Crystalline forms of tricyclic kinase inhibitors

Abstract

The present invention relates to salts of a tricyclic DNA-PK kinase inhibitor, N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purine-2-amine, crystalline forms or cocrystals of the salts, and methods for preparing the same. The crystalline forms all have the characteristics of high purity, high solubility, good disintegration and dissolution properties, and have good properties, fluidity, and compressibility, making them easy to produce, test, prepare, transport, and store. The preparation method is simple to operate, suitable for industrial production, and can significantly enhance the sensitivity of tumor cells to radiotherapy / chemotherapy and other anticancer agents.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a salt and a crystal form of a targeted DNA-PK kinase inhibitor and a preparation method thereof, and also relates to a pharmaceutical composition comprising the salt and the crystal form, and the use of these salts, crystal compounds and the composition thereof in the preparation of drugs for treating and / or preventing cancer diseases. Background Art

[0002] Cancer is a malignant disease that is difficult to treat worldwide. Its treatment is challenging, its mortality rate is high, and it places a heavy burden on patients and their families. It is a major health issue affecting Chinese residents. In recent years, the incidence of cancer in my country has increased significantly, and its mortality rate has also been gradually rising, posing a grim challenge to cancer prevention and control.

[0003] Currently, radiotherapy and chemotherapy are the most effective cancer treatments besides surgical resection. Radiotherapy is also the most effective non-surgical treatment for malignant tumors. Radiation and many anticancer drugs can directly or indirectly affect DNA or DNA metabolism, causing DNA damage. DNA double-strand breaks (DSBs) are the most lethal to cancer cells. DNA damage triggers a series of cellular responses, including repair of damaged DNA. This repair process enhances cancer cell survival, which is one of the mechanisms by which tumor cells resist radiotherapy and chemotherapy. If DNA double-strand breaks are not promptly and completely repaired, cancer cells will die due to apoptosis and / or mitotic arrest. Therefore, inhibiting the repair of these DNA lesions can increase cancer cell sensitivity to radiotherapy and chemotherapy, inhibiting cell proliferation.

[0004] In higher eukaryotic cells such as humans, DSB repair is primarily carried out through DNA nonhomologous end joining (NHEJ), a process driven by DNA-dependent protein kinases (DNA-PKs). This repair of damaged DNA maintains cell viability and genomic stability. NHEJ repair primarily occurs during the G1 / S phase of DNA damage and does not require a DNA end joining template. NHEJ repair requires the coordinated efforts of numerous proteins and signaling pathways. The active DNA-PK enzyme complex is comprised of a heterodimer of Ku70 / 80 subunits and the catalytic subunit, DNA-dependent protein kinase (DNA-PKcs).

[0005] DNA-PKcs is a serine / threonine protein kinase belonging to the phosphatidylinositol 3-kinase (PI3K) superfamily; the PI3K superfamily also includes ATM, ATR, mTOR, and four PI3K isoforms. DNA-PKcs' kinase activity is activated when it binds to broken DNA. A key function of Ku is to bind to DNA ends, recruit DNA-PKcs, and the two together form and activate the DNA-PK holoenzyme. Activated DNA-PKcs directs the Artemis protein (an endonuclease) to bind to the damaged site, where its nuclease activity processes the DNA ends to facilitate ligation repair. The XRCC4 / DNA-ligase IV complex is then recruited by activated DNA-PKcs, and DNA-ligase IV locates and ligates the broken DNA double-stranded ends, completing the repair. XRCC4 forms a complex with DNA-ligase IV, increasing its activity. DNA-PKcs has 40 autophosphorylated amino acid residues, with the most typical autophosphorylation sites occurring at Ser2056 (POR cluster) and Thr2609 (ABCDE cluster). NHEJ is believed to proceed through three key steps: DSB recognition—Ku70 / 80 binds to incomplete DNA ends and recruits two DNA-PKcs molecules to the adjacent sides of the DSB; DNA processing to remove unligatable ends or other forms of damage at the ends; and finally, ligation of the DNA ends.

[0006] Because tumor cells have higher basal levels of endogenous replication stress (oncogene-induced replication stress) and DNA damage, and the DNA repair mechanism is less efficient in tumor cells, tumor cells are more sensitive to DNA-PK.

[0007] Chinese patent application CN202110438932.4 discloses the compound N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purin-2-amine shown in formula (I), which has excellent DNA-PK activity, liver microsomal stability and pharmacokinetic properties, can significantly enhance the sensitivity of tumor cells to radio / chemotherapy and other anticancer agents, and has high safety.

[0008]

[0009] In order to better control the quality of drugs and meet the requirements of formulation, production, transportation, storage, etc., we have studied the salts of the compound of formula (I) and its crystal forms in order to find a crystal form with good properties.

[0010] In order to make the disclosure of this application more comprehensive, all technical contents in Chinese patent application CN202110438932.4 are introduced into this application. Summary of the Invention

[0011] The present disclosure relates to salts of the DNA-PK kinase inhibitor N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purin-2-amine represented by formula (I), and their crystal forms and cocrystals. The present disclosure also relates to pharmaceutical compositions of the above-mentioned salts, crystal forms, and cocrystals, as well as the use of these salts, crystal forms, cocrystals, or compositions in the preparation of medicaments for treating and / or preventing cancer.

[0012] In one aspect, the present disclosure provides a salt of a compound represented by formula (I), wherein:

[0013]

[0014] The salt is selected from hydrochloride, sulfate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, and malate.

[0015] In certain embodiments, the salt of the compound of formula (I) is characterized in that

[0016] The salt is a hydrochloride, and the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2;

[0017] Or the salt is a sulfate, and the molar ratio of the compound of formula (I) to sulfuric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to sulfuric acid is 1:1;

[0018] Or the salt is a methanesulfonate, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1;

[0019] Or the salt is p-toluenesulfonate, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1;

[0020] Or the salt is a maleate, and the molar ratio of the compound of formula (I) to maleic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to maleic acid is 1:1;

[0021] Or the salt is a fumarate, and the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to fumaric acid is 1:1-1:0.5;

[0022] Or the salt is malate, and the molar ratio of the compound of formula (I) to malic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to malic acid is 1:0.8.

[0023] The present disclosure also provides a crystalline form or co-crystal of a compound represented by formula (I), wherein:

[0024]

[0025] The crystal form or cocrystal is hydrochloride crystal form A, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 7.5±0.2°, 9.4±0.2°, 18.2±0.2°, 22.9±0.2°, 24.9±0.2°, 26.6±0.2°, and 27.5±0.2°;

[0026] Or the crystal form or cocrystal is sulfate crystal form A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 8.4±0.2°, 16.5±0.2°, 19.4±0.2°, 21.1±0.2°, and 22.5±0.2°;

[0027] Or the crystalline form or cocrystal is mesylate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.0±0.2°, 6.4±0.2°, 7.3±0.2°, 12.2±0.2°, 14.7±0.2°, 21.2±0.2°, 22.9±0.2°, and 26.6±0.2°;

[0028] Or the crystalline form or cocrystal is mesylate crystalline form B, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 13.4±0.2°, 14.4±0.2°, 16.0±0.2°, 19.5±0.2°, 24.0±0.2°, and 26.7±0.2°;

[0029] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.7±0.2°, 10.2±0.2°, 15.2±0.2°, 19.3±0.2°, 25.9±0.2°, and 27.4±0.2°;

[0030] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form B, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 5.5±0.2°, 6.3±0.2°, 12.6±0.2°, 16.4±0.2°, 18.3±0.2°, 21.8±0.2°, and 26.8±0.2°;

[0031] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form C, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°, 22.5±0.2°, and 26.4±0.2°;

[0032] Or the crystal form or cocrystal is maleic acid cocrystal A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 8.0±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 21.0±0.2°, and 21.5±0.2°;

[0033] Or the crystal form or cocrystal is fumaric acid cocrystal A, which uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 9.0±0.2°, 13.2±0.2°, 18.7±0.2°, 20.9±0.2°, 26.3±0.2°, and 27.8±0.2°;

[0034] Or the crystal form or cocrystal is fumaric acid cocrystal B, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 11.8±0.2°, 12.5±0.2°, 14.1±0.2°, 17.6±0.2°, 18.0±0.2°, 18.7±0.2°, 19.4±0.2°, 23.3±0.2°, and 26.7±0.2°;

[0035] Or the crystal form or cocrystal is malic acid cocrystal A, which uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 10.6±0.2°, 13.2±0.2°, 15.9±0.2°, 16.4±0.2°, 19.0±0.2°, and 19.8±0.2°.

[0036] In certain embodiments, the crystalline form or co-crystal of the compound of formula (I) is,

[0037] The crystal form or cocrystal is hydrochloride crystal form A, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 7.5±0.2°, 9.4±0.2°, 10.1±0.2°, 14.3±0.2°, 18.2±0.2°, 21.1±0.2°, 22.9±0.2°, 24.9±0.2°, 26.6±0.2°, 27.5±0.2°, and 27.9±0.2°;

[0038] Or the crystal form or cocrystal is sulfate crystal form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.4±0.2°, 12.8±0.2°, 14.2±0.2°, 16.5±0.2°, 16.9±0.2°, 19.4±0.2°, 19.9±0.2°, 21.1±0.2°, 21.5±0.2°, 22.5±0.2°, 24.9±0.2°, and 27.8±0.2°;

[0039] Or the crystalline form or cocrystal is mesylate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.0±0.2°, 6.4±0.2°, 7.3±0.2°, 12.2±0.2°, 14.3±0.2°, 14.7±0.2°, 15.2±0.2°, 18.3±0.2°, 19.3±0.2°, 21.2±0.2°, 22.9±0.2°, and 26.6±0.2°;

[0040] Or the crystalline form or cocrystal is mesylate crystalline form B, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 8.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.0±0.2°, 17.8±0.2°, 19.5±0.2°, 20.3±0.2°, 20.9±0.2°, 21.5±0.2°, 24.0±0.2°, 25.4±0.2°, 26.7±0.2°, and 28.0±0.2°;

[0041] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.3±0.2°, 15.2±0.2°, 16.6±0.2°, 19.3±0.2°, 20.9±0.2°, 22.5±0.2°, 24.1±0.2°, 25.9±0.2°, and 27.4±0.2°;

[0042] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form C, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°, 16.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.5±0.2°, 19.6±0.2°, 22.5±0.2°, 25.3±0.2°, and 26.4±0.2°;

[0043] Or the crystalline form or cocrystal is maleic acid cocrystal A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 8.0±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 18.9±0.2°, 20.4±0.2°, 21.0±0.2°, 21.5±0.2°, 26.5±0.2°, 27.2±0.2°, and 28.2±0.2°;

[0044] Or the crystal form or cocrystal is fumaric acid cocrystal A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 9.0±0.2°, 13.2±0.2°, 16.7±0.2°, 17.3±0.2°, 17.9±0.2°, 18.7±0.2°, 20.9±0.2°, 22.0±0.2°, 26.3±0.2°, and 27.8±0.2°;

[0045] Or the crystal form or cocrystal is fumaric acid cocrystal B, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 11.8±0.2°, 12.5±0.2°, 14.1±0.2°, 15.0±0.2°, 16.5±0.2°, 17.6±0.2°, 18.0±0.2°, 18.7±0.2°, 19.4±0.2°, 22.5±0.2°, 23.3±0.2°, 26.7±0.2°, 30.1±0.2°, and 31.2±0.2°;

[0046] Or the crystal form or cocrystal is malic acid cocrystal A, which uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 10.6±0.2°, 12.3±0.2°, 13.2±0.2°, 15.9±0.2°, 16.4±0.2°, 19.0±0.2°, 19.8±0.2°, 25.6±0.2°, 26.8±0.2°, and 28.7±0.2°.

[0047] In certain embodiments, the crystalline form or co-crystal of the compound of formula (I) is,

[0048] The crystal form or co-crystal is hydrochloride crystal form A, which has substantially the following Figure 1 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0049] Or the crystal form or co-crystal is sulfate crystal form A, which has substantially Figure 4 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0050] Or the crystal form or co-crystal is mesylate crystal form A, which has substantially Figure 7 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0051] Or the crystal form or co-crystal is mesylate crystal form B, which has substantially Figure 10 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0052] Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form A, which has substantially Figure 13 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0053] Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form B, which has substantially Figure 16 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0054] Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form C, which has substantially Figure 19 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0055] Or the crystal form or cocrystal is maleic acid cocrystal A, which has substantially Figure 22 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0056] Or the crystal form or cocrystal is fumaric acid cocrystal A, which has substantially Figure 25 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0057] Or the crystal form or cocrystal is fumaric acid cocrystal B, which has substantially Figure 28 The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown;

[0058] Or the crystal form or co-crystal is malic acid co-crystal A, which has substantially Figure 31The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0059] In certain embodiments, the crystalline forms and co-crystals of the compound of formula (I), wherein

[0060] The crystal form or co-crystal is hydrochloride crystal form A, and the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2;

[0061] Or the crystal form or co-crystal is sulfate crystal form A, and the molar ratio of the compound of formula (I) to sulfuric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to sulfuric acid is 1:1;

[0062] Or the crystalline form or co-crystal is mesylate crystalline form A, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1;

[0063] Or the crystalline form or co-crystal is mesylate crystalline form B, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1;

[0064] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form A, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1;

[0065] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form B, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1;

[0066] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form C, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1;

[0067] Or the crystal form or cocrystal is maleic acid cocrystal A, and the molar ratio of the compound of formula (I) to maleic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to maleic acid is 1:1;

[0068] Or the crystal form or cocrystal is fumaric acid cocrystal A, and the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to fumaric acid is 1:1;

[0069] Or the crystal form or cocrystal is fumaric acid cocrystal B, and the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to fumaric acid is 1:0.7;

[0070] Or the crystal form or cocrystal is malic acid cocrystal A, and the molar ratio of the compound of formula (I) to malic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to malic acid is 1:0.8.

