Crystalline form, salt form, and method for producing the same of bromodomain protein inhibitors

Abstract

Crystalline and salt forms of a bromodomain protein inhibitor represented by formula (I), methods for producing the same, and use of the crystal and salt forms in the manufacture of a medicament for treating a BET protein-mediated disease. [Formula 1] TIFF2023510610000055.tif33133

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to China Patent Application No. 202010057297.0 and China Patent Application No. 202010060110.2, both filed with the China National Intellectual Property Administration on January 19, 2020, and these applications are incorporated herein by reference as a whole.

[0002] This application belongs to the field of medicinal chemistry and specifically relates to the crystalline form of a bromodomain protein inhibitor, a method for producing the same, a crystalline composition containing the crystalline form, a pharmaceutical composition containing the crystalline form or the crystalline composition, and their uses. Furthermore, it relates to the hydrochloride, sulfate, phosphate, and mesylate salts of the bromodomain protein inhibitor, as well as their crystalline forms, methods for producing the salts, pharmaceutical compositions containing the salts, and their uses. [Background technology]

[0003] Epigenetic regulation of transcription genes plays a crucial role in the progression of tumors, inflammation, and metabolic diseases. Acetylation of the N-terminal residue of histone lysine in the nucleolus is particularly important for epigenetic gene regulation. Histone acetylation is generally most closely related to the activation of gene transcription, and the recognition of histone lysine acetylation is a crucial step for histone acetylation to be involved in epigenetic regulation. Bromodomains (BRDs) are conserved protein domains that can specifically recognize acetylated lysine (KAc) in histones. By binding to acetylated lysine, they promote the concentration of related proteins, such as chromatin remodeling factors and transcription factors, at specific gene transcription sites, altering RNAII polymerase activity and coordinating gene expression regulation.

[0004] BET (Bromodomain and Extra Terminal) proteins consist of two interrelated bromodomain centers and one extra terminal domain, and are classified into four types—Brd2, Brd3, Brd4, and BrdT—based on their amino acid sequence. Of these, Brd2 to Brd4 are widely distributed throughout various organs of the human body. BET is a type of transcriptional regulatory protein that plays a crucial role in regulating gene expression through its interaction with chromatin. BET proteins have bidirectional regulatory functions, co-activating and co-inhibiting, within the cellular network of signaling pathways. Examples include insulin transcription, adipogenesis in adipose tissue, and hematopoietic differentiation. Recent research has revealed that drugs targeting BET proteins can be used to treat cancer, inflammation, kidney disease, autoimmune diseases, and for male contraception. Therefore, BET proteins are attracting significant attention from major pharmaceutical companies and research institutions as an important target in the field of epigenetics. [Overview of the project] [Problems that the invention aims to solve]

[0005] In one aspect of the present application, a crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. [ka] The aforementioned crystal form is, The crystalline form I of compound (I) has characteristic diffraction peaks at 2θ angles of 12.4°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.4°±0.2°, and 24.7°±0.2° in its X-ray powder diffraction pattern. Crystalline form A of the hydrochloride salt of compound (I) whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2°, Crystalline form B of the hydrochloride salt of compound (I) has characteristic diffraction peaks at 2θ angles of 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, and 17.4°±0.2° in its X-ray powder diffraction pattern, The crystalline form C of the hydrochloride salt of the compound of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at 2θ angles of 6.8° ± 0.2°, 9.5° ± 0.2°, 12.9° ± 0.2°, 20.5° ± 0.2°, 24.6° ± 0.2°, and The crystalline form D of the sulfate salt of the compound of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at 2θ angles of 13.5° ± 0.2°, 14.7° ± 0.2°, 18.6° ± 0.2°, 21.2° ± 0.2°, 23.0° ± 0.2°, 24.1° ± 0.2°, and The crystalline form E of the phosphate salt of the compound of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at 2θ angles of 10.1° ± 0.2°, 10.5° ± 0.2°, 19.0° ± 0.2°, 21.0° ± 0.2°, 22.7° ± 0.2°, 24.0° ± 0.2°, and is selected from the crystalline form F of the mesylate salt of the compound of formula (I), the X-ray powder diffraction pattern of which has characteristic diffraction peaks at 2θ angles of 8.8° ± 0.2°, 10.1° ± 0.2°, 17.7° ± 0.2°, 18.0° ± 0.2°, 24.1° ± 0.2°, 24.8° ± 0.2°.

Means for Solving the Problems

[0006] In another aspect of the present application, crystalline form I of the compound of formula (I) is provided.

Chemical Formula

[0007] The crystalline form I is characterized in that the X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at 2θ = 12.4° ± 0.2°, 14.5° ± 0.2°, 17.4° ± 0.2°, 18.5° ± 0.2°, 20.4° ± 0.2°, 24.7° ± 0.2°.

[0008] In some embodiments, the crystalline form I has characteristic diffraction peaks at 2θ = 6.6° ± 0.2°, 9.3° ± 0.2°, 12.4° ± 0.2°, 14.5° ± 0.2°, 16.6° ± 0.2°, 17.4° ± 0.2°, 18.5° ± 0.2°, 20.0° ± 0.2°, 20.4° ± 0.2°, 24.7° ± 0.2° in the X-ray powder diffraction (XRPD) pattern.

[0009] In some embodiments, the crystalline form I has characteristic diffraction peaks at 2θ = 6.6° ± 0.2°, 9.3° ± 0.2°, 12.4° ± 0.2°, 14.5° ± 0.2°, 16.6° ± 0.2°, 17.4° ± 0.2°, 18.5° ± 0.2°, 20.0° ± 0.2°, 20.4° ± 0.2°, 21.5° ± 0.2°, 22.5° ± 0.2°, 23.7° ± 0.2°, 24.7° ± 0.2°, 25.2° ± 0.2° in the X-ray powder diffraction (XRPD) pattern.

[0010] In some embodiments, the positions and relative intensities of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of the crystalline form I are as shown in Table 1. [Table 1]

[0011] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form I has the characteristics represented by the XRPD pattern of FIG. 1.

[0012] In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form I has the characteristics represented by the DSC curve of FIG. 2.

[0013] In some embodiments, the DSC curve of the crystalline form I has an endothermic peak at 275°C ± 3°C.

[0014] In some embodiments, crystalline form I is produced in one or more mixed solvents selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, and dichloromethane. In some embodiments, crystalline form I is produced in one or more mixed solvents selected from water, methanol, dimethyl sulfoxide, dichloromethane, and acetonitrile. In some embodiments, crystalline form I is produced in dimethyl sulfoxide, methanol, or water. In some embodiments, crystalline form I is produced in a mixed solvent of dimethyl sulfoxide and water, a mixed solvent of dimethyl sulfoxide and methanol, a mixed solvent of dichloromethane and methanol, or a mixed solvent of acetonitrile and water.

[0015] In some embodiments, the particle size distribution X of the crystal form I 90 The particle size is less than 30 μm. In some embodiments, the particle size distribution X of the crystal form I 90 The particle size distribution X of the crystal form I is less than 20 μm. In some embodiments, 90 The particle size distribution X of the crystal form I is less than 15 μm. In some embodiments, the particle size distribution X 90 The particle size distribution X of the crystal form I is less than 12 μm. In some embodiments, 90 The particle size distribution X of the crystal form I is less than 10 μm. In some embodiments, the particle size distribution X 90 It is less than 7 μm.

[0016] In some embodiments, the particle size distribution X of the crystal form I 90 The particle size is 3.0 to 14.0 μm, preferably 3.5 to 13.5 μm, more preferably 4.0 to 13.0 μm, even more preferably 4.5 to 12.5 μm, and even more preferably 5.0 to 12.0 μm.

[0017] In some embodiments, the particle size distribution X of the crystal form I 90 The particle size is 3.5 to 8.5 μm, preferably 4.5 to 7.5 μm, and more preferably 5.5 to 6.5 μm.

[0018] In some embodiments, the particle size distribution X of the crystalline form I 90 is 9.5 to 13.5 μm, preferably 10.5 to 12.5 μm, and more preferably 11.0 to 12.0 μm.

[0019] In some embodiments, the particle size distribution X of the crystalline form I 90 is measured after the crystalline form I is pulverized by jet milling. In some embodiments, the pulverization pressure of the jet milling is selected from 0.1 to 0.7 MPa, preferably selected from 0.1 to 0.6 MPa. Alternatively, the pulverization pressure of the jet milling is selected from 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa or a range consisting of any of the above values.

[0020] In the present application, further, (1) The step of mixing the compound of formula (I) and solvent I; (2) The step of filtering and drying; A method for producing crystalline form I of the compound of formula (I) comprising is provided. The solvent I is preferably one or more mixed solvents selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, dichloromethane, more preferably one or more mixed solvents selected from water, acetonitrile, methanol, dimethyl sulfoxide, dichloromethane, still more preferably selected from water, dimethyl sulfoxide, and even more preferably a mixed solvent of dichloromethane and methanol.

[0021] In some embodiments, the method for producing crystalline form I of the compound of formula (I) is (1) The step of mixing the compound of formula (I) and solvent I; (2) The step of mixing the mixture of step (1) and solvent II; (3) The step of filtering and drying; and comprises. The solvents I and II are preferably independently selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, and dichloromethane, more preferably selected from water, acetonitrile, methanol, dimethyl sulfoxide, and dichloromethane, even more preferably selected from water, methanol, and dimethyl sulfoxide, and even more preferably dichloromethane and methanol.

[0022] In some embodiments, the method of mixing the mixture from step (1) with solvent II in step (2) includes, but is not limited to, a. adding the mixture from step (1) to solvent II, or b. adding solvent II to the mixture from step (1). In some embodiments, the method of adding is preferably dropwise.

[0023] In some embodiments, step (2) is to dropwise add the mixture from step (1) to solvent II at a suitable temperature. In some embodiments, the suitable temperature is -10 to 30°C. In some embodiments, the suitable temperature is -5 to 10°C. In some embodiments, the suitable temperature is 0°C.

[0024] In this application, further, (1) A step of mixing a pharmaceutically acceptable salt of compound (I) with solvent III, A method for producing crystalline form I of the compound of formula (I) is provided, comprising the steps of (2) filtering and drying. The solvent III is preferably a mixed solvent of one or more solvents selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, and acetone; more preferably a mixed solvent of one or more solvents selected from water, acetonitrile, and methanol; and even more preferably selected from water, a mixed solvent of acetonitrile and water, or a mixed solvent of methanol and water.

[0025] In some embodiments, after mixing a pharmaceutically acceptable salt of the compound of formula (I) with solvent III in step (1), the mixture is stirred for a predetermined time, preferably 3 to 4 hours. In some embodiments, the stirring is carried out at room temperature.

