Crystal form, salt form and preparation method of bromodomain protein inhibitor

Abstract

A crystal form and a salt form of a bromodomain protein inhibitor represented by formula (I) and a preparation method thereof, and use of the crystal form and the salt form in preparing a drug for treating diseases mediated by BET proteins.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority and benefits of Chinese Patent Application No. 202010057297.0 filed with the State Intellectual Property Office of China on January 19, 2020, and Chinese Patent Application No. 202010060110.2 filed with the State Intellectual Property Office of China on January 19, 2020, and the contents disclosed in the said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to a crystalline form of a bromodomain protein inhibitor, a preparation method thereof, a crystalline composition containing the crystalline form, a pharmaceutical composition containing the crystalline form or its crystalline composition, and their uses. The present application also relates to the hydrochloride, sulfate, phosphate, and methanesulfonate of the above-mentioned bromodomain protein inhibitor, as well as their crystalline forms, preparation methods, pharmaceutical compositions containing the above-mentioned salts, and their uses. Background Art

[0004] Epigenetic regulation of transcribed genes plays an important role in the development of diseases such as tumors, inflammation and metabolism. Acetylation of the N-terminal residues of nucleosomal histone lysine is particularly important for the regulation of genetic epigenetics. Histone acetylation is usually most related to the activation of gene transcription, and the recognition of histone lysine acetylation is a key step in the involvement of histone acetylation in epigenetic regulation. Bromodomains (BRDs) are a class of conserved protein domains that can specifically recognize acetylated lysine (KAc) in histones. By binding to acetylated lysine, they promote the enrichment of related proteins such as chromatin remodeling factors and transcription factors at specific gene transcription sites, change the activity of RNA II polymerase, and thus synergistically complete gene expression regulation.

[0005] BET (Bromodomain and Extra Terminal) proteins include two interrelated bromodomain centers and an extra-terminal domain. According to different amino acid sequences, they are divided into four proteins: Brd2, Brd3, Brd4 and BrdT. Among them, Brd2-Brd4 are widely distributed in various organs of the human body. BET is a type of transcriptional regulatory protein that plays a very important role in regulating gene expression through interaction with chromatin. BET proteins have a bidirectional regulatory function of co-activation or co-inhibition for the intracellular reticular signal transduction pathway, such as insulin transcription, adipogenesis in lipid tissue, differentiation of the hematopoietic system, etc. Studies in recent years have shown that drugs targeting BET proteins can be used to treat cancer, inflammation, kidney disease, autoimmune diseases and anti-male fertility. Therefore, BET proteins have increasingly become one of the important targets in the field of epigenetics, attracting great attention from major pharmaceutical companies and scientific research institutions. Summary of the invention

[0006] In one aspect, the present application provides a crystalline form of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein, the crystal form is selected from:

[0009] The crystalline form I of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 12.4°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 20.4°±0.2°, 24.7°±0.2°;

[0010] The crystalline form A of the hydrochloride salt of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles: 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 16.8°±0.2°;

[0011] The crystalline form B of the hydrochloride salt of the compound of formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles: 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°;

[0012] The crystalline form C of the hydrochloride salt of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 20.5°±0.2°, 24.6°±0.2°;

[0013] The crystalline form D of the sulfate salt of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, 24.1°±0.2°;

[0014] The crystalline form E of the phosphate of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.1°±0.2°, 10.5°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 22.7°±0.2°, 24.0°±0.2°; or

[0015] The crystalline form F of the mesylate salt of the compound of formula (I) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 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°.

[0016] On the other hand, the present application provides a crystalline form I of a compound of formula (I):

[0017]

[0018] The crystal form I is characterized in that it has characteristic diffraction peaks of 2θ=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 the X-ray powder diffraction (XRPD) spectrum.

[0019] In some embodiments, the crystalline Form I has characteristic diffraction peaks of 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°, and 24.7°±0.2° in the X-ray powder diffraction (XRPD) pattern.

[0020] In some embodiments, the crystalline Form I has characteristic diffraction peaks of 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°, and 25.2°±0.2° in the X-ray powder diffraction (XRPD) pattern.

[0021] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of the crystalline form I, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 1:

[0022] Table 1: Characteristic peak positions and relative intensities of X-ray powder diffraction patterns of Form I

[0023] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 6.6 20.0 12 21.5 20.9 2 9.3 16.2 13 21.8 8.1 3 12.4 63.4 14 22.5 21.8 4 14.5 100.0 15 23.3 8.0 5 14.7 27.5 16 23.7 26.4 6 15.2 10.2 17 24.7 36.7 7 16.6 21.1 18 25.2 26.9 8 17.4 32.4 19 26.9 11.1 9 18.5 99.2 20 29.3 15.5 10 20.0 25.3 21 29.7 14.8 11 20.4 45.0 22 30.3 12.5 .

[0024] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form I has the following Figure 1 The XRPD pattern shown represents the features.

[0025] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the crystalline form I has the following Figure 2 The DSC spectra shown represent the characteristics.

[0026] In some embodiments, the DSC spectrum of the crystalline form I has an endothermic peak at 275°C±3°C.

[0027] In some embodiments, the crystalline form I is prepared in a mixed solvent selected from one or more of water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, and dichloromethane. In some embodiments, the crystalline form I is prepared in a mixed solvent selected from one or more of water, methanol, dimethyl sulfoxide, dichloromethane, and acetonitrile. In some embodiments, the crystalline form I is prepared in dimethyl sulfoxide, methanol, or water. In some embodiments, the crystalline form I is prepared 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.

[0028] In some embodiments, the particle size distribution X of the crystalline form I is 90 In some embodiments, the particle size distribution X of the crystalline form I is 90 In some embodiments, the particle size distribution X of the crystalline form I is 90 In some embodiments, the particle size distribution X of the crystalline form I is 90 In some embodiments, the particle size distribution X of the crystalline form I is 90 In some embodiments, the particle size distribution X of the crystalline form I is 90 Less than 7μm.

[0029] In some embodiments, the particle size distribution X of the crystalline form I is90 The thickness is 3.0 to 14.0 μm, preferably 3.5 to 13.5 μm, more preferably 4.0 to 13.0 μm, further preferably 4.5 to 12.5 μm, and further preferably 5.0 to 12.0 μm.

[0030] In some embodiments, the particle size distribution X of the crystalline form I is 90 It is 3.5 to 8.5 μm, preferably 4.5 to 7.5 μm, and more preferably 5.5 to 6.5 μm.

[0031] In some embodiments, the particle size distribution X of the crystalline form I is 90 It is 9.5 to 13.5 μm, preferably 10.5 to 12.5 μm, and more preferably 11.0 to 12.0 μm.

[0032] In some embodiments, the particle size distribution X of the crystalline form I is 90 It is measured after the crystal form I is subjected to airflow pulverization. In some embodiments, the pulverization pressure of the airflow pulverization is selected from 0.1 MPa to 0.7 MPa, preferably from 0.1 MPa to 0.6 MPa; or the pulverization pressure of the airflow pulverization 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 formed by optionally selecting the above values.

[0033] The present application also provides a method for preparing the crystalline form I of the compound of formula (I), comprising:

[0034] (1) mixing the compound of formula (I) with solvent I;

[0035] (2) filtration and drying;

[0036] Wherein, the solvent I is preferably selected from one or more mixed solvents of water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide, and dichloromethane, preferably a mixed solvent of one or more mixed solvents of water, acetonitrile, methanol, dimethyl sulfoxide, and dichloromethane, more preferably water or dimethyl sulfoxide, and further preferably a mixed solvent of dichloromethane and methanol.

[0037] In some embodiments, the method for preparing the crystalline form I of the compound of formula (I) above comprises:

[0038] (1) mixing the compound of formula (I) with solvent I;

[0039] (2) mixing the mixture of step (1) with solvent II;

[0040] (3) filtration and drying;

[0041] Wherein, the solvent I and solvent II are each independently selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, acetone, dimethyl sulfoxide or dichloromethane, preferably water, acetonitrile, methanol, dimethyl sulfoxide or dichloromethane, more preferably water, methanol or dimethyl sulfoxide, further preferably dichloromethane and methanol.

[0042] In some embodiments, in step (2), the mixture of step (1) and solvent II are mixed in a manner including but not limited to: a. adding the mixture of step (1) to solvent II; b. adding solvent II to the mixture of step (1). In some embodiments, the above-mentioned adding manner is preferably dropwise addition.

[0043] In some embodiments, the above step (2) is to add the mixture of step (1) dropwise 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.

[0044] The present application also provides a method for preparing the crystalline form I of the compound of formula (I), comprising:

[0045] (1) mixing a pharmaceutically acceptable salt of a compound of formula (I) with a solvent III;

[0046] (2) filtration and drying;

[0047] Among them, the solvent III is preferably selected from one or more mixed solvents of water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, and acetone, preferably one or more mixed solvents of water, acetonitrile, and methanol, more preferably water, acetonitrile / water mixed solvent, or methanol / water mixed solvent.

[0048] In some embodiments, in step (1), after the pharmaceutically acceptable salt of the compound of formula (I) is mixed with solvent III, it is stirred for a period of time, preferably 3 h to 4 h. In some embodiments, the stirring is performed at room temperature.

