Crystal Forms of Tricyclic Kinase Inhibitors

Abstract

The present invention relates to crystal forms A, B, C, D, E, and F of the 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]purin-2-amine, and their preparation methods. The crystal forms all have the characteristics of high purity, relatively high solubility, good disintegration and dissolution properties; and have good physical properties, fluidity, and compressibility, which are convenient for production, detection, preparation of pharmaceutical preparations, transportation, and storage; the preparation methods are simple to operate, suitable for industrial production, and can significantly enhance the sensitivity of tumor cells to radiotherapy / chemotherapy and other anti-cancer agents.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a crystal form of a targeted DNA-PK kinase inhibitor, a preparation method thereof, a pharmaceutical composition containing the crystal form, and the use of these crystalline compounds and their compositions in the preparation of drugs for the treatment and / or prevention of cancer diseases. Background Art

[0002] Cancer is a malignant disease that is difficult to treat worldwide, with great treatment difficulty and high mortality rate, bringing a heavy burden to patients and their families, and is a major disease affecting the health of Chinese residents. In recent years, the incidence of cancer in China has increased significantly, and its mortality rate has also shown a gradually increasing trend. The prevention and treatment of cancer face a severe situation.

[0003] At present, radiotherapy and chemotherapy are the most effective means for treating cancer in addition to surgical resection. At the same time, radiotherapy is the most effective non-surgical treatment for malignant tumors. Radiation and a considerable number of anticancer drugs can directly or indirectly act on DNA or the DNA metabolism process, thereby causing DNA damage. Among them, DNA double-strand break (DSB) is the most lethal to cancer cells. After DNA damage, a series of cellular responses such as damaged DNA repair will be triggered, and the result of the repair is to increase the survival of cancer cells, which is also one of the mechanisms of tumor cell resistance to radiotherapy and chemotherapy. If DNA double-strand breaks are not repaired in a timely and complete manner, cancer cells will die due to apoptosis or / and mitotic disorders. Therefore, as long as the repair of these DNA damages is inhibited, the sensitivity of cancer cells to radiotherapy and chemotherapy can be increased, and cell proliferation can be inhibited.

[0004] In higher eukaryotic cells such as humans, the repair of DSB is mainly carried out by DNA non-homologous end joining (NHEJ) dominated by DNA-dependent protein kinase

[0005] (DNA-Dependent Protein Kinase, DNA-PK), thereby repairing the damaged DNA and maintaining cell viability and genomic stability. NHEJ repair mainly participates in DNA damage repair in the G1 / S phase and does not require a DNA end ligation template. NHEJ repair requires the coordinated action of many proteins and signaling pathways. The heterodimer of the Ku70 / 80 subunits and the catalytic subunit DNA-dependent protein kinase (DNA-PKcs) together form an active DNA-PK enzyme complex.

[0006] DNA-PKcs belongs to the phosphatidylinositol 3-kinase (PI3K) superfamily and is a serine / threonine protein kinase; the PI3K superfamily also includes ATM, ATR, mTOR, and four PI3K isoforms. The kinase activity of DNA-PK can only be activated when it binds to broken DNA. An important function of Ku is to bind to the DNA ends, recruit DNA-PKcs, and the two form the DNA-PK holoenzyme and activate DNA-PKcs; the activated DNA-PKcs guides the Artemis protein (an endonuclease) to bind to the damaged site, and relies on its ribozyme activity to process the DNA ends for ligation repair. Then, the XRCC4 / DNA ligase IV complex is recruited by the activated DNA-PKcs, and finally DNA ligase IV locates and ligates the ends of the broken DNA double strand to complete the repair. XRCC4 is a protein that forms a complex with DNA ligase IV and can increase the activity of DNA ligase IV. There are 40 amino acid residues in DNA-PKcs that can be autophosphorylated, and the most typical autophosphorylation sites occur at Ser2056 (POR cluster) and Thr2609 (ABCDE cluster). NHEJ is considered to proceed through three key steps: recognition of DSB - Ku70 / 80 binds to the incomplete DNA ends, recruiting two molecules of DNA-PKcs to the adjacent sides of the DSB; DNA processing to remove non-ligatable ends or other damaged forms at the ends; and finally ligating the DNA ends.

[0007] Due to the relatively high basal level of endogenous replication stress (oncogene-induced replication stress) and DNA damage in tumor cells, and the relatively low efficiency of DNA repair mechanisms in tumor cells, tumor cells are more sensitive to DNA-PK.

[0008] 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, hepatic microsomal stability, and pharmacokinetic properties, can significantly enhance the sensitivity of tumor cells to radiotherapy / chemotherapy and other anticancer agents, and has relatively high safety.

[0009]

[0010] In order to better control the quality of the drug and meet the requirements of formulation, production, transportation, storage, etc., we have studied the crystal forms of the compound of formula (I) with the expectation of discovering crystal forms with good properties.

[0011] To make the disclosure of this application more complete, all the technical content in Chinese Patent Application CN202110438932.4 is incorporated into this application. SUMMARY OF THE INVENTION

[0012] The present disclosure relates to crystalline forms A (referred to as crystalline form A for short), B (referred to as crystalline form B for short), C (referred to as crystalline form C for short), D (referred to as crystalline form D for short), E (referred to as crystalline form E for short), and F (referred to as crystalline form F for short) 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 shown in formula (I). The present disclosure also relates to the preparation methods of crystalline forms A, B, C, D, E, and F, pharmaceutical compositions comprising crystalline form A, B, C, D, E, or F, and the use of these compounds or compositions in the preparation of drugs for treating and / or preventing cancer.

[0013] On the one hand, the present disclosure provides a crystalline form of the compound shown in formula (I), wherein,

[0014]

[0015] the crystalline form is crystalline form A, which has characteristic peaks at 9.0±0.2°, 18.1±0.2°, and 20.1±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation;

[0016] or the crystalline form is crystalline form B, which has characteristic peaks at 10.4±0.2°, 11.9±0.2°, 17.6±0.2°, 18.4±0.2°, and 23.6±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation;

[0017] or the crystalline form is crystalline form C, which has characteristic peaks at 4.9±0.2°, 8.6±0.2°, 9.6±0.2°, 12.8±0.2°, 14.7±0.2°, 16.9±0.2°, and 19.2±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation;

[0018] or the crystalline form is crystalline form D, which has characteristic peaks at 10.7±0.2°, 12.0±0.2°, 18.2±0.2°, 19.1±0.2°, and 19.9±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation;

[0019] or the crystal form is crystal form E, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 7.0 ± 0.2°, 13.5 ± 0.2°, and 21.3 ± 0.2°;

[0020] or the crystal form is crystal form F, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 8.3 ± 0.2°, 9.0 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 19.1 ± 0.2°, 19.8 ± 0.2°, 22.3 ± 0.2°, and 26.2 ± 0.2°.

[0021] In certain embodiments, the crystal form of the compound of formula (I), wherein,

[0022] the crystal form is crystal form B, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 10.4 ± 0.2°, 11.9 ± 0.2°, 17.6 ± 0.2°, 18.4 ± 0.2°, 18.8 ± 0.2°, 21.2 ± 0.2°, 21.8 ± 0.2°, 23.6 ± 0.2°, 28.2 ± 0.2°, and 30.1 ± 0.2°;

[0023] or the crystal form is crystal form C, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 4.9 ± 0.2°, 8.6 ± 0.2°, 9.6 ± 0.2°, 12.8 ± 0.2°, 14.7 ± 0.2°, 16.9 ± 0.2°, 18.1 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 23.6 ± 0.2°, 24.2 ± 0.2°, 25.0 ± 0.2°, 25.8 ± 0.2°, and 26.4 ± 0.2°;

[0024] or the crystal form is crystal form D, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 10.7 ± 0.2°, 12.0 ± 0.2°, 18.2 ± 0.2°, 19.1 ± 0.2°, 19.9 ± 0.2°, 21.2 ± 0.2°, 22.1 ± 0.2°, 23.9 ± 0.2°, and 29.0 ± 0.2°.

[0025] or the crystalline form is crystalline form F, which, when using Cu-Kα radiation and expressed in 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 8.3±0.2°, 9.0±0.2°, 14.0±0.2°, 14.4±0.2°, 17.4±0.2°, 18.5±0.2°, 19.1±0.2°, 19.8±0.2°, 20.2±0.2°, 20.7±0.2°, 22.3±0.2°, 24.1±0.2°, 26.2±0.2°, 27.8±0.2°.

[0026] In certain embodiments, the crystalline form of the compound of formula (I), wherein,

[0027] the crystalline form is crystalline form A, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 1 shown;

[0028] or the crystalline form is crystalline form B, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 4 shown;

[0029] or the crystalline form is crystalline form C, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 7 shown;

[0030] or the crystalline form is crystalline form D, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 10 shown;

[0031] or the crystalline form is crystalline form E, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 13 shown;

[0032] or the crystalline form is crystalline form F, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 16 shown.

[0033] In certain embodiments, the crystalline form of the compound of formula (I), wherein,

[0034] the crystalline form is crystalline form A, the differential scanning calorimetry (DSC) analysis curve of which has an endothermic peak in the range of 35°C to 80°C and also has an endothermic peak in the range of 260°C to 290°C; preferably, the maximum endothermic transition temperature is 272.0±5°C; more preferably, the crystalline form A has a differential scanning calorimetry curve substantially as Figure 2 shown;

[0035] Or the crystal form is crystal form B, whose differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 110°C to 150°C and also has an endothermic peak in the range of 260°C to 290°C; preferably, the maximum endothermic transition temperature is 272.3 ± 5°C; more preferably, the crystal form B has a differential scanning calorimetry curve substantially as Figure 5 shown;

[0036] Or the crystal form is crystal form C, whose differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 250°C to 290°C; preferably, the maximum endothermic transition temperature is 271.9 ± 5°C; more preferably, the crystal form C has a differential scanning calorimetry curve substantially as Figure 8 shown;

[0037] Or the crystal form is crystal form D, whose differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 110°C to 160°C and also has an endothermic peak in the range of 260°C to 290°C; preferably, the maximum endothermic transition temperature is 272.2 ± 5°C; more preferably, the crystal form D has a differential scanning calorimetry curve substantially as Figure 11 shown;

[0038] Or the crystal form is crystal form E, whose differential scanning calorimetry (DSC) analysis curve has endothermic peaks in the ranges of 50°C to 100°C and 250°C to 280°C; preferably, the maximum endothermic transition temperature is 272.0 ± 5°C; more preferably, the crystal form E has a differential scanning calorimetry curve substantially as Figure 14 shown;

[0039] Or the crystal form is crystal form F, whose differential scanning calorimetry (DSC) analysis curve has an endothermic peak in each of the ranges of 50°C to 100°C, 125°C to 200°C, and 260°C to 290°C; preferably, the maximum endothermic transition temperature is 272.5 ± 5°C; more preferably, the crystal form F has a differential scanning calorimetry curve substantially as Figure 17 shown.