[0026] In some embodiments, the method for producing crystalline form I of the compound of formula (I) is as follows: (1) A step of mixing a pharmaceutically acceptable salt of compound (I) with solvent III, (2) The step of mixing the mixture from step (1) with solvent IV, (3) The process includes the steps of filtering and drying. The solvents III and IV are each preferably independently selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, and acetone, more preferably selected from water, acetonitrile, methanol, ethanol, and isopropanol, and even more preferably selected from water, acetonitrile, and methanol.

[0027] In some embodiments, the manner in which the mixture of step (1) and solvent IV are mixed in step (2) includes, but is not limited to, a. adding the mixture of step (1) to solvent IV, and b. adding solvent IV to the mixture of step (1). In some embodiments, the manner of addition is preferably dropwise.

[0028] In some embodiments, in step (2), the mixture from step (1) is mixed with solvent IV and then crystallized. In some embodiments, the crystallization is carried out at room temperature.

[0029] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride salt of the compound of formula (I). In some embodiments, the hydrochloride salt of the compound of formula (I) is selected from crystalline form A, crystalline form B, and crystalline form C, and is preferably crystalline form A.

[0030] The present invention further provides pharmaceutically acceptable salts (salt forms) of the compound of formula (I). The pharmaceutically acceptable salts are selected from the hydrochloride, sulfate, phosphate, and mesylate salts of the compound of formula (I).

[0031] In a further embodiment of the present application, a hydrochloride salt of the compound of formula (I) is provided. [ka]

[0032] This application further provides the crystalline form of the hydrochloride salt of the compound of formula (I), a method for producing the same, and a corresponding crystalline composition.

[0033] In some embodiments, the hydrochloride salt of the compound of formula (I) is a salt formed by the compound of formula (I) and hydrochloric acid in a molar ratio of 1:1.

[0034] In some embodiments, the hydrochloric acid content of the hydrochloride salt of the compound of formula (I) is 5 to 10 wt%, preferably 6 to 9 wt% or 6 to 8 wt%. Alternatively, the hydrochloride salt of the compound of formula (I) above is selected from the range consisting of 6.0wt%, 6.1wt%, 6.2wt%, 6.3wt%, 6.4wt%, 6.5wt%, 6.6wt%, 6.7wt%, 6.8wt%, 6.9wt%, 7.0wt%, 7.1wt%, 7.2wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.6wt%, 7.7wt%, 7.8wt%, 7.9wt%, 8.0wt%, 8.1wt%, 8.2wt%, 8.3wt%, 8.4wt%, 8.5wt%, 8.6wt%, 8.7wt%, 8.8wt%, 8.9wt%, 9.0wt%, or any of the above values.

[0035] In some embodiments, the crystalline form of the hydrochloride salt of the compound of formula (I) is a hydrate, which is selected from hemihydrate, monohydrate, dihydrate, trihydrate, and tetrahydrate, preferably monohydrate, dihydrate, and tetrahydrate, and more preferably monohydrate and tetrahydrate.

[0036] In some embodiments, the crystalline form of the hydrochloride salt of the compound of formula (I) is a monohydrate.

[0037] In some embodiments, the crystalline form of the hydrochloride salt of the compound of formula (I) is a tetrahydrate.

[0038] This application provides a crystalline form A of the hydrochloride salt of compound (I), characterized in that its X-ray powder diffraction (XRPD) pattern has diffraction peaks at 2θ = 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2°.

[0039] In some embodiments, the crystal form A is characterized by having diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 20.5°±0.2°, and 24.7°±0.2°.

[0040] In some embodiments, the crystal form A is characterized by having diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 19.2°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 23.3°±0.2°, and 24.7°±0.2°.

[0041] In some embodiments, the position and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of crystal form A are as shown in Table 2. [Table 2]

[0042] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal form A is characterized by being represented by the XRPD pattern in Figure 3.

[0043] In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form A is characterized by being represented by the DSC curve shown in Figure 4.

[0044] In some embodiments, the DSC curve of crystal form A has an endothermic peak at 149.61°C ± 3°C. In some embodiments, the DSC curve of crystal form A has an endothermic peak at 101.14°C ± 3°C. In some embodiments, the DSC curve of crystal form A has an endothermic peak at 80.15°C ± 3°C. In some embodiments, the DSC curve of crystal form A has an endothermic peak at 62.98°C ± 3°C. In some embodiments, the DSC curve of crystal form A has endothermic peaks at 149.61°C ± 3°C and / or 101.14°C ± 3°C and / or 80.15°C ± 3°C and / or 62.98°C ± 3°C.

[0045] In this application, all percentages used to indicate weight loss and moisture content are in wt%.

[0046] In some embodiments, the thermogravimetric analysis (TGA) curve of crystal form A is characterized by being represented by the TGA curve shown in Figure 5.

[0047] In some embodiments, the thermogravimetric analysis curve of crystal form A shows a weight loss of 2.37 ± 0.2% at 119.1 ± 3°C.

[0048] In some embodiments, the thermogravimetric analysis curve of crystal form A shows a weight loss of 2.37±0.2% at 119.1±3°C and / or a weight loss of 16.78±0.2% at 258.7±3°C and / or a weight loss of 38.60±0.2% at 494.1±3°C.

[0049] In some embodiments, crystalline form A is produced in a mixed solvent of one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, crystalline form A is produced in methanol, ethanol, or isopropanol. In some embodiments, crystalline form A is produced in methanol.

[0050] In this application, further, (1) The step of mixing compound (I) and solvent A, (2) The step of adding hydrochloric acid to the mixture in step (1), (3) The step of filtering and drying, A method for producing crystalline form A of the hydrochloride salt of a compound of formula (I) containing the compound is provided. The solvent A is a mixed solvent of one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably selected from methanol, ethanol, and isopropanol, and more preferably methanol.

[0051] In some embodiments, the water content of crystalline form A is 5.0 to 9.0%, preferably 5.5 to 8.5%, and more preferably 5.8 to 8.1%. In some embodiments, the water content of crystalline form A is 4.7%. In some embodiments, the water content of crystalline form A is 5.8%. In some embodiments, the water content of crystalline form A is 6.6%. In some embodiments, the water content of crystalline form A is 8.1%.

[0052] This application provides a crystalline form B of the hydrochloride salt of compound (I), characterized in that its X-ray powder diffraction (XRPD) pattern has diffraction peaks at 2θ = 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, and 17.4°±0.2°.

[0053] In some embodiments, the crystal form B is characterized by having diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 21.0°±0.2°, and 22.2°±0.2°.

[0054] In some embodiments, crystal form B is characterized by having diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 22.2°±0.2°, and 24.6°±0.2°.

[0055] In some embodiments, the position and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of crystal form B are as shown in Table 3. [Table 3]

[0056] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal form B is characterized by being represented by the XRPD pattern in Figure 6.

[0057] In some embodiments, the water content of crystalline form B is 2.0 to 5.5%, preferably 3.0 to 5.0%, and more preferably 3.6 to 4.6%. In some embodiments, the water content of crystalline form B is 3.6%. In some embodiments, the water content of crystalline form B is 4.6%.

[0058] In some embodiments, crystal form B is produced from crystal form A at 60±2℃.

[0059] The present invention further provides a method for producing crystalline form B of the hydrochloride salt of compound (I), which includes the step of allowing crystalline form A to stand at 60±2°C for 30 days.

[0060] This application provides a crystalline form C of the hydrochloride salt of compound (I), characterized in that its X-ray powder diffraction (XRPD) pattern has diffraction peaks at 2θ = 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 20.5°±0.2°, and 24.6°±0.2°.

[0061] In some embodiments, the crystalline form C is characterized by having diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 17.5°±0.2°, 20.5°±0.2°, 23.3°±0.2°, and 24.6°±0.2°.

[0062] In some embodiments, the crystalline form C is characterized in that its X-ray powder diffraction (XRPD) pattern has diffraction peaks at 2θ = 6.8°±0.2°, 9.5°±0.2°, 11.9°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 15.8°±0.2°, 17.5°±0.2°, 20.5°±0.2°, 23.3°±0.2°, 24.6°±0.2°, and 28.7°±0.2°.

[0063] In some embodiments, the position and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of the crystalline form C are as shown in Table 4. [Table 4]

[0064] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form C is characterized by being represented by the XRPD pattern in Figure 7.

[0065] In some embodiments, the water content of crystalline form C is 9.0 to 14.0%, preferably 9.5 to 13.5%, and more preferably 10.0 to 13.0%. In some embodiments, the water content of crystalline form C is 11.9%. In some embodiments, the water content of crystalline form C is 12.2%. In some embodiments, the water content of crystalline form C is 13.0%.

[0066] In some embodiments, crystal form C is produced from crystal form A at room temperature and a relative humidity of 92.5 ± 5%.

[0067] The present invention further provides a method for producing crystalline form C of the hydrochloride salt of compound (I), which includes the step of leaving crystalline form A to stand at room temperature and a relative humidity of 92.5±5% for 30 days.

[0068] In another aspect of the present application, a sulfate of the compound of formula (I) is provided. [ka]

[0069] In some embodiments, the sulfate of the compound of formula (I) is as shown in formula (II). [ka] In the formula, x is chosen from 0.5 to 1.

[0070] In some embodiments, x is selected from 0.5 and 1.

[0071] In some embodiments, x is selected from 1.

[0072] In some embodiments, the sulfate salt of the compound of formula (I) has a sulfuric acid content of 15-20 wt%, preferably 16-19 wt%, 17-19 wt%, or the sulfuric acid content of 16.1 wt%, 16.2 wt%, 16.3 wt%, 16.4 wt%, 16.5 wt%, 16.6 wt%, 16.7 wt%, 16.8 wt%, 16.9 wt%, 17.0 wt%, 17.1 wt%, 17.2 wt%, 17.3 wt%, 17.4 wt%, 17.5 wt%. The values ​​are selected from a range consisting of %, 17.6wt%, 17.7wt%, 17.8wt%, 17.9wt%, 18.0wt%, 18.1wt%, 18.2wt%, 18.3wt%, 18.4wt%, 18.5wt%, 18.6wt%, 18.7wt%, 18.8wt%, 18.9wt%, 19.0wt%, or any of the aforementioned values.

[0073] The present application further provides a crystalline form D of the compound of formula (II), where x is 1. The crystalline form D is characterized by having a X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks of 2θ = 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, and 24.1°±0.2°.

[0074] In some embodiments, the crystal form D has characteristic diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 7.1°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, and 24.1°±0.2°.

[0075] In some embodiments, the crystal form D has characteristic diffraction peaks in its X-ray powder diffraction (XRPD) pattern at 2θ = 7.1°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.5°±0.2°, 14.7°±0.2°, 16.3°±0.2°, 18.6°±0.2°, 19.7°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.0°±0.2°, 24.1°±0.2°, and 26.2°±0.2°.