[0049] In some embodiments, the method for preparing the crystalline form I of the compound of formula (I) above comprises:

[0050] (1) mixing a pharmaceutically acceptable salt of a compound of formula (I) with a solvent III;

[0051] (2) mixing the mixture of step (1) with solvent IV;

[0052] (3) filtration and drying;

[0053] Wherein, the solvent III and solvent IV are each independently selected from water, acetonitrile, methanol, ethanol, isopropanol, ethyl acetate or acetone, preferably from water, acetonitrile, methanol, ethanol or isopropanol, more preferably from water, acetonitrile or methanol.

[0054] In some embodiments, in step (2), the mixture of step (1) and solvent IV are mixed in a manner including but not limited to: a. adding the mixture of step (1) to solvent IV; b. adding solvent IV to the mixture of step (1). In some embodiments, the above-mentioned adding manner is preferably dropwise addition.

[0055] In some embodiments, in step (2), the mixture of step (1) is mixed with solvent IV and then crystallized. In some embodiments, the crystallization is performed at room temperature.

[0056] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride of the compound of formula (I). In some embodiments, the hydrochloride of the compound of formula (I) is selected from Form A, Form B, or Form C, preferably Form A.

[0057] The present application also provides a pharmaceutically acceptable salt (salt form) of the compound of formula (I), wherein the pharmaceutically acceptable salt is selected from the hydrochloride of the compound of formula (I), the sulfate of the compound of formula (I), the phosphate of the compound of formula (I) or the methanesulfonate of the compound of formula (I).

[0058] In another aspect, the present application provides the hydrochloride salt of the compound represented by formula (I):

[0059]

[0060] The present application also provides a crystalline form of the hydrochloride salt of the compound of formula (I), a preparation method thereof, and a corresponding crystalline composition.

[0061] In some embodiments, the hydrochloride salt of the compound represented by formula (I) is a salt formed by the compound represented by formula (I) and hydrochloric acid in a molar ratio of 1:1.

[0062] In some embodiments, the hydrochloric acid content in the hydrochloride of the compound of formula (I) is 5-10wt%, preferably 6-9wt%, 6-8wt%; or the hydrochloric acid content in the hydrochloride of the compound of formula (I) is selected from 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 a range formed by optionally selecting the above values.

[0063] In some embodiments, the crystalline form of the hydrochloride salt of the compound of formula (I) is a hydrate, and the hydrate is selected from hemihydrate, monohydrate, dihydrate, trihydrate and tetrahydrate, preferably monohydrate, dihydrate and tetrahydrate, and more preferably monohydrate and tetrahydrate.

[0064] In some embodiments, the crystalline form of the hydrochloride salt of the compound of formula (I) is a monohydrate.

[0065] In some embodiments, the crystalline form of the hydrochloride salt of the compound of formula (I) is a tetrahydrate.

[0066] The present application provides a crystalline form A of the hydrochloride salt of the compound of formula (I), characterized in that it has diffraction peaks of 2θ=6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, and 16.8°±0.2° in the X-ray powder diffraction (XRPD) spectrum.

[0067] In some embodiments, the crystalline form A is characterized in that it has diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0068] In some embodiments, the crystalline Form A is characterized in that it has diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0069] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of the crystalline form A, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 2:

[0070] Table 2: Characteristic peak positions and relative intensities of X-ray powder diffraction patterns of Form A

[0071] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 6.8 45.2 7 19.2 4.8 2 8.4 100.0 8 20.5 10.6 3 9.4 13.6 9 21.7 4.2 4 10.2 21.5 10 23.3 3.5 5 14.4 5.4 11 24.7 7.0 6 16.8 33.5 12 .

[0072] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form A has the following Figure 3 The XRPD pattern shown represents the features.

[0073] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the crystalline form A has the following Figure 4 The DSC spectra shown represent the characteristics.

[0074] In some embodiments, the DSC spectrum of the crystalline form A has an endothermic peak at 149.61°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form A has an endothermic peak at 101.14°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form A has an endothermic peak at 80.15°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form A has an endothermic peak at 62.98°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form A has an endothermic peak 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.

[0075] In this application, % when describing weight loss and moisture content refers to wt %.

[0076] In some embodiments, the thermogravimetric analysis (TGA) spectrum of Form A has the following Figure 5 The TGA spectra shown represent the features.

[0077] In some embodiments, the thermogravimetric analysis curve of the crystalline form A shows a weight loss of 2.37±0.2% at 119.1±3°C.

[0078] In some embodiments, the thermogravimetric analysis curve of the 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.

[0079] In some embodiments, the crystalline form A is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile. In some embodiments, the crystalline form A is prepared in methanol, ethanol, or isopropanol. In some embodiments, the crystalline form A is prepared in methanol.

[0080] The present application also provides a method for preparing the crystalline form A of the hydrochloride salt of the compound of formula (I), comprising the following steps:

[0081] (1) mixing the compound of formula (I) with solvent A;

[0082] (2) adding hydrochloric acid to the mixture of step (1);

[0083] (3) Filter and dry.

[0084] The solvent A is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, ethyl acetate and acetonitrile, preferably methanol, ethanol or isopropanol, more preferably methanol.

[0085] In some embodiments, the moisture content of the 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 moisture content of the crystalline form A is 4.7%. In some embodiments, the moisture content of the crystalline form A is 5.8%. In some embodiments, the moisture content of the crystalline form A is 6.6%. In some embodiments, the moisture content of the crystalline form A is 8.1%.

[0086] The present application provides a crystalline form B of the hydrochloride salt of the compound of formula (I), characterized in that it has diffraction peaks of 2θ=8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, and 17.4°±0.2° in the X-ray powder diffraction (XRPD) spectrum.

[0087] In some embodiments, the crystalline Form B is characterized in that it has diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0088] In some embodiments, the crystalline Form B is characterized in that it has diffraction peaks of 2θ=6.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°4±0.2°, 18.8°4±0.2°, 20.1°4±0.2°, 21.0°4±0.2°, 22.2°4±0.2°, and 24.6°±0.2° in the X-ray powder diffraction (XRPD) pattern.

[0089] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of the crystalline form B, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 3:

[0090] Table 3: Characteristic peak positions and relative intensities of X-ray powder diffraction pattern of Form B

[0091] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 6.8 7.8 7 18.8 10.4 2 8.7 100.0 8 20.1 10.6 3 9.5 14.9 9 21.0 13.9 4 10.5 48.3 10 22.2 13.3 5 14.5 16.6 11 24.6 12.7 6 17.4 35.9 12 .

[0092] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form B has the following Figure 6 The XRPD pattern shown represents the features.

[0093] In some embodiments, the moisture content of the 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 moisture content of the crystalline form B is 3.6%. In some embodiments, the moisture content of the crystalline form B is 4.6%.

[0094] In some embodiments, the crystalline form B is prepared from the crystalline form A at 60±2°C.

[0095] The present application also provides a method for preparing the crystalline form B of the hydrochloride salt of the compound of formula (I), comprising allowing the crystalline form A to stand at 60±2° C. for 30 days.

[0096] The present application provides a crystalline form C of the hydrochloride salt of the compound of formula (I), characterized in that it has diffraction peaks of 2θ=6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 20.5°±0.2°, and 24.6°±0.2° in the X-ray powder diffraction (XRPD) spectrum.

[0097] In some embodiments, the crystalline form C is characterized in that it has diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0098] In some embodiments, the crystalline Form C is characterized in that it has diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0099] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of the crystalline form C, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 4:

[0100] Table 4: Characteristic peak positions and relative intensities of X-ray powder diffraction patterns of Form C

[0101] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 6.8 69.1 9 20.5 46.3 2 9.5 100.0 10 21.7 12.8 3 11.9 14.6 11 23.3 19.9 4 12.9 20.2 12 23.9 9.9 5 14.8 16.7 13 24.6 50.5 6 15.8 15.7 14 26.0 10.2 7 16.5 10.5 15 28.2 12.6 8 17.5 17.2 16 28.7 24.0 .

[0102] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form C has the following Figure 7 The XRPD pattern shown represents the features.

[0103] In some embodiments, the moisture content of the 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 moisture content of the crystalline form C is 11.9%. In some embodiments, the moisture content of the crystalline form C is 12.2%. In some embodiments, the moisture content of the crystalline form C is 13.0%.

[0104] In some embodiments, the crystalline form C is prepared from the crystalline form A at room temperature and a relative humidity of 92.5±5%.

[0105] The present application also provides a method for preparing the crystalline form C of the hydrochloride salt of the compound of formula (I), comprising allowing the crystalline form A to stand at room temperature and a relative humidity of 92.5±5% for 30 days.

[0106] On the other hand, the present application provides a sulfate salt of a compound of formula (I):

[0107]

[0108] In some embodiments, the sulfate salt of the compound of formula (I) is as shown in formula II

[0109] Here, x is selected from 0.5 to 1.

[0110] In some embodiments, the above x is selected from 0.5 or 1.

[0111] In some embodiments, the above x is selected from 1.

[0112] In some embodiments, the sulfuric acid content in the sulfate of the compound of formula (I) is 15-20wt%, preferably 16-19wt%, 17-19wt%; or the sulfuric acid content in the sulfate of the compound of formula (I) is selected from 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%, 17.4wt%, 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 a range formed by any of the above values.

[0113] The present application also provides a crystalline form D of the compound shown in formula II, wherein x is 1, and the crystalline form D is characterized in that it has 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° in the X-ray powder diffraction (XRPD) spectrum.