[0071] In certain embodiments, the crystalline form or co-crystal of the compound of formula (I) is,

[0072] The crystal form or cocrystal is hydrochloride crystal form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 50°C to 100°C and an endothermic peak in the range of 210°C to 270°C; preferably, the maximum endothermic transition temperature is 253.0±5°C; more preferably, the hydrochloride crystal form A has substantially Figure 2 Differential scanning calorimetry curve shown;

[0073] Or the crystal form or co-crystal is sulfate crystal form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 50°C to 75°C, 75°C to 110°C, 175°C to 225°C, and 225°C to 250°C; preferably, the maximum endothermic transition temperature is 238.1±5°C; more preferably, the sulfate crystal form A has substantially Figure 5 Differential scanning calorimetry curve shown;

[0074] Or the crystalline form or co-crystal is mesylate crystalline form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 60°C to 100°C, 125°C to 150°C, 185°C to 200°C, and 225°C to 260°C, and an exothermic peak in the range of 160°C to 175°C and 200°C to 215°C; preferably, the maximum endothermic transition temperature is 244.3±5°C; more preferably, the mesylate crystalline form A has substantially Figure 8 Differential scanning calorimetry curve shown;

[0075] Or the crystal form or co-crystal is mesylate crystal form B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 75°C to 90°C, 100°C to 120°C, 210°C to 225°C, and 225°C to 250°C; preferably, the maximum endothermic transition temperature is 234.9±5°C; more preferably, the mesylate crystal form B has substantially Figure 11 Differential scanning calorimetry curve shown;

[0076] Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 125°C to 160°C and 230°C to 265°C, and also has an exothermic peak in the range of 175°C to 210°C; preferably, the maximum endothermic transition temperature is 251.6±5°C; more preferably, the p-toluenesulfonate crystalline form A has substantially Figure 14 Differential scanning calorimetry curve shown;

[0077] Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 85°C to 125°C and 130°C to 160°C; preferably, the maximum endothermic transition temperature is 145.3±5°C; more preferably, the p-toluenesulfonate crystalline form B has substantially Figure 17 Differential scanning calorimetry curve shown;

[0078] Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form C, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 75°C to 110°C, 190°C to 210°C, and 210°C to 230°C; preferably, the p-toluenesulfonate crystalline form C has substantially Figure 20 Differential scanning calorimetry curve shown;

[0079] Or the crystal form or cocrystal is maleic acid cocrystal A, whose differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 190°C to 200°C and an exothermic peak in the range of 200°C to 210°C; preferably, the maximum endothermic transition temperature is 200.0±5°C; more preferably, the maleic acid cocrystal A has substantially Figure 23 Differential scanning calorimetry curve shown;

[0080] Or the crystal form or cocrystal is fumaric acid cocrystal A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 60°C to 80°C, 90°C to 125°C, and 190°C to 225°C; preferably, the fumaric acid cocrystal A has substantially Figure 26 Differential scanning calorimetry curve shown;

[0081] Or the crystal form or cocrystal is fumaric acid cocrystal B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 100°C to 150°C and 210°C to 250°C; preferably, the maximum endothermic transition temperature is 231.2±5°C; more preferably, the fumaric acid cocrystal B has substantially Figure 29 Differential scanning calorimetry curve shown;

[0082] Or the crystal form or cocrystal is malic acid cocrystal A, whose differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 175°C to 210°C; preferably, the maximum endothermic transition temperature is 194.5±5°C; more preferably, the malic acid cocrystal A has substantially Figure 32 The differential scanning calorimetry curve is shown.

[0083] In certain embodiments, the crystalline form or co-crystal of the compound of formula (I) is,

[0084] The crystal form or co-crystal is hydrochloride crystal form A, which is a hydrate;

[0085] Or the crystal form or co-crystal is mesylate crystal form A, which is a hydrate;

[0086] Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form A, which is an ethanol solvate; preferably, in the p-toluenesulfonate crystalline form A, the molar ratio of the compound of formula (I) to ethanol is 1:1;

[0087] Or the crystal form or co-crystal is p-toluenesulfonate crystal form B, which is a hydrate; preferably, the p-toluenesulfonate crystal form B has a water content of 7.0±1% by weight;

[0088] Or the crystal form or co-crystal is p-toluenesulfonate crystal form C, which is a hydrate; preferably, the p-toluenesulfonate crystal form C has a water content of 6.0±1% by weight;

[0089] Or the crystal form or cocrystal is fumaric acid cocrystal A, which is an ethanol solvate; preferably, the weight percentage of ethanol in the fumaric acid cocrystal A is 8.2±1%;

[0090] Or the crystal form or cocrystal is fumaric acid cocrystal B, which is a tetrahydrofuran solvate; preferably, the weight percentage of tetrahydrofuran in the fumaric acid cocrystal B is 5.8±1%.

[0091] The present disclosure also provides a method for preparing a crystalline form or co-crystal of a compound of formula (I), comprising the following steps:

[0092] An organic solvent and 1-2 equivalents of an acid are added to the compound of formula (I), stirred at room temperature, and the solvent is separated to obtain a crystalline form or co-crystal of the compound of formula (I).

[0093] In certain embodiments, the acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, and malic acid.

[0094] In certain embodiments, the acid includes the acid alone and in solution.

[0095] In certain embodiments, in the method for preparing the crystalline form or co-crystal of the compound of formula (I), the organic solvent is selected from one or a combination of two or more of the following solvents:

[0096] (1) an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexanol, benzyl alcohol, phenylethyl alcohol, or phenylpropyl alcohol;

[0097] (2) a halogenated alkane solvent selected from dichloromethane or chloroform;

[0098] (3) a nitrile solvent selected from acetonitrile or propionitrile;

[0099] (4) an ester solvent selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate;

[0100] (5) a ketone solvent selected from acetone, butanone, isobutyl ketone, methyl isobutyl ketone or 4-methyl-2-pentanone;

[0101] (6) an alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane;

[0102] (7) Ether solvents, including diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane;

[0103] (8) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

[0104] In certain embodiments, the organic solvent is selected from: methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetone, or any combination of two or more of the above solvents.

[0105] In certain embodiments, the organic solvent is selected from ethanol, tetrahydrofuran, acetone, ethanol / tetrahydrofuran or ethanol / acetone.

[0106] In certain embodiments, the volume ratio of a single solvent in the mixed solvent of the combination of any two solvents is less than 1:10, more preferably, the volume ratio is less than 1:15.

[0107] In certain embodiments, the method for preparing the crystal form or co-crystal of the compound of formula (I) can be performed by crystallization, solvent separation, and drying after the reaction is completed to obtain the crystal form or co-crystal.

[0108] In certain embodiments, the crystallization is selected from room temperature crystallization or cooling crystallization.

[0109] In certain embodiments, the room temperature crystallization is selected from room temperature stirring crystallization and room temperature standing crystallization.

[0110] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0111] In certain embodiments, in the method for preparing the crystal form or cocrystal of the compound of formula (I), the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes the feeding process, the raw material dissolution process, the reaction process, and the crystallization process.

[0112] In certain embodiments, in the method for preparing the crystalline form of the compound of formula (I), the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, for example, 30°C-80°C, 30°C-70°C, 35°C-70°C, 40°C-65°C, 40°C-60°C, 40°C-50°C, 35°C-50°C, etc.; the drying process can be optionally performed multiple times at different temperatures.

[0113] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0114] In one aspect, the present disclosure provides a salt of a compound represented by formula (I),

[0115]

[0116] Wherein, the salt is hydrochloride.

[0117] The present disclosure also provides a hydrochloride crystalline form A of a compound of formula (I),

[0118]

[0119] It uses Cu-Kα radiation, and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 7.5±0.2°, 9.4±0.2°, 18.2±0.2°, 22.9±0.2°, 24.9±0.2°, 26.6±0.2°, and 27.5±0.2°.

[0120] In certain embodiments, the hydrochloride form A of the compound of formula (I) uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.5±0.2°, 9.4±0.2°, 10.1±0.2°, 14.3±0.2°, 18.2±0.2°, 21.1±0.2°, 22.9±0.2°, 24.9±0.2°, 26.6±0.2°, 27.5±0.2°, and 27.9±0.2°.

[0121] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) has substantially Figure 1 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0122] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) has a differential scanning calorimetry (DSC) analysis curve having an endothermic peak in the range of 50°C to 100°C, and also having an endothermic peak in the range of 210°C to 270°C.

[0123] In certain embodiments, the hydrochloride crystalline form A of the compound of formula (I) has a maximum endothermic transition temperature of 253.0±5°C in its differential scanning calorimetry (DSC) analysis curve.

[0124] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) has substantially Figure 2 The differential scanning calorimetry curve is shown.

[0125] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) is a hydrate.

[0126] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) has substantially Figure 2 Thermogravimetric analysis (TGA) curves are shown.

[0127] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) has substantially Figure 3 shown 1 H-NMR spectrum.

[0128] In certain embodiments, the hydrochloride salt form A of the compound of formula (I) is in a substantially pure form.

[0129] The present disclosure also provides a method for preparing hydrochloride crystalline form A of the compound of formula (I), comprising the following steps:

[0130] To the compound of formula (I), an organic solvent and 1-2 equivalents of hydrochloric acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain hydrochloride crystal form A of the compound of formula (I).

[0131] In certain embodiments, the hydrochloric acid is a hydrochloric acid solution; preferably, the hydrochloric acid solution is an ethanol solution containing hydrochloric acid; preferably, the concentration of the hydrochloric acid solution is 1 mol / L.

[0132] In certain embodiments, the organic solvent is selected from one of the following solvents or any combination of two or more solvents:

[0133] (1) an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexanol, benzyl alcohol, phenylethyl alcohol, or phenylpropyl alcohol;

[0134] (2) a halogenated alkane solvent selected from dichloromethane or chloroform;

[0135] (3) a nitrile solvent selected from acetonitrile or propionitrile;

[0136] (4) an ester solvent selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate;

[0137] (5) a ketone solvent selected from acetone, butanone, isobutyl ketone, methyl isobutyl ketone or 4-methyl-2-pentanone;

[0138] (6) an alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane;

[0139] (7) Ether solvents, including diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane;

[0140] (8) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

[0141] In certain embodiments, the organic solvent is selected from: methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetone, or any combination of two or more of the above solvents.

[0142] In certain embodiments, the organic solvent is selected from: methanol, ethanol, isopropanol, tetrahydrofuran, acetone, ethanol / tetrahydrofuran or ethanol / acetone; preferably, in the ethanol / tetrahydrofuran and ethanol / acetone mixed solvents, the volume ratio of ethanol is less than 1:10.

[0143] In certain embodiments, in the method for preparing the hydrochloride crystalline form A, the crystalline form obtained after separating the solvent can be further dried to obtain the hydrochloride crystalline form A.

[0144] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0145] In certain embodiments, in the preparation method of the hydrochloride salt form A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0146] In certain embodiments, in the preparation method of the hydrochloride crystalline form A, the drying is selected from air drying at room temperature, natural drying in a fume hood, infrared lamp drying, oven drying, and vacuum dryer drying. Preferably, the drying temperature under vacuum conditions is 30°C-100°C, for example, 30°C-80°C, for example, 35°C-70°C, for example, 40°C-65°C, for example, 35°C-50°C; the drying process can be optionally performed multiple times at different temperatures.

[0147] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0148] In another aspect, the present disclosure provides a salt of a compound represented by formula (I),

[0149]

[0150] Wherein, the salt is selected from sulfate.

[0151] The present disclosure also provides a sulfate crystalline form A of a compound of formula (I),

[0152]

[0153] It uses Cu-Kα radiation and expresses it in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.4±0.2°, 16.5±0.2°, 19.4±0.2°, 21.1±0.2°, and 22.5±0.2°.

[0154] In certain embodiments, the sulfate salt form A of the compound of formula (I) uses Cu-Kα radiation and has an X-ray powder diffraction pattern expressed in 2θ angles at 8.4±0.2°, 12.8±0.2°, 14.2±0.2°, 16.5±0.2°, 16.9±0.2°, 19.4±0.2°, 19.9±0.2°, 21.1±0.2°, 21.5±0.2°, 22.5±0.2°, 24.9±0.2°, and 27.8±0.2°.

[0155] In certain embodiments, the sulfate salt of the compound of formula (I) in Form A has substantially Figure 4 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0156] In certain embodiments, the sulfate salt form A of the compound of formula (I) has a differential scanning calorimetry (DSC) analysis curve with one endothermic peak in the ranges of 50°C to 75°C, 75°C to 110°C, 175°C to 225°C, and 225°C to 250°C.