[0076] In some embodiments, the position and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of crystal form D are as shown in Table 5. [Table 5]

[0077] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystal form D is characterized by being represented by the XRPD pattern in Figure 8.

[0078] In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form D is characterized by being represented by the DSC curve in Figure 9.

[0079] In some embodiments, the DSC curve of crystal form D has an exothermic peak at 262.82°C ± 3°C. In some embodiments, the DSC curve of crystal form D has an exothermic peak at 272.31°C ± 3°C. In some embodiments, the DSC curve of crystal form D has an exothermic peak at 272.31°C ± 3°C and / or 262.82°C ± 3°C.

[0080] In some embodiments, the thermogravimetric analysis (TGA) curve of the crystal form D is characterized by being represented by the TGA curve shown in Figure 10.

[0081] In some embodiments, the thermogravimetric analysis curve of crystal form D shows a weight loss of 40.74 ± 0.2% at 425.0 ± 3°C.

[0082] In some embodiments, the crystalline form D is produced in a mixed solvent selected from methanol, ethanol, isopropanol, acetone, and ethyl acetate. In some embodiments, the crystalline form D is produced in a mixed solvent selected from methanol, ethanol, or isopropanol. In some embodiments, the crystalline form D is produced in methanol.

[0083] The present invention further provides a method for producing crystalline form D of the sulfate of the compound of formula (I), comprising the step of contacting the compound of formula (I) with sulfuric acid.

[0084] In some embodiments, the method for producing the crystal form D is as follows: (1) A step of mixing compound (I) and solvent D, (2) Adding a solution of sulfuric acid solvent D to the mixture from step (1), (3) The process includes the steps of filtering and drying. The solvent D is a mixed solvent of one or more solvents selected from methanol, ethanol, isopropanol, acetone, and ethyl acetate, preferably selected from methanol, ethanol, and isopropanol, and more preferably methanol.

[0085] In a further embodiment of the present application, a phosphate of the compound of formula (I) is provided. [ka]

[0086] In some embodiments, the phosphate of the compound of formula (I) is as shown in formula (III). [ka] In the formula, x is chosen from 0.5 to 1.

[0087] In some embodiments, x is selected from 0.5 and 1.

[0088] In some embodiments, x is selected from 1.

[0089] In some embodiments, the phosphate content of the phosphate salt of the compound of formula (I) is 10 to 20 wt%, preferably 12 to 19 wt%. Alternatively, the phosphate content of the phosphate salt of the compound of formula (I) is 12.1 wt%, 12.2 wt%, 12.3 wt%, 12.4 wt%, 12.5 wt%, 12.6 wt%, 12.7 wt%, 12.8 wt%, 12.9 wt%, 13.0 wt%, 13.1 wt%, 13.2 wt%, 13.3 wt%, 13.4 wt%, 13.5 wt%, 13.6 wt%. %, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 1 4.6wt%, 14.7wt%, 14.8wt%, 14.9wt%, 15.0wt%, 15.1wt%, 15.2wt%, 15.3wt%, 15.4wt%, 15.5w t%, 15.6wt%, 15.7wt%, 15.8wt%, 15.9wt%, 16.0wt%, 16.1wt%, 16.2wt%, 16.3wt%, 16.4wt%, 16.5wt%, 16.6wt%, 16.7wt%, 16.8wt%, 16.9wt%, 17.0wt%, 17.1wt%, 17.2wt%, 17.3wt%, 17.4 wt%, 17.5wt%, 17.6wt%, 17.7wt%, 17.8wt%, 17.9wt%, 18.0wt%, 18.1wt%, 18.2wt%, 18.3wt%, 18.4wt%, 18.5wt%, 18.6wt%, 18.7wt%, 18.8wt%, 18.9wt%, 19.0wt%, or any of the above values ​​selected from the range.

[0090] The present invention further provides a crystalline form E of the compound of formula (III). The crystalline form E is characterized in that its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at 2θ = 10.1°±0.2°, 10.5°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 22.7°±0.2°, and 24.0°±0.2°.

[0091] In some embodiments, the crystal form E is characterized by having a X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks at 2θ = 9.0°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.7°±0.2°, and 24.0°±0.2°.

[0092] In some embodiments, the crystal form E is characterized by having a characteristic diffraction peak in its X-ray powder diffraction (XRPD) pattern at 2θ = 5.2°±0.2°, 9.0°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 15.5°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, and 24.0°±0.2°.

[0093] In some embodiments, the position and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of crystal form E are as shown in Table 6. [Table 6]

[0094] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystal form E is characterized by being represented by the XRPD pattern in Figure 11.

[0095] In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form E is characterized by being represented by the DSC curve shown in Figure 12.

[0096] In some embodiments, the DSC curve of crystal form E has an endothermic peak at 171.37°C ± 3°C. In some embodiments, the DSC curve of crystal form E has an endothermic peak at 159.07°C ± 3°C. In some embodiments, the DSC curve of crystal form E has an endothermic peak at 141.12°C ± 3°C. In some embodiments, the DSC curve of crystal form E has an endothermic peak at 116.46°C ± 3°C. In some embodiments, the DSC curve of crystal form E has endothermic peaks at 171.37°C ± 3°C and / or 159.07°C ± 3°C and / or 141.12°C ± 3°C and / or 116.46°C ± 3°C.

[0097] In some embodiments, the thermogravimetric analysis (TGA) curve of the crystal form E is characterized by being represented by the TGA curve shown in Figure 13.

[0098] In some embodiments, the thermogravimetric analysis curve of the crystal form E shows a weight loss of 2.24 ± 0.2% at 157.5 ± 3°C.

[0099] In some embodiments, the thermogravimetric analysis curve of the crystal form E shows a weight loss of 2.24±0.2% at 157.5±3°C and / or a weight loss of 7.85±0.2% at 270.8±3°C and / or a weight loss of 27.85±0.2% at 493.8±3°C.

[0100] In some embodiments, the crystalline form E is produced in a mixed solvent of one or more selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystalline form E is produced in a mixed solvent of one or more selected from ethyl acetate and acetonitrile. In some embodiments, the crystalline form E is produced in acetonitrile.

[0101] The present invention further provides a method for producing crystalline form E of the phosphate of the compound of formula (I), comprising the step of contacting the compound of formula (I) with phosphoric acid.

[0102] In some embodiments, the method for producing the crystal form E is as follows: (1) A step of mixing compound (I) and solvent E, (2) The step of adding phosphoric acid to the mixture from step (1), (3) The process includes the steps of filtering and drying. The solvent E is one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably selected from ethyl acetate and acetonitrile, and more preferably acetonitrile.

[0103] In a further embodiment of the present application, a mesylate of the compound of formula (I) is provided. [ka]

[0104] In some embodiments, the mesylate of the compound of formula (I) is as shown in formula (IV). [ka] In the formula, x is chosen from 0.5 to 1.

[0105] In some embodiments, x is selected from 0.5 and 1.

[0106] In some embodiments, x is selected from 1.

[0107] In some embodiments, the methanesulfonic acid content of the mesylate of the compound of formula (I) is 10 to 20 wt%, preferably 12 to 19 wt%. Alternatively, the methanesulfonic acid content of the mesylate of the compound of formula (I) is 12.1 wt%, 12.2 wt%, 12.3 wt%, 12.4 wt%, 12.5 wt%, 12.6 wt%, 12.7 wt%, 12.8 wt%, 12.9 wt%, 13.0 wt%, 13.1 wt%, 13.2 wt%, 13.3 wt%, 13.4 wt%, 13.5 wt%, 1 3.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5w t%, 14.6wt%, 14.7wt%, 14.8wt%, 14.9wt%, 15.0wt%, 15.1wt%, 15.2wt%, 15.3wt%, 15.4wt%, 15 .5wt%, 15.6wt%, 15.7wt%, 15.8wt%, 15.9wt%, 16.0wt%, 16.1wt%, 16.2wt%, 16.3wt%, 16.4wt %, 16.5wt%, 16.6wt%, 16.7wt%, 16.8wt%, 16.9wt%, 17.0wt%, 17.1wt%, 17.2wt%, 17.3wt%, 17. The range is selected from 4wt%, 17.5wt%, 17.6wt%, 17.7wt%, 17.8wt%, 17.9wt%, 18.0wt%, 18.1wt%, 18.2wt%, 18.3wt%, 18.4wt%, 18.5wt%, 18.6wt%, 18.7wt%, 18.8wt%, 18.9wt%, 19.0wt%, or any of the aforementioned values.

[0108] The present application further provides a crystalline form F of the compound of formula (IV). The crystalline form F is characterized in that its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at 2θ = 8.8°±0.2°, 10.1°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2°.

[0109] In some embodiments, the crystal form F is characterized by having a characteristic diffraction pattern of 2θ = 8.8°±0.2°, 10.1°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 24.8°±0.2°, and 26.6°±0.2°.

[0110] In some embodiments, the crystal form F is characterized by having a characteristic diffraction peak in its X-ray powder diffraction (XRPD) pattern at 2θ = 8.8°±0.2°, 10.1°±0.2°, 13.1°±0.2°, 14.3°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 20.2°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 26.0°±0.2°, and 26.6°±0.2°.

[0111] In some embodiments, the position and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction (XRPD) pattern of the crystal form F are as shown in Table 7. [Table 7]

[0112] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystal form F is characterized by being represented by the XRPD pattern in Figure 14.

[0113] In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form F is characterized by being represented by the DSC curve shown in Figure 15.

[0114] In some embodiments, the DSC curve of the crystal form F has an exothermic peak at 282.74°C ± 3°C. In some embodiments, the DSC curve of the crystal form F has an endothermic peak at 221.41°C ± 3°C. In some embodiments, the DSC curve of the crystal form F has an endothermic peak at 167.36°C ± 3°C. In some embodiments, the DSC curve of the crystal form F has an endothermic peak at 167.36°C ± 3°C and / or an endothermic peak at 221.41°C ± 3°C and / or an exothermic peak at 282.74°C ± 3°C.

[0115] In some embodiments, the thermogravimetric analysis (TGA) curve of the crystal form F is characterized by being represented by the TGA curve shown in Figure 16.

[0116] In some embodiments, the thermogravimetric analysis curve of the crystalline form F shows a weight loss of 2.80 ± 0.2% at 170.2 ± 3°C.

[0117] In some embodiments, the thermogravimetric analysis curve of the crystalline form F shows a weight loss of 2.80±0.2% at 170.2±3°C and / or a weight loss of 5.28±0.2% at 261.4±3°C and / or a weight loss of 9.21±0.2% at 311.4±3°C and / or a weight loss of 25.22±0.2% at 396.3±3°C and / or a weight loss of 13.88±0.2% at 554.9±3°C.