[0114] In some embodiments, the crystalline form D has characteristic diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0115] In some embodiments, the crystalline form D has characteristic diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0116] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of the crystalline form D, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 5:

[0117] Table 5: Characteristic peak positions and relative intensities of X-ray powder diffraction pattern of Form D

[0118] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 7.1 7.8 14 20.9 10.1 2 8.9 8.7 15 21.2 29.8 3 9.8 28.1 16 21.9 22.5 4 13.2 29.4 17 22.4 13.0 5 13.5 30.4 18 23.0 100.0 6 13.8 12.3 19 24.1 46.2 7 14.7 90.8 20 26.2 31.9 8 16.3 19.7 21 27.5 17.2 9 17.3 12.9 22 27.8 17.1 10 18.0 14.6 23 28.6 10.2 11 18.6 42.9 24 29.7 12.7 12 19.7 25.8 25 33.1 16.1 13 20.1 20.9 .

[0119] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form D has the following Figure 8 The XRPD pattern shown represents the features.

[0120] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the crystalline form D has the following Fig. 9 The DSC spectra shown represent the characteristics.

[0121] In some embodiments, the DSC spectrum of the crystalline form D has an exothermic peak at 262.82°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form D has an exothermic peak at 272.31°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form D has an exothermic peak at 272.31°C ± 3°C, and / or 262.82°C ± 3°C.

[0122] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystalline form D has the following Fig.10 The TGA spectra shown represent the features.

[0123] In some embodiments, the thermogravimetric analysis curve of the crystalline form D shows a weight loss of 40.74±0.2% at 425.0±3°C.

[0124] In some embodiments, the crystalline form D is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, and ethyl acetate. In some embodiments, the crystalline form D is prepared in one or more mixed solvents selected from methanol, ethanol, or isopropanol. In some embodiments, the crystalline form D is prepared in methanol.

[0125] The present application also provides a method for preparing the crystalline form D of the sulfate salt of the compound of formula (I), comprising contacting the compound of formula (I) with sulfuric acid.

[0126] In some embodiments, the preparation method of the above-mentioned crystal form D comprises the following steps:

[0127] (1) mixing the compound of formula (I) with solvent D;

[0128] (2) adding a solution of sulfuric acid in solvent D to the mixture of step (1);

[0129] (3) Filter and dry.

[0130] The solvent D is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone and ethyl acetate, preferably methanol, ethanol or isopropanol, and more preferably methanol.

[0131] In another aspect, the present application provides a phosphate salt of a compound of formula (I):

[0132]

[0133] In some embodiments, the phosphate salt of the compound of formula (I) is as shown in formula III

[0134] Here, x is selected from 0.5 to 1.

[0135] In some embodiments, the above x is selected from 0.5 or 1.

[0136] In some embodiments, the above x is selected from 1.

[0137] In some embodiments, the phosphoric acid content of the phosphate of the compound of formula (I) is 10-20wt%, preferably 12-19wt%; or the phosphoric acid content of the phosphate of the compound of formula (I) is selected from 12.1wt%, 12.2wt%, 12.3wt%, 12.4wt%, 12.5wt%, 12.6wt%, 12.7wt%, 12.8wt%, 12.9wt%, 13.0wt%, 13.1wt%, 13.2wt%, 13.3wt%, 13.4wt%, 13.5wt%, 13.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 14.6wt%, 14.7wt%, 14.8wt%, 14.9wt%, 14.1wt%, 14. 3.2wt%, 13.3wt%, 13.4wt%, 13.5wt%, 13.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt%, 1 4.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 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. %, 18.8wt%, 18.9wt%, 19.0wt% or a range formed by any of the above values.

[0138] The present application also provides a crystalline form E of a compound of formula (III), wherein the crystalline form E is characterized in that it has characteristic diffraction peaks of 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° in an X-ray powder diffraction (XRPD) spectrum.

[0139] In some embodiments, the crystalline form E is characterized in that it has characteristic diffraction peaks of 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° in the X-ray powder diffraction (XRPD) pattern.

[0140] In some embodiments, the crystalline form E is characterized in that it has characteristic diffraction peaks 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° in the X-ray powder diffraction (XRPD) pattern.

[0141] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of Form E, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 6:

[0142] Table 6: Characteristic peak positions and relative intensities of X-ray powder diffraction pattern of Form E

[0143] serial number 2θ angle (±0.2°) Relative strength (%) serial number 2θ angle (±0.2°) Relative strength (%) 1 5.2 4.2 15 21.7 31.8 2 9.0 12.3 16 22.2 24.3 3 10.1 32.7 17 22.7 40.6 4 10.5 30.9 18 23.4 29.7 5 13.6 10.2 19 24.0 32.1 6 14.3 14.3 20 25.8 10.7 7 15.5 25.0 21 26.1 12.2 8 15.7 20.5 22 27.4 11.7 9 17.0 18.6 23 28.9 13.8 10 17.3 16.4 24 29.2 15.7 11 18.0 30.1 25 29.4 14.2 12 19.0 37.6 26 29.6 16.0 13 20.2 22.9 27 33.3 13.3 14 21.0 100.0 .

[0144] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form E has the following Fig.11 The XRPD pattern shown represents the features.

[0145] In some embodiments, the differential scanning calorimetry (DSC) spectrum of Form E has the following Fig.12 The DSC spectra shown represent the characteristics.

[0146] In some embodiments, the DSC spectrum of the crystalline form E has an endothermic peak at 171.37°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form E has an endothermic peak at 159.07°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form E has an endothermic peak at 141.12°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form E has an endothermic peak at 116.46°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form E has an endothermic peak 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.

[0147] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystalline form E has the following Fig.13 The TGA spectra shown represent the features.

[0148] In some embodiments, the thermogravimetric analysis curve of the crystalline form E shows a weight loss of 2.24±0.2% at 157.5±3°C.

[0149] In some embodiments, the thermogravimetric analysis curve of the 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.

[0150] In some embodiments, the crystalline form E is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystalline form E is prepared in one or more mixed solvents selected from ethyl acetate and acetonitrile. In some embodiments, the crystalline form E is prepared in acetonitrile.

[0151] The present application also provides a method for preparing the crystalline form E of the phosphate of the compound of formula (I), comprising contacting the compound of formula (I) with phosphoric acid.

[0152] In some embodiments, the preparation method of the above-mentioned crystal form E comprises the following steps:

[0153] (1) mixing the compound of formula (I) with solvent E;

[0154] (2) adding phosphoric acid to the mixture of step (1);

[0155] (3) Filter and dry.

[0156] The solvent E is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably ethyl acetate and acetonitrile, and more preferably acetonitrile.

[0157] In another aspect, the present application provides a methanesulfonate salt of a compound of formula (I):

[0158]

[0159] In some embodiments, the mesylate salt of the compound of formula (I) is as shown in formula IV

[0160] Here, x is selected from 0.5 to 1.

[0161] In some embodiments, the above x is selected from 0.5 or 1.

[0162] In some embodiments, the above x is selected from 1.

[0163] In some embodiments, the methanesulfonic acid content of the methanesulfonic acid salt of the compound of formula (I) is 10-20wt%, preferably 12-19wt%; or the methanesulfonic acid content of the methanesulfonic acid salt of the compound of formula (I) is selected from 12.1wt%, 12.2wt%, 12.3wt%, 12.4wt%, 12.5wt%, 12.6wt%, 12.7wt%, 12.8wt%, 12.9wt%, 13.0wt%, 13.1wt%. %, 13.2wt%, 13.3wt%, 13.4wt%, 13.5wt%, 13.6wt%, 13.7wt%, 13.8wt%, 13.9wt%, 14.0wt%, 14.1wt% , 14.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 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%, 1 6.2wt%, 16.3wt%, 16.4wt%, 16.5wt%, 16.6wt%, 16.7wt%, 16.8wt%, 16.9wt%, 17.0wt%, 17.1wt%, 17 .2wt%, 17.3wt%, 17.4wt%, 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 a range formed by any of the above values.

[0164] The present application also provides a crystalline form F of the compound of formula (IV), wherein the crystalline form F is characterized in that it has characteristic diffraction peaks of 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° in the X-ray powder diffraction (XRPD) spectrum.

[0165] In some embodiments, the crystalline form F is characterized in that it has characteristic diffraction peaks 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° in the X-ray powder diffraction (XRPD) pattern.

[0166] In some embodiments, the crystalline form F is characterized in that it has characteristic diffraction peaks 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° in the X-ray powder diffraction (XRPD) pattern.

[0167] In some embodiments, in the X-ray powder diffraction (XRPD) spectrum of the crystalline form F, the positions and relative intensities of the characteristic diffraction peaks are shown in Table 7:

[0168] Table 7: Characteristic peak positions and relative intensities of X-ray powder diffraction pattern of Form F

[0169]

[0170]

[0171] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form F has the following Fig.14 The XRPD pattern shown represents the features.

[0172] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the crystalline form F has the following Fig.15 The DSC spectra shown represent the characteristics.

[0173] In some embodiments, the DSC spectrum of the crystalline form F has an exothermic peak at 282.74°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form F has an endothermic peak at 221.41°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline form F has an endothermic peak at 167.36°C ± 3°C. In some embodiments, the DSC spectrum of the crystalline 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.

[0174] In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystalline form F has the following Fig.16 The TGA spectra shown represent the features.

[0175] In some embodiments, the thermogravimetric analysis curve of the Form F shows a weight loss of 2.80±0.2% at 170.2±3°C.

[0176] 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.

