OD500. 570 Detection at nM. IC is calculated using GraphPad Prism software. 50 value.

[0284] Table 28 Results of the test compounds' inhibitory activity against MDA-MB-436 cell clones

[0285] Note: A < 200 nM

[0286] Conclusion: The compound of formula (I) of this invention has a good inhibitory effect on the formation of MDA-MB-436 cell clones.

[0287] Test Example 4: Mouse Pharmacokinetic Test

[0288] Experimental animals: Male ICR mice, 25–30 g. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0289] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0290] Table 29 Test Information Table

[0291] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose)

[0292] Blood samples were collected via the orbital rim before and after drug administration at designated time points. The samples were placed in EDTAK2 centrifuge tubes and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. All samples were stored below -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0293] Table 30 Pharmacokinetic parameters of the tested compounds in mouse plasma

[0294] *Note: The compound was administered via gavage (ig).

[0295] Conclusion: The compound of formula (I) of this invention has good oral absorption performance in mice.

Claims

1. A crystalline form of a compound of Formula (I): ###00001### (I) ​ 2. The crystalline form of claim 1, wherein, said crystalline form is Form A, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Q positions using Cu-Ka radiation: 6.60°±0.2°, 9.50°±0.2°, 10.02°±0.2°, 13.27°±0.2°, 19.98°±0.2°; or having characteristic diffraction peaks at the following 2Q positions: 6.60°±0.2°, 9.50°±0.2°, 10.02°±0.2°, 10.44°±0.2°, 11.90°±0.2°, 13.27°±0.2°, 17.19°±0.2°, 17.22°±0.2°, 19.03°±0.2°, 19.43°±0.2°, 19.98°±0.2°, 21.54°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 2.

3. The crystalline form of claim 1, wherein, said crystalline form is Form B, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Q positions using Cu-Ka radiation: 5.90°±0.2°, 6.89°±0.2°, 9.96°±0.2°, 11.89°±0.2°, 12.51°±0.2°, 13.83°±0.2°, 14.32°±0.2°, 19.39°±0.2°; or having characteristic diffraction peaks at the following 2Q positions: 5.90°±0.2°, 6.89°±0.2°, 9.96°±0.2°, 11.89°±0.2°, 12.51°±0.2°, 13.83°±0.2°, 14.32°±0.2°, 14.91°±0.2°, 16.21°±0.2°, 17.92°±0.2°, 19.39°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 4.

4. The crystalline form of claim 1, wherein, said crystalline form is Form C, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Q positions using Cu-Ka radiation: 12.18°±0.2°, 16.71°±0.2°, 17.10°±0.2°; preferably, using Cu-Ka radiation, the X-ray powder diffraction pattern of said Form C has characteristic diffraction peaks at the following 2Q positions: 12.18°±0.2°, 16.71°±0.2°, 17.10°±0.2°, 17.35°±0.2°, 19.47°±0.2°; preferably, using Cu-Ka radiation, an X-ray powder diffraction pattern of said Form C is substantially as shown in Figure 6.

5. The crystalline form of claim 1, wherein, said crystalline form is Form D, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Q positions using Cu-Ka radiation: 7.31°±0.2°, 7.74°±0.2°; or having characteristic diffraction peaks at the following 2Q positions: 7.31°±0.2°, 7.74°±0.2°, 13.02°±0.2°, 19.60°±0.2°, 19.74°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 9; or the crystalline form is Form E, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 6.95°±0.2°, 10.02°±0.2°, 13.96°±0.2°, 14.37°±0.2°; or characteristic diffraction peaks at 5.94°±0.2°, 6.95°±0.2°, 10.02°±0.2°, 11.93°±0.2°, 12.60°±0.2°, 13.96°±0.2°, 14.37°±0.2°, 19.53°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 11 ; or the crystalline form is Form F, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 11.44°±0.2°, 18.20°±0.2°, 20.02°±0.2°, 20.23°±0.2°; or characteristic diffraction peaks at 6.90°±0.2°, 8.29°±0.2°, 9.76°±0.2°, 10.68°±0.2°, 11.44°±0.2°, 12.66°±0.2°, 13.90°±0.2°, 15.87°±0.2°, 16.68°±0.2°, 18.20°±0.2°, 18.80°±0.2°, 19.15°±0.2°, 20.02°±0.2°, 20.23°±0.2°, 21.25°±0.2°, 21.51°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 13; or the crystalline form is Form G, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 6.90°±0.2°, 10.01°±0.2°, 13.89°±0.2°; or characteristic diffraction peaks at 5.90°±0.2°, 6.90°±0.2°, 10.01°±0.2°, 11.89°±0.2°, 12.59°±0.2°, 13.89°±0.2°, 14.34°±0.2°, 20.82°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 15; or the crystalline form is Form H, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 9.99°±0.2°, 13.87°±0.2°; or characteristic diffraction peaks at 6.90°±0.2°, 9.99°±0.2°, 12.55°±0.2°, 13.87°±0.2°, 14.33°±0.2°, 16.34°±0.2°, 19.39°±0.2°, 20.65°±0.2°, 20.88°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 17; or the crystalline form is Form I, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 6.90°±0.2°, 10.01°±0.2°, 13.86°±0.2°, 14.27°±0.2°, 20.90°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 19; or the crystalline form is Form J, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 9.96°±0.2°, 13.82°±0.2°; or characteristic diffraction peaks at 5.91°±0.2°, 6.87°±0.2°, 9.96°±0.2°, 11.90°±0.2°, 12.49°±0.2°, 13.82°±0.2°, 14.32°±0.2°, 14.90°±0.2°, 16.25°±0.2°, 17.90°±0.2°, 19.41°±0.2°, 20.82°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 21; or the crystalline form is Form K, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 10.01°±0.2°, 14.33°±0.2°; or characteristic diffraction peaks at 6.90°±0.2°, 10.01°±0.2°, 12.64°±0.2°, 13.61°±0.2°, 13.86°±0.2°, 14.33°±0.2°, 20.86°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 23; or the crystalline form is Form L, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 5.38°±0.2°, 10.84°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 25; or the crystalline form is Form M, which has an X-ray powder diffraction pattern using Cu-Ka radiation with characteristic diffraction peaks at 9.89°±0.2°, 13.85°±0.2°; or characteristic diffraction peaks at 5.90°±0.2°, 6.86°±0.2°, 9.89°±0.2°, 11.89°±0.2°, 13.85°±0.2°, 14.31°±0.2°, 14.91°±0.2°, 19.37°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 27.

6. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 1-5, preferably 1-1500 mg, and a pharmaceutically acceptable carrier and / or excipient.

7. Use of the crystalline form of any one of claims 1-5, or the pharmaceutical composition of claim 6, for the manufacture of a medicament for treating a tumor associated with USP1.

8. A method for treating a tumor disease associated with USP1, the method comprising administering to a subject a therapeutically effective amount of the crystalline form of any one of claims 1-5 or the pharmaceutical composition of claim 6, preferably 1-1500 mg, preferably the disease is a tumor.

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