[0118] In some embodiments, the crystalline form F is produced in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystalline form F is produced in one or more mixed solvents selected from ethyl acetate and acetonitrile. In some embodiments, the crystalline form F is produced in acetonitrile.

[0119] The present invention further provides a method for producing crystalline form F, which includes the step of contacting the compound of formula (I) with methanesulfonic acid.

[0120] In some embodiments, the method for producing the crystal form F is as follows: (1) A step of mixing the compound of formula (I) with solvent F, (2) The step of adding methanesulfonic acid to the mixture from step (1), (3) The process includes the steps of filtering and drying. The solvent F is a mixed solvent of one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably selected from ethyl acetate and acetonitrile, and more preferably acetonitrile.

[0121] In a further aspect of the present application, a crystalline composition comprising the crystalline form is provided, wherein the crystalline form accounts for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, of the weight of the crystalline composition.

[0122] In further embodiments of the present application, a pharmaceutical composition comprising the crystalline form or a crystalline composition thereof is provided. The pharmaceutical composition may optionally comprise pharmaceutically acceptable carriers, excipients and / or media. The pharmaceutical composition of the present application may further comprise one or more other therapeutic agents.

[0123] In some embodiments, the pharmaceutical composition comprises crystalline form I or its crystalline composition, crystalline form A or its crystalline composition, crystalline form B or its crystalline composition, crystalline form C or its crystalline composition, crystalline form D or its crystalline composition, crystalline form E or its crystalline composition, or crystalline form F or its crystalline composition. In some embodiments, the pharmaceutical composition comprises crystalline form I, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F. In some embodiments, the pharmaceutical composition comprises 0.0001 to 500 mg of crystalline form I, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F, preferably 0.001 to 250 mg of crystalline form I, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F, more preferably 0.005 to 100 mg of crystalline form I, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F, and most preferably 0.005 to 50 mg of crystalline form I, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F. The present application further provides a method for treating a mammalian BET protein-mediated disease, comprising administering a therapeutically effective amount of the crystalline form, or salt form thereof, or a crystalline composition thereof, or the pharmaceutical composition to a mammal (preferably human) in need of treatment.

[0124] The present invention further provides uses for the crystalline form, salt form, crystalline composition thereof, or pharmaceutical composition in the manufacture of therapeutic drugs for BET protein-mediated diseases.

[0125] The present invention further provides the crystalline form, or salt form, or a crystalline composition thereof, or a pharmaceutical composition for treating BET protein-mediated diseases.

[0126] The present invention further provides uses for the crystalline form, salt form, crystalline composition thereof, or pharmaceutical composition for treating BET protein-mediated diseases.

[0127] In some embodiments of the present application, the BET protein-mediated disease is selected from cancer. Preferably, the cancer is selected from solid tumors and hematological malignancies. More preferably, the solid tumor is selected from breast cancer and prostate cancer. More preferably, the hematological malignancy is selected from acute myeloid leukemia, multiple myeloma and diffuse large B-cell lymphoma. [Effects of the Invention]

[0128] The crystalline form of this invention exhibits good stability, showing favorable results in stability tests under high humidity, high temperature, or light. It demonstrates good pharmacological activity in in vivo or in vitro tests. When used as a raw material in pharmaceutical formulations, the product exhibits favorable properties in dissolution, release, and pharmacokinetics, indicating that the crystalline form of this invention possesses good pharmaceutical properties and is readily convertible into a drug. The crystalline form of this invention provides valuable insights for obtaining the solid form of the compound.

[0129] "Definition" Unless otherwise specified, the following terms used herein have the following meanings. Certain terms, unless specifically defined, should be understood in their ordinary meaning in the art, rather than as undefined or ambiguous. Where a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0130] Furthermore, the position or relative intensity of peaks in the X-ray powder diffraction pattern may vary depending on the measuring device, measurement method / conditions, etc. Even with any determined crystal form, there may be errors in the peak position, and the measurement error for the 2θ angle may be ±0.2°. Therefore, when determining various crystal forms, such errors should be taken into consideration, and those within the error range are included within the scope of this application.

[0131] Furthermore, even with the same crystal form, the position of the endothermic peak in DSC may differ depending on the measuring device, measurement method / conditions, etc. Even with any determined crystal form, there may be an error in the position of the endothermic peak, and this error may be ±5°C or ±3°C. Therefore, when determining various crystal forms, this error should be taken into consideration, and those within this error range are included within the scope of this application.

[0132] In the pharmaceutical field, the term "hydrate" refers to a solid cocrystal produced by the hydration reaction of a drug molecule with water of crystallization. One molecule of the compound of this application can bond with one water molecule, for example, to obtain a monohydrate. Another molecule of the compound of this application can bond with two or more water molecules, for example, to obtain a dihydrate, trihydrate, or tetrahydrate. Another molecule of the compound of this application can bond with less than one water molecule, for example, to obtain a hemihydrate. The hydrates described in this application retain the bioavailability of the unhydrated form of the compound.

[0133] The aforementioned term "comprise," similar terms, and equivalent English expressions, such as "comprises," "comprising," or equivalents, are understood as open and non-exclusive expressions meaning "including, but not limited to, ...."

[0134] The term “pharmaceutically acceptable” is used for compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human or animal tissue, are non-toxic or irritating, are medically judged not to cause allergic reactions, other problems or complications, and have a reasonable benefit-to-risk balance. “pharmaceutically acceptable additives” are inert substances administered together with an active ingredient to facilitate the administration of the active ingredient, and include, but are not limited to, any flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers approved by the China National Food and Drug Administration for use in humans or animals (e.g., livestock). Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0135] The term "pharmaceutical composition" refers to a mixture consisting of one or more compounds of the present application or salts thereof and pharmaceutically acceptable additives. The pharmaceutical composition is intended to facilitate the administration of the compounds of the present application to a living organism.

[0136] The pharmaceutical compositions of the present application can be manufactured by combining the compounds of the present application with appropriate pharmaceutically acceptable additives, for example, as solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc.

[0137] Typical routes of administration of the crystalline form or pharmaceutical composition thereof described in this application include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0138] The pharmaceutical composition of this application can be manufactured by conventional methods known in the art, such as mixing, dissolving, granulation, sugar coating, grinding, emulsification, and freeze-drying.

[0139] In some embodiments, the pharmaceutical composition is for oral administration. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable additives well known in the art. With such additives, the compound of the present application can be formulated as tablets, pills, sugar-coated preparations, capsules, liquid preparations, gel preparations, syrups, suspensions, etc., for oral administration to patients.

[0140] The therapeutic dose of the compound of this application is determined by the purpose of treatment, the method of administration of the compound, the patient's health condition, and the judgment of the prescribing physician. The proportion or concentration of the compound of this application in a pharmaceutical composition is not necessarily constant and is determined by various factors such as dosage, chemical properties (e.g., hydrophobicity), and route of administration. The term "treatment" means administering the compound or preparation described in this application to improve or resolve a disease or one or more symptoms associated with said disease, and includes the following: (i) To inhibit a disease or disease state, that is, to suppress its progression, (ii) To alleviate a disease or disease state, that is, to eliminate the disease or disease state.

[0141] The term "prevention" means administering the compounds or formulations described in this application to prevent a disease or one or more symptoms associated with said disease, and also includes preventing the onset of a disease or disease state in mammals, in particular prevention when mammals susceptible to the disease state have not been diagnosed with the disease state.

[0142] When used for drugs or pharmacologically active agents, the term "therapeutic effective dose" refers to a sufficient dose of the drug or its preparation that is non-toxic and produces the desired effect. This effective dose is determined by the age and general condition of the recipient and varies depending on the type of active substance. In actual administration, a person skilled in the art can appropriately determine the effective dose through standard testing.

[0143] The water content described in this application is measured according to the water content measurement method (Chinese Pharmacopoeia 2015 Edition, Four General Rules 0832, Section 1, Method 1).

[0144] The term “particle size distribution 90 This refers to the particle size corresponding to the point where the cumulative distribution percentage in a powder sample reaches 90%.

[0145] Particle size distribution X described in this application 90 It is measured according to the light scattering method (Chinese Pharmacopoeia 2020 Edition, Four General Rules 0982, Method 3 for Measuring Particle Size and Particle Size Distribution).

[0146] The therapeutically effective dose of the crystalline form described in this application is approximately 0.0001 to 20 mg / kg body weight / day, for example, 0.001 to 10 mg / kg body weight / day.

[0147] The dosage and frequency of administration of the crystalline form described herein are determined by the patient's condition, for example, once or twice a day, or more than once a day. Administration may be intermittent, for example, by administering the daily dose of the crystalline form to the patient for a certain number of days, and then not administering the daily dose of the crystalline form to the patient for the same number of days or a longer period.

[0148] The intermediate compounds of this application include the following specific embodiments, embodiments combined with other chemical synthesis methods, and alternative substitutions familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of this application, and can be produced by a variety of synthesis methods familiar to those skilled in the art.

[0149] The chemical reactions of the specific embodiments of this application are carried out in a suitable solvent, which is suitable for the chemical changes and reagents and starting materials used in this application. To obtain the compounds of this application, it may be necessary for those skilled in the art to select or modify synthesis steps or reaction processes based on existing embodiments.

[0150] In this specification, unless otherwise specified, singular terms cover cases where there are multiple referents, and vice versa.

[0151] In this specification, unless otherwise specified, all parameter values ​​(including 2θ angles and reaction conditions) are considered to be approximate, including measurement errors, and may have an error of, for example, ±5% from the stated values.