[0177] In some embodiments, the crystalline form F is prepared in one or more mixed solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile. In some embodiments, the crystalline form F is prepared in one or more mixed solvents selected from ethyl acetate and acetonitrile. In some embodiments, the crystalline form F is prepared in acetonitrile.

[0178] The present application also provides a method for preparing the crystalline form F, comprising contacting the compound of formula (I) with methanesulfonic acid.

[0179] In some embodiments, the preparation method of the above-mentioned crystal form F comprises the following steps:

[0180] (1) mixing the compound of formula (I) with solvent F;

[0181] (2) adding methanesulfonic acid to the mixture of step (1);

[0182] (3) Filter and dry.

[0183] The solvent F is selected from one or more mixed solvents of methanol, ethanol, isopropanol, acetone, ethyl acetate, and acetonitrile, preferably ethyl acetate and acetonitrile, and more preferably acetonitrile.

[0184] On the other hand, the present application provides a crystalline composition comprising the above-mentioned crystal form, wherein the crystal form accounts for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0185] In another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned crystal form or its crystalline composition. The pharmaceutical composition may also optionally include a pharmaceutically acceptable carrier, excipient and / or medium. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0186] In some embodiments, the pharmaceutical composition comprises Form I or its crystalline composition, Form A or its crystalline composition, Form B or its crystalline composition, Form C or its crystalline composition, Form D or its crystalline composition, Form E or its crystalline composition, or Form F or its crystalline composition. In some embodiments, the pharmaceutical composition comprises Form I, Form A, Form B, Form C, Form D, Form E, or Form F. In some embodiments, the pharmaceutical composition comprises 0.0001 to 500 mg of Form I, Form A, Form B, Form C, Form D, Form E, or Form F, preferably 0.001 to 250 mg of Form I, Form A, Form B, Form C, Form D, Form E, or Form F, more preferably 0.005 to 100 mg of Form I, Form A, Form B, Form C, Form D, Form E, or Form F, and most preferably 0.005 to 50 mg of Form I, Form A, Form B, Form C, Form D, Form E, or Form F. The present application also provides a method for treating a disease mediated by a BET protein in a mammal, comprising administering a therapeutically effective amount of the above-mentioned crystal form, or salt form, or a crystalline composition or pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0187] The present application also provides the use of the above-mentioned crystal form, salt form, or crystalline composition or pharmaceutical composition thereof in the preparation of drugs for treating diseases mediated by BET proteins.

[0188] The present application also provides the above-mentioned crystal form, salt form, or crystalline composition or pharmaceutical composition thereof for treating diseases mediated by BET proteins.

[0189] The present application also provides the use of the above-mentioned crystal form, salt form, or crystal composition or pharmaceutical composition thereof for treating diseases mediated by BET proteins.

[0190] In some embodiments of the present application, the disease mediated by BET proteins is selected from cancer. Preferably, the cancer is selected from solid tumors or blood tumors. More preferably, the solid tumor is selected from breast cancer or prostate cancer. More preferably, the blood tumor is selected from acute myeloid leukemia, multiple myeloma or diffuse large B-cell lymphoma.

[0191] Technical Effects

[0192] The crystal form of the present application has good stability, and shows good results in stability tests such as high humidity, high temperature or light; it shows good pharmacological activity in in vivo or in vitro tests; when used as a raw material in a preparation, the resulting product has good dissolution, dissolution or pharmacokinetic properties, indicating that the crystal form of the present application has good pharmaceutical properties and a high drug development prospect. The crystal form of the present application has made a contribution to the solid form of the compound.

[0193] definition

[0194] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0195] It should be noted that in the powder X-ray diffraction spectrum, the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, there may be an error in the position of the peak, and the measurement error of the 2θ value may be ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0196] It should be noted that for the same crystal form, the position of the endothermic peak of DSC may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the position of the endothermic peak may have an error, which may be ±5°C or ±3°C. Therefore, when determining each crystal form, this error should be taken into account, and the error is also within the scope of this application.

[0197] In the pharmaceutical field, the term "hydrate" refers to a state of a eutectic solid material formed by a hydration reaction between a drug molecule and crystal water. One molecule of the compound of the present application can be combined with one water molecule, such as a monohydrate; one molecule of the compound of the present application can also be combined with more than one water molecule, such as a dihydrate, a trihydrate or a tetrahydrate; one molecule of the compound of the present application can also be combined with less than one water molecule, such as a hemihydrate. The hydrates described in the present application retain the biological effectiveness of the non-hydrated form of the compound.

[0198] The word "comprise" or "comprises" and English variations such as "comprises" or "comprising" or equivalents should be construed as having an open, non-exclusive meaning, ie, "including but not limited to".

[0199] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. "Pharmaceutically acceptable excipients" refer to inert substances that are administered together with the active ingredient and are conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Non-limiting examples of the excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0200] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0201] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0202] Typical routes of administration of the crystalline forms described herein or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0203] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0204] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0205] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific purpose of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0206] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0207] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0208] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0209] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0210] The moisture content described in this application is measured according to the moisture determination method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Rules 0832, Method 1).

[0211] The term "particle size distribution X 90 ” indicates the particle size corresponding to 90% of the volume cumulative distribution number in the powder sample.

[0212] The particle size distribution X described in this application 90 It is determined according to the light scattering method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0982 Particle Size and Particle Size Distribution Determination Method 3).

[0213] The therapeutically effective amount of the crystalline form described herein is from about 0.0001 to 20 mg / Kg body weight / day, for example, from 0.001 to 10 mg / Kg body weight / day.

[0214] The dosage frequency of the crystal form described in the present application is determined by the needs of individual patients, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of the crystal form, and then during a period of several days or more days, the patient does not receive a daily dose of the crystal form.

[0215] The intermediate compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0216] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0217] Herein, singular terms include plural referents and vice versa unless the context clearly dictates otherwise.

[0218] Herein, unless otherwise indicated, each parameter value (including 2θ values, reaction conditions) is deemed to be modified by the term "about" to reflect the measurement error that exists for each value, for example, there is an error of ±5% relative to a given value.

[0219] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country. BRIEF DESCRIPTION OF THE DRAWINGS

[0220] Figure 1 : XRPD pattern of Form I;

[0221] Figure 2 : DSC spectrum of Form I;

[0222] Figure 3 : XRPD pattern of Form A;

[0223] Figure 4 : DSC spectrum of Form A;

[0224] Figure 5 : TGA spectrum of Form A;

[0225] Figure 6 : XRPD pattern of Form B;

[0226] Figure 7: XRPD pattern of Form C;

[0227] Figure 8 : XRPD pattern of Form D;

[0228] Fig. 9 : DSC spectrum of Form D;

[0229] Fig.10 : TGA spectrum of type D;

[0230] Fig.11 : XRPD pattern of Form E;

[0231] Fig.12 : DSC spectrum of Form E;

[0232] Fig.13 : TGA spectrum of Form E;

[0233] Fig.14 : XRPD pattern of Form F;

[0234] Fig.15 : DSC spectrum of Form F;

[0235] Fig.16 : TGA spectrum of Form F. DETAILED DESCRIPTION

[0236] In order to better understand the content of the present application, the following is further explained in conjunction with specific examples, but the specific implementation method is not a limitation on the content of the present application. All solvents used in the present application are commercially available and can be used without further purification. The following abbreviations are used in the present application: DCM represents dichloromethane; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; MeOH represents methanol; ACN represents acetonitrile; EtOAc represents ethyl acetate; PE represents petroleum ether; CDCl3 represents deuterated chloroform; (Boc)2O represents di-tert-butyl dicarbonate; Boc represents tert-butyloxycarbonyl; DMAP represents 4-dimethylaminopyridine; N2 represents nitrogen; MS represents mass spectrometry; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; XantPhos represents 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Xphos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl. The "room temperature" in this application refers to normal temperature, generally 10-30°C.

[0237] Specific methods of XRPD, DSC, and TGA (including equipment models and parameters)

[0238] The present invention relates to powder X-ray diffraction (XRPD) method.

[0239] Instrument model: Bruker D8 Advance X-ray diffractometer

[0240] The detailed XRPD parameters are as follows:

[0241] Target type: Cu

[0242] Light tube voltage: 40kV, light tube current: 40mA

[0243] Scanning angle range: 3.00-60.00 degrees

[0244] Step size: 0.02°

[0245] Scan interval: 0.1s

[0246] Differential Scanning Calorimeter (DSC) method

[0247] Instrument model: METTLER TOLEDO DSC1 differential thermal analyzer

[0248] Temperature range: 50-320℃

[0249] Heating rate: 10K / min

[0250] Thermogravimetric analysis (TGA) method of this application

[0251] Instrument model: NETZSCH TG 209F3 thermogravimetric analyzer

[0252] Temperature range: 30-700℃

[0253] Heating rate: 10K / min

[0254] Example 1: Compound of formula (I)

[0255]

[0256] Step A: Ethyl 5-fluoropicolinate

[0257]

[0258] At 0°C, DMF (0.1 mL) and thionyl chloride (5.6 mL) were slowly added dropwise to a solution of 5-fluoropicolinic acid (5.00 g) in ethanol (42 mL). After addition, stirring was continued for 15 minutes, and then slowly heated to reflux for 4 hours. The mixture was cooled and concentrated under reduced pressure. The residue was poured into ice water, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate for 3 times. The extracts were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the product (5.50 g).