[0040] In certain embodiments, the crystal form of the compound of formula (I), wherein,

[0041] the crystal form is crystal form A, which is a hydrate; preferably, the water content percentage by weight of the crystal form A is 7.4 ± 2%;

[0042] Or the crystal form is crystal form B, which is an ethanol solvate; preferably, the molar ratio of the compound of formula (I) to ethanol in the crystal form B is 1:1;

[0043] Or the crystal form is crystal form C, which is an anhydrate;

[0044] Or the crystal form is crystal form D, which is a methanol solvate; preferably, the molar ratio of the compound of formula (I) to methanol in crystal form D is 1:1;

[0045] Or the crystal form is crystal form E, which is a hydrate; preferably, the water content by weight percentage in crystal form E is 21.1 ± 2%;

[0046] Or the crystal form is crystal form F, which is a formic acid solvate; preferably, the formic acid content by weight percentage in crystal form F is 8.5 ± 2%.

[0047] The present disclosure also provides a method for preparing a crystal form of a compound of formula (I), comprising the following operations:

[0048] Dissolve or suspend the compound of formula (I) in an organic solvent, water, or a mixed solvent of an organic solvent and water, react at room temperature or heat to 40 - 60 °C for reaction, and separate by solvent evaporation, separation, or cooling to obtain the crystal form of the compound of formula (I).

[0049] In certain embodiments, in the method for preparing the crystal form of the compound of formula (I), the organic solvent is selected from one or any combination of two or more of the following solvents:

[0050] (1) Alcohol solvents, selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol, cyclohexylethanol, benzyl alcohol, phenethyl alcohol, or phenylpropyl alcohol;

[0051] (2) Halogenated alkane solvents, selected from dichloromethane or chloroform;

[0052] (3) Nitrile solvents, selected from acetonitrile or propionitrile;

[0053] (4) Ester solvents, selected from ethyl formate, methyl formate, butyl formate, ethyl acetate, or isopropyl acetate;

[0054] (5) Ketone solvents, selected from acetone, butanone, isobutanone, methyl isobutyl ketone, or 4-methyl-2-pentanone;

[0055] (6) Alkane solvents, selected from n-pentane, n-hexane, n-heptane, or cyclohexane;

[0056] (7) Aromatic hydrocarbon solvents, selected from toluene;

[0057] (8) Ether solvents, diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4-dioxane;

[0058] (9) Dimethyl sulfoxide, dimethylformamide, or N-methylpyrrolidone.

[0059] In certain embodiments, the organic solvent is selected from: methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, acetonitrile, ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, toluene, diethyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dimethylformamide, or any combination of two or more of the above solvents.

[0060] In certain embodiments, in the mixed solvent of any two solvent combinations, the volume ratio of the two single solvents is 1:10 - 10:1.

[0061] In certain embodiments, in the mixed solvent of the organic solvent and water, the volume ratio of the organic solvent to water is selected from 1:10 - 10:1.

[0062] In certain embodiments, for the method for preparing the crystal form of the compound of formula (I), after the reaction is completed, crystallization, separation, and drying are carried out to obtain the crystal form.

[0063] In certain embodiments, the crystallization is selected from crystallization at room temperature or cooling crystallization.

[0064] In certain embodiments, the crystallization at room temperature is selected from crystallization by stirring at room temperature and crystallization by standing at room temperature.

[0065] In certain embodiments, the separation is selected from normal pressure filtration, vacuum filtration, centrifugation to remove the liquid, or evaporation of the solvent.

[0066] In certain embodiments, in the method for preparing the crystal form of the compound of formula (I), the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0067] In certain embodiments, in the method for preparing the crystal form of the compound of formula (I), the drying is selected from natural air drying at room temperature, natural 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, such as 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.; during the drying process, multiple dryings can optionally be carried out at different temperatures.

[0068] The room temperature described in the present disclosure is the indoor temperature, which changes with the seasons and is usually in the range of 10°C - 30°C.

[0069] The present disclosure also provides a method for preparing a crystal form of a compound of formula (I), comprising the following operations:

[0070] Dissolve or suspend the compound of formula (I) in an organic solvent, water, or a mixed solvent of an organic solvent and water, stir at room temperature or heat to 40 - 60 °C, then add a second solvent or place the reaction system in an atmosphere of the second solvent and continue the reaction, and separate by solvent evaporation, separation, or cooling to obtain the crystal form of the compound of formula (I); wherein, among the organic solvent, water, and the second solvent, when one is a good solvent for the compound of formula (I), the other is a poor solvent for the compound of formula (I);

[0071] The second solvent is selected from an organic solvent or water.

[0072] In certain embodiments, in the method for preparing the crystal form of the compound of formula (I), the organic solvent is selected from one or any combination of two or more of the following solvents:

[0073] (1) Alcohol solvents, selected from methanol, ethanol, n - propanol, isopropanol, n - butanol, sec - butanol, tert - butanol, n - pentanol, n - hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol, cyclohexylethanol, benzyl alcohol, phenethyl alcohol, or phenylpropyl alcohol;

[0074] (2) Halogenated alkane solvents, selected from dichloromethane or chloroform;

[0075] (3) Nitrile solvents, selected from acetonitrile or propionitrile;

[0076] (4) Ester solvents, selected from ethyl formate, methyl formate, butyl formate, ethyl acetate, or isopropyl acetate;

[0077] (5) Ketone solvents, selected from acetone, butanone, isobutanone, methyl isobutyl ketone, or 4 - methyl - 2 - pentanone;

[0078] (6) Alkane solvents, selected from n - pentane, n - hexane, n - heptane, or cyclohexane;

[0079] (7) Aromatic hydrocarbon solvents, selected from toluene;

[0080] (8) Ether solvents, diethyl ether, propyl ether, isopropyl ether, methyl tert - butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4 - dioxane;

[0081] (9) Dimethyl sulfoxide, dimethylformamide, or N - methylpyrrolidone.

[0082] In certain embodiments, the organic solvent is selected from: methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, acetonitrile, ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, toluene, diethyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dimethylformamide, or any combination of two or more of the above solvents.

[0083] In certain embodiments, in the mixed solvent of any two solvent combinations, the volume ratio of the two single solvents is 1:10 - 10:1.

[0084] In certain embodiments, in the mixed solvent of the organic solvent and water, the volume ratio of the organic solvent to water is selected from 1:10 - 10:1.

[0085] In certain embodiments, for the method for preparing the crystal form of the compound of formula (I), after the reaction is completed, crystallization, separation, and drying are carried out to obtain the crystal form.

[0086] In certain embodiments, the crystallization is selected from crystallization at room temperature or cooling crystallization.

[0087] In certain embodiments, the crystallization at room temperature is selected from crystallization by stirring at room temperature and crystallization by standing at room temperature.

[0088] In certain embodiments, the separation is selected from normal pressure filtration, vacuum filtration, centrifugation followed by removing the liquid, or evaporating the solvent.

[0089] In certain embodiments, in the method for preparing the crystal form of the compound of formula (I), the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0090] In certain embodiments, in the method for preparing the crystal form of the compound of formula (I), the drying is selected from natural air drying at room temperature, natural 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, such as 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.; during the drying process, multiple dryings can optionally be carried out at different temperatures.

[0091] The room temperature as described in the present disclosure is the indoor temperature, which varies with the seasons and is usually in the range of 10°C - 30°C.

[0092] On the one hand, the present disclosure provides a crystalline form A of a compound represented by formula (I), wherein, using Cu-Kα radiation, expressed in 2θ angle, the X-ray powder diffraction pattern has characteristic peaks at 9.0 ± 0.2°, 18.1 ± 0.2°, and 20.1 ± 0.2°.

[0093]

[0094] In certain embodiments, the crystalline form A has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 1 shown.

[0095] In certain embodiments, for the crystalline form A, its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 35 °C to 80 °C and also has an endothermic peak in the range of 260 °C to 290 °C.

[0096] In certain embodiments, for the crystalline form A, the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.0 ± 5 °C.

[0097] In certain embodiments, the crystalline form A has a differential scanning calorimetry curve substantially as Figure 2 shown.

[0098] In certain embodiments, the crystalline form A is a hydrate.

[0099] In certain embodiments, in the crystalline form A, the weight percentage of water is 7.4 ± 2%.

[0100] In certain embodiments, the crystalline form A has a thermogravimetric analysis (TGA) curve substantially as Figure 2 shown.

[0101] In certain embodiments, for the crystalline form A of the compound of formula (I), its crystal structure is in a substantially pure form.

[0102] The present disclosure also provides a method for preparing crystalline form A of a compound of formula (I), comprising the following operations:

[0103] Dissolve or suspend the compound of formula (I) in water, heat to 40 - 60 °C for reaction to obtain crystalline form A.

[0104] The present disclosure also provides a method for preparing crystalline form A of a compound of formula (I), comprising the following operations:

[0105] Dissolve or suspend the compound of formula (I) in a mixed solvent of an organic solvent and water, react at room temperature or heat to 40 - 60 °C to obtain crystalline form A.

[0106] In certain embodiments, the method for preparing polymorph A, wherein after the reaction is completed, polymorph A is obtained through cooling, separation, and drying.

[0107] In certain embodiments of the method for preparing polymorph A, the organic solvent is selected from ethylene glycol monomethyl ether, dimethylformamide, and dimethyl sulfoxide, and the volume ratio of the organic solvent to water in the mixed solvent is 1:10 - 10:1; preferably, the volume ratio of the organic solvent to water in the mixed solvent is 1:10 - 1:1.

[0108] In certain embodiments, the separation is selected from atmospheric pressure filtration, vacuum filtration, centrifugation followed by removal of the liquid, or evaporation of the solvent.

[0109] In certain embodiments of the method for preparing polymorph A, the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0110] In certain embodiments of the method for preparing polymorph A, the drying is selected from natural air drying at room temperature, natural 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, such as 30°C - 80°C, such as 35°C - 70°C, such as 40°C - 65°C, such as 35°C - 50°C; the drying process can optionally be carried out at different temperatures multiple times.