[0157] In certain embodiments, the sulfate salt crystalline form A of the compound of formula (I) has a maximum endothermic transition temperature of 238.1±5° C. in the differential scanning calorimetry (DSC) analysis curve. In certain embodiments, the sulfate salt crystalline form A of the compound of formula (I) has substantially Figure 5 The differential scanning calorimetry curve is shown.

[0158] In certain embodiments, the sulfate salt of the compound of formula (I) in Form A has substantially Figure 5 Thermogravimetric analysis (TGA) curves are shown.

[0159] In certain embodiments, the sulfate salt of the compound of formula (I) in Form A has substantially Figure 6 shown 1 H-NMR spectrum.

[0160] In certain embodiments, the sulfate salt of the compound of formula (I) in Form A has a crystal structure that is in a substantially pure form.

[0161] The present disclosure also provides a method for preparing the sulfate crystalline form A of the compound of formula (I), comprising the following operations:

[0162] An organic solvent and 1-2 equivalents of sulfuric acid are added to the compound of formula (I), stirred at room temperature, and the solvent is separated to obtain sulfate salt form A of the compound of formula (I).

[0163] In certain embodiments, the sulfuric acid is a sulfuric acid solution; preferably, the sulfuric acid solution is an ethanol solution containing sulfuric acid; more preferably, the concentration of the sulfuric acid solution is 1 mol / L.

[0164] In certain embodiments, the organic solvent is selected from one of the following solvents or any combination of two or more solvents:

[0165] (1) an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexanol, benzyl alcohol, phenylethyl alcohol, or phenylpropyl alcohol;

[0166] (2) a halogenated alkane solvent selected from dichloromethane or chloroform;

[0167] (3) a nitrile solvent selected from acetonitrile or propionitrile;

[0168] (4) an ester solvent selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate;

[0169] (5) a ketone solvent selected from acetone, butanone, isobutyl ketone, methyl isobutyl ketone or 4-methyl-2-pentanone;

[0170] (6) an alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane;

[0171] (7) Ether solvents, including diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane;

[0172] (8) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

[0173] In certain embodiments, the organic solvent is selected from: methanol, ethanol, isopropanol, tetrahydrofuran, acetone, ethanol / tetrahydrofuran or ethanol / acetone; preferably, in the ethanol / tetrahydrofuran and ethanol / acetone mixed solvents, the volume ratio of ethanol is less than 1:10.

[0174] In certain embodiments, in the method for preparing the sulfate salt crystal form A, the crystal form obtained after separating the solvent can be further dried to obtain the sulfate salt crystal form A.

[0175] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0176] In certain embodiments, in the preparation method of the sulfate crystal form A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0177] In certain embodiments, in the method for preparing the sulfate salt crystal form A, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, for example, 30°C-80°C, for example, 35°C-70°C, for example, 40°C-65°C, for example, 35°C-50°C; the drying process can be optionally performed multiple times at different temperatures.

[0178] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0179] The present disclosure provides a salt of a compound represented by formula (I),

[0180]

[0181] Wherein, the salt is methanesulfonate.

[0182] In certain embodiments, the methanesulfonate salt of the compound of formula (I) is characterized in that the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5.

[0183] In certain embodiments, the methanesulfonate salt of the compound of formula (I) is characterized in that the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1.

[0184] The present disclosure also provides a mesylate crystalline form A of a compound of formula (I),

[0185]

[0186] It uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.0±0.2°, 6.4±0.2°, 7.3±0.2°, 12.2±0.2°, 14.7±0.2°, 21.2±0.2°, 22.9±0.2°, and 26.6±0.2°.

[0187] In certain embodiments, the mesylate salt form A of the compound of formula (I) uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.0±0.2°, 6.4±0.2°, 7.3±0.2°, 12.2±0.2°, 14.3±0.2°, 14.7±0.2°, 15.2±0.2°, 18.3±0.2°, 19.3±0.2°, 21.2±0.2°, 22.9±0.2°, and 26.6±0.2°.

[0188] In certain embodiments, the mesylate salt of the compound of formula (I) in Form A has substantially Figure 7 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0189] In certain embodiments, in the crystalline form A of the methanesulfonate of the compound of formula (I), the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1.

[0190] In certain embodiments, the mesylate salt form A of the compound of formula (I) has a differential scanning calorimetry (DSC) analysis curve with an endothermic peak in the range of 60°C to 100°C, 125°C to 150°C, 185°C to 200°C, and 225°C to 260°C, and an exothermic peak in the range of 160°C to 175°C and 200°C to 215°C.

[0191] In certain embodiments, the mesylate salt form A of the compound of formula (I) has a maximum endothermic transition temperature of 244.3±5° C. in the differential scanning calorimetry (DSC) analysis curve. In certain embodiments, the mesylate salt form A of the compound of formula (I) has substantially Figure 8 The differential scanning calorimetry curve is shown.

[0192] In certain embodiments, the mesylate salt form A of the compound of formula (I) is a hydrate.

[0193] In certain embodiments, the mesylate salt of the compound of formula (I) in Form A has substantially Figure 8 Thermogravimetric analysis (TGA) curves are shown.

[0194] In certain embodiments, the mesylate salt of the compound of formula (I) in Form A has substantially Figure 9 shown 1 H-NMR spectrum.

[0195] In certain embodiments, the mesylate salt of the compound of formula (I) in Form A has a crystal structure that is in a substantially pure form.

[0196] The present disclosure also provides a method for preparing the mesylate crystalline form A of the compound of formula (I), comprising the following steps:

[0197] To the compound of formula (I), an organic solvent and 1-2 equivalents of methanesulfonic acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain the mesylate crystal form A of the compound of formula (I).

[0198] In certain embodiments, the methanesulfonic acid is a methanesulfonic acid solution; preferably, the methanesulfonic acid solution is an ethanol solution containing methanesulfonic acid; preferably, the concentration of the methanesulfonic acid solution is 1 mol / L.

[0199] In certain embodiments, the organic solvent is selected from methanol, ethanol or isopropanol.

[0200] In certain embodiments, in the method for preparing the mesylate salt crystalline form A, the crystalline form obtained after separating the solvent can be further dried to obtain the mesylate salt crystalline form A.

[0201] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0202] In certain embodiments, in the preparation method of the mesylate salt form A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0203] In certain embodiments, in the method for preparing the mesylate salt crystalline form A, the drying is selected from the group consisting of air drying at room temperature, air drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C to 100°C, for example, 30°C to 80°C, for example, 35°C to 70°C, for example, 40°C to 65°C, for example, 35°C to 50°C; the drying process can be optionally performed multiple times at different temperatures.

[0204] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0205] The present disclosure also provides a mesylate crystal form B of the compound represented by formula (I),

[0206]

[0207] It uses Cu-Kα radiation, and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 13.4±0.2°, 14.4±0.2°, 16.0±0.2°, 19.5±0.2°, 24.0±0.2°, and 26.7±0.2°.

[0208] In certain embodiments, the mesylate salt form B of the compound of formula (I) uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 8.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.0±0.2°, 17.8±0.2°, 19.5±0.2°, 20.3±0.2°, 20.9±0.2°, 21.5±0.2°, 24.0±0.2°, 25.4±0.2°, 26.7±0.2°, and 28.0±0.2°.

[0209] In certain embodiments, the mesylate salt of the compound of formula (I) in Form B has substantially the following Figure 10 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0210] In certain embodiments, in the mesylate salt form B of the compound of formula (I), the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5; preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1.

[0211] In certain embodiments, the mesylate salt form B of the compound of formula (I) has a differential scanning calorimetry (DSC) analysis curve with one endothermic peak in the range of 75°C to 90°C, 100°C to 120°C, 210°C to 225°C, and 225°C to 250°C.

[0212] In certain embodiments, the mesylate salt form B of the compound of formula (I) has a maximum endothermic transition temperature of 234.9±5°C in the differential scanning calorimetry (DSC) analysis curve.

[0213] In certain embodiments, the mesylate salt of the compound of formula (I) in Form B has substantially the following Figure 11 The differential scanning calorimetry curve is shown.

[0214] In certain embodiments, the mesylate salt of the compound of formula (I) in Form B has substantially the following Figure 11 Thermogravimetric analysis (TGA) curves are shown.

[0215] In certain embodiments, the mesylate salt of the compound of formula (I) in Form B has substantially the following Figure 12 shown 1 H-NMR spectrum.

[0216] In certain embodiments, the mesylate salt Form B of the compound of Formula (I) is in a substantially pure form.

[0217] The present disclosure also provides a method for preparing a mesylate salt crystalline form B of a compound of formula (I), comprising the following steps:

[0218] An organic solvent and 1-2 equivalents of methanesulfonic acid are added to the compound of formula (I), stirred at room temperature, and the solvent is separated to obtain the mesylate crystal form B of the compound of formula (I).

[0219] In certain embodiments, the methanesulfonic acid is a methanesulfonic acid solution; preferably, the methanesulfonic acid solution is an ethanol solution containing methanesulfonic acid; preferably, the concentration of the methanesulfonic acid solution is 1 mol / L.

[0220] In certain embodiments, the organic solvent is selected from tetrahydrofuran, acetone, ethanol / tetrahydrofuran or ethanol / acetone; preferably, in the mixed solvents of ethanol / tetrahydrofuran and ethanol / acetone, the volume ratio of ethanol is less than 1:10.

[0221] In certain embodiments, in the method for preparing the mesylate salt Form B, the crystalline form obtained after separating the solvent can be further dried to obtain the mesylate salt Form B.

[0222] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0223] In certain embodiments, in the preparation method of the mesylate salt form B, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0224] In certain embodiments, in the method for preparing the mesylate salt Form B, the drying is selected from the group consisting of air drying at room temperature, air drying in a fume hood, drying under an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C to 100°C, for example, 30°C to 80°C, for example, 35°C to 70°C, for example, 40°C to 65°C, for example, 35°C to 50°C; the drying process can be optionally performed multiple times at different temperatures.

[0225] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0226] In one aspect, the present disclosure provides a salt of a compound represented by formula (I),

[0227]

[0228] Wherein, the salt is p-toluenesulfonate.

[0229] In certain embodiments, the p-toluenesulfonate salt of the compound represented by formula (I), the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1.

[0230] The present disclosure also provides a p-toluenesulfonate crystalline form A of a compound of formula (I),

[0231]

[0232] It uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.7±0.2°, 10.2±0.2°, 15.2±0.2°, 19.3±0.2°, 25.9±0.2°, and 27.4±0.2°.

[0233] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.3±0.2°, 15.2±0.2°, 16.6±0.2°, 19.3±0.2°, 20.9±0.2°, 22.5±0.2°, 24.1±0.2°, 25.9±0.2°, and 27.4±0.2°.

[0234] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) has substantially Figure 13 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0235] In certain embodiments, in the p-toluenesulfonate crystalline form A of the compound represented by formula (I), the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1.

[0236] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) has a differential scanning calorimetry (DSC) analysis curve with an endothermic peak in the range of 125°C to 160°C and an exothermic peak in the range of 230°C to 265°C, and an exothermic peak in the range of 175°C to 210°C.

[0237] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) has a maximum endothermic transition temperature of 251.6±5° C. in the differential scanning calorimetry (DSC) analysis curve.

[0238] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) has substantially Figure 14 The differential scanning calorimetry curve is shown.

[0239] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) is an ethanol solvate.

[0240] In certain embodiments, the p-toluenesulfonate salt form A of the compound represented by formula (I) is an ethanol solvate, and the molar ratio of the compound of formula (I) to ethanol is 1:1.

[0241] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) has substantially Figure 14 Thermogravimetric analysis (TGA) curves are shown.

[0242] In certain embodiments, the p-toluenesulfonate crystalline form A of the compound represented by formula (I) has substantially Figure 15 shown 1 H-NMR spectrum.

[0243] In certain embodiments, the p-toluenesulfonic acid salt of the compound of formula (I) in Form A has a crystal structure that is in a substantially pure form.

[0244] The present disclosure also provides a method for preparing a p-toluenesulfonate crystalline form A of a compound of formula (I), comprising the following steps:

[0245] To the compound of formula (I), an organic solvent and 1-2 equivalents of p-toluenesulfonic acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain p-toluenesulfonate crystalline form A of the compound of formula (I).

[0246] In certain embodiments, the organic solvent is selected from methanol, ethanol or isopropanol.

[0247] In certain embodiments, in the method for preparing the p-toluenesulfonate crystalline form A, the crystalline form obtained after separating the solvent can be further dried to obtain the p-toluenesulfonate crystalline form A.

[0248] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0249] In certain embodiments, in the preparation method of the p-toluenesulfonate salt form A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0250] In certain embodiments, in the method for preparing the p-toluenesulfonate crystalline form A, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature under vacuum conditions is 30°C to 100°C, for example, 30°C to 80°C, for example, 35°C to 70°C, for example, 40°C to 65°C, for example, 35°C to 50°C; the drying process can be optionally performed multiple times at different temperatures.