[0259] Step B: Ethyl 5-(2,4-difluorophenoxy)picolinate

[0260]

[0261] At room temperature, 2,4-difluorophenol (4.15 g) and potassium carbonate (8.82 g) were added to a solution of ethyl 5-fluoropicolinate (5.40 g) in DMF (60 mL), and the mixture was heated to 100°C and reacted overnight. The mixture was cooled, diluted with water (400 mL), and extracted with ethyl acetate three times. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the product (8.40 g).

[0262] 1 H NMR (400MHz, CDCl3) δ8.48 (d, J=2.8Hz, 1H), 8.10 (d, J=8.8Hz, 1H), 7.15-7.24 (m, 2H), 6.92-7.04m, 2H), 4.46 (q, J=7.2Hz, 2H), 1.44 (t, J=7.2Hz, 3H).

[0263] Step C: 5-(2,4-difluorophenoxy)-2-(ethoxycarbonyl)pyridine 1-oxide

[0264]

[0265] At room temperature, add 85% m-chloroperbenzoic acid (1.45 g) to a solution of ethyl 5-(2,4-difluorophenoxy)picolinate (1.00 g) in dichloromethane (30 mL), and react overnight at room temperature. After the reaction is complete, add saturated sodium bicarbonate solution (40 mL), stir for 15 minutes, and extract with dichloromethane three times. Combine the extracts, wash with saturated sodium thiosulfate solution, water and saturated brine in turn, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain the product (1.00 g).

[0266] 1H NMR (400MHz, CDCl3) δ7.95 (d, J=2.4Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.19 (td, J=8.8Hz, 5.6Hz, 1H) , 6.93-7.04 (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).

[0267] Step D: Ethyl 6-bromo-5-(2,4-difluorophenoxy)picolinate

[0268]

[0269] At 0°C, tetramethylammonium bromide (1.37 g) and methanesulfonic anhydride (1.24 g) were added to a DMF (15 mL) solution of 5-(2,4-difluorophenoxy)-2-(ethoxycarbonyl)pyridine 1-oxide (1.00 g) in sequence. After addition, the temperature was slowly raised to room temperature and the reaction was continued for 3 hours. After the reaction was completed, sodium bicarbonate solution (40 mL) containing ice water was poured in, stirred for 5 minutes, and extracted with ethyl acetate 3 times. The extracts were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE=1 / 5-1 / 1) to obtain the product (0.80 g).

[0270] 1 H NMR (400MHz, CDCl3) δ7.99 (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).

[0271] Step E: 6-Bromo-5-(2,4-difluorophenoxy)picolinic acid

[0272]

[0273] At 0°C, add 30% potassium hydroxide solution (1.50 mL) to a solution of ethyl 6-bromo-5-(2,4-difluorophenoxy)picolinate (0.60 g) in tetrahydrofuran (10 mL). After addition, warm to room temperature and react for 2 hours. After the reaction is complete, concentrate under reduced pressure, add water, adjust the pH to 4-5 with dilute hydrochloric acid, stir for 5 minutes, and collect the solid by filtration to obtain the product (0.50 g).

[0274] Step F: tert-Butyl [6-bromo-5-(2,4-difluorophenoxy)pyridin-2-yl]carbamate

[0275]

[0276] At room temperature, diphenylphosphoryl azide (0.75 g), triethylamine (0.80 mL) and di-tert-butyl dicarbonate (1.19 g) were added to a solution of 6-bromo-5-(2,4-difluorophenoxy)picolinic acid (0.45 g) in anhydrous tert-butyl alcohol (10 mL) in sequence. After addition, the temperature was raised to 90°C and the reaction was continued for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, poured into a saturated sodium bicarbonate solution (20 mL) containing ice water, and extracted with ethyl acetate three times. The extracts were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE=1 / 10-1 / 3) to obtain the product (0.31 g).

[0277] 1 H NMR (400MHz, CDCl3) δ7.84 (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).

[0278] Step G: 6-Bromo-5-(2,4-difluorophenoxy)pyridin-2-amine

[0279]

[0280] At 0°C, concentrated hydrochloric acid (5 mL) was added dropwise to a solution of tert-butyl [6-bromo-5-(2,4-difluorophenoxy)pyridin-2-yl]carbamate (0.31 g) in dioxane (10 mL). The mixture was heated to room temperature and reacted for 24 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, poured into a saturated sodium bicarbonate solution (20 mL) containing ice water, and extracted with ethyl acetate three times. The extracts were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (0.22 g).

[0281] 1 H NMR (400MHz, CDCl3) δ7.09 (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 (brs, 2H).

[0282] Step H: 2-Bromo-3-(2,4-difluorophenoxy)-6-iodopyridine

[0283]

[0284] At room temperature, iodine (0.27 g) and cuprous iodide (0.20 g) were added to a solution of 6-bromo-5-(2,4-difluorophenoxy)pyridin-2-amine (0.32 g) in diiodomethane (4 mL), heated to 80°C, and isoamyl nitrite (0.34 g) was added dropwise. The reaction was continued for 2 hours. After the reaction was completed, the mixture was cooled, poured into a sodium bicarbonate solution (20 mL) containing ice water, and extracted with dichloromethane 3 times. The extracts were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / PE=1 / 10-1 / 3) to obtain the product (0.20 g).

[0285] 1 H NMR (400MHz, CDCl3) δ7.55 (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).

[0286] Step I: ((6-bromo-5-(2,4-difluorophenoxy)pyridin-2-yl)imino)dimethyl-λ 6 -Sulfonimide

[0287]

[0288] Under N2 protection, 2-bromo-3-(2,4-difluorophenoxy)-6-iodopyridine (0.09 g), dimethylsulfenyl imide (25 mg), cesium carbonate (0.14 g), Xantphos (10 mg) and Pd2(dba)3 (8 mg) were added to anhydrous dioxane (4 mL) in sequence, followed by heating to 100°C and stirring for 3 hours. The reaction mixture was cooled to room temperature, water was added, and 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 using a preparative thin layer plate (EtOAc / PE=1 / 1) to obtain the product.

[0289] 1 H NMR (400MHz, CDCl3) δ7.10 (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).

[0290] Step J: tert-Butyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

[0291]

[0292] To a solution of 4-bromo-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.73 g) in acetonitrile (20 mL) were added (Boc)2O (2.47 g) and DMAP (1.44 g) in sequence and stirred at room temperature overnight. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 20) to give the product (2.10 g).

[0293] 1 H NMR (400MHz, CDCl3) δ7.55 (d, J=3.6Hz, 1H), 7.21 (s, 1H), 6.35 (d, J=3.6Hz, 1H), 3.55 (s, 3H), 1.62 (s, 9H).

[0294] 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-carboxylic acid tert-butyl ester

[0295]

[0296] Under N2 protection, to a mixed solvent of 1,4-dioxane (20 mL) and water (2 mL) were added tert-butyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.53 g), biboric acid pinacol ester (0.66 g), Xphos (31 mg), potassium acetate (0.28 g) and Pd2(dba)3 (30 mg) in sequence, heated to 80°C and stirred overnight, cooled to room temperature, the reaction solution was dispersed in ethyl acetate, washed with saturated NaHCO3 aqueous solution, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (EtOAc / PE=1 / 3~1 / 1) to obtain the product.

[0297] 1 H NMR (400MHz, CDCl3) δ7.60 (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).

[0298] Step L: 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 -sulfydene]amino}-pyridin-2-yl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester

[0299]

[0300] Under nitrogen protection, to a 80% dioxane aqueous solution (3 mL) were added ((6-bromo-5-(2,4-difluorophenoxy)pyridin-2-yl)imino)dimethyl-λ 6 -sulfonylimide (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-carboxylic acid tert-butyl ester (65 mg), cesium fluoride (83 mg) and PdCl2 (AtaPhos) (9 mg), then heated to 85°C and stirred overnight. Cooled to room temperature, added with water, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated with a preparative thin layer plate (MeOH / DCM=1 / 20) to obtain the product (58 mg).

[0301] 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.58-7.59 (m, 1H), 7.23 (d, J=8.4Hz, 1H), 7.15-7.1 7(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).

[0302] Step M: 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 -sulfydene]amino}-pyridin-2-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0303]

[0304] At room temperature, 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 4 mol / L of hydrogen chloride dioxane solution (1 mL) was added to tert-butyl ester (50 mg) of 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate. After addition, the mixture was heated to room temperature and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and a sodium bicarbonate solution (5 mL) containing ice water was poured into the mixture. The mixture was extracted with ethyl acetate three times. The extracts were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (35 mg).

[0305] 1H NMR (400MHz, CDCl3) δ12.01 (brs, 1H), 9.56 (brs, 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).

[0306] Example 2: Preparation method of crystal form I

[0307] Method 1:

[0308] Take 1g of the compound of formula (I), add 10ml of DMSO, heat to 80°C, and stir until dissolved. Take 30ml of purified water, stir in an ice bath, add dropwise the DMSO solution of the compound of formula (I), stir for 10min, filter the precipitated solid, and dry the filter cake under reduced pressure at 60°C for 2h to obtain the product. Test XRPD, which is Form I.

[0309] Method 2:

[0310] Take 1 g of the compound of formula (I), add 5 ml of DMSO, heat to 100°C, stir until dissolved, cool naturally to crystallize, filter, and dry the filter cake at 60°C under reduced pressure to obtain the product. XRPD test shows that it is Form I.