[0111] The room temperature as described in the present disclosure is the indoor temperature, which varies with the seasons and is generally in the range of 10°C - 30°C.

[0112] On the other hand, the present disclosure provides a polymorph B of the compound represented by formula (I), wherein, using Cu - Kα radiation and expressed in 2θ angle, the X - ray powder diffraction pattern has characteristic peaks at 10.4 ± 0.2°, 11.9 ± 0.2°, 17.6 ± 0.2°, 18.4 ± 0.2°, 23.6 ± 0.2°.

[0113]

[0114] In certain embodiments, for the polymorph B, when using Cu - Kα radiation and expressed in 2θ angle, the X - ray powder diffraction pattern has characteristic peaks at 10.4 ± 0.2°, 11.9 ± 0.2°, 17.6 ± 0.2°, 18.4 ± 0.2°, 18.8 ± 0.2°, 21.2 ± 0.2°, 21.8 ± 0.2°, 23.6 ± 0.2°, 28.2 ± 0.2°, 30.1 ± 0.2°.

[0115] In certain embodiments, the crystalline form B has substantially as Figure 4 shown by the X-ray powder diffraction pattern obtained using Cu-Kα radiation.

[0116] In certain embodiments, the crystalline form B has an endothermic peak in the range of 110°C to 150°C and also has an endothermic peak in the range of 260°C to 290°C in its differential scanning calorimetry (DSC) analysis curve.

[0117] In certain embodiments, for the crystalline form B, the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.3 ± 5°C.

[0118] In certain embodiments, the crystalline form B has substantially as Figure 5 shown by the differential scanning calorimetry curve.

[0119] In certain embodiments, the crystalline form B is an ethanol solvate.

[0120] In certain embodiments, the molar ratio of the compound of formula (I) to ethanol in the crystalline form B is 1:1.

[0121] In certain embodiments, the crystalline form B has substantially as Figure 5 shown by the thermogravimetric analysis (TGA) curve.

[0122] The present disclosure also provides a method for preparing the crystalline form B of the compound of formula (I), comprising the following operations:

[0123] Dissolve or suspend the compound of formula (I) in an organic solvent, react at room temperature or heated to 40 - 60°C, and separate by solvent evaporation, separation, or cooling to obtain the crystalline form B.

[0124] In certain embodiments, in the method for preparing the crystalline form B, the organic solvent is selected from: ethanol.

[0125] In certain embodiments, the organic solvent is selected from ethylene glycol monomethyl ether / ethanol, dimethylformamide / ethanol, dimethyl sulfoxide / ethanol, dichloromethane / ethanol, chloroform / ethanol, and the volume ratio of the two single solvents in the mixed solvent is 1:10 - 10:1.

[0126] In certain embodiments, the separation is selected from normal pressure filtration, reduced pressure suction filtration, centrifugation to remove the liquid, or solvent evaporation.

[0127] In certain embodiments, the preparation process can be optionally carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0128] In certain embodiments, in the method for preparing polymorph B, the separated polymorph can be dried, and the drying methods include natural air drying at room temperature, natural 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 - 100°C, such as 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.; during the drying process, multiple drying operations can be optionally carried out at different temperatures.

[0129] In certain embodiments, the room temperature is the indoor temperature, which varies with the seasons and is generally in the range of 10°C - 30°C.

[0130] On the other hand, the present disclosure provides a polymorph C of the compound represented by formula (I), wherein, using Cu-Kα radiation and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 4.9 ± 0.2°, 8.6 ± 0.2°, 9.6 ± 0.2°, 12.8 ± 0.2°, 14.7 ± 0.2°, 16.9 ± 0.2°, 19.2 ± 0.2°.

[0131]

[0132] In certain embodiments, for the polymorph C, using Cu-Kα radiation and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 4.9 ± 0.2°, 8.6 ± 0.2°, 9.6 ± 0.2°, 12.8 ± 0.2°, 14.7 ± 0.2°, 16.9 ± 0.2°, 18.1 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 23.6 ± 0.2°, 24.2 ± 0.2°, 25.0 ± 0.2°, 25.8 ± 0.2°, 26.4 ± 0.2°.

[0133] In certain embodiments, the polymorph C has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 7 shown.

[0134] In certain embodiments, for the polymorph C, its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 250°C to 290°C.

[0135] In certain embodiments, for the polymorph C, the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 271.9 ± 5°C.

[0136] In certain embodiments, the polymorph C has a differential scanning calorimetry curve substantially as Figure 8 shown.

[0137] In certain embodiments, the crystalline form C is an anhydrate.

[0138] In certain embodiments, the crystalline form C has a thermogravimetric analysis (TGA) curve substantially as Figure 8 shown.

[0139] The present disclosure also provides a method for preparing crystalline form C of a compound of formula (I), comprising the following operations:

[0140] The compound of formula (I) is dissolved or suspended in an organic solvent and reacted at room temperature or heated to 40 - 60 °C, and the solvent is volatilized, separated, or separated after cooling to obtain crystalline form C.

[0141] In certain embodiments, the organic solvent is any one or any combination of two or more of the following solvents:

[0142] (1) Alcohol solvents, selected from n - propanol, isopropanol, n - butanol, sec - butanol, tert - butanol, n - pentanol, n - hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol, cyclohexylethanol, benzyl alcohol, phenethyl alcohol, or phenylpropyl alcohol;

[0143] (2) Halogenated alkane solvents, selected from dichloromethane or chloroform;

[0144] (3) Nitrile solvents, selected from acetonitrile or propionitrile;

[0145] (4) Ester solvents, selected from ethyl acetate or isopropyl acetate;

[0146] (5) Ketone solvents, selected from acetone, butanone, isobutanone, methyl isobutyl ketone, or 4 - methyl - 2 - pentanone;

[0147] (6) Alkane solvents, selected from n - pentane, n - hexane, n - heptane, or cyclohexane;

[0148] (7) Aromatic hydrocarbon solvents, selected from toluene;

[0149] (8) Ether solvents, diethyl ether, propyl ether, isopropyl ether, methyl tert - butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or 1,4 - dioxane;

[0150] (9) Dimethyl sulfoxide, dimethylformamide, or N - methylpyrrolidone.

[0151] In certain embodiments, the organic solvent is selected from: n-propanol, isopropanol, dichloromethane, chloroform, acetonitrile, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, toluene, diethyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dimethylformamide, or any combination of two or more of the above solvents.

[0152] In certain embodiments, the organic solvent is a mixed solvent composed of a combination of two organic solvents. Among them, in the mixed solvent, one organic solvent is selected from ethylene glycol monomethyl ether, dimethylformamide, dimethyl sulfoxide, dichloromethane, and chloroform; the other organic solvent is selected from n-propanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and tetrahydrofuran.

[0153] In certain embodiments, the volume ratio of the two single solvents in the mixed solvent of any two solvent combinations is 1:10 - 10:1.

[0154] The present disclosure also provides a method for preparing crystalline form C of another compound of formula (I), including the following operations:

[0155] Dissolve or suspend the compound of formula (I) in an organic solvent, stir at room temperature or heat to 40 - 60 °C, then add a second solvent or place the reaction system in an atmosphere of the second solvent to continue the reaction, and separate by solvent evaporation, separation, or cooling to obtain crystalline form C of the compound of formula (I); wherein, among the organic solvent and the second solvent, when one is a good solvent for the compound of formula (I), the other is a poor solvent for the compound of formula (I); the second solvent is selected from organic solvents.

[0156] In certain embodiments, the good solvent for the compound of formula (I) is selected from ethylene glycol monomethyl ether, dimethylformamide, dimethyl sulfoxide, dichloromethane, or chloroform; the poor solvent for the compound of formula (I) is selected from n-propanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and tetrahydrofuran.

[0157] In certain embodiments, the volume ratio of the good solvent to the poor solvent for the compound of formula (I) is 1:10 - 10:1.

[0158] In certain embodiments, in the method for preparing crystalline form C of the compound of formula (I), the crystalline form obtained after separation can be further dried to obtain crystalline form C.

[0159] In certain embodiments, the separation is selected from atmospheric pressure filtration, vacuum filtration, centrifugation followed by removal of the liquid or evaporation of the solvent.

[0160] In certain embodiments, in the method for preparing polymorph C of the compound of formula (I), the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0161] In certain embodiments, in the method for preparing polymorph C of the compound of formula (I), the drying is selected from natural air drying at room temperature, natural 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 - 100°C, such as 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.; during the drying process, multiple drying operations can optionally be carried out at different temperatures.

[0162] In certain embodiments, the room temperature is the indoor temperature, which varies with the seasons and is usually in the range of 10°C - 30°C.

[0163] On the other hand, the present disclosure provides a polymorph D of the compound represented by formula (I), wherein, using Cu-Kα radiation, expressed in 2θ angle, the X-ray powder diffraction pattern has characteristic peaks at 10.7 ± 0.2°, 12.0 ± 0.2°, 18.2 ± 0.2°, 19.1 ± 0.2°, 19.9 ± 0.2°.

[0164]

[0165] In certain embodiments, for the polymorph D, using Cu-Kα radiation, expressed in 2θ angle, the X-ray powder diffraction pattern has characteristic peaks at 10.7 ± 0.2°, 12.0 ± 0.2°, 18.2 ± 0.2°, 19.1 ± 0.2°, 19.9 ± 0.2°, 21.2 ± 0.2°, 22.1 ± 0.2°, 23.9 ± 0.2°, 29.0 ± 0.2°.

[0166] In certain embodiments, the polymorph D has substantially as Figure 10 shown in the X-ray powder diffraction pattern obtained using Cu-Kα radiation.

[0167] In certain embodiments, the differential scanning calorimetry (DSC) analysis curve of the polymorph D has an endothermic peak in the range of 110°C to 160°C and also has an endothermic peak in the range of 260°C to 290°C.

[0168] In certain embodiments, for polymorph D, the maximum endothermic transition temperature in the differential scanning calorimetry (DSC) analysis curve is 272.2 ± 5 °C.

[0169] In certain embodiments, polymorph D has a differential scanning calorimetry curve substantially as Figure 11 shown.

[0170] In certain embodiments, polymorph D is a methanol solvate.

[0171] In certain embodiments, in polymorph D, the molar ratio of the compound of formula (I) to methanol is 1:1.