[0251] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0252] The present disclosure also provides a p-toluenesulfonate crystalline form B of a compound of formula (I),

[0253]

[0254] It uses Cu-Kα radiation, and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 5.5±0.2°, 6.3±0.2°, 12.6±0.2°, 16.4±0.2°, 18.3±0.2°, 21.8±0.2°, and 26.8±0.2°.

[0255] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) has substantially Figure 16 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0256] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I), the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1.

[0257] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) has a differential scanning calorimetry (DSC) analysis curve with an endothermic peak in the range of 85°C to 125°C and 130°C to 160°C.

[0258] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) has a maximum endothermic transition temperature of 145.3±5° C. in the differential scanning calorimetry (DSC) analysis curve.

[0259] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) has substantially Figure 17 The differential scanning calorimetry curve is shown.

[0260] In certain embodiments, the p-toluenesulfonate salt form B of the compound represented by formula (I) is a hydrate.

[0261] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) is a hydrate, and the weight percentage of water in the p-toluenesulfonate crystalline form B is 7.0±1%.

[0262] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) has substantially Figure 17 Thermogravimetric analysis (TGA) curves are shown.

[0263] In certain embodiments, the p-toluenesulfonate crystalline form B of the compound represented by formula (I) has substantially Figure 18 shown 1 H-NMR spectrum.

[0264] In certain embodiments, the p-toluenesulfonic acid salt Form B of the compound of formula (I) is in a substantially pure form.

[0265] The present disclosure also provides a method for preparing a p-toluenesulfonate crystalline form B of a compound of formula (I), comprising the following steps:

[0266] To the compound of formula (I), an organic solvent and 1-2 equivalents of p-toluenesulfonic acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain p-toluenesulfonate crystalline form B of the compound of formula (I).

[0267] In certain embodiments, the organic solvent is selected from tetrahydrofuran.

[0268] In certain embodiments, in the method for preparing the p-toluenesulfonate crystalline Form B, the crystalline form obtained after separating the solvent can be further dried to obtain the p-toluenesulfonate crystalline Form B.

[0269] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0270] In certain embodiments, in the preparation method of the p-toluenesulfonate salt form B, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0271] In certain embodiments, in the method for preparing the p-toluenesulfonate salt Form B, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, e.g., 30°C-80°C, e.g., 35°C-70°C, e.g., 40°C-65°C, e.g., 35°C-50°C; the drying process can optionally be performed multiple times at different temperatures.

[0272] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0273] The present disclosure also provides a p-toluenesulfonate crystalline form C of a compound of formula (I),

[0274]

[0275] It uses Cu-Kα radiation, and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°, 22.5±0.2°, and 26.4±0.2°.

[0276] In certain embodiments, the p-toluenesulfonate salt form C of the compound represented by the formula (I) uses Cu-Kα radiation and, expressed in 2θ angles, has an X-ray powder diffraction pattern with characteristic peaks at 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°, 16.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.5±0.2°, 19.6±0.2°, 22.5±0.2°, 25.3±0.2°, and 26.4±0.2°.

[0277] In certain embodiments, the p-toluenesulfonate crystalline form C of the compound represented by formula (I) has substantially Figure 19 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0278] In certain embodiments, in the p-toluenesulfonate crystalline form C of the compound represented by formula (I), the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1.

[0279] In certain embodiments, the p-toluenesulfonate crystalline form C of the compound represented by formula (I) has a differential scanning calorimetry (DSC) analysis curve with one endothermic peak in the range of 75°C to 110°C, 190°C to 210°C, and 210°C to 230°C.

[0280] In certain embodiments, the p-toluenesulfonate crystalline form C of the compound represented by formula (I) has substantially Figure 20 The differential scanning calorimetry curve is shown.

[0281] In certain embodiments, the p-toluenesulfonate salt form C of the compound represented by formula (I) is a hydrate.

[0282] In certain embodiments, the p-toluenesulfonate crystalline form C of the compound represented by formula (I) is a hydrate, and the weight percentage of water in the p-toluenesulfonate crystalline form C is 6.0±1%.

[0283] In certain embodiments, the p-toluenesulfonate crystalline form C of the compound represented by formula (I) has substantially Figure 20 Thermogravimetric analysis (TGA) curves are shown.

[0284] In certain embodiments, the p-toluenesulfonate crystalline form C of the compound represented by formula (I) has substantially Figure 21 shown 1 H-NMR spectrum.

[0285] In certain embodiments, the p-toluenesulfonic acid salt of the compound of formula (I), Form C, has a crystal structure that is in a substantially pure form.

[0286] The present disclosure also provides a method for preparing a p-toluenesulfonate crystalline form C of a compound of formula (I), comprising the following steps:

[0287] To the compound of formula (I), an organic solvent and 1-2 equivalents of p-toluenesulfonic acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain p-toluenesulfonate crystalline form C of the compound of formula (I).

[0288] In certain embodiments, the organic solvent is selected from: acetone.

[0289] In certain embodiments, in the method for preparing the p-toluenesulfonate crystalline Form C, the crystalline form obtained after separating the solvent can be further dried to obtain the p-toluenesulfonate crystalline Form C.

[0290] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0291] In certain embodiments, in the preparation method of the p-toluenesulfonate salt form C, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0292] In certain embodiments, in the method for preparing the p-toluenesulfonate salt Form C, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C to 100°C, e.g., 30°C to 80°C, e.g., 35°C to 70°C, e.g., 40°C to 65°C, e.g., 35°C to 50°C; the drying process can optionally be performed multiple times at different temperatures.

[0293] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0294] In one aspect, the present disclosure provides a salt of a compound represented by formula (I),

[0295]

[0296] Wherein, the salt is maleate.

[0297] In certain embodiments, the molar ratio of the maleate salt of the compound represented by formula (I) to maleic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound represented by formula (I) to maleic acid is 1:1.

[0298] The present disclosure also provides a maleic acid cocrystal A of a compound of formula (I),

[0299]

[0300] It uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 21.0±0.2°, and 21.5±0.2°.

[0301] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 18.9±0.2°, 20.4±0.2°, 21.0±0.2°, 21.5±0.2°, 26.5±0.2°, 27.2±0.2°, and 28.2±0.2°.

[0302] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) has substantially Figure 22 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0303] In certain embodiments, in the maleic acid cocrystal A of the compound of formula (I), the molar ratio of the compound of formula (I) to maleic acid is 1:2-1:0.5. Preferably, the molar ratio of the compound of formula (I) to maleic acid is 1:1.

[0304] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) has a differential scanning calorimetry (DSC) analysis curve having an endothermic peak in the range of 190°C to 200°C and an exothermic peak in the range of 200°C to 210°C.

[0305] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) has a maximum endothermic transition temperature of 200.0±5°C in the differential scanning calorimetry (DSC) analysis curve.

[0306] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) has substantially Figure 23 The differential scanning calorimetry curve is shown.

[0307] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) has substantially Figure 23 Thermogravimetric analysis (TGA) curves are shown.

[0308] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) has substantially Figure 24 shown 1 H-NMR spectrum.

[0309] In certain embodiments, the maleic acid cocrystal A of the compound of formula (I) is in a substantially pure form.

[0310] The present disclosure also provides a method for preparing maleic acid cocrystal A of the compound of formula (I), comprising the following operations:

[0311] To the compound of formula (I), an organic solvent and 1-2 equivalents of maleic acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain maleic acid cocrystal A of the compound of formula (I).

[0312] In certain embodiments, the organic solvent is selected from one of the following solvents or any combination of two or more solvents:

[0313] (1) an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexanol, benzyl alcohol, phenylethyl alcohol, or phenylpropyl alcohol;

[0314] (2) a halogenated alkane solvent selected from dichloromethane or chloroform;

[0315] (3) a nitrile solvent selected from acetonitrile or propionitrile;

[0316] (4) an ester solvent selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate;

[0317] (5) a ketone solvent selected from acetone, butanone, isobutyl ketone, methyl isobutyl ketone or 4-methyl-2-pentanone;

[0318] (6) an alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane;

[0319] (7) Ether solvents, including diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane;

[0320] (8) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

[0321] In certain embodiments, the organic solvent is selected from tetrahydrofuran.

[0322] In certain embodiments, in the method for preparing maleic acid cocrystal A, the crystalline form obtained after separating the solvent can be further dried to obtain maleic acid cocrystal A.

[0323] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0324] In certain embodiments, in the method for preparing maleic acid eutectic A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0325] In certain embodiments, in the method for preparing maleic acid cocrystal A, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, e.g., 30°C-80°C, e.g., 35°C-70°C, e.g., 40°C-65°C, e.g., 35°C-50°C; the drying process can optionally be performed multiple times at different temperatures.

[0326] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0327] The present disclosure provides a salt of a compound represented by formula (I),

[0328]

[0329] Wherein, the salt is fumarate.

[0330] In certain embodiments, the fumarate salt of the compound of formula (I) is characterized in that the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to fumaric acid is 1:1-1:0.5.

[0331] The present disclosure also provides a fumaric acid cocrystal A of a compound of formula (I),

[0332]

[0333] It uses Cu-Kα radiation and expresses it in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 9.0±0.2°, 13.2±0.2°, 18.7±0.2°, 20.9±0.2°, 26.3±0.2°, and 27.8±0.2°.

[0334] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 9.0±0.2°, 13.2±0.2°, 16.7±0.2°, 17.3±0.2°, 17.9±0.2°, 18.7±0.2°, 20.9±0.2°, 22.0±0.2°, 26.3±0.2°, and 27.8±0.2°.

[0335] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) has substantially Figure 25 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0336] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) is characterized in that the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to fumaric acid is 1:1.

[0337] In certain embodiments, the differential scanning calorimetry (DSC) analysis curve of the fumaric acid cocrystal A of the compound of formula (I) has an endothermic peak in the range of 60°C to 80°C, 90°C to 125°C, and 190°C to 225°C.

[0338] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) has substantially Figure 26 The differential scanning calorimetry curve is shown.

[0339] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) is an ethanol solvate.

[0340] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) is an ethanol solvate, and the weight percentage of ethanol in the fumaric acid cocrystal A is 8.2±1%.

[0341] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) has substantially Figure 26 Thermogravimetric analysis (TGA) curves are shown.

[0342] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) has substantially Figure 27 shown 1 H-NMR spectrum.

[0343] In certain embodiments, the fumaric acid cocrystal A of the compound of formula (I) is in a substantially pure form.

[0344] The present disclosure also provides a method for preparing fumaric acid cocrystal A of a compound of formula (I), comprising the following operations:

[0345] To the compound of formula (I), an organic solvent and 1-2 equivalents of fumaric acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain fumaric acid cocrystal A of the compound of formula (I).

[0346] In certain embodiments, the organic solvent is selected from methanol, ethanol or isopropanol.

[0347] In certain embodiments, in the method for preparing fumaric acid cocrystal A, the crystalline form obtained after separating the solvent can be further dried to obtain fumaric acid cocrystal A.

[0348] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0349] In certain embodiments, in the preparation method of the fumaric acid eutectic A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0350] In certain embodiments, in the method for preparing fumaric acid eutectic A, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying under an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, e.g., 30°C-80°C, e.g., 35°C-70°C, e.g., 40°C-65°C, e.g., 35°C-50°C; the drying process can optionally be performed multiple times at different temperatures.

[0351] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0352] The present disclosure also provides a fumaric acid cocrystal B of a compound of formula (I),

[0353]

[0354] It uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 11.8±0.2°, 12.5±0.2°, 14.1±0.2°, 17.6±0.2°, 18.0±0.2°, 18.7±0.2°, 19.4±0.2°, 23.3±0.2°, and 26.7±0.2°.

[0355] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 11.8±0.2°, 12.5±0.2°, 14.1±0.2°, 15.0±0.2°, 16.5±0.2°, 17.6±0.2°, 18.0±0.2°, 18.7±0.2°, 19.4±0.2°, 22.5±0.2°, 23.3±0.2°, 26.7±0.2°, 30.1±0.2°, and 31.2±0.2°.

[0356] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) has substantially Figure 28 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0357] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) is characterized in that the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to fumaric acid is 1:0.7.

[0358] In certain embodiments, the differential scanning calorimetry (DSC) analysis curve of the fumaric acid cocrystal B of the compound of formula (I) has an endothermic peak in the range of 100°C to 150°C and 210°C to 250°C.

[0359] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) has a maximum endothermic transition temperature of 231.2±5°C in a differential scanning calorimetry (DSC) analysis curve.

[0360] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) has substantially Figure 29 The differential scanning calorimetry curve is shown.

[0361] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) is a tetrahydrofuran solvate.

[0362] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) is a tetrahydrofuran solvate, and the weight percentage of tetrahydrofuran in the fumaric acid cocrystal B is 5.8±1%.

[0363] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) has substantially Figure 29 Thermogravimetric analysis (TGA) curves are shown.

[0364] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) has substantially Figure 30shown 1 H-NMR spectrum.

[0365] In certain embodiments, the fumaric acid cocrystal B of the compound of formula (I) is in a substantially pure form.

[0366] The present disclosure also provides a method for preparing fumaric acid cocrystal B of a compound of formula (I), comprising the following operations:

[0367] To the compound of formula (I), an organic solvent and 1-2 equivalents of fumaric acid are added, the mixture is stirred at room temperature, and the solvent is separated to obtain fumaric acid cocrystal B of the compound of formula (I).