[0311] Method 3:

[0312] Take 1g of the compound of formula (I), add 10ml of DMSO, heat to 80°C, and stir until dissolved. Take 30ml of anhydrous methanol, stir in an ice bath, dropwise add the DMSO solution of the compound of formula (I), stir for 10min, filter the precipitated solid, and dry the filter cake at 60°C under reduced pressure for 3.5h to obtain the product. Test XRPD, which is Form I. Its XRPD spectrum is as follows: Figure 1 shown.

[0313] Method 4:

[0314] Take 1.0g of the compound of formula (I), add 400ml of DCM and 100ml of methanol, stir at room temperature until the solution becomes clear, concentrate under reduced pressure at 30-35°C, and dry under reduced pressure at 35°C to obtain the product. XRPD test shows that it is Form I. Its DSC spectrum is as follows: Figure 2 shown.

[0315] Method 5:

[0316] Take 10 g of the hydrochloride of the compound of formula (I), add 200 ml of purified water, stir at room temperature for 4 h, filter, collect the filter cake, and dry under reduced pressure at 50° C. for 3.5 h to obtain the product. XRPD test shows that it is Form I.

[0317] Method 6:

[0318] Take 0.5 g of the hydrochloride of the compound of formula (I), add 10 ml of 20% acetonitrile / water solution, stir at room temperature for 3 h, filter, collect the filter cake, and dry under reduced pressure at 50° C. for 4 h to obtain the product. XRPD test shows that it is Form I.

[0319] Method 7:

[0320] Take 1 g of the hydrochloride of the compound of formula (I), add 15 ml of methanol, raise the temperature to 60°C, stir until dissolved, add 30 ml of water, cool to room temperature for crystallization for 0.5 h, filter, and dry the filter cake at 60°C for 3 h to obtain the product. Test XRPD, which is Form I.

[0321] The hydrochloride salt of the compound of formula (I) used in methods five to seven is in crystalline form A.

[0322] Example 3: Preparation method of hydrochloride salt crystal form

[0323] Preparation method of Form A: Take 100g of the compound of formula (I), add 1300ml of anhydrous methanol, add 160ml of 6mol / L hydrochloric acid, stir until dissolved, add 10g of activated carbon, decolorize for 10min, filter, and collect the filtrate. Concentrate to a feed liquid weight of about 380g, heat the feed liquid to a clear solution, cool naturally to crystallize, crystallize at 0℃, filter, and dry the filter cake at 50℃ under reduced pressure for more than 4h to obtain a product. Test XRPD, which is Form A, with a moisture content of 5.8%. Its XRPD spectrum is as follows: Figure 3 Its DSC spectrum is shown as Figure 4 Its TGA spectrum is shown as Figure 5 The hydrochloric acid content of the obtained product is 7.7%.

[0324] Preparation method of crystal form B: crystal form A is placed at 60±2°C for 30 days to obtain a product, which is crystal form B with a moisture content of 4.6%. Its XRPD spectrum is as follows Figure 6 shown.

[0325] Preparation method of Form C: Form A was placed at room temperature and relative humidity of 92.5±5% for 30 days to obtain a product. The XRPD test showed that the product was Form C with a moisture content of 11.9%. The XRPD pattern is as follows: Figure 7 shown.

[0326] Example 4: Preparation method of sulfate crystal form

[0327] Take 12g of the compound of formula (I), add 100ml of methanol, disperse evenly, add 2.2ml of 3mol / L sulfuric acid / methanol solution, stir at room temperature for 3h, filter, collect the filter cake, and dry under reduced pressure at 50°C for more than 4h to obtain the product. Test XRPD, which is Form D. Its XRPD spectrum is as follows: Figure 8 Its DSC spectrum is shown as Fig. 9 Its TGA spectrum is shown as Fig.10 The sulfuric acid content of the obtained product is 18.3%.

[0328] Example 5: Preparation method of phosphate crystal form

[0329] Method 1:

[0330] Take 0.4 g of the compound of formula (I), add 4 ml of acetonitrile, add 0.22 g of 85% phosphoric acid at room temperature, heat to 70°C and stir for 0.5 h, cool naturally to room temperature, filter, and dry the filter cake at 50°C under reduced pressure for 4 h to obtain the product. XRPD test shows that it is Form E.

[0331] Method 2:

[0332] Take 3.5g of the compound of formula (I), add 35ml of acetonitrile, raise the temperature to 70°C, add 4.5g of 85% phosphoric acid, keep warm and stir for 2h, cool to room temperature, and filter. Collect the filter cake, dry under reduced pressure at 60°C for 6h to obtain the product, test XRPD, which is Form E. Its XRPD spectrum is as follows: Fig.11 Its DSC spectrum is shown as Fig.12 Its TGA spectrum is shown as Fig.13 shown.

[0333] Example 6: Preparation of Methanesulfonate Crystalline Form

[0334] Take 3.5g of the compound of formula (I), add 17.5g of acetonitrile, heat to 70°C, add 1.89g of methanesulfonic acid, keep warm and stir for 0.5h, slowly cool to room temperature, stir in an ice bath for 2h, filter, collect the filter cake, dry under reduced pressure at 60°C for 6.5h to obtain the product, test XRPD, which is Form F. Its XRPD spectrum is as follows: Fig.14 Its DSC spectrum is shown as Fig.15 Its TGA spectrum is shown as Fig.16 The methanesulfonic acid content of the obtained product is 17.9%.

[0335] Experimental Example 1: Study on the stability of influencing factors

[0336] In order to evaluate the solid stability of the crystal form of the present application, the stability of the influencing factors (high temperature, high humidity and light) of the crystal form I, crystal form A, crystal form D, crystal form E and crystal form F were investigated respectively. The above crystal forms were placed under high temperature (60°C ± 2°C, open (weighing bottle)) and high humidity (room temperature, 92.5% RH ± 5%, open (weighing bottle) and packaged) for 5 days, 10 days and 30 days respectively, according to the ICH lighting conditions (5500Lux, 0.9w / m 2 , closed (weighing bottle) and packaged) were placed for 5 days and 10 days. The inner packaging material of the packaged samples was a medicinal low-density polyethylene bag, and the outer packaging material was a polyester / aluminum / polyethylene medicinal composite bag. The samples after placement were characterized for properties, purity (HPLC), crystal form (XRD), and moisture to detect changes in crystal form and purity; the results are shown in Tables 8 to 12 ("#" indicates ICH conditions).

[0337] Table 8: Results of stability study on factors affecting Form I

[0338]

[0339] Table 9: Results of stability study on factors affecting Form A

[0340]

[0341] Table 10: Results of stability study on factors affecting Form D

[0342]

[0343] Table 11: Results of stability study on factors affecting Form E

[0344]

[0345] Table 12: Results of stability study on factors affecting Form F

[0346]

[0347] Experimental conclusion: The product of this application has good stability and is easy to make into medicine.

[0348] Experimental Example 2: Stability Study of Form I

[0349] 1. Study on the stability of influencing factors

[0350] In order to evaluate the solid stability of the crystal form I of the present application, the stability of the influencing factors (high temperature, high humidity and light) was investigated. Crystal form I was placed 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) and with packaging) for 5 days, 10 days, and 30 days, and placed for 5 days and 10 days according to ICH lighting conditions (5500Lux, 0.9w / m2, open (weighing bottle) and with packaging). The inner packaging material of the packaged sample is a double-layer medicinal low-density polyethylene bag, and the outer packaging material is a polyester / aluminum / polyethylene composite bag for drug packaging. The properties, related substances (HPLC), crystal form (XRD), moisture and content of the placed samples were determined to investigate the effects of high temperature, high humidity and light conditions on this product. The results are shown in Table 13 ("#" indicates ICH conditions).

[0351] Table 13: Results of stability study on factors affecting Form I

[0352]

[0353] 2. Accelerated stability and long-term stability studies

[0354] The accelerated and long-term stability of the crystal form I of the present application was investigated, and the samples were placed under accelerated conditions (40±2°C, 75%RH±5%, with packaging) for 1, 2, 3, and 6 months, and under long-term conditions (25±2°C, 65%RH±5%, with packaging) for 3, 6, 9, 12, 18, 24, and 36 months. The inner packaging material of the packaged samples is a double-layer medicinal low-density polyethylene bag, and the outer packaging material is a polyester / aluminum / polyethylene composite bag for drug packaging. The properties, related substances (HPLC), crystal form (XRD), moisture and content of the samples after placement were determined to investigate the stability of the product.

[0355] Table 14: Accelerated stability and long-term stability study results of Form I

[0356]

[0357]

[0358] Experimental conclusion: The crystal form I of the present application has good stability and is easy to make into medicine.