[0172] In certain embodiments, polymorph D has a thermogravimetric analysis (TGA) curve substantially as Figure 11 shown.

[0173] The present disclosure also provides a method for preparing polymorph D of the compound of formula (I), comprising the following operations:

[0174] Dissolve or suspend the compound of formula (I) in an organic solvent, stir at room temperature or heated to 40 - 60 °C, and separate by solvent evaporation, separation, or cooling to obtain polymorph D.

[0175] In certain embodiments, the organic solvent is selected from methanol, ethylene glycol monomethyl ether / methanol, dimethylformamide / methanol, dimethyl sulfoxide / methanol, dichloromethane / methanol, chloroform / methanol.

[0176] In certain embodiments, when the organic solvent is a mixed solvent of two organic solvents, the volume ratio of the two is 1:10 - 10:1.

[0177] In certain embodiments, in the method for preparing polymorph D, the obtained polymorph after separation can be further dried to obtain polymorph D.

[0178] In certain embodiments, the separation is selected from normal pressure filtration, vacuum filtration, centrifugation to remove the liquid, or solvent evaporation.

[0179] In certain embodiments, in the method for preparing polymorph D, the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0180] In certain embodiments, in the method for preparing the crystalline form D, the drying is selected from natural air drying at room temperature, natural 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, such as 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.; during the drying process, multiple dryings can be optionally carried out at different temperatures.

[0181] In certain embodiments, the room temperature is the indoor temperature, which varies with the seasons and is generally in the range of 10°C - 30°C.

[0182] On the other hand, the present disclosure provides a crystalline form E of the compound represented by formula (I), wherein, using Cu-Kα radiation, expressed in 2θ angle, the X-ray powder diffraction pattern has characteristic peaks at 7.0 ± 0.2°, 13.5 ± 0.2°, and 21.3 ± 0.2°.

[0183]

[0184] In certain embodiments, the crystalline form E has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 13 shown.

[0185] In certain embodiments, for the crystalline form E, its differential scanning calorimetry (DSC) analysis curve has endothermic peaks in the ranges of 50°C to 100°C and 250°C to 280°C.

[0186] In certain embodiments, for the crystalline form E, the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.0 ± 5°C.

[0187] In certain embodiments, the crystalline form E has a differential scanning calorimetry curve substantially as Figure 14 shown.

[0188] In certain embodiments, the crystalline form E is a hydrate.

[0189] In certain embodiments, in the crystalline form E, the water content by weight percentage is 21.1 ± 2%.

[0190] In certain embodiments, the crystalline form E has a thermogravimetric analysis (TGA) curve substantially as Figure 14 shown.

[0191] The present disclosure also provides a method for preparing the crystalline form E of the compound of formula (I), comprising the following operations:

[0192] Suspend the compound of formula (I) in water, react at room temperature, separate, and obtain crystalline form E.

[0193] The present disclosure also provides another method for preparing crystalline form E, comprising the following operations:

[0194] Dissolve the compound of formula (I) in an organic solvent, then add a certain amount of water, react at room temperature, separate, and obtain crystalline form E.

[0195] In certain embodiments, the organic solvent is selected from ethylene glycol monomethyl ether, dimethylformamide, or dimethyl sulfoxide.

[0196] In certain embodiments, in the method for preparing crystalline form E, the volume ratio of the organic solvent to water is 1:5 - 1:10.

[0197] In certain embodiments, in the method for preparing crystalline form E, the obtained crystalline form after separation can be further dried to obtain crystalline form E.

[0198] In certain embodiments, the separation is selected from normal pressure filtration, reduced pressure suction filtration, centrifugation to remove the liquid, or evaporation of the solvent.

[0199] In certain embodiments, in the method for preparing crystalline form E, the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0200] In certain embodiments, in the method for preparing crystalline form E, the drying is selected from natural air drying at room temperature, natural 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 - 70°C, such as 40°C - 60°C, such as 40°C - 50°C; the drying process can optionally be carried out at different temperatures for multiple times.

[0201] The room temperature referred to in the present disclosure is the indoor temperature, which changes with the seasons and is generally in the range of 10°C - 30°C.

[0202] On the other hand, the present disclosure provides a crystalline form F of the compound represented by formula (I), wherein, using Cu - Kα radiation, expressed in 2θ angle, the X - ray powder diffraction pattern has characteristic peaks at 8.3 ± 0.2°, 9.0 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 19.1 ± 0.2°, 19.8 ± 0.2°, 22.3 ± 0.2°, 26.2 ± 0.2°.

[0203]

[0204] In certain embodiments, for the crystalline form F, when using Cu-Kα radiation and expressed in 2θ angles, the X-ray powder diffraction pattern has characteristic peaks at 8.3±0.2°, 9.0±0.2°, 14.0±0.2°, 14.4±0.2°, 17.4±0.2°, 18.5±0.2°, 19.1±0.2°, 19.8±0.2°, 20.2±0.2°, 20.7±0.2°, 22.3±0.2°, 24.1±0.2°, 26.2±0.2°, 27.8±0.2°.

[0205] In certain embodiments, the crystalline form F has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as Figure 16 shown.

[0206] In certain embodiments, for the crystalline form F, there is an endothermic peak in the differential scanning calorimetry (DSC) analysis curve in the ranges of 50°C to 100°C, 125°C to 200°C, and 260°C to 290°C.

[0207] In certain embodiments, for the crystalline form F, the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.5±5°C.

[0208] In certain embodiments, the crystalline form F has a differential scanning calorimetry curve substantially as Figure 17 shown.

[0209] In certain embodiments, the crystalline form F is a formic acid solvate.

[0210] In certain embodiments, in the crystalline form F, the weight percentage of formic acid is 8.5±2%.

[0211] In certain embodiments, the crystalline form F has a thermogravimetric analysis (TGA) curve substantially as Figure 17 shown.

[0212] The present disclosure also provides a method for preparing crystalline form F of a compound of formula (I), comprising the following operations:

[0213] The compound of formula (I) is dissolved or suspended in an organic solvent, reacted at room temperature or heated to 40 - 60°C, and after the solvent volatilizes, separates, or cools and then separates to obtain crystalline form F.

[0214] In certain embodiments, the organic solvent is selected from: ethyl formate or butyl formate.

[0215] In certain embodiments, the organic solvent is selected from: a mixed solvent of ethylene glycol monomethyl ether / butyl formate, dichloromethane / butyl formate, or chloroform / butyl formate.

[0216] In certain embodiments, the volume ratio of the two single solvents in the mixed solvent is 1:10 - 10:1.

[0217] In certain embodiments, for the method for preparing Form F, the obtained form after separation can be further dried to obtain Form F.

[0218] In certain embodiments, the separation is selected from atmospheric pressure filtration, vacuum filtration, centrifugation followed by removing the liquid, or volatilizing the solvent.

[0219] In certain embodiments, in the method for preparing Form F, the preparation process can optionally be carried out under stirring conditions, wherein the stirring mode is selected from mechanical stirring and magnetic stirring; the preparation process includes a feeding process, a raw material dissolution process, a reaction occurrence process, and a crystallization process.

[0220] In certain embodiments, in the method for preparing Form F, the drying is selected from natural air drying at room temperature, natural 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, such as 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.; during the drying process, multiple drying operations can optionally be carried out at different temperatures.

[0221] In certain embodiments, the room temperature is the indoor temperature, which varies with the seasons and is usually in the range of 10°C - 30°C.

[0222] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, or polymorph F of the compound of formula (I) described herein, and optionally one or more pharmaceutical carriers and / or diluents. In certain embodiments, the pharmaceutical composition comprising a polymorph of the compound of formula (I) (such as polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, or polymorph F) and optionally one or more pharmaceutical carriers and / or diluents can be in any pharmaceutically acceptable dosage form. It is administered to a patient in need thereof by oral, parenteral, rectal, or pulmonary administration, etc. For oral administration, it can be formulated into conventional solid dosage forms such as tablets, capsules, pills, granules, etc.; it can also be formulated into oral liquid dosage forms such as oral solutions, oral suspensions, syrups, etc. For parenteral administration, it can be formulated into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating into injections, it can be produced by conventional methods in the existing pharmaceutical field. When formulating injections, additives may not be added, or appropriate additives can be added according to the nature of the drug. For rectal administration, it can be formulated into suppositories, etc. For pulmonary administration, it can be formulated into inhalants or sprays, etc.

[0223] Further, the present disclosure relates to a pharmaceutical composition comprising polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, or polymorph F of the compound of formula (I), and further comprising one or more second therapeutic active agents, wherein the second therapeutic active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, DNA intercalators, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor regulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors, and protein prenyltransferase inhibitors.

[0224] In certain embodiments, the present disclosure further provides the use of polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F of the compound of formula (I), or the pharmaceutical composition of the present disclosure in the preparation of a drug for treating and / or preventing DNA-PK-mediated related diseases.

[0225] Further, the present disclosure further provides the use of polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F of the compound of formula (I), or the pharmaceutical composition of the present disclosure in the preparation of a drug for treating and / or preventing benign tumors or cancers. The cancers include carcinoma in situ and metastatic cancers.

[0226] In certain embodiments, the present disclosure provides the use of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) or the pharmaceutical composition of the present disclosure in the preparation of a medicament for sensitizing cancer cells to an anti-cancer agent and / or ionizing radiation.

[0227] In another aspect, the present disclosure also provides a method for treating a disease associated with overactivation of DNA-PK, the method comprising administering to a patient in need thereof an effective amount of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) of the present invention or the aforementioned pharmaceutical composition; the disease associated with overactivation of DNA-PK is selected from benign tumors or cancers, and the cancers include carcinoma in situ and metastatic cancers.

[0228] Further, the present disclosure also provides a method for treating a disease associated with overactivation of DNA-PK, the method comprising administering to a patient before / after radiotherapy an effective amount of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) of the present invention or the aforementioned pharmaceutical composition; the disease associated with overactivation of DNA-PK is selected from benign tumors or cancers, and the cancers include carcinoma in situ and metastatic cancers.

[0229] Further, the present disclosure also provides a method for treating a disease associated with overactivation of DNA-PK, the method comprising administering to a patient before / after chemotherapy an effective amount of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) of the present invention or the aforementioned pharmaceutical composition; the disease associated with overactivation of DNA-PK is selected from benign tumors or cancers, and the cancers include carcinoma in situ and metastatic cancers.