[0368] In certain embodiments, the organic solvent is selected from tetrahydrofuran.

[0369] In certain embodiments, in the method for preparing fumaric acid cocrystal B, the crystalline form obtained after separating the solvent can be further dried to obtain fumaric acid cocrystal B.

[0370] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0371] In certain embodiments, in the preparation method of the fumaric acid eutectic B, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction process, and a crystallization process.

[0372] In certain embodiments, in the method for preparing fumaric acid eutectic B, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying under an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, e.g., 30°C-80°C, e.g., 35°C-70°C, e.g., 40°C-65°C, e.g., 35°C-50°C; the drying process can optionally be performed multiple times at different temperatures.

[0373] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0374] In another aspect, the present disclosure provides a salt of a compound represented by formula (I),

[0375]

[0376] Wherein, the salt is selected from malate.

[0377] In certain embodiments, the malate salt of the compound represented by formula (I) is characterized in that the molar ratio of the compound of formula (I) to malic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to malic acid is 1:0.8.

[0378] The present disclosure also provides a malic acid cocrystal A of a compound of formula (I),

[0379]

[0380] It uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 10.6±0.2°, 13.2±0.2°, 15.9±0.2°, 16.4±0.2°, 19.0±0.2°, and 19.8±0.2°.

[0381] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation, expressed in 2θ angles, with characteristic peaks at 8.0±0.2°, 10.6±0.2°, 12.3±0.2°, 13.2±0.2°, 15.9±0.2°, 16.4±0.2°, 19.0±0.2°, 19.8±0.2°, 25.6±0.2°, 26.8±0.2°, and 28.7±0.2°.

[0382] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has substantially Figure 31 The X-ray powder diffraction pattern shown was obtained using Cu-Kα radiation.

[0383] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) is characterized in that the molar ratio of the compound of formula (I) to malic acid is 1:2-1:0.5, preferably, the molar ratio of the compound of formula (I) to malic acid is 1:0.8.

[0384] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has an endothermic peak in the range of 175°C to 210°C according to a differential scanning calorimetry (DSC) analysis curve.

[0385] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has a maximum endothermic transition temperature of 194.5±5°C in a differential scanning calorimetry (DSC) analysis curve.

[0386] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has substantially Figure 32 The differential scanning calorimetry curve is shown.

[0387] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has substantially Figure 32 Thermogravimetric analysis (TGA) curves are shown.

[0388] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) has substantially Figure 33 shown 1 H-NMR spectrum.

[0389] In certain embodiments, the malic acid cocrystal A of the compound of formula (I) is in a substantially pure form.

[0390] The present disclosure also provides a method for preparing malic acid cocrystal A of a compound of formula (I), comprising the following operations:

[0391] An organic solvent and 1-2 equivalents of malic acid are added to the compound of formula (I), stirred at room temperature, and the solvent is separated to obtain malic acid cocrystal A of the compound of formula (I).

[0392] In certain embodiments, the organic solvent is selected from one of the following solvents or any combination of two or more solvents:

[0393] (1) an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexanol, benzyl alcohol, phenylethyl alcohol, or phenylpropyl alcohol;

[0394] (2) a halogenated alkane solvent selected from dichloromethane or chloroform;

[0395] (3) a nitrile solvent selected from acetonitrile or propionitrile;

[0396] (4) an ester solvent selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate;

[0397] (5) a ketone solvent selected from acetone, butanone, isobutyl ketone, methyl isobutyl ketone or 4-methyl-2-pentanone;

[0398] (6) an alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane;

[0399] (7) Ether solvents, including diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane;

[0400] (8) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

[0401] In certain embodiments, the organic solvent is selected from tetrahydrofuran.

[0402] In certain embodiments, in the method for preparing malic acid eutectic A, the crystalline form obtained after separating the solvent can be further dried to obtain malic acid eutectic A.

[0403] In certain embodiments, the solvent separation is selected from the group consisting of normal pressure filtration, reduced pressure filtration, removal of liquid after centrifugation, or volatilization of the solvent.

[0404] In certain embodiments, in the method for preparing malic acid eutectic A, the preparation process can be optionally carried out under stirring conditions, wherein the stirring is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolving process, a reaction process, and a crystallization process.

[0405] In certain embodiments, in the method for preparing malic acid eutectic A, the drying is selected from the group consisting of air-drying at room temperature, air-drying in a fume hood, drying with an infrared lamp, drying in an oven, and drying in a vacuum dryer. Preferably, the drying temperature for drying under vacuum conditions is 30°C-100°C, e.g., 30°C-80°C, e.g., 35°C-70°C, e.g., 40°C-65°C, e.g., 35°C-50°C; the drying process can optionally be performed multiple times at different temperatures.

[0406] The room temperature mentioned in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C-30°C.

[0407] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a salt, a crystalline form, or a cocrystal of a compound of formula (I) as described herein, and optionally one or more pharmaceutically acceptable carriers and / or diluents. In certain embodiments, the pharmaceutical composition comprising a salt, a crystalline form, or a cocrystal of a compound of formula (I) as described herein, and optionally one or more pharmaceutically acceptable carriers and / or diluents as described herein can be in any pharmaceutically acceptable dosage form. It can be administered to a patient in need thereof by oral, parenteral, rectal, or transpulmonary administration. For oral administration, it can be formulated into conventional solid preparations such as tablets, capsules, pills, granules, etc.; it can also be formulated into oral liquid preparations such as oral solutions, oral suspensions, syrups, etc. For parenteral administration, it can be formulated into an injectable formulation, including an injectable solution, a sterile powder for injection, and a concentrated solution for injection. When formulating an injectable formulation, it can be produced using conventional methods in the pharmaceutical field. When formulating an injectable formulation, additives may be omitted, or appropriate additives may be added depending on the properties of the drug. For rectal administration, it can be formulated into a suppository, etc. When used for pulmonary administration, it can be made into an inhaler or a spray.

[0408] Furthermore, the present disclosure relates to a pharmaceutical composition comprising a salt, a crystalline form of the salt or a cocrystal of the compound of formula (I), and one or more second therapeutically active agents, wherein the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, DNA chimeras, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors and protein prenyl transferase inhibitors.

[0409] In certain embodiments, the present disclosure also provides the use of a salt of the compound of formula (I), a crystal form of the salt, a co-crystal, or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing diseases mediated by DNA-PK.

[0410] Furthermore, the present disclosure also provides the use of a salt, a crystal form of the salt, a co-crystal, or a pharmaceutical composition of the present disclosure of the compound of formula (I) in the preparation of a medicament for treating and / or preventing benign tumors or cancers, including carcinoma in situ and metastatic cancers.

[0411] In certain embodiments, the present disclosure provides use of a salt, a crystalline form of a salt, a cocrystal, or a pharmaceutical composition of the present disclosure of a compound of formula (I) for the preparation of a medicament for sensitizing cancer cells to anticancer agents and / or ionizing radiation.

[0412] On the other hand, the present disclosure also provides a method for treating a disease associated with excessive activation of DNA-PK, comprising administering an effective amount of a salt, a crystalline form of the salt, a co-crystal, or the aforementioned pharmaceutical composition of a compound of formula (I) of the present invention to a patient in need thereof; the disease associated with excessive activation of DNA-PK is selected from benign tumors or cancers, and the cancer includes in situ carcinoma and metastatic cancer.

[0413] Furthermore, the present disclosure also provides a method for treating a disease associated with excessive activation of DNA-PK, comprising administering an effective amount of a salt, a crystalline form of the salt, a co-crystal, or the aforementioned pharmaceutical composition of a compound of formula (I) of the present invention to a patient before or after receiving radiotherapy; the disease associated with excessive activation of DNA-PK is selected from benign tumors or cancers, and the cancer includes in situ carcinoma and metastatic cancer.

[0414] Furthermore, the present disclosure also provides a method for treating a disease associated with excessive activation of DNA-PK, comprising administering an effective amount of a salt, a crystalline form of the salt, a co-crystal, or the aforementioned pharmaceutical composition of a compound of formula (I) of the present invention to a patient before / after receiving chemotherapy; the disease associated with excessive activation of DNA-PK is selected from benign tumors or cancers, and the cancer includes in situ carcinoma and metastatic cancer.

[0415] On the other hand, the present disclosure also provides a method for enhancing a patient's sensitivity to anticancer agents or radiotherapy, comprising administering to a patient in need thereof an effective amount of a salt, a crystalline form of the salt, a cocrystal, or the aforementioned pharmaceutical composition of a compound of formula (I) of the present invention; the anticancer agent is as described above.

[0416] Furthermore, the present invention also provides a method for enhancing a patient's sensitivity to anticancer agents or radiotherapy, comprising administering an effective amount of a salt, a crystalline form of the salt, a cocrystal, or the aforementioned pharmaceutical composition of the compound of formula (I) of the present invention to a patient before or after receiving radiotherapy; the anticancer agent is as described above.

[0417] Furthermore, the present invention also provides a method for enhancing a patient's sensitivity to anticancer agents or radiotherapy, comprising administering an effective amount of a salt, a crystalline form of the salt, a cocrystal, or the aforementioned pharmaceutical composition of the compound of formula (I) of the present invention to a patient before or after receiving chemotherapy; the anticancer agent is as described above.

[0418] The "chemotherapy" mentioned in the present invention is the abbreviation of chemical drug treatment, which mainly achieves the purpose of treatment by using chemical therapeutic drugs to kill cancer cells.

[0419] The "radiotherapy" mentioned in the present invention refers to a tumor treatment method, namely tumor radiotherapy, which mainly uses radiation to treat local tumors. The "radiation" mentioned includes α, β, and γ rays produced by radioactive isotopes and X-rays, electron beams, proton beams and other particle beams produced by various X-ray therapy machines or accelerators.

[0420] The "any combination of two or more solvents" in the organic solvent described in the present disclosure refers to a solvent formed by mixing the same or different types of solvents in a certain proportion in an organic solvent. The mixed solvent formed by the same type of solvent includes but is not limited to the following specific examples: methanol / ethanol, methanol / isopropanol, methanol / ethanol / isopropanol, methanol / tert-butanol, methanol / cyclopentanol, methanol / benzyl alcohol, ethanol / isopropanol, ethanol / tert-butanol, ether / tetrahydrofuran, acetone / butanone, etc. The mixed solvent formed by different types of solvents includes but is not limited to the following mixed solvent systems: ethanol / acetonitrile, ethanol / acetone, ethanol / tetrahydrofuran, dichloromethane / acetonitrile, dichloromethane / acetone, dichloromethane / butanone, 1,4-dioxane / ethyl acetate, etc.

[0421] The term "effective amount" of a salt, crystalline form of a salt, or co-crystal of a compound of formula (I) as disclosed herein refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of a salt, crystalline form of a salt, co-crystal, or pharmaceutical composition of a compound of formula (I) as disclosed herein must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound or crystalline form thereof being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound or crystalline form thereof being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound or crystalline form thereof being used; and similar factors well known in the medical field. For example, it is common practice in the art to start the dose of a compound or crystalline form thereof at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0422] The main advantages of the salts, crystal forms or co-crystals of the compound of formula (I) disclosed herein include:

[0423] (1) The preparation method is simple to operate and suitable for industrial production;

[0424] (2) Having good properties, flowability, compressibility, disintegration and dissolution, which facilitates production, testing, formulation preparation, transportation and storage;

[0425] (3) High purity, low residual solvent, high solubility, high stability under high temperature and light conditions, and easy quality control;

[0426] (4) have good inhibitory activity against DNA-PK and good exposure and / or bioavailability in vivo;

[0427] (5) It has good in vitro and in vivo efficacy and can be used to treat and / or prevent diseases mediated by DNA-PK. BRIEF DESCRIPTION OF THE DRAWINGS

[0428] The drawings described herein are used to provide a further understanding of the present disclosure and constitute a part of this application. The illustrative embodiments of the present disclosure and their descriptions are used to explain the present disclosure and do not constitute an improper limitation of the present disclosure. In the drawings:

[0429] Figure 1 The figure is an X-ray powder diffraction (XRPD) pattern of the hydrochloride salt form A of the compound of formula (I), wherein the ordinate represents the diffraction intensity (intensity) and the abscissa represents the diffraction angle (2θ).

[0430] Figure 2This is a TGA-DSC analysis chart of the hydrochloride crystal form A of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0431] Figure 3 H is the hydrochloride form A of the compound of formula (I) 1 -NMR spectrum.

[0432] Figure 4 The figure is an X-ray powder diffraction (XRPD) pattern of the sulfate salt crystal form A of the compound of formula (I), wherein the ordinate represents the diffraction intensity (intensity) and the abscissa represents the diffraction angle (2θ).

[0433] Figure 5 This is a TGA-DSC analysis chart of the sulfate crystal form A of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0434] Figure 6 H is the sulfate crystal form A of the compound of formula (I) 1 -NMR spectrum.

[0435] Figure 7 The figure is an X-ray powder diffraction (XRPD) pattern of the mesylate salt form A of the compound of formula (I), wherein the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2θ).