[0152] This specification incorporates, by reference and in whole, patents, patent applications, or existing publications for explanatory and disclosure purposes. These publications are available because they were published prior to the filing date of this application. Statements regarding the disclosure dates or contents thereof of these documents are based on information available to the applicant and do not constitute an endorsement that the disclosure dates or contents thereof are accurate. Furthermore, the reference of these publications to this specification does not constitute an endorsement that such publications have become common knowledge in the art in all applicable countries. [Brief explanation of the drawing]

[0153] [Figure 1] Figure 1 shows the XRPD pattern of crystal form I. [Figure 2] Figure 2 shows the DSC curve for crystal form I. [Figure 3] Figure 3 shows the XRPD pattern of crystal form A. [Figure 4] Figure 4 shows the DSC curve for crystal form A. [Figure 5] Figure 5 shows the TGA curve for crystal form A. [Figure 6] Figure 6 shows the XRPD pattern of crystal form B. [Figure 7] Figure 7 shows the XRPD pattern of crystal form C. [Figure 8] Figure 8 shows the XRPD pattern of crystal form D. [Figure 9] Figure 9 shows the DSC curve for crystal form D. [Figure 10] Figure 10 shows the TGA curve for crystal form D. [Figure 11] Figure 11 shows the XRPD pattern of crystal form E. [Figure 12] Figure 12 shows the DSC curve for crystal form E. [Figure 13] Figure 13 shows the TGA curve for crystal form E. [Figure 14] Figure 14 shows the XRPD pattern of crystal form F. [Figure 15] Figure 15 shows the DSC curve for crystal form F. [Figure 16] Figure 16 shows the TGA curve for crystal form F. [Modes for carrying out the invention]

[0154] Next, to further understand the content of this application, specific embodiments will be used for further explanation. However, these specific embodiments are not limitations to the content of this application. [Examples]

[0155] All solvents used in this application are commercially available and can be used without purification. The abbreviations used in this application and their meanings are as follows: DCM is dichloromethane. DMF is N,N-dimethylformamide. DMSO is dimethyl sulfoxide. MeOH is methanol. ACN is acetonitrile. siRNA is ethyl acetate. PE is petroleum ether. CDCl3 is deuterated chloroform. (Boc)2O is di-tert-butyl dicarbonate. Boc is tert-butoxycarbonyl group. DMAP is 4-dimethylaminopyridine. N2 is nitrogen gas. MS is mass spectrometry. Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium. XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Xphos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. In this application, "room temperature" refers to ambient temperature, which is generally between 10 and 30°C.

[0156] XRPD, DSC, TGA configuration (device model number, parameters, etc.): The powder X-ray diffraction (XRPD) method of this application: Instrument model: Bruker D8 Advance X-ray diffractometer. The detailed XRPD parameters are as follows: Source: Cu Tube voltage: 40kV, Tube current: 40mA Scanning angle range: 3.00~60.00° Angle step: 0.02° Scanning interval: 0.1 seconds. The differential scanning calorimetry (DSC) method of this application: Instrument model: METTLER TOLEDO DSC1 differential scanning calorimeter Temperature range: 50~320℃ Heating rate: 10K / min. The thermogravimetric analysis (TGA) method of this application: Instrument model: NETZSCH TG 209F3 thermogravimetric analyzer Temperature range: 30~700℃ Heating rate: 10K / min.

[0157] Example 1: Compound of formula (I) [ka]

[0158] Step A: Ethyl 5-fluoropyridine forate [ka] At 0°C, 5.00 g of 5-fluoropyridineformic acid was slowly added dropwise to a 42 mL solution of ethanol, with 0.1 mL of DMF and 5.6 mL of thionyl chloride added in that order. After completion, the mixture was stirred for 15 minutes, then slowly heated under reflux and reacted for 4 hours. The mixture was cooled, concentrated under reduced pressure, and the residue was poured into ice water. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent and obtain the product (5.50 g).

[0159] Step B: Ethyl 5-(2,4-difluorophenoxy)pyridinformate [ka] At room temperature, 2,4-difluorophenol (4.15 g) and potassium carbonate (8.82 g) were added in that order to a solution of ethyl 5-fluoropyridineformate (5.40 g) in DMF (60 mL). After completion, the mixture was heated to 100 °C and reacted overnight. The mixture was cooled, diluted with water (400 mL), and extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent and obtain the product (8.40 g). 1 H NMR(400MHz,CDCl3)δ 8.48(d,J=2.8Hz,1H),8.10(d,J=8.8Hz,1H),7.15~7.24(m,2H),6.92~7.04(m,2H),4.46(q,J=7.2Hz,2H),1.44(t,J=7.2Hz,3H).

[0160] Step C: 5-(2,4-difluorophenoxy)-2-(ethoxycarbonyl)pyridine 1-oxide [ka] At room temperature, 1.00 g of ethyl 5-(2,4-difluorophenoxy)pyridinformate was added to 30 mL of dichloromethane, and 1.45 g of 85% metachloroperbenzoic acid was added. The mixture was then allowed to react overnight at room temperature. After the reaction was complete, 40 mL of saturated sodium bicarbonate solution was added, the mixture was stirred for 15 minutes, and the solution was extracted three times with dichloromethane. The extracts were combined, washed with saturated sodium thiosulfate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent and obtain the product (1.00 g). 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=2.4Hz,1H),7.63(d,J=8.8Hz,1H),7.19(td,J=8.8Hz,5.6Hz,1H),6.93~7.0 4(m,2H),6.86(dd,J=8.8Hz,2.4Hz,1H),4.44(q,J=7.2Hz,2H),1.40(t,J=7.2Hz,3H).

[0161] Step D: Ethyl 6-bromo-5-(2,4-difluorophenoxy)pyridinformate [ka] At 0°C, 1.00 g of 5-(2,4-difluorophenoxy)-2-(ethoxycarbonyl)pyridine 1-oxide was added to 15 mL of DMF in which order tetramethylammonium bromide and methanesulfonic anhydride were added. After this, the mixture was slowly raised to room temperature and allowed to react for 3 hours. After the reaction was complete, 40 mL of sodium bicarbonate solution with ice water was added, the mixture was stirred for 5 minutes, and the solution was extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Depositphotos:PE = 1:5 to 1:1) to obtain the product (0.80 g). 1 H NMR(400MHz, CDCl3)δ 7.99(d,J=8.0Hz,1H),7.20(td,J=8.8Hz,5.6Hz,1H),6.94~7.05(m,3H),4.46(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H).

[0162] Step E: 6-Bromo-5-(2,4-difluorophenoxy)pyridingumic acid [ka] At 0°C, 0.60 g of ethyl 6-bromo-5-(2,4-difluorophenoxy)pyridinformate was added to 10 mL of tetrahydrofuran solution with 1.50 mL of 30% potassium hydroxide solution. After this, the mixture was raised to room temperature and allowed to react for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, water was added, the pH was adjusted to 4-5 with dilute hydrochloric acid, the mixture was stirred for 5 minutes, filtered, and the solid was collected to obtain the product (0.50 g).

[0163] Step F: [6-bromo-5-(2,4-difluorophenoxy)pyridine-2-yl]tert-butylcarbamate [ka] At room temperature, 6-bromo-5-(2,4-difluorophenoxy)pyridingive acid (0.45 g) was added in 10 mL of tert-butanol anhydride to a solution of tert-butanol anhydride (10 mL). Diphenyl phosphoryl azide (0.75 g), triethylamine (0.80 mL), and di-tert-butyl dicarbonate (1.19 g) were added in that order. After this, the temperature was raised to 90 °C and the reaction was allowed to proceed for 4 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution with ice water (20 mL) was added. The solution was extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Depositphotos:PE = 1:10~1:3) to obtain the product (0.31 g). 1 H NMR(400MHz, CDCl3)δ 7.84(d,J=8.8Hz,1H),7.21(s,1H),7.15(d,J=8.8Hz,1H),6.92-6.99(m,2H),6.81~6.87(m,1H),1.51(s,9H).

[0164] Step G: 6-Bromo-5-(2,4-difluorophenoxy)pyridine-2-amine [ka] At 0°C, concentrated hydrochloric acid (5 mL) was added dropwise to a solution of [6-bromo-5-(2,4-difluorophenoxy)pyridine-2-yl]tert-butylcarbamate (0.31 g) in dioxane (10 mL). After this, the mixture was raised to room temperature and allowed to react for 24 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution containing ice water (20 mL) was added. The solution was then extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (0.22 g). 1 H NMR(400MHz, CDCl3)δ 7.09(d,J=8.4Hz,1H),6.91~6.97(m,1H),6.75~6.86(m,2H),6.42(d,J=8.4Hz,1H),4.52(br s,2H).

[0165] Step H: 2-Bromo-3-(2,4-difluorophenoxy)-6-iodopyridine [ka] At room temperature, iodine (0.27 g) and cuprous iodide (0.20 g) were added in that order to a solution of 6-bromo-5-(2,4-difluorophenoxy)pyridine-2-amine (0.32 g) in diiodomethane (4 mL). The mixture was heated to 80 °C, and isoamyl nitrite (0.34 g) was added dropwise. The reaction was then continued for 2 hours. After the reaction was complete, the mixture was cooled, and a sodium bicarbonate solution containing ice water (20 mL) was poured over it. The mixture was extracted three times with dichloromethane. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:PE = 1:10~1:3) to obtain the product (0.20 g). 1 H NMR(400MHz, CDCl3)δ 7.55(d,J=8.4Hz,1H),7.11(td,J=8.8Hz,5.6Hz,1H),6.97~7.02(m,1H),6.89~6.94(m,1H),6.67(dd,J=8.4Hz,0.8Hz,1H).

[0166] Step I: ((6-bromo-5-(2,4-difluorophenoxy)pyridine-2-yl)imino)dimethyl-λ 6 -Sulfonylumine [ka] Under N2 protection, 2-bromo-3-(2,4-difluorophenoxy)-6-iodopyridine (0.09 g), dimethyl sulfoximine (25 mg), cesium carbonate (0.14 g), Xantphos (10 mg), and Pd2(dba)3 (8 mg) were added in that order to anhydrous dioxane (4 mL), and the mixture was then heated to 100°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated on a preparative thin-layer plate (siRNA:PE=1:1) to obtain the product. 1 H NMR(400MHz,CDCl3)δ 7.10(d,J=8.4Hz,1H),6.92~6.97(m,1H),6.87(td,J=8.8Hz,5.6Hz,1H),6.77~6.82(m,1H),6.69(d,J=8.4Hz,1H),3.37(s,6H).

[0167] Step J: 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-formate tert-butyl [ka] To a solution of 4-bromo-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (1.73 g) in acetonitrile (20 mL), (Boc)2O (2.47 g) and DMAP (1.44 g) were added in that order and stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:20) to obtain the product (2.10 g). 1 H NMR (400MHz, CDCl3) δ 7.55(d,J=3.6Hz,1H),7.21(s,1H),6.35(d,J=3.6Hz,1H),3.55(s,3H),1.62(s,9H).

[0168] Step K: 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-formate tert-butyl [ka] Under N2 protection, tert-butyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-formate (0.53 g), bis(pinacolato)diborone (0.66 g), Xphos (31 mg), potassium acetate (0.28 g), and Pd2(dba)3 (30 mg) were added in that order to a mixed solvent of 1,4-dioxane (20 mL) and water (2 mL). The mixture was heated to 80°C and stirred overnight, then cooled to room temperature. The reaction mixture was dispersed in ethyl acetate, washed with saturated aqueous NaHCO3 solution and then water, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (siRNA:PE = 1:3~1:1) to obtain the product. 1 H NMR(400MHz, CDCl3)δ 7.60(s,1H),7.55(d,J=3.6Hz,1H),6.79(d,J=3.6Hz,1H),3.62(s,3H),1.65(s,9H),1.341.65(s,12H).