[0230] In another aspect, the present disclosure also provides a method for enhancing a patient's sensitivity to an anti-cancer agent or radiotherapy, the method comprising administering to a patient in need thereof an effective amount of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) of the present invention or the aforementioned pharmaceutical composition; the anti-cancer agent is as described above.

[0231] Further, the present invention also provides a method for enhancing a patient's sensitivity to an anti-cancer agent or radiotherapy, the method comprising administering to a patient before / after radiotherapy an effective amount of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) of the present invention or the aforementioned pharmaceutical composition; the anti-cancer agent is as described above.

[0232] Further, the present invention also provides a method for enhancing the sensitivity of a patient to an anti-cancer agent or radiotherapy, which method comprises administering to a patient before / after chemotherapy an effective amount of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) of the present invention or the aforementioned pharmaceutical composition; the anti-cancer agent is as described above.

[0233] As used herein, "chemotherapy" is an abbreviation for chemotherapy, which mainly aims to kill cancer cells by using chemotherapeutic drugs.

[0234] As used herein, "radiotherapy" refers to a tumor treatment method, namely tumor radiotherapy, which mainly uses radiation for local tumor treatment. The "radiation" includes α, β, γ rays generated by radioactive isotopes and x-rays, electron beams, proton beams and other particle beams generated by various x-ray therapy machines or accelerators.

[0235] As used herein, a "good solvent" refers to a solvent with good solubility for a certain substance. In the present disclosure, it mainly refers to a solvent with a solubility of more than 10 mg / mL for the compound of formula (I).

[0236] As used herein, a "poor solvent" refers to a solvent with poor solubility for a certain substance. In the present disclosure, it mainly refers to a solvent with a solubility of less than 2 mg / mL for the compound of formula (I).

[0237] As used herein, "any combination between two or more solvents" in the organic solvent refers to a solvent formed by mixing solvents of the same type or different types in a certain proportion in the organic solvent. The mixed solvents formed by solvents of the same type include, but are 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 solvents formed by solvents of different types include, but are not limited to, the following mixed solvent systems: ethanol / acetonitrile, dichloromethane / acetonitrile, dichloromethane / acetone, dichloromethane / butanone, 1,4-dioxane / ethyl acetate, etc.

[0238] The term "effective amount" of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F of the compound of formula (I) as described in the present disclosure refers to an amount of the compound sufficient to treat a disorder with a reasonable efficacy / risk ratio applicable to any medical treatment and / or prophylaxis. It should be recognized, however, that the total daily dosage of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F of the compound of formula (I) as described in the present disclosure and the pharmaceutical composition must be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound or its crystalline form being employed; the specific composition being employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the excretion rate of the specific compound or its crystalline form being employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound or its crystalline form being employed; and like factors well known in the medical arts. For example, it is the practice in the art to start a compound or its crystalline form at a dosage level below that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0239] The main advantages of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, and crystalline form F of the compound of formula (I) as described in the present disclosure include:

[0240] (1) The preparation method is simple and easy to operate, suitable for industrial production;

[0241] (2) It has good properties, fluidity, compressibility, disintegration, and dissolution properties, facilitating production, detection, preparation of pharmaceutical preparations, transportation, and storage;

[0242] (3) It has high purity, low residual solvents, relatively high solubility, high stability under high temperature and light conditions, and is easy to control the quality;

[0243] (4) It has good inhibitory activity against DNA-PK and has good exposure and / or bioavailability in vivo;

[0244] (5) It has good in vivo and in vitro pharmacodynamic effects and can be used to treat and / or prevent DNA-PK-mediated related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0245] The drawings described herein are used to provide a further understanding of the present disclosure, form a part of this application, and the illustrative embodiments and descriptions thereof of the present disclosure are used to explain the present disclosure and do not constitute an improper limitation of the present disclosure. In the drawings:

[0246] Figure 1 is the X-ray powder diffraction (XRPD) pattern of crystalline form A of the compound of formula (I), where the vertical axis represents the diffraction intensity and the horizontal axis represents the diffraction angle (2θ).

[0247] Figure 2 It is the TGA-DSC analysis chart of crystalline form A of the compound of formula (I). The left vertical coordinate represents weight (%), the right vertical coordinate represents heat flow (W / g), and the horizontal coordinate represents temperature T (°C).

[0248] Figure 3 It is the H 1 -NMR spectrum of crystalline form A of the compound of formula (I).

[0249] Figure 4 It is the X-ray powder diffraction (XRPD) pattern of crystalline form B of the compound of formula (I). The vertical coordinate represents diffraction intensity, and the horizontal coordinate represents diffraction angle (2θ).

[0250] Figure 5 It is the TGA-DSC analysis chart of crystalline form B of the compound of formula (I). The left vertical coordinate represents weight (%), the right vertical coordinate represents heat flow (W / g), and the horizontal coordinate represents temperature T (°C).

[0251] Figure 6 It is the H 1 -NMR spectrum of crystalline form B of the compound of formula (I).

[0252] Figure 7 It is the X-ray powder diffraction (XRPD) pattern of crystalline form C of the compound of formula (I). The vertical coordinate represents diffraction intensity, and the horizontal coordinate represents diffraction angle (2θ).

[0253] Figure 8 It is the TGA-DSC analysis chart of crystalline form C of the compound of formula (I). The left vertical coordinate represents weight (%), the right vertical coordinate represents heat flow (W / g), and the horizontal coordinate represents temperature T (°C).

[0254] Figure 9 It is the H 1 -NMR spectrum of crystalline form C of the compound of formula (I).

[0255] Figure 10 It is the X-ray powder diffraction (XRPD) pattern of crystalline form D of the compound of formula (I). The vertical coordinate represents diffraction intensity, and the horizontal coordinate represents diffraction angle (2θ).

[0256] Figure 11 It is the TGA-DSC analysis chart of crystalline form D of the compound of formula (I). The left vertical coordinate represents weight (%), the right vertical coordinate represents heat flow (W / g), and the horizontal coordinate represents temperature T (°C).

[0257] Figure 12 It is the H 1 -NMR spectrum of crystalline form D of the compound of formula (I).

[0258] Figure 13 It is the X-ray powder diffraction (XRPD) pattern of crystalline form E of the compound of formula (I), where the vertical axis represents the diffraction intensity and the horizontal axis represents the diffraction angle (2θ).

[0259] Figure 14 It is the TGA-DSC analysis chart of crystalline form E of the compound of formula (I). The left vertical axis represents the weight (%), the right vertical axis represents the heat flow (W / g), and the horizontal axis represents the temperature T (°C).

[0260] Figure 15 It is the H 1 -NMR spectrum of crystalline form E of the compound of formula (I).

[0261] Figure 16 It is the X-ray powder diffraction (XRPD) pattern of crystalline form F of the compound of formula (I), where the vertical axis represents the diffraction intensity and the horizontal axis represents the diffraction angle (2θ).

[0262] Figure 17 It is the TGA-DSC analysis chart of crystalline form F of the compound of formula (I). The left vertical axis represents the weight (%), the right vertical axis represents the heat flow (W / g), and the horizontal axis represents the temperature T (°C).

[0263] Figure 18 It is the H 1 -NMR spectrum of crystalline form F of the compound of formula (I). Detailed implementation manners

[0264] The following will further illustrate the substantial content of the present disclosure in combination with specific embodiments of the present disclosure. It should be understood that the following embodiments are only used to illustrate the present disclosure, but do not limit the protection scope of the present disclosure. For those conditions not specified in the following embodiments, they are carried out according to conventional conditions or as recommended by the manufacturer. For those drugs or reagents without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0265] Although many of the materials and operation methods used in the following embodiments are well known in the art, the present disclosure still describes them in as much detail as possible herein. Those skilled in the art are aware that if not otherwise specified, the materials and operation methods used in the following embodiments are well known in the art.

[0266] Preparation Example 1:

[0267] Preparation of the compound of formula (I)

[0268] 1. Preparation of 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-9H-imidazo[2,1-f]purine

[0269]

[0270] 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 then the reaction was carried out at 100 °C for 18 hours. After the system was cooled to 20 °C, EA (80 mL) and water (40 mL) were added, and extraction and liquid separation were performed. The organic phase was concentrated and purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain a crude product (1.2 g). Then, it was purified by a reverse-phase C18 column (water / methanol = 1 / 1) to obtain a crude product (200 mg). Finally, it was purified by preparative TLC large plate (DCM:MeOH = 15:1) to obtain the product (130 mg, yield 15.1%).

[0271] 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

[0272]

[0273] 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). Then, the system was reacted at 100 °C for 2 hours under a N2 atmosphere. After the system was cooled to 20 °C and concentrated, it was purified by silica gel column chromatography (DCM:MeOH = 30:1) to obtain a crude product of the product (110 mg). Then, methanol (2 mL) was added and sonicated to precipitate a solid (70 mg). Finally, it was purified by a silica gel preparative large plate (DCM:MeOH = 30:1) to obtain the target compound (35 mg, yield 25.0%).

[0274] Molecular formula: C 19 H 19 N9O Molecular weight: 389.4 LC-MS (M / e): 389.9 (M+H)

[0275] 1HNMR(400 MHz, DMSO-d6): δ 9.14 (s, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.39 (s, 1H), 7.72 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 1.6 Hz, 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).

[0276] Preparation method of crystalline form A of the compound of formula (I)

[0277] Preparation method 1: Take the compound of formula (I) (20 mg) obtained in Preparation Example 1 above in an EP tube, add water (1.0 mL), stir at 50 °C for one day, centrifuge the suspension, and vacuum dry the obtained solid. After XRPD detection, the obtained solid is crystalline form A.

[0278] Preparation method 2: Take the compound of formula (I) (20 mg) obtained in Preparation Example 1 above, add ethylene glycol monomethyl ether / water (volume ratio 1:4, total 1.0 mL), stir at room temperature for 7 days, centrifuge the suspension, vacuum dry the solid, and after XRPD detection, the obtained solid is crystalline form A.

[0279] Preparation method of crystalline form B of the compound of formula (I)

[0280] Preparation method 1: Take 2 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg each portion, add ethanol (1.0 mL) respectively. Stir one portion at room temperature for 7 days and the other portion at 50 °C for 1 day. After cooling, centrifuge the suspension, vacuum dry the solid. After XRPD detection, both obtained solids are crystalline form B.