[0436] Figure 8 This is a TGA-DSC analysis chart of the mesylate crystal form A of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0437] Figure 9 is H of the mesylate salt form A of the compound of formula (I) 1 -NMR spectrum.

[0438] Figure 10 The figure is an X-ray powder diffraction (XRPD) pattern of the mesylate salt form B of the compound of formula (I), wherein the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2θ).

[0439] Figure 11 This is a TGA-DSC analysis chart of the mesylate crystal form B of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0440] Figure 12 is H of the mesylate salt form B of the compound of formula (I) 1 -NMR spectrum.

[0441] Figure 13 The figure is an X-ray powder diffraction (XRPD) pattern of the p-toluenesulfonate salt of the compound of formula (I) in Form A. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle (2θ).

[0442] Figure 14 This is a TGA-DSC analysis chart of the p-toluenesulfonate crystalline form A of the compound of formula (I), the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0443] Figure 15 is H of the p-toluenesulfonate crystalline form A of the compound of formula (I) 1 -NMR spectrum.

[0444] Figure 16 The figure is an X-ray powder diffraction (XRPD) pattern of the p-toluenesulfonate salt of the compound of formula (I) in Form B. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle (2θ).

[0445] Figure 17 This is a TGA-DSC analysis chart of the p-toluenesulfonate crystalline form B of the compound of formula (I), the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0446] Figure 18 is H of the p-toluenesulfonate crystalline form B of the compound of formula (I) 1 -NMR spectrum.

[0447] Figure 19 The figure is an X-ray powder diffraction (XRPD) pattern of the p-toluenesulfonate salt of the compound of formula (I) in Form C. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle (2θ).

[0448] Figure 20 This is a TGA-DSC analysis chart of the p-toluenesulfonate crystalline form C of the compound of formula (I), the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0449] Figure 21 is H of the p-toluenesulfonate crystalline form C of the compound of formula (I) 1 -NMR spectrum.

[0450] Figure 22 The figure is the X-ray powder diffraction (XRPD) pattern of maleic acid cocrystal A of the compound of formula (I), wherein the ordinate represents the diffraction intensity (intensity) and the abscissa represents the diffraction angle (2θ).

[0451] Figure 23 This is a TGA-DSC analysis chart of maleic acid cocrystal A of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0452] Figure 24 is H of the compound of formula (I) maleic acid cocrystal A 1 -NMR spectrum.

[0453] Figure 25 The figure is the X-ray powder diffraction (XRPD) pattern of the fumaric acid cocrystal A of the compound of formula (I), wherein the ordinate represents the diffraction intensity (intensity) and the abscissa represents the diffraction angle (2θ).

[0454] Figure 26 This is a TGA-DSC analysis chart of fumaric acid cocrystal A of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0455] Figure 27 is H of the compound of formula (I) fumaric acid cocrystal A 1 -NMR spectrum.

[0456] Figure 28 The figure is the X-ray powder diffraction (XRPD) pattern of the fumaric acid cocrystal B of the compound of formula (I), wherein the ordinate represents the diffraction intensity and the abscissa represents the diffraction angle (2θ).

[0457] Figure 29 This is a TGA-DSC analysis chart of fumaric acid cocrystal B of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0458] Figure 30 is H of the compound of formula (I) fumaric acid cocrystal B 1 -NMR spectrum.

[0459] Figure 31 The figure is the X-ray powder diffraction (XRPD) pattern of the compound of formula (I) malic acid cocrystal A, wherein the ordinate represents the diffraction intensity (intensity) and the abscissa represents the diffraction angle (2θ).

[0460] Figure 32 This is a TGA-DSC analysis chart of malic acid cocrystal A of the compound of formula (I), where the left ordinate represents weight (%), the right ordinate represents heat flow (W / g), and the abscissa represents temperature T (°C).

[0461] Figure 33 is H of the compound of formula (I) malic acid cocrystal A1 -NMR spectrum. DETAILED DESCRIPTION

[0462] The substantive content of the present disclosure is further illustrated below in conjunction with the specific examples of the present disclosure. It should be understood that the following examples are only used to illustrate the present disclosure and are not intended to limit the scope of protection of the present disclosure. In the following examples, if no specific conditions are specified, the conventional conditions or manufacturer's recommendations are followed. The drugs or reagents used, if the manufacturer is not specified, are all conventional products that can be obtained commercially.

[0463] Although many of the materials and procedures used in the following examples are well known in the art, the present disclosure is still described in as much detail as possible. It will be clear to those skilled in the art that, unless otherwise specified, the materials and procedures used in the following examples are well known in the art.

[0464] Preparation Example 1:

[0465] Preparation of compounds of formula (I)

[0466] 1. Preparation of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purine

[0467]

[0468] 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-8-amine (800 mg, 3.1 mmol) and chloroacetaldehyde (742 mg, 9.45 mmol) were added to DMA (20 mL) and reacted at 100°C for 18 hours. The temperature was then cooled to 20°C, and EA (80 mL) and water (40 mL) were added. Extraction and separation were performed, and the organic phase was concentrated and purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain a crude product (1.2 g). This was then purified by reverse-phase C18 column chromatography (water / methanol = 1 / 1) to obtain a crude product (200 mg). This was then purified by preparative TLC (DCM:MeOH = 15:1) to obtain the product (130 mg, 15.1% yield).

[0469] 2. Preparation of N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purin-2-amine

[0470]

[0471] 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purine (100 mg, 0.36 mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (80 mg, 0.54 mmol), cesium carbonate (351.9 mg, 1.1 mmol), and BrettPhos Pd G3 (33 mg, 0.036 mmol) were dissolved in dioxane (10 mL). The system was reacted at 100°C under N2 for 2 hours. The temperature was then lowered to 20°C, concentrated, and purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain a crude product (110 mg). Methanol (2 mL) was then added and sonicated to precipitate a solid (70 mg). The solid was then purified on a silica gel preparative plate (DCM:MeOH=30:1) to obtain the title compound (35 mg, 25.0% yield).

[0472] Molecular formula: C 19 H 19 N9O molecular weight: 389.4 LC-MS (M / e): 389.9 (M+H)

[0473] 1 HNMR (400MHz, DMSO-d6): δ9.14(s,1H),9.00(s,1H),8.66(s,1H),8.39(s,1H),7.72(s,1H),7.68(d,J=1.6Hz,1H),7.03(d, J=1.6Hz,1H),4.75-4.65(m,1H),4.05-3.97(m,2H),3.48-3.41(m,2H),2.60-2.50(m,2H),2.39(s,3H),1.86-1.78(m,2H).

[0474] Preparation method of crystal form and co-crystal of compound of formula (I)

[0475] A certain amount of the compound of formula (I) was weighed, 1 equivalent of acid and an organic solvent (1 mL) were added, stirred at room temperature for 2-4 days, centrifuged, the solvent was separated, and the obtained solid was vacuum dried. The obtained solid was subjected to XRD, DSC / TGA, 1 H-NMR characterization was performed to obtain a crystalline form or co-crystal of the compound of formula (I). The specific reaction results are shown in the following table:

[0476]

[0477] a: 1 mol / L ethanol solution.

[0478] XRPD testing

[0479] X-ray powder diffraction measurement conditions: The solid samples obtained in the experiment were analyzed using an X-ray powder diffractometer Bruker D8Advance (Bruker, GER). Cu palladium, Kα1 1.54060, 2θ scanning angle from 3° to 45°, scanning step size of 0.02°, exposure time of 0.12 seconds. When testing the sample, the tube voltage and current were 40kV and 40mA respectively, and the sample disk was a zero background sample disk.

[0480] Differential Scanning Calorimetry

[0481] The crystalline forms and co-crystals of the salts of the compound of formula (I) were investigated by differential scanning calorimetry (DSC).

[0482] Measurement conditions: Differential Scanning Calorimetry (DSC) was performed using a TA Discovery 2500 (TA, US). A 1-2 mg sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated at a rate of 10°C / min to the final temperature. A nitrogen purge rate of 50 mL / min was used within the furnace. The plot was taken with the endothermic peak facing downward.

[0483] Thermogravimetric analysis

[0484] Test conditions: Thermogravimetric analyzer (TA Discovery 55, US) was used. A 2-5 mg sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed within the TGA furnace. The sample was heated at a rate of 10°C / min to the final temperature. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0485] Nuclear magnetic analysis (1H NMR)

[0486] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE-III (Bruker, Germany).

[0487] Experimental plan

[0488] The following provides exemplary experimental schemes of some compounds of the present invention to show the beneficial activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental schemes are merely examples of the content of the present invention, rather than limitations on the scope of the present invention.

[0489] Experimental Example 1 In vitro enzymatic activity of the compound of formula (I) of the present invention

[0490] abbreviation

[0491] EDTA: Ethylenediaminetetraacetic acid

[0492] DMSO: dimethyl sulfoxide

[0493] Tris: Tris(hydroxymethyl)aminomethane

[0494] Brij-35: Lauryl Ether

[0495] DTT: dithiothreitol

[0496] Test sample: Compound of formula (I) of the present invention, whose structural formula and preparation method are shown in the preparation examples.

[0497] Experimental reagents:

[0498] name brand ADP-Glo Kinase Assay Promege DNA-PK Promege

[0499] Experimental methods:

[0500] 1. Prepare 1x kinase buffer

[0501] 1) Prepare 1x kinase buffer using the following:

[0502] 40 mM Tris, pH 7.5;

[0503] 0.0055% Brij-35;

[0504] 20 mM MgCl2;

[0505] 0.05mM DTT.

[0506] 2. Compound Preparation

[0507] 1) The starting concentration of the compound for testing is 1 μM, and a 100-fold dilution (i.e., 100 μM) is prepared. Take 2 μl of a 10 mM compound and add 198 μl of 100% DMSO to prepare a 100 μM compound solution. Add 100 μl of the 100-fold dilution to the second well of a 96-well plate, and 60 μl of 100% DMSO to the remaining wells. Add 30 μl of the compound from the second well to the third well, and continue with the three-fold dilutions for a total of 10 dilutions.

[0508] 2) Transfer 100 μl of 100% DMSO and the highest concentration of the positive control wortmannin (400 nM) to two empty wells as Max wells and Min wells, respectively.

[0509] 3) Use Echo to transfer 50 nl of compound to a 384-well plate.

[0510] 3. Prepare 2x Kinase Solution

[0511] 1) Prepare 2x DNA-PK kinase solution using 1x kinase buffer.

[0512] 2) Transfer 2.5 μl of 2x enzyme solution to the reaction wells of a 384-well plate.

[0513] 3) Oscillate, mix well, and let stand at room temperature.

[0514] 4. Prepare 2x substrate solution

[0515] 1) Prepare 2x substrate solution using 1x kinase buffer.

[0516] 2) Transfer 2.5 μl of 2x substrate solution to the reaction wells of a 384-well plate to start the reaction.

[0517] 3) Oscillate and mix well.

[0518] 5. Kinase Reaction and Termination

[0519] 1) Cover the 384-well plate and incubate at 28°C for 3 hours.

[0520] 2) Transfer 5 μl of ADP-Glo reagent and incubate at 28°C for 2 hours.

[0521] 6. Detection of reaction results

[0522] 1) Transfer 10 μl of kinase assay reagent to each well of a 384-well plate to terminate the reaction.

[0523] 2) Let stand at room temperature for 30 minutes.

[0524] 7. Data reading

[0525] Read the sample values in Envision.

[0526] 8. Calculation of inhibition rate

[0527] 1) Copy data from Envision.

[0528] 2) Convert it into inhibition rate data.

[0529] Inhibition percentage = (max-conversion) / (max-min)*100, where max refers to the conversion rate of the DMSO control, min refers to the conversion rate of the no enzyme control, and conversion refers to the conversion rate at each concentration of the test compound.

[0530] 3) Perform curve fitting on the data to obtain IC 50 value.

[0531] Experimental results:

[0532] Table 1 In vitro enzymatic activity data of the compounds of the present invention

[0533] Compound <![CDATA[DNA-PK IC 50 (nM)]]> Compound of formula (I) 2.1

[0534] Experimental conclusion:

[0535] The results showed that the compound of formula (I) of the present invention has a good inhibitory effect on DNA-PK kinase activity.

[0536] Experimental Example 2 Metabolic Stability Experiment of Compounds of Formula (I) of the Present Invention in Liver Microsomes of Different Species

[0537] Test sample: Compound of formula (I) of the present invention, homemade. Its preparation method is shown in the preparation examples.

[0538] Experimental Materials:

[0539] Cynomolgus monkey pooled liver microsomes were purchased from Reed Liver Disease Research Center (Shanghai Co., Ltd.), and the liver microsomal protein concentration was 20 mg mL -1 .

[0540] Mixed liver microsomes from humans, Beagle dogs, and SD rats were purchased from Corning, and the liver microsomal protein concentration was 20 mg mL -1 .

[0541] The experimental initiation factor β-NADPH was purchased from Solarbio; pH 7.4 phosphate buffer (PBS) was homemade in our laboratory.

[0542] Preparation of test solution:

[0543] Accurately weigh an appropriate amount of test sample powder, add an appropriate amount of dimethyl sulfoxide (DMSO) to dissolve it to 1 mM, and then dilute it 20 times with methanol to a working solution of 50 μM.