[0169] Step L: 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 -thio]amino}pyridine-2-yl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-formate tert-butyl [ka] Under nitrogen protection, ((6-bromo-5-(2,4-difluorophenoxy)pyridine-2-yl)imino)dimethyl-λ in 80% dioxane aqueous solution (3 mL). 6-Sulfonylimine (59 mg), 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-formate tert-butyl (65 mg), cesium fluoride (83 mg), and PdCl2(AtaPhos) (9 mg) were added in this order, and the mixture was then heated to 85°C and stirred overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated on a preparative thin-layer plate (MeOH:DCM=1:20) to obtain the product (58 mg). 1 H NMR(400MHz,CDCl3)δ 7.82(s,1H),7.58~7.59(m,1H),7.23(d,J=8.4Hz,1H),7.15~7.17(m,1H),6 .85~6.92(m,1H),6.65~6.75(m,3H),3.63(s,3H),3.33(s,6H),1.65(s,9H).

[0170] Step M: 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 -thio]amino}pyridine-2-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one [ka] At room temperature, 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 50 mg of tert-butyl-thioaminopyridine-2-yl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-formate was added to 1 mL of a 4 mol / L solution of dioxane with hydrogen chloride, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and 5 mL of sodium bicarbonate solution with ice water was added. The mixture was then extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (35 mg). 1H NMR(400MHz,CDCl3)δ 12.01(br s,1H),9.56(br s,1H),7.72(s,1H),7.24(d,J=8.8Hz,1H),7.14(t,J=2.4Hz,1H),6.85~6.91(m,1H),6.64~6.76(m,3H),3.66(s,3H),3.35(s,6H).

[0171] Example 2: Method for producing crystal form I Method 1: 1 g of compound (I) was added to 10 mL of DMSO, the temperature was raised to 80°C, and the mixture was stirred to dissolve it. 30 mL of purified water was added dropwise to the DMSO solution of compound (I) while stirring in an ice bath, and the mixture was stirred for 10 minutes. The precipitated solid was filtered, and the cake was dried under reduced pressure at 60°C for 2 hours to obtain the product. The XRPD was measured and it was found to be crystalline form I.

[0172] Method 2: 1 g of compound (I) was mixed with 5 mL of DMSO, the temperature was raised to 100°C, stirred to clarify, allowed to cool naturally to crystallize, filtered, and the cake was dried under reduced pressure at 60°C to obtain the product. The XRPD was measured and it was found to be crystal form I.

[0173] Method 3: 1 g of compound (I) was added to 10 mL of DMSO, the temperature was raised to 80°C, and the mixture was stirred to dissolve it. 30 mL of anhydrous methanol was added dropwise to the DMSO solution of compound (I) while stirring in an ice bath, and the mixture was stirred for 10 minutes. The precipitated solid was filtered, and the cake was dried under reduced pressure at 60°C for 3.5 hours to obtain the product. The XRPD was measured and determined to be crystal form I. The XRPD pattern is shown in Figure 1.

[0174] Method 4: 1.0 g of compound (I) was added to 400 mL of DCM and 100 mL of methanol, stirred at room temperature to clarify, concentrated under reduced pressure at 30-35°C, and dried under reduced pressure at 35°C to obtain the product. The XRPD was measured and it was found to be crystal form I. The DSC curve is shown in Figure 2.

[0175] Method 5: 10 g of the hydrochloride salt of compound (I) was added to 200 mL of purified water, stirred at room temperature for 4 hours, filtered, and the cake was collected. The product was dried under reduced pressure at 50°C for 3.5 hours to obtain the product, and the XRPD was measured to determine that it was of crystalline form I.

[0176] Method 6: 0.5 g of the hydrochloride salt of compound (I) was added to 10 mL of 20% acetonitrile / aqueous solution, stirred at room temperature for 3 hours, filtered, and the cake was collected. The product was dried under reduced pressure at 50°C for 4 hours to obtain the product, and the XRPD was measured to determine that it was of crystalline form I.

[0177] Method 7: 1 g of the hydrochloride salt of compound (I) was added to 15 mL of methanol, the temperature was raised to 60°C, and the mixture was stirred to clarify it. 30 mL of water was added, and the mixture was allowed to crystallize for 30 minutes at room temperature. The mixture was filtered, and the cake was dried under reduced pressure at 60°C for 3 hours to obtain the product. The XRPD was measured and it was found to be crystal form I.

[0178] The hydrochloride salt of the compound of formula (I) used in methods 5 to 7 was of crystalline form A.

[0179] Example 3: Method for producing the crystalline form of hydrochloride salt The method for producing crystalline form A is as follows: 100 g of compound (I) was mixed with 1300 mL of anhydrous methanol and 160 mL of 6 mol / L hydrochloric acid, stirred to dissolve, 10 g of activated carbon was added, decolorized for 10 minutes, filtered, and the filtrate was collected. The liquid was concentrated to a weight of approximately 380 g, the temperature of the liquid was raised to clarify it, and it was allowed to cool naturally to crystallize. Crystallization was carried out at 0°C, filtered, and the cake was dried under reduced pressure at 50°C for more than 4 hours to obtain the product. The XRPD was measured and confirmed to be crystalline form A, with a water content of 5.8%. The XRPD pattern, DSC curve, and TGA curve are shown in Figures 3, 4, and 5, respectively. The hydrochloric acid content of the product was 7.7%.

[0180] The method for producing crystal form B is as follows: Crystal form A was left to stand at 60±2°C for 30 days to obtain the product. The XRPD was measured and confirmed to be crystal form B, with a water content of 4.6%. The XRPD pattern is shown in Figure 6.

[0181] The method for producing crystalline form C is as follows: Crystalline form A was left to stand at room temperature and a relative humidity of 92.5±5% for 30 days to obtain the product. The XRPD was measured and confirmed to be crystalline form C, with a water content of 11.9%. The XRPD pattern is shown in Figure 7.

[0182] Example 4: Method for producing crystalline sulfate 12 g of compound (I) was mixed with 100 mL of methanol and dispersed uniformly. 2.2 mL of a 3 mol / L sulfuric acid:methanol solution was added, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, the cake was collected, and the product was dried under reduced pressure at 50°C for at least 4 hours to obtain the product. The XRPD was measured and determined to be of crystal form D. The XRPD pattern, DSC curve, and TGA curve are shown in Figures 8, 9, and 10, respectively. The sulfuric acid content of the product was 18.3%.

[0183] Example 5: Method for producing crystalline phosphate Method 1: 0.4 g of compound (I) was added to 4 mL of acetonitrile, and 0.22 g of 85% phosphoric acid was added at room temperature. The mixture was heated to 70°C and stirred for 30 minutes. After natural cooling to room temperature, the mixture was filtered, and the cake was dried under reduced pressure at 50°C for 4 hours to obtain the product. The XRPD was measured and the crystal form was E.

[0184] Method 2: 3.5 g of compound (I) was added to 35 mL of acetonitrile, the temperature was raised to 70°C, 4.5 g of 85% phosphoric acid was added, the mixture was kept warm and stirred for 2 hours, then cooled to room temperature and filtered. The cake was collected and dried under reduced pressure at 60°C for 6 hours to obtain the product. The XRPD was measured and determined to be crystal form E. The XRPD pattern, DSC curve, and TGA curve are shown in Figures 11, 12, and 13, respectively.

[0185] Example 6: Method for Producing Crystal Form of Mesylate Salt 17.5 g of acetonitrile was added to 3.5 g of the compound of formula (I), the temperature was raised to 70 °C, 1.89 g of methanesulfonic acid was added, the mixture was kept warm and stirred for 30 minutes, slowly cooled to room temperature, stirred in an ice bath for 2 hours, filtered, the cake was collected, and dried under reduced pressure at 60 °C for 6.5 hours to obtain a product. XRPD was measured and it was found to be Crystal Form F. The XRPD pattern, DSC curve, and TGA curve are as shown in Figures 14, 15, and 16 respectively. The methanesulfonic acid content of the product was 17.9%.

[0186] Experimental Example 1: Study on Stability under Influencing Factors To evaluate the stability of the solid of the crystal form of the present application, the stability of Crystal Form I, Crystal Form A, Crystal Form D, Crystal Form E, and Crystal Form F under influencing factors (high temperature, high humidity, light) was examined respectively. The above crystal forms were each allowed to stand at high temperature (60 °C ± 2 °C, open (weighing bottle)), high humidity (room temperature, 92.5% RH ± 5%, open (weighing bottle), with package) for 5 days, 10 days, 30 days, and under ICH light irradiation conditions (5500 Lux, 0.9 W / m 2 ², closed (weighing bottle), with package) for 5 days, 10 days. The inner packaging material of the packaged sample was a pharmaceutical low-density polyethylene bag, and the outer packaging material was a polyester:aluminum:polyethylene pharmaceutical composite bag. By determining the properties, purity (HPLC), crystal form (XRD), and moisture of the sample after standing, changes in the crystal form and purity were detected. The results are shown in Tables 8 to 12 (where " # " represents the ICH conditions).

Table 8

Table 9

Table 10

Table 11

Table 12

[0187] Experimental conclusion: The crystal form of this application has high stability and is likely to become a drug.

[0188] Experimental Example 2: Research on the stability of Crystal Form I 1. Research on stability under influencing factors To evaluate the solid stability of Crystal Form I of this application, the stability under influencing factors (high temperature, high humidity, light) was examined. Crystal Form I was left standing at high temperature (40°C, open (weighing bottle)), high temperature (60°C, open (weighing bottle)), high humidity (room temperature, 75% RH, open (weighing bottle)), high humidity (room temperature, 92.5% RH, open (weighing bottle), with package) for 5 days, 10 days, 30 days respectively, and left standing under ICH light irradiation conditions (5500 Lux, 0.9 W / m 2 , open (weighing bottle), with package) for 5 days and 10 days. The inner packaging material of the packaged sample was two layers of pharmaceutical low-density polyethylene bags, and the outer packaging material was a polyester: aluminum: polyethylene composite bag for pharmaceutical packaging. By measuring the properties, target substance (HPLC), crystal form (XRD), moisture, and content of the sample after standing, the influence of high temperature, high humidity, and light conditions on this product was examined. The results are shown in Table 13 (「 # 」represents the ICH conditions).