[0281] Preparation method 2: Take 5 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg each portion, and add ethylene glycol monomethyl ether / ethanol (volume ratio 1:4, total 1.0 mL), dimethylformamide / ethanol (volume ratio 1:4, total 1.0 mL), dimethyl sulfoxide / ethanol (volume ratio 1:4, total 1.0 mL), dichloromethane / ethanol (volume ratio 1:4, total 1.0 mL), chloroform / ethanol (volume ratio 1:4, total 1.0 mL) respectively. Stir at room temperature for 7 days, centrifuge the suspension, vacuum dry the solid. After XRPD detection, the obtained solids are all crystalline form B.

[0282] Preparation method of crystalline form C of the compound of formula (I)

[0283] Preparation Method 1: Take 2 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, dissolve them in dichloromethane (0.5 mL) and chloroform (0.4 mL) respectively, let the clear solution stand and volatilize at room temperature until the solvent is completely volatilized. The obtained solid is detected by XRPD, and all the obtained solids are crystalline form C.

[0284] Preparation Method 2: Take 5 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add n-propanol (1.0 mL), dioxane (1.0 mL), ethylene glycol dimethyl ether (1.0 mL), tetrahydrofuran (1.0 mL), acetone (1.0 mL) respectively to make a suspension, stir at room temperature for 7 days, centrifuge, and dry the solid under vacuum at room temperature. The obtained solid is detected by XRPD, and all the obtained solids are crystalline form C.

[0285] Preparation Method 3: Take 4 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add n-propanol (1.0 mL), dioxane (1.0 mL), ethylene glycol dimethyl ether (1.0 mL), tetrahydrofuran (1.0 mL) respectively to make a suspension, stir at 50 °C for 1 day, cool down, centrifuge, and dry the solid under vacuum at room temperature. The obtained solid is detected by XRPD, and all the obtained solids are crystalline form C.

[0286] Preparation Method 4: Take 5 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add ethylene glycol methyl ether / isopropanol (1:4, 1.0 mL), dimethylformamide / tert-butyl formate (1:4, 1.0 mL), dimethyl sulfoxide / isopropyl acetate (1:4, 1.0 mL), dichloromethane / n-heptane (1:4, 1.0 mL), chloroform / isopropanol (1:4, 1.0 mL) respectively to make a suspension, stir at room temperature for 7 days, centrifuge, and dry the solid under vacuum at room temperature. The obtained solid is detected by XRPD, and all the obtained solids are crystalline form C.

[0287] Preparation Method 5: Take 3 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion. At 50 °C, add isopropanol (1.0 mL), acetonitrile (1.0 mL), isopropyl acetate (1.0 mL) respectively, and number them 1, 2, 3 in sequence. Then, add dimethylformamide (1.0 mL) dropwise to No. 1, dimethyl sulfoxide (0.7 mL) dropwise to No. 2, and chloroform (1.3 mL) dropwise to No. 3 until the solid is completely dissolved. Transfer the solution quickly to room temperature for cooling and crystallization. If no solid precipitates after 48 hours, place the solution at 0 °C or -15 °C for crystallization. After solid precipitation, centrifuge, and dry the solid under vacuum at room temperature. The obtained solid is detected by XRPD, and all the obtained solids are crystalline form C.

[0288] Preparation method of crystalline form D of the compound of formula (I)

[0289] Preparation Method 1: Take 2 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add methanol (1.0 mL) respectively. One portion is stirred at room temperature for 7 days, and the other portion is stirred at 50 °C for 1 day. After cooling, the suspension is centrifuged, and the solid is dried under vacuum. After being detected by XRPD, both of the obtained solids are Crystal Form D.

[0290] Preparation Method 2: Take 4 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add ethylene glycol methyl ether / methanol (volume ratio 1:4, total 1.0 mL), dimethylformamide / methanol (volume ratio 1:4, total 1.0 mL), dichloromethane / methanol (volume ratio 1:4, total 1.0 mL), chloroform / methanol (volume ratio 1:4, total 1.0 mL) respectively, stir at room temperature for 7 days, centrifuge the suspension, dry the solid under vacuum. After being detected by XRPD, the obtained solids are all Crystal Form D.

[0291] Preparation method of Crystal Form E of the compound of formula (I)

[0292] Preparation Method 1: Take the compound of formula (I) (20 mg) obtained in Preparation Example 1 above in an EP tube, add water (1.0 mL), stir at room temperature for 7 days, centrifuge the suspension, dry the obtained solid under vacuum. After being detected by XRPD, the obtained solid is Crystal Form E.

[0293] Preparation method of Crystal Form F of the compound of formula (I)

[0294] Preparation Method 1: Take 2 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add ethyl formate (1.0 mL) and butyl formate (1.0 mL) respectively, stir at room temperature for 7 days, centrifuge the suspension, dry the solid under vacuum. After being detected by XRPD, both of the obtained solids are Crystal Form F.

[0295] Preparation Method 2: Take 2 portions of the compound of formula (I) obtained in Preparation Example 1 above, 20 mg for each portion, add ethylene glycol methyl ether / butyl formate (1:4, 1.0 mL) and dichloromethane / butyl formate (1:4, 1.0 mL) respectively, stir at room temperature for 7 days, centrifuge the suspension, dry the solid under vacuum. After being detected by XRPD, both of the obtained solids are Crystal Form F.

[0296] XRPD Test

[0297] Conditions for X-ray powder diffraction measurement: Cu target, 1.54060, 2θ scanning angle ranges from 3° to 45°, scanning step size is 0.02°, exposure time is 0.12 s. When testing the sample, the tube voltage and current are 40 kV and 40 mA respectively, and the sample disk is a zero-background sample disk.

[0298] The X-ray powder diffraction pattern of polymorph A of the compound of formula (I) is shown in Figure 1 .

[0299] The X-ray powder diffraction pattern of polymorph B of the compound of formula (I) is shown in Figure 4 .

[0300] The X-ray powder diffraction pattern of polymorph C of the compound of formula (I) is shown in Figure 7 .

[0301] The X-ray powder diffraction pattern of polymorph D of the compound of formula (I) is shown in Figure 10 .

[0302] The X-ray powder diffraction pattern of polymorph E of the compound of formula (I) is shown in Figure 13 .

[0303] The X-ray powder diffraction pattern of polymorph F of the compound of formula (I) is shown in Figure 16 .

[0304] Differential scanning calorimetry

[0305] The solid-state thermal properties of polymorph A, polymorph B, polymorph C, polymorph D, polymorph E and polymorph F of the compound of formula (I) were studied by differential scanning calorimetry (DSC).

[0306] Determination conditions: 1 - 2 mg of the sample was accurately weighed and placed in a perforated DSC Tzero sample pan, heated to the final temperature at a rate of 10 °C / min, the nitrogen purge rate in the furnace was 50 mL / min, and the graph was plotted with the endothermic peak facing down.

[0307] Determination results: The differential scanning calorimetry analysis chart of polymorph A of the compound of formula (I) is as shown in Figure 2 ; the differential scanning calorimetry analysis chart of polymorph B is as shown in Figure 5 ; the differential scanning calorimetry analysis chart of polymorph C is as shown in Figure 8 ; the differential scanning calorimetry analysis chart of polymorph D is as shown in Figure 11 ; the differential scanning calorimetry analysis chart of polymorph E is as shown in Figure 14 ; the differential scanning calorimetry analysis chart of polymorph F is as shown in Figure 17 .

[0308] Thermogravimetric analysis

[0309] Test conditions: 2 - 5 mg of the sample was placed in an open aluminum sample pan that had been equilibrated, and automatically weighed in a TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, the nitrogen purge rate at the sample was 60 mL / min, and the nitrogen purge rate at the balance was 40 mL / min..

[0310] Determination results: The TGA curve of polymorph A of the compound of formula (I) is as shown in Figure 2 ; the TGA curve of polymorph B of the compound of formula (I) is as shown in Figure 5 ; the TGA curve of polymorph C is as shown in Figure 8 ; the TGA curve of polymorph D is as shown in Figure 11 ; the TGA curve of polymorph E is as shown in Figure 14 ; the TGA curve of polymorph F is as shown in Figure 17 .

[0311] Experimental protocol

[0312] The following provides exemplary experimental protocols for some compounds of the present invention to demonstrate the advantageous activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental protocols are merely examples of the content of the present invention and not limitations on the scope of the present invention.

[0313] Experimental Example 1: In Vitro Enzymatic Activity of the Compound of Formula (I) of the Present Invention

[0314] Abbreviations

[0315] EDTA: Ethylenediaminetetraacetic acid

[0316] DMSO: Dimethyl sulfoxide

[0317] Tris: Tris(hydroxymethyl)aminomethane

[0318] Brij-35: Polyoxyethylene lauryl ether

[0319] DTT: Dithiothreitol

[0320] Test substance: The compound of formula (I) of the present invention, and its structural formula and preparation method are shown in the preparation examples.

[0321] Experimental reagents:

[0322] Name Brand ADP-Glo Kinase Assay Promege DNA-PK Promege

[0323] Experimental methods:

[0324] 1. Prepare 1-fold kinase buffer

[0325] 1) Prepare 1-fold kinase buffer from the following substances or solutions:

[0326] 40 mM Tris, pH 7.5;

[0327] 0.0055% Brij-35;

[0328] 20 mM MgCl2;

[0329] 0.05 mM DTT.

[0330] 2. Preparation of the compound

[0331] 1) The initial detection concentration of the compound is 1 μM, which is prepared into 100-fold concentration, i.e., 100 μM. Take 2 μl of 10 mM compound and add 198 μl of 100% DMSO to prepare a 100 μM compound solution. Add 100 μl of 100-fold compound to the second well of the 96-well plate, and add 60 μl of 100% DMSO to the other wells. Take 30 μl of the compound from the second well and add it to the third well, and perform 3-fold dilution successively downwards for a total of 10 concentrations.

[0332] 2) Transfer 100 μl of 100% DMSO and the highest concentration (400 nM) of the positive control wortmannin to two empty wells as the Max well and the Min well respectively.

[0333] 3) Use Echo to transfer 50 nl of the compound to the 384-well plate.

[0334] 3. Prepare 2x kinase solution

[0335] 1) Prepare 2-fold DNA-PK kinase solution using 1-fold kinase buffer.

[0336] 2) Transfer 2.5 μl of the 2-fold enzyme solution to the reaction wells of the 384-well plate.

[0337] 3) Oscillate, mix well, and let stand at room temperature.