[0544] Experimental methods:

[0545] Table 2. Composition of the incubation system for the liver microsome metabolic stability experiment

[0546]

[0547] Experimental steps:

[0548] (1) Prepare the incubation system mixture 1 (without microsomes, test sample, and β-NADPH) by adding 5.85 mL of 100 mM PBS, 0.585 mL of 20 mM MgCl₂ solution, and 3.57 mL of H₂O to each compound according to the proportions listed in Table 2 above. Verapamil, the antagonist of the experimental incubation system (easily metabolized in liver microsomes of all tested species), was also added to confirm normal liver microsomal enzyme activity.

[0549] (2) Take out liver microsomes (20 mg protein / mL) from the -80°C freezer and place them in a 37°C water bath in a constant temperature oscillator for pre-incubation for 3 min.

[0550] (3) For each compound and species, 1.9 mL of the incubation system mixed solution 1 was taken and 56 μL of microsomes of different species were added to prepare the incubation system mixed solution 2 (without the test sample and β-NADPH).

[0551] (4) Sample group (containing microsomes and β-NADPH): Take 616 μL of the incubation system mixed solution 2, add 14 μL of the test sample working solution at a concentration of 50 μM, and add 70 μL of the 10 mM β-NADPH working solution. Mix well and repeat. Sampling time points are 0 min, 5 min, 10 min, 20 min, 30 min, and 60 min. This sample group is used to evaluate the metabolic stability of the compound mediated by β-NADPH.

[0552] (5) Control group (containing microsomes but without β-NADPH, with water replacing β-NADPH): Take 264 μL of the incubation system mixed solution 2, add 6 μL of the test sample working solution at a concentration of 50 μM, and add 30 μL of water. Mix well and repeat the sample. Sampling time points are 0 min and 60 min. This negative control group is used to evaluate whether there is non-β-NADPH-mediated metabolism of the compound in the liver microsome incubation system.

[0553] (6) At each predetermined time point, 50 μL of the sample was taken from the incubation sample tube and added to the termination sample tube (containing 300 μL of cold terminator and acetonitrile solution containing 50 ng / mL of internal standard tolbutamide), vortexed, and the reaction was terminated.

[0554] (7) Vortex for 10 minutes and centrifuge for 5 minutes (12000 rpm).

[0555] (8) Take 100 μL of the supernatant, add 100 μL of water, vortex mix, and inject for LC-MS / MS analysis.

[0556] Data Analysis:

[0557] The ratio of the peak area of the test sample to the internal standard is converted into the residual amount percentage using the following formula.

[0558]

[0559] Experimental results:

[0560] Table 3 Liver microsomal stability results of the compounds of the present invention

[0561]

[0562] Experimental conclusion:

[0563] The compound of formula (I) of the present invention has good stability in human, monkey, dog and rat liver microsomes.

[0564] Experimental Example 3 Pharmacokinetics of the compound of formula (I) of the present invention in SD rats

[0565] Test sample: Compound of formula (I) of the present invention, homemade. Its preparation method is shown in the preparation examples.

[0566] Test animals: SD rats, male, weighing 190-210 g, 3 rats / group.

[0567] Preparation of test solution:

[0568] Preparation method of blank solvent (1): Weigh 28g HP-β-CD, add appropriate amount of injection water to dissolve, then dilute to 100mL with injection water, vortex mix, and obtain 28% HP-β-CD.

[0569] Preparation method of blank solvent (2): Weigh 20g HPC, slowly add it into 500mL of stirred purified water, then add 1mL Tween 80, stir until clear and transparent, adjust the volume to 1000mL, and stir evenly to obtain 2% HPC + 0.1% Tween 80.

[0570] IV (intravenous push) administration:

[0571] Take the compound of formula (I) of the present invention (appropriate amount), add DMA (3%-10%, v / v), vortex to dissolve, then add PEG400 (3%-10%, v / v), vortex to mix, and finally add blank solvent (1) (appropriate amount), vortex to mix, and keep warm at 50°C for 20 minutes to prepare a clear solution with an appropriate concentration (which can be 1 mg / mL) as the IV dosing solution of the test compound.

[0572] PO (oral) administration:

[0573] The compound of formula (I) of the present invention (appropriate amount) is weighed and placed in a tissue grinder. An appropriate amount of blank solvent (2) is added and the mixture is ground uniformly at a speed of 1200 rpm to obtain a suspension solution with a concentration of 10 mg / mL. The above suspension solution (appropriate amount) is taken and placed in a centrifuge tube. An appropriate amount of blank solvent (2) is added and the mixture is vortexed to prepare a suspension solution with an appropriate concentration (which may be 0.4 mg / mL) as the PO administration solution of the test compound.

[0574] Experimental methods

[0575] The IV dose was 2 mg / kg, the concentration was 1 mg / mL, and the volume was 2 mL / kg.

[0576] The PO dose is 4 mg / kg, the dosing concentration is 0.4 mg / mL, and the dosing volume is 10 mL / kg.

[0577] IV blood collection time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration.

[0578] Blood sampling time points for PO administration: 0.167, 0.5, 1, 2, 4, 6, 8, and 24 h after administration.

[0579] At each time point, approximately 100 μL of whole blood was collected through the tail vein and placed in an anticoagulant tube containing EDTA-K2 anticoagulant. Plasma samples were obtained by centrifugation at 8000 rpm for 6 minutes at 4°C. The plasma was frozen at -80°C until analysis.

[0580] Plasma sample analysis

[0581] The protein precipitation method was used: 20 μL of plasma sample was taken, 200 μL of internal standard (acetonitrile solution containing 50 ng / mL tolbutamide) was added, and the sample was vortexed for 10 minutes, then centrifuged at 4000 rpm for 20 minutes. 100 μL of the supernatant was taken, 100 μL of water was added, and the sample was vortexed for 3 minutes before LC-MS / MS analysis.

[0582] Experimental results and conclusions

[0583] The test results show that the compound of formula (I) of the present invention has good pharmacokinetic properties, and has a high exposure and bioavailability.

[0584] Experimental Example 4: Thermal Transformation Experiment

[0585] Experimental purpose: To determine whether solvent or water participates in the crystal formation in certain crystal forms

[0586] Test samples: hydrochloride salt form A, sulfate salt form A, methanesulfonate salt form A / B, p-toluenesulfonate salt form A / B / C, and fumaric acid cocrystal A / B of the compound of formula (I).

[0587] Experimental method: On a hot stage, heat the test sample to a certain temperature at 10°C / min and keep the temperature constant for 5 minutes.

[0588] Experimental results: After heating, the test samples were tested by XRPD. The test temperature and results are shown in Table 4 below:

[0589] Table 4: Thermal transformation test results

[0590]

[0591] Experimental conclusion:

[0592] The sulfate salt form A and the methanesulfonate salt form B of the compound of formula (I) are anhydrous crystals, and the TGA weight loss is due to adsorbed water; the hydrochloride salt form A, the methanesulfonate salt form A, the p-toluenesulfonate salt forms A / B / C, and the fumaric acid eutectic A / B are solvates or hydrates, and the solvent or water participates in the crystal formation. Specifically, the hydrochloride salt form A, the methanesulfonate salt form A, and the p-toluenesulfonate salt forms B / C are all hydrates, the p-toluenesulfonate salt form A and the fumaric acid eutectic A are both ethanol solvates, and the fumaric acid eutectic B is a tetrahydrofuran solvate.

[0593] Experimental Example 5 Dynamic Water Sorption and Desorption Analysis (DVS) Test

[0594] Test sample: maleic acid cocrystal A of compound of formula (I)

[0595] Test conditions: Measurements were performed using a DVS Intrinsic (SMS, UK). A gradient mode was used, with humidity changes from 50% to 95% to 0% to 50%, with each step increasing by 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt (rate of change of mass over time) method, with a dm / dt of less than 0.002% maintained for 10 minutes. After completion of the test, the sample was analyzed by XRPD to confirm any changes in the solid form.

[0596] Test results:

[0597] The test results show that the test sample gained 0.09% weight at 80% RH, gained 0.32% weight at 95% RH, and lost 0.24% weight at 0% RH. Therefore, the maleic acid cocrystal A of the compound of formula (I) has almost no hygroscopicity.

[0598] The XRPD test results showed that the crystal form did not change before and after the DVS test.

[0599] Experimental Example 6 Physical stability test

[0600] Test sample: maleic acid cocrystal A of the compound of formula (I).

[0601] Experimental method: Take four portions of maleic acid eutectic A, each 15 mg, and place them under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 lux), and accelerated (40°C / 75% RH) conditions respectively. After 15 days, XRPD characterization is performed. The test conditions are the same as those in the preparation example.

[0602] Experimental results: After 15 days of storage under different conditions, the crystal form did not change and remained maleic acid eutectic A.

[0603] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present disclosure and not to limit it. Although the present disclosure has been described in detail with reference to the preferred embodiments, ordinary technicians in the relevant field should understand that the specific implementation methods of the present disclosure can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present disclosure, which should all be included in the scope of the technical solutions requested for protection in the present disclosure.

Claims

1. A salt of a compound represented by the following formula (I), characterized in that: The salt is selected from hydrochloride, sulfate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, and malate.

2. The salt according to claim 1, wherein The salt is a hydrochloride, and the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2-1:0.5; Or the salt is a sulfate, and the molar ratio of the compound of formula (I) to sulfuric acid is 1:2-1:0.5; Or the salt is a methanesulfonate, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5; Or the salt is p-toluenesulfonate, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5; Or the salt is a maleate, and the molar ratio of the compound of formula (I) to maleic acid is 1:2-1:0.5; Or the salt is a fumarate, and the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5; Or the salt is malate, and the molar ratio of the compound of formula (I) to malic acid is 1:2-1:0.

5.

3. The salt according to claim 2, wherein The salt is a hydrochloride, and the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2; Or the salt is a sulfate, and the molar ratio of the compound of formula (I) to sulfuric acid is 1:1; Or the salt is a methanesulfonate, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1; Or the salt is p-toluenesulfonate, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1; Or the salt is a maleate, and the molar ratio of the compound of formula (I) to maleic acid is 1:1; Or the salt is a fumarate, and the molar ratio of the compound of formula (I) to fumaric acid is 1:1-1:0.5; Or the salt is malate, and the molar ratio of the compound of formula (I) to malic acid is 1:0.

8.

4. A crystalline form or co-crystal of a compound represented by the following formula (I), characterized in that: The crystal form or cocrystal is hydrochloride crystal form A, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 7.5±0.2°, 9.4±0.2°, 18.2±0.2°, 22.9±0.2°, 24.9±0.2°, 26.6±0.2°, and 27.5±0.2°; Or the crystal form or cocrystal is sulfate crystal form A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 8.4±0.2°, 16.5±0.2°, 19.4±0.2°, 21.1±0.2°, and 22.5±0.2°; Or the crystalline form or cocrystal is mesylate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.0±0.2°, 6.4±0.2°, 7.3±0.2°, 12.2±0.2°, 14.7±0.2°, 21.2±0.2°, 22.9±0.2°, and 26.6±0.2°; Or the crystalline form or cocrystal is mesylate crystalline form B, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 13.4±0.2°, 14.4±0.2°, 16.0±0.2°, 19.5±0.2°, 24.0±0.2°, and 26.7±0.2°; Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.7±0.2°, 10.2±0.2°, 15.2±0.2°, 19.3±0.2°, 25.9±0.2°, and 27.4±0.2°; Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form B, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 5.5±0.2°, 6.3±0.2°, 12.6±0.2°, 16.4±0.2°, 18.3±0.2°, 21.8±0.2°, and 26.8±0.2°; Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form C, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°, 22.5±0.2°, and 26.4±0.2°; Or the crystal form or cocrystal is maleic acid cocrystal A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 8.0±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 21.0±0.2°, and 21.5±0.2°; Or the crystal form or cocrystal is fumaric acid cocrystal A, which uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 9.0±0.2°, 13.2±0.2°, 18.7±0.2°, 20.9±0.2°, 26.3±0.2°, and 27.8±0.2°; Or the crystal form or cocrystal is fumaric acid cocrystal B, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 11.8±0.2°, 12.5±0.2°, 14.1±0.2°, 17.6±0.2°, 18.0±0.2°, 18.7±0.2°, 19.4±0.2°, 23.3±0.2°, and 26.7±0.2°; Or the crystal form or cocrystal is malic acid cocrystal A, which uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 10.6±0.2°, 13.2±0.2°, 15.9±0.2°, 16.4±0.2°, 19.0±0.2°, and 19.8±0.2°.