Table 13

[0189] 2. Research on stability under accelerated conditions and long-term stability The stability of crystal form I of this application was investigated under accelerated and long-term conditions. Samples were allowed to stand for 1, 2, 3, and 6 months under accelerated conditions (40±2℃, 75%RH±5%, packaged) and for 3, 6, 9, 12, 18, 24, and 36 months under long-term conditions (25±2℃, 65%RH±5%, packaged). The inner packaging material of the packaged samples was a two-layer pharmaceutical low-density polyethylene bag, and the outer packaging material was a polyester:aluminum:polyethylene pharmaceutical packaging composite bag. The stability of this product was investigated by measuring the properties, target substance (HPLC), crystal form (XRD), moisture content, and content of the samples after standing. [Table 14]

[0190] Experimental conclusion: Crystal form I of the present invention is highly stable and readily converts to drug form.

[0191] Experimental Example 3: Biological Activity Test 1. In vitro enzyme BRD4 (BD2) activity measurement In this application, we express the inhibition of the compound of formula (I) against the BRD4 (BD2) enzyme binding reaction by homogeneous time-resolved fluorescence (HTRF) spectroscopy. 50The values ​​were measured. Compound (I) was gradient diluted fivefold from 1 mM to 100% DMSO (seven concentrations in total). For each concentration, 2 μL of compound (I) was added to 18 μL of reaction buffer (pH 7.5, 20 mM HEPES, 150 mM NaCl, 5 mM DTT, 0.005% polysorbate 20, 100 μg / mL BSA) for dilution, and after homogeneous mixing, 2 μL of compound (I) was added to 48 μL of the reaction buffer for each concentration for further dilution and homogeneous mixing (the final concentration of DMSO in compound (I) was 0.1%). 2.5 μL was set aside and added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer). Then, 5 μL of GST-BRD4 (BD2, 349-460aa) (final concentration 2 nM) was added, and the mixture was centrifuged to ensure homogeneity. A further 2.5 μL of biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV peptide (final concentration 200 nM) was added to initiate the reaction (total reaction volume 10 μL). The 384-well plate was placed in an incubator and reacted at 23°C for 1 hour, after which 5 μL of Eu was added. 3+ The reaction was stopped by adding cryptotate-labeled anti-GST antibody (purchased from Cisbio) and 5 μL of streptavidin-XL-665 (purchased from Cisbio). After incubation again for 1 hour in an incubator, fluorescence values ​​were read using Envision (purchased from PerkinElmer) (excitation at 320 nm, emission at 665 nm and 620 nm was detected, and the ratio of the two was the enzyme binding signal). The binding strength of compound (I) and BRD4 (BD2) protein was measured at seven different concentrations, and the IC of compound (I) was calculated from the data using GraphPad Prism. 50 The value was calculated.

[0192] 2. In vitro enzyme BRD4 (BD1) activity measurement In this application, we express the inhibition of the compound of formula (I) against the BRD4 (BD1) enzyme binding reaction by homogeneous time-resolved fluorescence (HTRF) spectroscopy. 50 The values ​​were measured. Compound (I) was gradient diluted fivefold from 0.2 mM to 100% DMSO (seven concentrations in total). For each concentration, 2 μL of compound (I) was added to 48 μL of reaction buffer (pH 7.5, 20 mM HEPES, 150 mM NaCl, 5 mM DTT, 0.005% polysorbate 20, 100 μg / mL BSA) and mixed homogeneously. 2.5 μL was set aside and added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer). Then, 5 μL of GST-BRD4 (BD1, 44-168aa) (final concentration 1 nM) was added, and the mixture was centrifuged to ensure homogeneity. A further 2.5 μL of biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV) short peptide (final concentration 100 nM) was added to initiate the reaction (total reaction volume 10 μL). The 384-well plate was placed in an incubator and reacted at 23°C for 1 hour. After that, 5 μL of Eu was added. 3+ The reaction was stopped by adding cryptotate-labeled anti-GST antibody (purchased from Cisbio) and 5 μL of streptavidin-XL-665 (purchased from Cisbio). After incubation again for 1 hour in an incubator, fluorescence values ​​were read using Envision (purchased from PerkinElmer) (excitation at 320 nm, emission at 665 nm and 620 nm was detected, and the ratio of the two was the enzyme binding signal). The binding strength of compound (I) and BRD4 (BD1) protein was measured at seven different concentrations, and the IC of compound (I) was calculated from the data using GraphPad Prism. 50 The value was calculated.

[0193] The results of the above measurements are shown in Table 15. [Table 15]

[0194] 3. Measurement of MV4-11 cell proliferation activity Human acute lymphoblastic leukemia cell line MV4-11 was cultured in PRIM1640 medium, 10% fetal bovine serum (FBS, purchased from Biological Industries (BI)), and 1% penicillin / streptomycin (P / S, purchased from Life Technologies) under culture conditions of 37°C and 5% CO2. The day before measuring compound (I), MV4-11 cells were plated into 96-well plates (purchased from Corning) at a concentration of 8000 cells / 195 μL / well. After 24 hours, compound (I) was gradient diluted fourfold from 10 mM with 100% DMSO (a total of nine concentrations), and then each concentration was diluted by adding 2 μL of compound (I) to 48 μL of PRIM1640 medium. 5 μL of each diluted concentration of compound (I) was plated and added to the cell suspension. Compound (I) and cells were incubated in a cell incubator for 72 hours (3 days), after which 35 μL of Cell-Titer Blue (purchased from Promega) was added and incubated for a further 4 hours. Subsequently, fluorescence values ​​were read using Flexstation III (excited at 560 nm and detected at 590 nm), and ICs representing the inhibition of compound (I) by cell proliferation were analyzed using GraphPad Prism. 50 The value was calculated.

[0195] 4. Measurement of Kasumi-1 cell proliferation activity Human acute myeloblastic leukemia cell line Kasumi-1 cells were cultured in PRIM1640 medium, 20% fetal bovine serum (FBS, purchased from Biological Industries (BI)), and 1% penicillin / streptomycin (P / S, purchased from Life Technologies) under culture conditions of 37°C and 5% CO2. The day before measuring compound (I), Kasumi-1 cells were plated into 96-well plates (purchased from Corning) at a concentration of 5000 cells / 195 μL / well. After 24 hours, compound (I) was gradient diluted fourfold from 10 mM with 100% DMSO (a total of nine concentrations), and then each concentration was diluted by adding 2 μL of compound (I) to 48 μL of PRIM1640 medium. 5 μL of each diluted concentration of compound (I) was plated and added to the cell suspension. Compound (I) and cells were incubated in a cell incubator for 72 hours (3 days), after which 35 μL of Cell-Titer Blue (purchased from Promega) was added and incubated for a further 4 hours. Subsequently, fluorescence values ​​were read using Flexstation III (excited at 560 nm and detected at 590 nm), and ICs representing the inhibition of compound (I) by cell proliferation were analyzed using GraphPad Prism. 50 The values ​​were calculated. The results of the above measurements are shown in Table 16. [Table 16]

[0196] 5. Animal pharmacokinetic studies In the animal pharmacokinetic experiment, three healthy adult male rats provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. were used. The compound of formula (I) was suspended in 2% absolute ethanol, 5% polysorbate 80, 20% polyethylene glycol 400, 73% (5% hydroxypropyl methylcellulose in water) (V:V:V:V) at a concentration of 1 mg / mL, and the administration volume was 5 mL / kg. It was administered by single-dose forced oral administration at a dose of 5 mg / kg. Before the experiment, the animals were fasted overnight, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The animals were lightly anesthetized with isoflurane, and about 0.4 mL of whole blood was collected from the orbital venous plexus with a glass blood collection tube and placed in a heparin anticoagulation tube. The sample was centrifuged at 4200 rpm for 5 minutes at 4°C, and the plasma was transferred to a centrifuge tube and stored at -80°C for analysis. The analysis of plasma samples was performed by acetonitrile protein precipitation method to extract the test compound and internal standard substance (warfarin or propranolol) from rat plasma, and the extract was analyzed by LC / MS / MS method. The measured plasma concentration-time data of the animal individuals were analyzed by the non-compartmental model of WinNonlin (version 5.2.1, Pharsight), and the following maximum (peak) plasma drug concentration C max , time to reach the highest blood concentration T max , half-life T 1 / 2 , area under the plasma concentration-time curve up to infinite time AUC 0~inf were obtained.

Table 17

[0197] It was found that the compound of formula (I) had good activity and good pharmacokinetic properties.