[0338] 4. Prepare 2x substrate solution

[0339] 1) Prepare 2-fold substrate solution using 1-fold kinase buffer.

[0340] 2) Transfer 2.5 μl of the 2-fold substrate solution to the reaction wells of the 384-well plate to initiate the reaction.

[0341] 3) Oscillate, mix well.

[0342] 5. Kinase reaction and termination

[0343] 1) Cover the 384-well plate and incubate at 28 °C for 3 hours.

[0344] 2) Transfer 5 μl of ADP-Glo reagent and incubate at 28 °C for 2 hours.

[0345] 6. Detection of reaction results

[0346] 1) Transfer 10 μl of kinase detection reagent to the reaction wells of the 384-well plate to terminate the reaction.

[0347] 2) Let stand at room temperature for 30 minutes.

[0348] 7. Data reading

[0349] Read the sample values on Envision.

[0350] 8. Inhibition rate calculation

[0351] 1) Copy the data from Envision.

[0352] 2) Convert it into inhibition rate data.

[0353] Inhibition percentage = (max - conversion) / (max - min) * 100. Where max is the conversion rate of the DMSO control, min is the conversion rate of the enzyme - free control, and conversion is the conversion rate at each concentration of the test compound.

[0354] 3) Perform curve fitting on the data to obtain the IC 50 value.

[0355] Experimental results:

[0356] Table 1 In vitro enzymatic activity data of the compounds of the present invention

[0357]

[0358] Experimental conclusion:

[0359] The results show that the compounds of formula (I) of the present invention have good inhibitory effects on the activity of DNA - PK kinase.

[0360] Experimental Example 2: Liver Microsomal Metabolism Stability Experiment of the Compound of Formula (I) of the Present Invention in Different Species

[0361] Test article: The compound of formula (I) of the present invention, self - made, and its preparation method can be seen in the preparation examples.

[0362] Experimental materials:

[0363] Cynomolgus monkey mixed liver microsomes were purchased from Shanghai Reeder Liver Disease Research Center Co., Ltd., and the protein concentration of liver microsomes was 20 mg·mL -1 .

[0364] Mixed liver microsomes of human, Beagle dog, and SD rat were all purchased from Corning, and the protein concentration of liver microsomes was 20 mg·mL -1 .

[0365] The experimental initiation factor β - NADPH was purchased from Solarbio Co., Ltd.; the phosphate - buffered saline (PBS) with pH 7.4 was self - made in this laboratory.

[0366] Preparation of test article solution:

[0367] Accurately weigh an appropriate amount of the test sample powder, add an appropriate amount of dimethyl sulfoxide (DMSO) to dissolve it to 1 mM, and then dilute it 20-fold with methanol to a working solution of 50 μM.

[0368] Experimental method:

[0369] Table 2. Composition of the incubation system for hepatic microsomal metabolic stability experiment

[0370]

[0371]

[0372] Experimental operation steps:

[0373] (1) According to the ratio in Table 2 "Composition of the experimental incubation system" above, take 5.85 mL of 100 mM PBS, 0.585 mL of 20 mM MgCl2 solution and 3.57 mL of H2O for each compound to prepare the incubation system mixed solution 1 (without microsomes, test sample and β-NADPH). Verapamil, the positive control drug for the experimental incubation system (which is easily metabolized in hepatic microsomes of various test species), is used in this experiment to prove the normal activity of hepatic microsomal enzymes.

[0374] (2) Take out the hepatic microsomes (20 mg protein / mL) from the -80 °C refrigerator and pre-incubate them in a 37 °C water bath thermostatic oscillator for 3 min.

[0375] (3) Take 1.9 mL of the incubation system mixed solution 1 for each compound and each species, add 56 μL of microsomes of different species to prepare the incubation system mixed solution 2 (without the test sample and β-NADPH).

[0376] (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 with a concentration of 50 μM, and add 70 μL of the 10 mM β-NADPH working solution. Mix well and make replicates. The 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.

[0377] (5) Control group (containing microsomes, without β-NADPH, using water instead of β-NADPH): Take 264 μL of the incubation system mixed solution 2, add 6 μL of the test sample working solution with a concentration of 50 μM, and add 30 μL of water. Mix well and make replicates. The 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 hepatic microsomal incubation system.

[0378] (6) At each predetermined time point, 50 μL of the incubated sample was taken from the incubation sample tube and added to the termination sample tube (containing 300 μL of cold terminator, an acetonitrile solution containing 50 ng / mL of the internal standard tolbutamide), vortexed to terminate the reaction.

[0379] (7) After vortexing for 10 min, centrifuge for 5 min (12000 rpm).

[0380] (8) Take 100 μL of the supernatant, add 100 μL of water, vortex to mix evenly, and analyze by LC-MS / MS injection.

[0381] Data analysis:

[0382] Convert to the percentage of the remaining amount through the ratio of the peak areas of the test substance and the internal standard in the following formula.

[0383]

[0384] Experimental results:

[0385] Table 3 Results of the hepatic microsomal stability of the compounds of the present invention

[0386]

[0387]

[0388] Experimental conclusion:

[0389] The compound of formula (I) of the present invention has good stability in human, monkey, dog and rat hepatic microsomes.

[0390] Experimental Example 3: In Vivo Pharmacokinetics Experiment of the Compound of Formula (I) of the Present Invention in SD Rats

[0391] Test substance: The compound of formula (I) of the present invention, self-made, and its preparation method is shown in the preparation example.

[0392] Test animals: SD rats, male, body weight 190 - 210 g, 3 rats / group.

[0393] Preparation of the test substance solution:

[0394] Preparation method of blank solvent (1): Weigh 28 g of HP-β-CD, add an appropriate amount of water for injection to dissolve, and then make up the volume to 100 mL with water for injection, vortex to mix evenly to obtain 28% HP-β-CD.

[0395] Preparation method of blank solvent (2): Weigh 20 g of HPC, slowly add it to 500 mL of stirred purified water, then add 1 mL of Tween 80, stir until clear and transparent, make up the volume to 1000 mL, and stir evenly to obtain 2% HPC + 0.1% Tween 80.

[0396] IV (intravenous bolus) administration:

[0397] Take the compound of formula (I) of the present invention (2.65 mg), add DMA (130 μL), vortex to dissolve, then add PEG400 (130 μL), vortex to mix evenly, and finally add blank solvent (1) (2.33 mL), vortex to mix evenly, incubate at 50 °C for 20 min to prepare a clear solution of 1 mg / mL as the IV administration solution of the compound of formula (I).

[0398] PO (gavage) administration:

[0399] Weigh the compound of formula (I) of the present invention (130.49 mg), place it in a tissue grinder, add blank solvent (2) (12.77 mL), grind evenly at a speed of 1200 revolutions per minute to obtain a suspension medicine solution with a concentration of 10 mg / mL. Take the above suspension (0.5 mL), place it in a centrifuge tube, add blank solvent (2) (12.0 mL), vortex to mix evenly to prepare a suspension medicine solution of 0.4 mg / mL as the PO administration medicine solution of the compound of formula (I).

[0400] Experimental method

[0401] The IV administration dose is 2 mg / kg, the administration concentration is 1 mg / mL, and the administration volume is 2 mL / kg.

[0402] The PO administration dose is 4 mg / kg, the administration concentration is 0.4 mg / mL, and the administration volume is 10 mL / kg.

[0403] IV blood sampling time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration.

[0404] PO administration blood sampling time points: 0.167, 0.5, 1, 2, 4, 6, 8, 24 h after administration.

[0405] At each time point, about 100 μL of whole blood is collected from the tail vein, placed in an anticoagulation tube containing EDTA-K2 anticoagulant, centrifuged at 8000 revolutions per minute for 6 minutes at 4 °C to obtain plasma samples, and the plasma is frozen at -80 °C in a refrigerator for analysis.

[0406] Plasma sample analysis

[0407] Adopt the protein precipitation method: Take 20 μL of plasma sample, add internal standard (acetonitrile solution containing 50 ng / mL of tolbutamide) 200 μL, vortex for 10 min, then centrifuge at 4000 revolutions per minute for 20 minutes, take 100 μL of the supernatant, add 100 μL of water, vortex to mix evenly for 3 min, and then perform LC-MS / MS analysis.

[0408] Experimental results and conclusions

[0409] It was found through testing that the compound of formula (I) of the present invention has good pharmacokinetic properties, and has a high exposure and bioavailability.

[0410] Experimental Example 4: Thermal Polymorphic Transformation Experiment

[0411] Test samples: Polymorph A, Polymorph B, Polymorph D, and Polymorph F of the compound of formula (I).

[0412] Experimental method: On a hot stage, Polymorph A, Polymorph B, Polymorph D, and Polymorph F were respectively heated to 100 °C, 150 °C, 150 °C, and 200 °C, and kept at a constant temperature for 5 minutes.

[0413] Experimental results: After heat treatment, all the test samples were converted to Polymorph C as detected by XRPD.

[0414] Experimental Example 5: Dynamic Vapor Sorption (DVS) Test

[0415] Test sample: Polymorph C of the compound of formula (I)

[0416] Test conditions: Determination was carried out using DVS Intrinsic (SMS, UK). The test used a gradient mode, with the humidity changing as 50% - 95% - 0% - 50%. The humidity change amount for each gradient within the range of 0% to 90% was 10%. The gradient end point was judged by the way of dm / dt (rate of change of mass with time), and the gradient end point was defined as dm / dt less than 0.002% and maintained for 10 minutes. After the test was completed, XRPD analysis was performed on the sample to confirm whether the solid form had changed.

[0417] Test results:

[0418] The test results showed that the test sample gained 0.06% in weight at 80% RH, gained 0.22% in weight at 95% RH, and lost 0.18% in weight at 0% RH. Therefore, Polymorph C of the compound of formula (I) has almost no hygroscopicity.

[0419] The XRPD test results showed that the crystal form did not change before and after the DVS test.

[0420] Experimental Example 6: Physical Stability Test

[0421] Test sample: Polymorph C of the compound of formula (I).

[0422] Experimental method: Three portions of Polymorph C, each 15 mg, were taken and placed under the conditions of high temperature (60 °C), light (25 °C, 4500 lux), and acceleration (40 °C / 75% RH). After 15 days, XRPD characterization was carried out, and the test conditions were the same as those in the preparation example.

[0423] Experimental results: After being placed for 15 days under different conditions, the crystal form did not change and remained crystal form C.