5. The crystalline form or co-crystal of the compound of formula (I) according to claim 4, characterized in that: The crystal form or cocrystal is hydrochloride crystal form A, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 7.5±0.2°, 9.4±0.2°, 10.1±0.2°, 14.3±0.2°, 18.2±0.2°, 21.1±0.2°, 22.9±0.2°, 24.9±0.2°, 26.6±0.2°, 27.5±0.2°, and 27.9±0.2°; Or the crystal form or cocrystal is sulfate crystal form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.4±0.2°, 12.8±0.2°, 14.2±0.2°, 16.5±0.2°, 16.9±0.2°, 19.4±0.2°, 19.9±0.2°, 21.1±0.2°, 21.5±0.2°, 22.5±0.2°, 24.9±0.2°, and 27.8±0.2°; Or the crystalline form or cocrystal is mesylate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.0±0.2°, 6.4±0.2°, 7.3±0.2°, 12.2±0.2°, 14.3±0.2°, 14.7±0.2°, 15.2±0.2°, 18.3±0.2°, 19.3±0.2°, 21.2±0.2°, 22.9±0.2°, and 26.6±0.2°; Or the crystalline form or cocrystal is mesylate crystalline form B, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 8.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.0±0.2°, 17.8±0.2°, 19.5±0.2°, 20.3±0.2°, 20.9±0.2°, 21.5±0.2°, 24.0±0.2°, 25.4±0.2°, 26.7±0.2°, and 28.0±0.2°; Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form A, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 7.0±0.2°, 9.7±0.2°, 10.2±0.2°, 14.3±0.2°, 15.2±0.2°, 16.6±0.2°, 19.3±0.2°, 20.9±0.2°, 22.5±0.2°, 24.1±0.2°, 25.9±0.2°, and 27.4±0.2°; Or the crystalline form or cocrystal is p-toluenesulfonate crystalline form C, which uses Cu-Kα radiation, expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 6.6±0.2°, 7.2±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°, 16.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.5±0.2°, 19.6±0.2°, 22.5±0.2°, 25.3±0.2°, and 26.4±0.2°; Or the crystalline form or cocrystal is maleic acid cocrystal A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 8.0±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 18.9±0.2°, 20.4±0.2°, 21.0±0.2°, 21.5±0.2°, 26.5±0.2°, 27.2±0.2°, and 28.2±0.2°; Or the crystal form or cocrystal is fumaric acid cocrystal A, which uses Cu-Kα radiation, expressed in 2θ angles, and has characteristic peaks in the X-ray powder diffraction pattern at 9.0±0.2°, 13.2±0.2°, 16.7±0.2°, 17.3±0.2°, 17.9±0.2°, 18.7±0.2°, 20.9±0.2°, 22.0±0.2°, 26.3±0.2°, and 27.8±0.2°; Or the crystal form or cocrystal is fumaric acid cocrystal B, which uses Cu-Kα radiation and is expressed in 2θ angles. The X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 11.8±0.2°, 12.5±0.2°, 14.1±0.2°, 15.0±0.2°, 16.5±0.2°, 17.6±0.2°, 18.0±0.2°, 18.7±0.2°, 19.4±0.2°, 22.5±0.2°, 23.3±0.2°, 26.7±0.2°, 30.1±0.2°, and 31.2±0.2°; Or the crystal form or cocrystal is malic acid cocrystal A, which uses Cu-Kα radiation and is expressed in 2θ angles, and the X-ray powder diffraction pattern has characteristic peaks at 8.0±0.2°, 10.6±0.2°, 12.3±0.2°, 13.2±0.2°, 15.9±0.2°, 16.4±0.2°, 19.0±0.2°, 19.8±0.2°, 25.6±0.2°, 26.8±0.2°, and 28.7±0.2°.

6. The crystalline form or co-crystal of the compound of formula (I) according to claim 4, characterized in that The crystalline form or co-crystal is hydrochloride Form A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 1; or the crystalline form or co-crystal is sulfate crystalline form A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 4; or the crystalline form or co-crystal is mesylate Form A, having an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in FIG7 ; or the crystalline form or co-crystal is mesylate Form B, having an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 10; or the crystalline form or co-crystal is p-toluenesulfonate Form A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 13; or the crystalline form or co-crystal is p-toluenesulfonate Form B, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 16; or the crystalline form or co-crystal is p-toluenesulfonate Form C, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 19; or the crystalline form or co-crystal is maleic acid co-crystal A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 22; or the crystalline form or co-crystal is fumaric acid co-crystal A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 25; or the crystalline form or co-crystal is fumaric acid co-crystal B, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 28; Or the crystalline form or co-crystal is malic acid co-crystal A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 31.

7. The crystalline form or co-crystal of the compound of formula (I) according to claim 4, wherein The crystal form or co-crystal is hydrochloride crystal form A, and the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2-1:0.5; Or the crystal form or co-crystal is sulfate crystal form A, and the molar ratio of the compound of formula (I) to sulfuric acid is 1:2-1:0.5; Or the crystalline form or co-crystal is mesylate form A, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5; Or the crystalline form or co-crystal is mesylate crystalline form B, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:2-1:0.5; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form A, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form B, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form C, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:2-1:0.5; Or the crystal form or cocrystal is maleic acid cocrystal A, and the molar ratio of the compound of formula (I) to maleic acid is 1:2-1:0.5; Or the crystal form or cocrystal is fumaric acid cocrystal A, and the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5; Or the crystal form or cocrystal is fumaric acid cocrystal B, and the molar ratio of the compound of formula (I) to fumaric acid is 1:2-1:0.5; Or the crystal form or co-crystal is malic acid co-crystal A, and the molar ratio of the compound of formula (I) to malic acid is 1:2-1:0.

5.

8. The crystalline form or co-crystal of the compound of formula (I) according to claim 7, wherein The crystal form or co-crystal is hydrochloride crystal form A, and the molar ratio of the compound of formula (I) to hydrochloric acid is 1:2; Or the crystal form or co-crystal is sulfate crystal form A, and the molar ratio of the compound of formula (I) to sulfuric acid is 1:1; Or the crystalline form or co-crystal is mesylate form A, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1; Or the crystalline form or co-crystal is mesylate form B, and the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form A, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form B, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form C, and the molar ratio of the compound of formula (I) to p-toluenesulfonic acid is 1:1; Or the crystalline form or cocrystal is maleic acid cocrystal A, and the molar ratio of the compound of formula (I) to maleic acid is 1:1; Or the crystal form or cocrystal is fumaric acid cocrystal A, and the molar ratio of the compound of formula (I) to fumaric acid is 1:1; Or the crystal form or cocrystal is fumaric acid cocrystal B, and the molar ratio of the compound of formula (I) to fumaric acid is 1:0.7; Or the crystal form or co-crystal is malic acid co-crystal A, and the molar ratio of the compound of formula (I) to malic acid is 1:0.

8.

9. The crystalline form or co-crystal of the compound of formula (I) according to any one of claims 4 to 8, characterized in that The crystal form or cocrystal is hydrochloride crystal form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 50°C to 100°C and also has an endothermic peak in the range of 210°C to 270°C; Or the crystal form or co-crystal is sulfate crystal form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 50°C to 75°C, 75°C to 110°C, 175°C to 225°C, and 225°C to 250°C respectively; Or the crystalline form or co-crystal is mesylate crystalline form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 60°C to 100°C, 125°C to 150°C, 185°C to 200°C, and 225°C to 260°C, and an exothermic peak in the range of 160°C to 175°C and 200°C to 215°C; Or the crystal form or co-crystal is mesylate crystal form B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the ranges of 75°C to 90°C, 100°C to 120°C, 210°C to 225°C, and 225°C to 250°C respectively; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 125°C to 160°C and 230°C to 265°C, and also has an exothermic peak in the range of 175°C to 210°C; Or the crystal form or co-crystal is p-toluenesulfonate crystal form B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 85°C to 125°C and 130°C to 160°C respectively; Or the crystal form or co-crystal is p-toluenesulfonate crystal form C, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 75°C to 110°C, 190°C to 210°C, and 210°C to 230°C respectively; Or the crystal form or cocrystal is maleic acid cocrystal A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 190°C to 200°C and an exothermic peak in the range of 200°C to 210°C; Or the crystal form or cocrystal is fumaric acid cocrystal A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 60°C to 80°C, 90°C to 125°C, and 190°C to 225°C respectively; Or the crystal form or cocrystal is fumaric acid cocrystal B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 100°C to 150°C and 210°C to 250°C respectively; Or the crystal form or cocrystal is malic acid cocrystal A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 175°C to 210°C.

10. The crystalline form or co-crystal of the compound of formula (I) according to claim 9, characterized in that: The crystal form or co-crystal is hydrochloride crystal form A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 253.0±5°C; Or the crystal form or co-crystal is sulfate crystal form A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 238.1±5°C; Or the crystal form or co-crystal is mesylate crystal form A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 244.3±5°C; Or the crystal form or co-crystal is mesylate crystal form B, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 234.9±5°C; Or the crystal form or co-crystal is p-toluenesulfonate crystal form A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 251.6±5°C; Or the crystal form or co-crystal is p-toluenesulfonate crystal form B, and its differential scanning calorimetry (DSC) analysis curve has a maximum endothermic transition temperature of 145.3±5°C; Or the crystal form or cocrystal is maleic acid cocrystal A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 200.0±5°C; Or the crystal form or cocrystal is fumaric acid cocrystal B, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 231.2±5°C; Or the crystal form or cocrystal is malic acid cocrystal A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 194.5±5°C.

11. The crystalline form or co-crystal of the compound of formula (I) according to claim 9, characterized in that: The crystalline form or co-crystal is hydrochloride crystalline form A, characterized in that the hydrochloride crystalline form A has a differential scanning calorimetry curve substantially as shown in Figure 2; Or the crystal form or co-crystal is sulfate crystal form A, characterized in that the sulfate crystal form A has a differential scanning calorimetry curve substantially as shown in Figure 5; Or the crystalline form or co-crystal is mesylate crystalline form A, characterized in that the mesylate crystalline form A has a differential scanning calorimetry curve substantially as shown in Figure 8; Or the crystalline form or co-crystal is mesylate crystalline Form B, characterized in that the mesylate crystalline Form B has a differential scanning calorimetry curve substantially as shown in Figure 11; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline form A, characterized in that the p-toluenesulfonate crystalline form A has a differential scanning calorimetry curve substantially as shown in Figure 14; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline Form B, characterized in that the p-toluenesulfonate crystalline Form B has a differential scanning calorimetry curve substantially as shown in Figure 17; Or the crystalline form or co-crystal is p-toluenesulfonate crystalline Form C, characterized in that the p-toluenesulfonate crystalline Form C has a differential scanning calorimetry curve substantially as shown in Figure 20; Or the crystal form or cocrystal is maleic acid cocrystal A, characterized in that the maleic acid cocrystal A has a differential scanning calorimetry curve substantially as shown in Figure 23; Or the crystal form or cocrystal is fumaric acid cocrystal A, characterized in that the fumaric acid cocrystal A has a differential scanning calorimetry curve substantially as shown in Figure 26; Or the crystal form or cocrystal is fumaric acid cocrystal B, characterized in that the fumaric acid cocrystal B has a differential scanning calorimetry curve substantially as shown in Figure 29; Or the crystal form or co-crystal is malic acid co-crystal A, characterized in that the malic acid co-crystal A has a differential scanning calorimetry curve substantially as shown in Figure 32.

12. A method for preparing a crystalline form or co-crystal of the compound of formula (I) according to any one of claims 4 to 11, comprising the following steps: Adding an organic solvent and 1-2 equivalents of an acid to the compound of formula (I), stirring at room temperature, and separating the solvent to obtain the crystal form or cocrystal according to any one of claims 3 to 7; The acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, and malic acid; The organic solvent is selected from one of the following solvents or any combination of two or more solvents: (1) an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexanol, benzyl alcohol, phenylethyl alcohol, or phenylpropyl alcohol; (2) a halogenated alkane solvent selected from dichloromethane or chloroform; (3) a nitrile solvent selected from acetonitrile or propionitrile; (4) an ester solvent selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate; (5) a ketone solvent selected from acetone, butanone, isobutyl ketone, methyl isobutyl ketone or 4-methyl-2-pentanone; (6) an alkane solvent selected from n-pentane, n-hexane, n-heptane or cyclohexane; (7) Ether solvents, including diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane; (8) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

13. The preparation method according to claim 12, wherein The organic solvent is selected from: methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetone or any combination of two or more of the above solvents.

14. A pharmaceutical preparation comprising the salt of claims 1 to 3 or the crystalline form or co-crystal of any one of claims 4 to 11, characterized in that: Containing one or more pharmaceutically acceptable excipients, the pharmaceutical preparation is in any pharmaceutically acceptable dosage form.

15. A pharmaceutical composition comprising a salt according to claim 1 or a crystalline form or cocrystal according to any one of claims 4 to 11; optionally, the pharmaceutical composition further comprises one or more second therapeutically active agents, wherein the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, DNA chimeras, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors and protein prenyl transferase inhibitors.

16. Use of the salt of claims 1-3 or the crystalline form or co-crystal of any one of claims 4-11 in the preparation of a medicament for preventing and / or treating benign tumors or cancer, including carcinoma in situ and metastatic cancer; Optionally, the salt, crystalline form or co-crystal is used in combination with radiotherapy and / or one or more anti-cancer agents, the anti-cancer agent being as described in claim 15.

17. Use of the salt of claims 1 to 3 or the crystalline form or co-crystal of any one of claims 4 to 11 in the preparation of a medicament for sensitizing cancer cells to an anticancer agent and / or radiotherapy, wherein the anticancer agent is as claimed in claim 15.

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