[0359] Experimental Example 3: Biological Activity Test

[0360] 1. In vitro enzymatic activity assay of BRD4 (BD2)

[0361] In the present application, the inhibitory IC of the compound of formula (I) on the BRD4 (BD2) enzyme binding reaction is 50The values ​​were measured by homogeneous time-resolved fluorescence (HTRF) method. The compound of formula (I) was diluted 5 times with 100% DMSO starting from 1 mM (7 concentrations in total), 2 μL of the compound of formula (I) was added to 18 μL of reaction buffer (20 mM HEPES pH 7.5, 150 mM NaCl, 5 mM DTT, 0.005% Tween 20 and 100 μg / mL BSA) for dilution, and 2 μL of the compound of formula (I) was added to 48 μL of the above reaction buffer for further dilution and mixing after mixing (the final DMSO concentration of the compound of formula (I) was 0.1%). Take 2.5 μL and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-BRD4 (BD2, 349-460aa) (final concentration of 2 nM), centrifuge and mix, then add 2.5 μL of Biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV peptide (final concentration of 200 nM) to start the reaction (total reaction volume of 10 μL). Place the 384-well plate in an incubator at 23°C for 1 hour, then add 5 μL of Eu3+cryptate-labled anti-GST antibody (purchased from Cisbio) and 5 μL of Streptavidin-XL-665 (purchased from Cisbio) to stop the reaction. After incubation in the incubator for another hour, the fluorescence value was read on Envision (purchased from PerkinElmer) (excitation at 320 nm, detection of emission light at 665 nm and 620 nm, the ratio of the two being the binding signal of the enzyme). The binding strength of the compound of formula (I) to the BRD4 (BD2) protein was measured at 7 concentrations, and the data were calculated using GraphPad Prism software to obtain the IC value of the compound of formula (I). 50 value.

[0362] 2. In vitro enzymatic activity assay of BRD4 (BD1)

[0363] In the present application, the inhibitory IC of the compound of formula (I) on the BRD4 (BD1) enzyme binding reaction is 50The values ​​were measured by homogeneous time-resolved fluorescence (HTRF) method. The compound of formula (I) was diluted 5 times with 100% DMSO starting from 0.2 mM (7 concentrations in total), and 2 μL of the compound of formula (I) was added to 48 μL of reaction buffer (20 mM HEPES pH 7.5, 150 mM NaCl, 5 mM DTT, 0.005% Tween 20 and 100 μg / ml BSA) for dilution and mixing. Take 2.5 μL and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 5 μL of GST-BRD4 (BD1, 44-168aa) (final concentration of 1 nM), centrifuge and mix, then add 2.5 μL of Biotin-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV) short peptide (final concentration of 100 nM) to start the reaction (total reaction volume of 10 μL). Place the 384-well plate in an incubator at 23°C for 1 hour, then add 5 μL of Eu3+cryptate-labled anti-GST antibody (purchased from Cisbio) and 5 μL of Streptavidin-XL-665 (purchased from Cisbio) to stop the reaction. After incubation in the incubator for another hour, the fluorescence value was read on Envision (purchased from PerkinElmer) (excitation at 320 nm, detection of emission light at 665 nm and 620 nm, the ratio of the two being the binding signal of the enzyme). The binding strength of the compound of formula (I) to the BRD4 (BD1) protein was measured at 7 concentrations, and the data were calculated using GraphPad Prism software to obtain the IC value of the compound of formula (I). 50 value.

[0364] The above test results are shown in Table 15.

[0365] Table 15: In vitro enzymatic activity results

[0366]

[0367] 3. MV4-11 cell proliferation activity assay

[0368] Human acute lymphoblastic leukemia cell line MV4-11 was cultured using PRIM1640 medium plus 10% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin double antibody (P / S, purchased from LifeTechonology), and the culture conditions were 37°C, 5% CO2. One day before the detection of the compound of formula (I), MV4-11 cells were plated in a 96-well plate (purchased from Corning) at a concentration of 8000 cells / 195 μL / well. After 24 hours, the compound of formula (I) was diluted 4 times from 10 mM with 100% DMSO (a total of 9 concentrations), and then 2 μL of the compound of formula (I) was added to 48 μL of PRIM1640 medium for dilution at each concentration. 5 μL of each diluted compound of formula (I) was added to the cell suspension, and the compound of formula (I) and cells were co-incubated in a cell culture incubator for 72 hours (3 days), and then 35 μL of Cell-Titer Blue (purchased from Promega) reagent was added and incubated again for 4 hours. After that, the fluorescence value was read on Flexstation III (560 nm excitation, 590 nm detection), and the data were calculated using GraphPad Prism software to obtain the IC value of the compound of formula (I) for inhibiting cell proliferation. 50 value.

[0369] 4. Kasumi-1 cell proliferation activity assay

[0370] Kasumi-1 cells, a human acute myeloblastic leukemia cell line, were cultured using PRIM1640 medium supplemented with 20% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin (P / S, purchased from LifeTechonology) at 37°C and 5% CO2. One day before the detection of the compound of formula (I), Kasumi-1 cells were plated in a 96-well plate (purchased from Corning) at a concentration of 5000 cells / 195 μL / well. After 24 hours, the compound of formula (I) was diluted 4 times from 10 mM using 100% DMSO (9 concentrations in total), and then 2 μL of the compound of formula (I) was added to 48 μL of PRIM1640 medium for dilution at each concentration. 5 μL of each diluted compound of formula (I) was added to the cell suspension, and the compound of formula (I) and cells were co-incubated in a cell culture incubator for 72 hours (3 days), and then 35 μL of Cell-Titer Blue (purchased from Promega) reagent was added and incubated again for 4 hours. After that, the fluorescence value was read on Flexstation III (560 nm excitation, 590 nm detection), and the data were calculated using GraphPad Prism software to obtain the IC value of the compound of formula (I) for inhibiting cell proliferation. 50 The above test results are shown in Table 16.

[0371] Table 16: In vitro cytological activity results

[0372]

[0373] 5. Animal pharmacokinetic studies

[0374] Animal pharmacokinetic experiments used 3 healthy adult male rats from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The compound of formula (I) was suspended in 2% anhydrous ethanol, 5% Tween 80, 20% polyethylene glycol 400, 73% (5% hydroxypropyl methylcellulose in water) (V / V / V / V) at a concentration of 1 mg / mL, a dosing volume of 5 mL / kg, and a single oral administration at a dose of 5 mg / kg. The animals were fasted overnight before the experiment, 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, placed in a heparin anticoagulant tube, and the sample was centrifuged at 4°C and 4200 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma sample analysis The test compound and internal standard (warfarin or propranolol) in rat plasma were extracted by acetonitrile protein precipitation, and the extract was analyzed by LC / MS / MS. The plasma concentration-time data of individual animals were analyzed by non-compartmental model using WinNonlin (version 5.2.1; Pharsight) software to obtain the pharmacokinetic parameters shown in Table 17 below: Maximum (peak) plasma drug concentration C max ; Peak time T max ; Half-life T 1 / 2 and the area under the plasma concentration-time curve extrapolated to infinite time AUC 0-inf .

[0375] Table 17: Study results of pharmacokinetic parameters

[0376] parameter unit Compound of formula (I) <![CDATA[t 1 / 2 ]]> hr 5.25 <![CDATA[T max ]]> hr 2.67 <![CDATA[C max ]]> ng / mL 372 <![CDATA[AUC 0-inf ]]> hr·ng / mL 3466

[0377] It can be seen that the compound of formula (I) has good activity and good pharmacokinetic properties.

[0378] Experimental Example 4: Particle size distribution test

[0379] After the crystal form I was air flow crushed, the particle size distribution test was carried out with reference to the third method (light scattering method) of particle size and particle size distribution determination in 0982 of the fourth part of the 2020 edition of the Chinese Pharmacopoeia, as follows: 10 mg of the sample was weighed and placed in a laser scattering particle size distribution analyzer for testing (trigger conditions: 10s, 1%; dispersion pressure: 2.0 bar). The test results are shown in Table 18.

[0380] Table 18: Particle size distribution test results

[0381]

Claims

1. Crystalline Form I of the compound of formula (I): ， in, The X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 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°.

2. The crystalline form I of the compound of formula (I) according to claim 1, wherein The X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 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°.

3. The crystalline form I of the compound of formula (I) according to claim 2, wherein: The X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2θ angles: 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°, and 25.2°±0.2°.

4. The crystalline form I of the compound of formula (I) according to claim 3, wherein: The X-ray powder diffraction pattern of the crystalline form I has the following XRPD pattern analysis data: 。 5. The crystalline form I of the compound of formula (I) according to claim 4, wherein: The X-ray powder diffraction pattern of the crystalline form I has the characteristics represented by the XRPD pattern shown in FIG1 .

6. The crystalline form I of the compound of formula (I) according to claim 1, wherein The particle size distribution X of the crystal form I 90 Less than 30μm.

7. The crystalline form I of the compound of formula (I) according to claim 6, wherein: The particle size distribution X 90 Less than 20 μm.

8. The crystalline form I of the compound of formula (I) according to claim 7, wherein The particle size distribution X 90 Less than 15 μm.

9. The crystalline form I of the compound of formula (I) according to claim 1, wherein The particle size distribution X of the crystal form I 90 3.0~14.0 μm.

10. The hydrochloride salt of the compound of formula (I), 。 11. The hydrochloride of the compound of formula (I) according to claim 10, wherein The hydrochloride is a salt formed by the compound of formula (I) and hydrochloric acid in a molar ratio of 1:

1.

12. The hydrochloride of the compound of formula (I) according to claim 10, wherein The hydrochloric acid content in the hydrochloride is 5-10wt%.

13. A crystalline form of the hydrochloride salt of the compound of formula (I), wherein: The crystal form is the crystal form A of the hydrochloride salt of the compound of formula (I), and its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 6.8°±0.2°, 8.4°±0.2°, 9.4°±0.2°, 10.2°±0.2°, 16.8°±0.2°, 。 14. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 13, wherein: The X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 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°.

15. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 14, wherein: The X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 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°.

16. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 15, wherein: The X-ray powder diffraction pattern of the crystalline form A has the following XRPD pattern analysis data: 。 17. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 16, wherein: The X-ray powder diffraction pattern of the crystalline form A has the characteristics represented by the XRPD pattern shown in FIG3 .

18. A crystalline form of the hydrochloride salt of the compound of formula (I), wherein: The crystal form is the crystal form B of the hydrochloride salt of the compound of formula (I), and its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 8.7°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 17.4°±0.2°, 。 19. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 18, wherein: The X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 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°.

20. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 19, wherein: The X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2θ angles: 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°.

21. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 20, wherein: The X-ray powder diffraction pattern of the crystalline form B has the following XRPD pattern analysis data: 。 22. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 21, wherein: The X-ray powder diffraction pattern of the crystalline form B has the characteristics represented by the XRPD pattern shown in FIG6 .

23. A crystalline form of the hydrochloride salt of the compound of formula (I), wherein: The crystal form is the crystal form C of the hydrochloride salt of the compound of formula (I), and its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 6.8°±0.2°, 9.5°±0.2°, 12.9°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 。 24. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 23, wherein: The X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 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°.

25. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 24, wherein: The X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2θ angles: 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°.

26. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 25, wherein: The X-ray powder diffraction pattern of the crystalline form C has the following XRPD pattern analysis data: 。 27. The crystalline form of the hydrochloride salt of the compound of formula (I) according to claim 26, wherein: The X-ray powder diffraction pattern of the crystalline form C has the characteristics represented by the XRPD pattern shown in FIG. 7 .

28. A sulfate salt of a compound of formula (I), 。 29. The sulfate salt of the compound of formula (I) according to claim 28, wherein The sulfate is as shown in Formula II, ， Among them, x is selected from 0.5~1.

30. The sulfate salt of the compound of formula (I) according to claim 28, wherein The sulfuric acid content in the sulfate is 15-20wt%.

31. A crystalline form of the sulfate salt of the compound of formula (I), wherein: The crystal form is the crystal form D of the sulfate of the compound of formula (I), and its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 13.5°±0.2°, 14.7°±0.2°, 18.6°±0.2°, 21.2°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 。 32. The crystalline form of the sulfate salt of the compound of formula (I) according to claim 31, wherein: The X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 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°.

33. The crystalline form of the sulfate salt of the compound of formula (I) as claimed in claim 32, wherein: The X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2θ angles: 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°.

34. The crystalline form of the sulfate salt of the compound of formula (I) according to claim 33, wherein: The X-ray powder diffraction pattern of the crystal form D has the following XRPD pattern analysis data: 。 35. The crystalline form of the sulfate salt of the compound of formula (I) according to claim 33, wherein: The X-ray powder diffraction pattern of the crystalline form D has the characteristics represented by the XRPD pattern shown in FIG8 .

36. A phosphate salt of a compound of formula (I), 。 37. The phosphate salt of the compound of formula (I) according to claim 36, wherein The phosphate is as shown in formula III, ， Among them, x is selected from 0.5~1.

38. The phosphate salt of the compound of formula (I) according to claim 36, wherein The phosphoric acid content in the phosphate is 10-20wt%.

39. A crystalline form of a phosphate salt of a compound of formula (I), wherein: The crystal form is the crystal form E of the phosphate of the compound of formula (I), and its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 10.1°±0.2°, 10.5°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 22.7°±0.2°, 24.0°±0.2°, 。 40. The crystalline form of the phosphate salt of the compound of formula (I) as claimed in claim 39, wherein: The X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 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°.

41. The crystalline form of the phosphate salt of the compound of formula (I) as claimed in claim 40, wherein: The X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2θ angles: 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°.

42. The crystalline form of the phosphate salt of the compound of formula (I) as claimed in claim 41, wherein: The X-ray powder diffraction pattern of the crystalline form E has the following XRPD pattern analysis data: 。 43. The crystalline form of the phosphate salt of the compound of formula (I) as claimed in claim 42, wherein: The X-ray powder diffraction pattern of the crystalline form E has the characteristics represented by the XRPD pattern shown in FIG11 .

44. A methanesulfonate salt of a compound of formula (I), 。 45. The mesylate salt of the compound of formula (I) according to claim 44, wherein The mesylate is shown in Formula IV ， Among them, x is selected from 0.5~1.

46. ​​The mesylate salt of the compound of formula (I) according to claim 44, wherein The content of methanesulfonic acid in the methanesulfonate is 10-20 wt %.

47. A crystalline form of a mesylate salt of a compound of formula (I), wherein: The crystal form is the crystal form F of the mesylate salt of the compound of formula (I), and its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 8.8°±0.2°, 10.1°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 。 48. The crystalline form of the mesylate salt of the compound of formula (I) as claimed in claim 47, wherein: The X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 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°.

49. The crystalline form of the mesylate salt of the compound of formula (I) as claimed in claim 48, wherein: The X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2θ angles: 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°.

50. The crystalline form of the mesylate salt of the compound of formula (I) as claimed in claim 49, wherein: The X-ray powder diffraction pattern of the crystalline form F has the following XRPD pattern analysis data: 。 51. The crystalline form of the mesylate salt of the compound of formula (I) as claimed in claim 50, wherein: The X-ray powder diffraction pattern of the crystalline form F has the characteristics represented by the XRPD pattern shown in FIG14 .

52. A crystalline composition comprising the crystalline form of any one of claims 1-9, 13-27, 31-35, 39-43 or 47-51, wherein The crystal form accounts for more than 50% by weight of the crystalline composition.

53. The crystalline composition of claim 52, wherein The crystal form accounts for more than 80% by weight of the crystalline composition.

54. The crystalline composition of claim 53, wherein The crystal form accounts for more than 90% by weight of the crystalline composition.

55. The crystalline composition of claim 54, wherein The crystal form accounts for more than 95% by weight of the crystalline composition.

56. A pharmaceutical composition comprising a therapeutically effective amount of an active ingredient selected from the following group: a crystalline form as described in any one of claims 1-9, 13-27, 31-35, 39-43 or 47-51, a salt as described in any one of claims 10-12, 28-30, 36-38 or 44-46, and a crystalline composition as described in any one of claims 52-55.

57. Use of the crystalline form of any one of claims 1-9, 13-27, 31-35, 39-43 or 47-51, or the salt of any one of claims 10-12, 28-30, 36-38 or 44-46, the crystalline composition of any one of claims 52-55, or the pharmaceutical composition of claim 56 in the preparation of a medicament for treating a disease mediated by a BET protein.

58. The use according to claim 57, characterized in that The disease mediated by BET proteins is selected from cancer.

59. The use according to claim 58, characterized in that The cancer is selected from a solid tumor or a hematological tumor.

60. The use according to claim 59, characterized in that The solid tumor is selected from breast cancer or prostate cancer.

61. The use according to claim 59, characterized in that The hematological tumor is selected from acute myeloid leukemia, multiple myeloma or diffuse large B-cell lymphoma.

62. A method for preparing the crystalline form I of the compound of formula (I) according to claim 1, comprising the following steps: (1) mixing the compound of formula (I) with solvent I; (2) Filtration and drying; in, The solvent I is selected from dimethyl sulfoxide solvent or a mixed solvent of dichloromethane and methanol.

63. A method for preparing the crystalline form I of the compound of formula (I) according to claim 1, comprising the following steps: (1) mixing the compound of formula (I) with solvent I; (2) mixing the mixture of step (1) with solvent II; (3) Filtration and drying; in, The solvent I is selected from dimethyl sulfoxide, and the solvent II is selected from water or methanol.

64. A method for preparing the crystalline form I of the compound of formula (I) according to claim 1, comprising the following steps: (1) mixing a pharmaceutically acceptable salt of a compound of formula (I) with a solvent III; (2) Filtration and drying; in, The solvent III is selected from water, or a mixed solvent of acetonitrile and water; the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride of the compound of formula (I).

65. A method for preparing the crystalline form I of the compound of formula (I) according to claim 1, comprising the following steps: (1) mixing a pharmaceutically acceptable salt of a compound of formula (I) with a solvent III; (2) mixing the mixture of step (1) with solvent IV; (3) Filtration and drying; in, The solvent III is selected from methanol, the solvent IV is selected from water; the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride of the compound of formula (I).

66. A method for preparing the crystalline form A of the hydrochloride salt of the compound of formula (I) according to claim 13, comprising the following steps: (1) mixing the compound of formula (I) with solvent A; (2) adding hydrochloric acid to the mixture of step (1); (3) Filtration and drying; in, The solvent A is selected from methanol.

67. A method for preparing the crystalline form D of the sulfate salt of the compound of formula (I) according to claim 31, comprising the following steps: (1) mixing the compound of formula (I) with solvent D; (2) adding a solution of sulfuric acid in solvent D to the mixture of step (1); (3) Filtration and drying; in, The solvent D is selected from methanol.

68. A method for preparing the crystalline form E of the phosphate of the compound of formula (I) according to claim 39, comprising the following steps: (1) mixing the compound of formula (I) with solvent E; (2) adding phosphoric acid to the mixture of step (1); (3) Filtration and drying; in, The solvent E is selected from acetonitrile.

69. A method for preparing the crystalline form F of the mesylate salt of the compound of formula (I) according to claim 47, comprising the following steps: (1) mixing the compound of formula (I) with solvent F; (2) adding methanesulfonic acid to the mixture of step (1); (3) Filtration and drying; in, The solvent F is selected from acetonitrile.

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