[0424] 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 them; although the present disclosure has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that it is still possible to modify the specific implementation manners of the present disclosure or perform equivalent replacements for some technical features; without departing from the spirit of the technical solutions of the present disclosure, they should all be covered within the scope of the technical solutions claimed by the present disclosure.

Claims

1. The crystal form of the compound represented by the following formula (I), characterized in that the crystal form is crystal form A, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 9.0 ± 0.2°, 18.1 ± 0.2°, and 20.1 ± 0.2°; or the crystal form is crystal form B, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 10.4 ± 0.2°, 11.9 ± 0.2°, 17.6 ± 0.2°, 18.4 ± 0.2°, and 23.6 ± 0.2°; or the crystal form is crystal form C, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 4.9 ± 0.2°, 8.6 ± 0.2°, 9.6 ± 0.2°, 12.8 ± 0.2°, 14.7 ± 0.2°, 16.9 ± 0.2°, and 19.2 ± 0.2°; or the crystal form is crystal form D, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 10.7 ± 0.2°, 12.0 ± 0.2°, 18.2 ± 0.2°, 19.1 ± 0.2°, and 19.9 ± 0.2°; or the crystal form is crystal form E, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 7.0 ± 0.2°, 13.5 ± 0.2°, and 21.3 ± 0.2°; or the crystal form is crystal form F, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 8.3 ± 0.2°, 9.0 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 19.1 ± 0.2°, 19.8 ± 0.2°, 22.3 ± 0.2°, and 26.2 ± 0.2°.

2. The crystal form according to claim 1, characterized in that the crystal form is crystal form B, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 10.4 ± 0.2°, 11.9 ± 0.2°, 17.6 ± 0.2°, 18.4 ± 0.2°, 18.8 ± 0.2°, 21.2 ± 0.2°, 21.8 ± 0.2°, 23.6 ± 0.2°, 28.2 ± 0.2°, and 30.1 ± 0.2°; or the crystal form is crystal form C, which, using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 4.9 ± 0.2°, 8.6 ± 0.2°, 9.6 ± 0.2°, 12.8 ± 0.2°, 14.7 ± 0.2°, 16.9 ± 0.2°, 18.1 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°, 23.6 ± 0.2°, 24.2 ± 0.2°, 25.0 ± 0.2°, 25.8 ± 0.2°, and 26.4 ± 0.2°; Or the crystalline form is crystalline form D, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 10.7 ± 0.2°, 12.0 ± 0.2°, 18.2 ± 0.2°, 19.1 ± 0.2°, 19.9 ± 0.2°, 21.2 ± 0.2°, 22.1 ± 0.2°, 23.9 ± 0.2°, 29.0 ± 0.2°; Or the crystalline form is crystalline form F, which, when using Cu-Kα radiation and expressed in terms of 2θ angle, has characteristic peaks in the X-ray powder diffraction pattern at 8.3 ± 0.2°, 9.0 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 19.1 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°, 20.7 ± 0.2°, 22.3 ± 0.2°, 24.1 ± 0.2°, 26.2 ± 0.2°, 27.8 ± 0.2°; 3. The crystalline form according to claim 1, wherein the crystalline form is crystalline 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 is crystalline form B, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 4; or the crystalline form is crystalline form C, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 7; or the crystalline form is crystalline form D, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 10; or the crystalline form is crystalline form E, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 13; or the crystalline form is crystalline form F, which has an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in Figure 16.

4. The crystalline form according to claim 1, wherein the crystalline form is crystalline form A, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 35°C to 80°C and also has an endothermic peak in the range of 260°C to 290°C; or the crystalline form is crystalline form B, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 110°C to 150°C and also has an endothermic peak in the range of 260°C to 290°C; or the crystalline form is crystalline form C, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 250°C to 290°C; or the crystalline form is crystalline form D, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in the range of 110°C to 160°C and also has an endothermic peak in the range of 260°C to 290°C; or the crystalline form is crystalline form E, and its differential scanning calorimetry (DSC) analysis curve has endothermic peaks in the ranges of 50°C to 100°C and 250°C to 280°C; or the crystalline form is crystalline form F, and its differential scanning calorimetry (DSC) analysis curve has an endothermic peak in each of the ranges of 50°C to 100°C, 125°C to 200°C, and 260°C to 290°C.

5. The crystalline form according to claim 4, wherein the crystalline form is crystalline form A, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.0 ± 5 °C; or the crystalline form is crystalline form B, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.3 ± 5 °C; or the crystalline form is crystalline form C, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 271.9 ± 5 °C; or the crystalline form is crystalline form D, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.2 ± 5 °C; or the crystalline form is crystalline form E, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.0 ± 5 °C; or the crystalline form is crystalline form F, and the maximum endothermic transition temperature of its differential scanning calorimetry (DSC) analysis curve is 272.5 ± 5 °C.

6. The crystalline form according to claim 4, wherein the crystalline form is crystalline form A, and it has a differential scanning calorimetry curve substantially as shown in Figure 2; or the crystalline form is crystalline form B, and it has a differential scanning calorimetry curve substantially as shown in Figure 5; or the crystalline form is crystalline form C, and it has a differential scanning calorimetry curve substantially as shown in Figure 8; or the crystalline form is crystalline form D, and it has a differential scanning calorimetry curve substantially as shown in Figure 11; or the crystalline form is crystalline form E, and it has a differential scanning calorimetry curve substantially as shown in Figure 14; or the crystalline form is crystalline form F, and it has a differential scanning calorimetry curve substantially as shown in Figure 17.

7. The crystalline form according to any one of claims 1 to 6, wherein the crystalline form is crystalline form A, and it is a hydrate; or the crystalline form is crystalline form B, and it is an ethanol solvate; or the crystalline form is crystalline form C, and it is an anhydrate; or the crystalline form is crystalline form D, and it is a methanol solvate; or the crystalline form is crystalline form E, and it is a hydrate; or the crystalline form is crystalline form F, and it is a formic acid solvate.

8. The crystalline form according to claim 7, wherein the crystalline form is crystalline form A, and the water content by weight of crystalline form A is 7.4 ± 2%; or the crystalline form is crystalline form B, and the molar ratio of the compound of formula (I) to ethanol in crystalline form B is 1:1; or the crystalline form is crystalline form D, and the molar ratio of the compound of formula (I) to methanol in crystalline form D is 1:1; or the crystalline form is crystalline form E, and the water content by weight of crystalline form E is 21.1 ± 2%; or the crystalline form is crystalline form F, and the formic acid content by weight of crystalline form F is 8.5 ± 2%.

9. A method for preparing the crystalline form according to any one of claims 1 - 8, comprising the following operations: Dissolving or suspending the compound of formula (I) in an organic solvent, water, or a mixed solvent of an organic solvent and water, reacting at room temperature or heating to 40 - 60 °C for reaction, and separating by solvent evaporation, separation, or cooling to obtain the crystalline form according to any one of claims 1 - 8; The organic solvent is selected from one of the following solvents or any combination between two or more of the following solvents: (1) Alcohol solvents, selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol, cyclohexylethanol, benzyl alcohol, phenethyl alcohol or phenylpropyl alcohol; (2) Halogenated alkane solvents, selected from dichloromethane or chloroform; (3) Nitrile solvents, selected from acetonitrile or propionitrile; (4) Ester solvents, selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate; (5) Ketone solvents, selected from acetone, butanone, isobutanone, methyl isobutyl ketone or 4-methyl-2-pentanone; (6) Alkane solvents, selected from n-pentane, n-hexane, n-heptane or cyclohexane; (7) Aromatic hydrocarbon solvents, selected from toluene; (8) Ether solvents, diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or 1,4-dioxane; (9) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

10. The preparation method according to claim 9, wherein the organic solvent is selected from: methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, acetonitrile, ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, toluene, diethyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dimethylformamide or any combination of two or more of the above solvents.

11. A method for preparing the crystal form according to any one of claims 1-8, comprising the following operations: Dissolve or suspend the compound of formula (I) in an organic solvent, water, or a mixed solvent of an organic solvent and water, stir at room temperature or heat to 40-60 °C, then add a second solvent or place the reaction system in an atmosphere of the second solvent to continue the reaction, and separate by solvent evaporation, separation, or after cooling to obtain the crystal form described in any one of claims 1-8; wherein, Among the organic solvent, water and the second solvent, when one is a good solvent for the compound of formula (I), the other is a poor solvent for the compound of (I); The second solvent is selected from an organic solvent or water; The organic solvent is selected from one of the following solvents or any combination of two or more solvents: (1) Alcohol solvents, selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol, glycerol, cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol, cyclohexylethanol, benzyl alcohol, phenethyl alcohol or phenylpropyl alcohol; (2) Halogenated alkane solvents, selected from dichloromethane or chloroform; (3) Nitrile solvents, selected from acetonitrile or propionitrile; (4) Ester solvents, selected from ethyl formate, methyl formate, butyl formate, ethyl acetate or isopropyl acetate; (5) Ketone solvents, selected from acetone, butanone, isobutanone, methyl isobutyl ketone or 4-methyl-2-pentanone; (6) Alkane solvents, selected from n-pentane, n-hexane, n-heptane or cyclohexane; (7) Aromatic hydrocarbon solvents, selected from toluene; (8) Ether solvents, diethyl ether, propyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or 1,4-dioxane; (9) Dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone.

12. The preparation method according to claim 11, wherein The organic solvent described above is selected from: methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, acetonitrile, ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone, n-heptane, cyclohexane, toluene, diethyl ether, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dimethylformamide, or any combination of two or more of the above solvents.

13. A pharmaceutical preparation containing the crystal form according to any one of claims 1-8, characterized in that, Containing one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation is any pharmaceutically acceptable dosage form.

14. A pharmaceutical composition containing the crystal form according to any one of claims 1-8; optionally, the pharmaceutical composition further contains one or more second therapeutic active agents, and the second therapeutic active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, DNA intercalating agents, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor regulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and isoprenyl protein transferase inhibitors.

15. Use of the crystal form according to any one of claims 1-8 in the preparation of a drug for preventing and / or treating benign tumors or cancers, and the cancers include carcinoma in situ and metastatic cancers; Optionally, the crystal form is used in combination with radiotherapy and / or one or more anticancer agents, and the anticancer agents are as described in claim 14.

16. Use of the crystal form according to any one of claims 1-8 in the preparation of a drug for making cancer cells sensitive to anticancer agents and / or radiotherapy, and the anticancer agents are as described in claim 14.

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