[0198] Experimental Example 4: Measurement of Particle Size Distribution Crystal form I was ground by jet milling, and then the particle size distribution was measured according to the third method (light scattering method) of particle size and particle size distribution measurement in the Chinese Pharmacopoeia 2020 Edition, General Rules for Four Parts 0982. The details are as follows: A 10 mg sample was weighed and measured using a laser diffraction / scattering particle size distribution analyzer (trigger conditions: 10 seconds, 1%, dispersion pressure: 2.0 bar). The measurement results are shown in Table 18. [Table 18] Several embodiments are shown below. Item 1 A crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, [ka] Crystal form I of compound (I) having characteristic diffraction peaks at 2θ angles of 12.4°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.4°±0.2°, and 24.7°±0.2° in its X-ray powder diffraction pattern, Crystalline form A of the hydrochloride salt of compound (I) having characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2° in its X-ray powder diffraction pattern, Crystalline form B of the hydrochloride salt of compound (I) having characteristic diffraction peaks at 2θ angles of 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, and 17.4°±0.2° in its X-ray powder diffraction pattern, The crystalline form C of the hydrochloride salt of compound (I) has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 20.5°±0.2°, and 24.6°±0.2° in its X-ray powder diffraction pattern, The crystalline form D of the sulfate of compound (I) has characteristic diffraction peaks at 2θ angles of 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, and 24.1°±0.2° in its X-ray powder diffraction pattern. The crystalline form E of the phosphate of compound (I) has characteristic diffraction peaks at 2θ angles of 10.1°±0.2°, 10.5°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 22.7°±0.2°, and 24.0°±0.2° in its X-ray powder diffraction pattern. The crystal form F of the mesylate of compound (I) has characteristic diffraction peaks at 2θ angles of 8.8°±0.2°, 10.1°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2° in its X-ray powder diffraction pattern. The aforementioned crystal form selected from the above. Section 2 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 6.6°±0.2°, 9.3°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, and 24.7°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 6.6°±0.2°, 9.3°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 21.5°±0.2°, 22.5°±0.2°, 23.6°±0.2°, 24.7°±0.2°, and 25.2°±0.2°. More typically, [Table 19] Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 1. The crystalline form I of the compound of formula (I) described in item 1, or the crystalline form of a pharmaceutically acceptable salt thereof. Section 3 The crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in item 1, wherein the crystalline form is the crystalline form of the hydrochloride salt of the compound of formula (I), preferably the crystalline form is a hydrate, more preferably the hydrate is selected from hemihydrate, monohydrate, dihydrate, trihydrate, and tetrahydrate, even more preferably the hydrate is selected from monohydrate, dihydrate, and tetrahydrate, and most preferably the hydrate is selected from monohydrate and tetrahydrate. Section 4 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 20.5°±0.2°, and 24.7°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 19.2°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 23.3°±0.2°, and 24.7°±0.2°. More typically, Table 20 Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 3. The crystalline form A of the hydrochloride salt of the compound of formula (I) as described in item 3, or a pharmaceutically acceptable crystalline form of its salt. Section 5 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 21.0°±0.2°, and 22.2°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 22.2°±0.2°, and 24.6°±0.2°. More typically, Table 21 Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 6. The crystalline form B of the hydrochloride salt of the compound of formula (I) as described in item 3, or a pharmaceutically acceptable crystalline form of its salt. Section 6 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 17.5°±0.2°, 20.5°±0.2°, 23.3°±0.2°, and 24.6°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 6.8°±0.2°, 9.5°±0.2°, 11.9°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 15.8°±0.2°, 17.5°±0.2°, 20.5°±0.2°, 23.3°±0.2°, 24.6°±0.2°, and 28.7°±0.2°. More typically, Table 22 Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 7. The crystalline form C of the hydrochloride salt of the compound of formula (I) as described in item 3, or a pharmaceutically acceptable crystalline form of its salt. Section 7 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 7.1°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, and 24.1°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 7.1°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.5°±0.2°, 14.7°±0.2°, 16.3°±0.2°, 18.6°±0.2°, 19.7°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.0°±0.2°, 24.1°±0.2°, and 26.2°±0.2°. More typically, Table 23 Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 8. The crystalline form D of the sulfate of the compound of formula (I) described in item 1, or a pharmaceutically acceptable crystalline form of its salt. Section 8 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 9.0°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.7°±0.2°, and 24.0°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 5.2°±0.2°, 9.0°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 15.5°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, and 24.0°±0.2°. More typically, Table 24 Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 11. The crystalline form E of the phosphate of the compound of formula (I) described in item 1, or a pharmaceutically acceptable crystalline form thereof. Section 9 The X-ray powder diffraction pattern is Characteristic diffraction peaks are found at 2θ angles of 8.8°±0.2°, 10.1°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 24.8°±0.2°, and 26.6°±0.2°. Typically, characteristic diffraction peaks are found at 2θ angles of 8.8°±0.2°, 10.1°±0.2°, 13.1°±0.2°, 14.3°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 20.2°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 26.0°±0.2°, and 26.6°±0.2°. More typically, Table 25 Having the above XRPD pattern analysis data, Most typically, the XRPD pattern has the characteristics represented by the XRPD pattern in Figure 14. Crystalline form F of the mesylate of the compound of formula (I) as described in item 1, or a pharmaceutically acceptable salt thereof. Item 10 A pharmaceutically acceptable salt of the compound of formula (I),

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Claims

1. A crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 The crystalline form of compound (I) having characteristic diffraction peaks at 2θ angles of 12.4°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.4°±0.2°, and 24.7°±0.2° in its X-ray powder diffraction pattern, The crystalline form of the hydrochloride salt of compound (I) having characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2° in its X-ray powder diffraction pattern, The crystalline form of the hydrochloride salt of compound (I) having characteristic diffraction peaks at 2θ angles of 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, and 17.4°±0.2° in its X-ray powder diffraction pattern, The crystalline form of the hydrochloride salt of compound (I) having characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 20.5°±0.2°, and 24.6°±0.2° in its X-ray powder diffraction pattern, The crystalline form of the sulfate of compound (I) whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, and 24.1°±0.2°, The crystalline form of the phosphate of compound (I) having characteristic diffraction peaks at 2θ angles of 10.1°±0.2°, 10.5°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 22.7°±0.2°, and 24.0°±0.2° in its X-ray powder diffraction pattern, The crystal form is selected from the crystal forms of the mesylate salt of the compound of formula (I) having characteristic diffraction peaks at 2θ angles of 8.8°±0.2°, 10.1°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2° in its X-ray powder diffraction pattern.

2. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.6°±0.2°, 9.3°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, and 24.7°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 6.6°±0.2°, 9.3°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 21.5°±0.2°, 22.5°±0.2°, 23.6°±0.2°, 24.7°±0.2°, and 25.2°±0.2°. Or, Table 1 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the XRPD pattern is the crystalline form of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 1 below.

3. The crystalline form is the crystalline form of the hydrochloride salt of the compound of formula (I), or the crystalline form of the hydrochloride salt of the compound of formula (I), and the crystalline form is a hydrate, according to claim 1, or a crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

4. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 20.5°±0.2°, and 24.7°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 19.2°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 23.3°±0.2°, and 24.7°±0.2°. Or, Table 2 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein the XRPD pattern is the crystalline form of the hydrochloride salt of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 3 below.

5. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 21.0°±0.2°, and 22.2°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 22.2°±0.2°, and 24.6°±0.2°. Or, Table 3 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein the XRPD pattern is the crystalline form of the hydrochloride salt of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 6 below.

6. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 17.5°±0.2°, 20.5°±0.2°, 23.3°±0.2°, and 24.6°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 9.5°±0.2°, 11.9°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 15.8°±0.2°, 17.5°±0.2°, 20.5°±0.2°, 23.3°±0.2°, 24.6°±0.2°, and 28.7°±0.2°. Or, Table 4 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein the XRPD pattern is the crystalline form of the hydrochloride salt of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 7 below.

7. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 7.1°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, and 24.1°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 7.1°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.5°±0.2°, 14.7°±0.2°, 16.3°±0.2°, 18.6°±0.2°, 19.7°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.0°±0.2°, 24.1°±0.2°, and 26.2°±0.2°. Or, Table 5 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the XRPD pattern is the crystalline form of the sulfate of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 8 below.

8. The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 9.0°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.7°±0.2°, and 24.0°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 5.2°±0.2°, 9.0°±0.2°, 10.1°±0.2°, 10.5°±0.2°, 15.5°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 20.2°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, and 24.0°±0.2°. Or, Table 6 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the XRPD pattern is the crystalline form of the phosphate of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 11 below.

9. The X-ray powder diffraction pattern exhibits characteristic diffraction peaks at 2θ angles of 8.8°±0.2°, 10.1°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 24.8°±0.2°, and 26.6°±0.2°. Alternatively, it has characteristic diffraction peaks at 2θ angles of 8.8°±0.2°, 10.1°±0.2°, 13.1°±0.2°, 14.3°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 20.2°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 26.0°±0.2°, and 26.6°±0.2°. Or, Table 7 Having the above XRPD pattern analysis data, Alternatively, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the XRPD pattern is the crystalline form of the mesylate salt of the compound of formula (I) having the characteristics represented by the XRPD pattern in Figure 14 below.

10. A pharmaceutically acceptable salt of the compound of formula (I), 【Chemistry 2】 A pharmaceutically acceptable salt of formula (I), wherein the pharmaceutically acceptable salt is selected from the hydrochloride salt of formula (I), the sulfate salt of formula (I), the phosphate salt of formula (I), and the mesylate salt of formula (I).

11. The hydrochloride salt is a salt formed by the compound of formula (I) and hydrochloric acid in a molar ratio of 1:

1. Alternatively, the sulfate is represented by formula (II), where x is selected from 0.5 to 1. 【Transformation 3】 Alternatively, the phosphate is represented by formula (III), where x is selected from 0.5 to 1. 【Chemistry 4】 Alternatively, the pharmaceutically acceptable salt according to claim 10, wherein the mesylate is represented by formula (IV), where x is selected from 0.5 to 1. 【Transformation 5】

12. A crystalline composition comprising the crystalline form described in any one of claims 1 to 9, wherein the crystalline form accounts for 50% or more, 80% or more, 90% or more, or 95% or more of the weight of the crystalline composition.

13. A pharmaceutical composition comprising, in a therapeutically effective amount, an active ingredient selected from the group consisting of the crystalline form described in any one of claims 1 to 9, the pharmaceutically acceptable salt described in any one of claims 10 to 11, and the crystalline composition described in claim 12.

14. Use of the crystalline form according to any one of claims 1 to 9, or the pharmaceutically acceptable salt according to any one of claims 10 to 11, the crystalline composition according to claim 12, or the pharmaceutical composition according to claim 13 in the manufacture of a therapeutic agent for BET protein-mediated diseases.

15. The use according to claim 14, characterized in that the BET protein-mediated disease is selected from cancer.

16. The use according to claim 15, characterized in that the cancer is selected from solid tumors and hematological malignancies.

17. The use according to claim 16, characterized in that the solid tumor is selected from breast cancer and prostate cancer, or the hematological malignancy is selected from acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma.

18. (1) A step of mixing the compound of formula (I) with solvent I, wherein optionally a step of mixing the mixture from step (1) with solvent II, (2) The step of filtering and drying, A method for producing the crystalline form of the compound of formula (I) according to claim 1, wherein solvent I and solvent II are one or more mixed solvents selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, and dichloromethane, or one or more mixed solvents selected from water, acetonitrile, methanol, dimethyl sulfoxide, and dichloromethane, or selected from water and dimethyl sulfoxide, or a mixed solvent of dichloromethane and methanol.

19. (1) A step of mixing the hydrochloride salt of the compound of formula (I) with solvent III, wherein optionally a step of mixing the mixture from step (1) with solvent IV, (2) The step of filtering and drying, The solvent III and solvent IV are each independently selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, and acetone, or selected from water, acetonitrile, methanol, ethanol, and isopropanol, or selected from water, acetonitrile, and methanol. A method for producing the crystalline form of the compound of formula (I) according to claim 1, wherein the hydrochloride salt of the compound of formula (I) is selected from the crystalline forms of the hydrochloride salt of the compound of formula (I) described in claim 1, or the hydrochloride salt of the compound of formula (I) is selected from the crystalline forms of the hydrochloride salt of the compound of formula (I), and the X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2°.

20. A method for producing a pharmaceutically acceptable crystalline form of the compound of formula (I) described in claim 1, (1) A step of mixing the compound of formula (I) with solvent A, (2) Adding hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid to the mixture from step (1), (3) The step of filtering and drying, The solvent A is a mixed solvent of one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, or selected from methanol, ethanol, isopropanol, ethyl acetate, and acetonitrile, or selected from methanol and acetonitrile. The crystalline form is selected from the crystalline forms of hydrochloride salts described in claim 1, and the X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2°. Alternatively, the crystalline form is the crystalline form of the sulfate described in claim 1. Alternatively, the crystalline form is the crystalline form of the phosphate according to claim 1. Alternatively, the method wherein the crystalline form is the crystalline form of the mesylate described in claim 1.

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