Salt of nitrogen-containing fused heterocyclic compound or crystal form thereof, and preparation method therefor, pharmaceutical composition thereof, and use thereof

Abstract

A salt of a nitrogen-containing fused heterocyclic compound or a crystal form thereof, and a preparation method therefor, a pharmaceutical composition thereof, and a use thereof, in particular, a salt of compound I as shown below or a crystal form thereof, and a preparation method, a pharmaceutical composition and a use. The salt of compound I or the crystal form thereof exhibits at least one of the following advantages: improved bioavailability, great mechanical properties, improved chemical stability, excellent fluidity, great compressibility, and improved dissolution characteristics.

Description

Salt, crystal form, preparation method, pharmaceutical composition and use of nitrogen-containing fused heterocyclic compound Technical Field

[0001] The present invention relates to N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, and specifically to a salt, a crystal form, a preparation method, a pharmaceutical composition and uses of the compound. Background Art

[0002] Compound I, N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(2-(dimethylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine, has the following structure:

[0003]

[0004] Compound I has been disclosed in CN106928219A and WO2017114512A1 (the entire disclosure of which is incorporated herein by reference, as if described herein). It has high selectivity for cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) at the molecular level, and has high inhibitory activity against CDK4 and CDK6. It has a significant inhibitory effect on the proliferation of tumor cells associated with cyclin-dependent kinase activity at the cellular and animal levels. It can be used to treat malignant tumors such as breast cancer, colon cancer, non-small cell carcinoma, brain astrocytoma, chronic myeloid leukemia, pancreatic cancer, acute monocytic leukemia, liver cancer (including hepatocellular carcinoma, hepatic adenocarcinoma), gastric cancer, non-small cell lung cancer, malignant glioblastoma and prostate adenocarcinoma. In addition, it has good stability in liver microsomes of humans, mice, etc., has no obvious inhibition of metabolic enzymes, has good absorption properties in mice and rats, high bioavailability, and good drugability.

[0005] However, there remains a need to provide Compound I with desirable processing properties, such as ease of handling, ease of processing, improved solubility characteristics, improved shelf life, ease of purification, etc., to improve the performance characteristics of pharmaceuticals.

[0006] Summary of the Invention

[0007] The present invention provides salts, crystalline forms, preparation methods, pharmaceutical compositions, and uses of Compound I. The salts or crystalline forms of Compound I exhibit at least one of the following advantages: improved bioavailability, good mechanical properties, improved chemical stability, excellent flow properties, good compressibility, and improved solubility characteristics.

[0008] In one aspect, the present invention provides a salt of Compound 1 as shown below, wherein the salt is selected from the group consisting of maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate,

[0009]

[0010] The salt of Compound I can be obtained by conventional methods for preparing salt compounds in the art, for example, by reacting the free base of Compound I with the corresponding acid, or by an acid displacement reaction, or can be prepared according to the methods described below in this application and the methods disclosed in the examples, combined with common technical knowledge in the art.

[0011] The salt may be one or more selected from the group consisting of maleate crystalline form A, maleate crystalline form B, maleate crystalline form C, hydrochloride crystalline form A, hydrochloride crystalline form B, phosphate crystalline form A, lactate crystalline form A, fumarate crystalline form A, succinate crystalline form A, malate crystalline form A, adipate crystalline form A, hippurate crystalline form A, glycolate crystalline form A, benzoate crystalline form A and nicotinate crystalline form A of Compound I.

[0012] More particularly, the salt may be one or more selected from the group consisting of maleate crystalline form A, fumarate crystalline form A, adipate crystalline form A and benzoate crystalline form A of Compound I.

[0013] More particularly, the salt may be the maleate salt form A of Compound I.

[0014] More particularly, the salt may be the fumarate crystalline form A of Compound I.

[0015] More particularly, the salt may be the adipate salt form A of Compound I.

[0016] More particularly, the salt may be the benzoate salt form A of Compound I.

[0017] In one embodiment, the salt of Compound 1 is a maleate salt.

[0018] In one embodiment, the maleate salt of Compound 1 exists in the form of Form A, Form B or Form C.

[0019] The X-ray powder diffraction (XRPD) pattern of the maleate salt crystalline form A has characteristic peaks at diffraction angles 2θ of approximately 5.48±0.2°, 8.55±0.2°, 10.92±0.2°, 12.04±0.2°, 12.98±0.2°, 13.81±0.2°, 16.40±0.2°, 19.59±0.2°, and 27.46±0.2°, and preferably, at 6.11±0.2°, 7.84±0.2°, 15.32±0.2°, 18.70±0.2°, 21.55±0.2°, There are diffraction peaks at one or more of 22.21±0.2°, 22.80±0.2°, 23.32±0.2°, 24.57±0.2°, 25.62±0.2°, 26.07±0.2°, 28.23±0.2°, 28.68±0.2°, 33.08±0.2° and 38.76±0.2°, preferably at a diffraction angle 2θ of about 5.48±0.2°, 6.11±0.2°, 7.84±0.2°, 8.55±0.2°, 10.92±0.2°, 12.04±0.2°, 12.98±0.2°, 13.81±0.2°, 15.32±0 .2°, 16.40±0.2°, 18.70±0.2°, 19.59±0.2°, 21.55±0.2°, 22.21±0.2°, 22.80±0.2°, 23.32±0.2°, 24.57±0.2°, 25.62±0.2°, 26.07±0.2°, 27.46±0.2°, 28.23±0.2°, 28.68±0.2°, 33.08±0.2° and 38.76±0.2°, in particular, the maleate salt form A has an XRPD pattern substantially as shown in Figure 1, and the target used in the XRPD is a Cu target.

[0020] The differential scanning calorimetry (DSC) graph of the maleate salt crystalline form A has an endothermic peak with an onset temperature of about 222.8° C. and an endothermic peak with a peak temperature of about 235.3° C., particularly, the maleate salt crystalline form A has a DSC graph substantially as shown in FIG2 .

[0021] The thermogravimetric analysis (TGA) graph of the maleate salt Form A shows that the sample loses approximately 4.1% weight at approximately 200°C and loses approximately 17.5% weight in the temperature range of approximately 200-290°C, presumably due to deacidification (the theoretical weight loss due to deacidification is approximately 18.7%). In particular, the maleate salt Form A has a TGA graph substantially as shown in FIG2 .

[0022] through 1H NMR analysis revealed that the molar ratio of maleic acid to free base in the maleate salt Form A was approximately 1:1. Variable temperature XRPD (VT-XRPD) analysis revealed that the maleate salt Form A remained unchanged after heating to approximately 170°C and cooling to approximately 30°C under N2 protection. Therefore, it is speculated that the maleate salt Form A is an anhydrous form.

[0023] The X-ray powder diffraction (XRPD) pattern of the maleate salt form B has characteristic peaks at diffraction angles 2θ of approximately 5.75±0.2°, 9.72±0.2°, 14.91±0.2°, 15.76±0.2°, 17.43±0.2°, 18.09±0.2°, 22.20±0.2°, 23.23±0.2°, 25.17±0.2°, and 27.96±0.2°. In particular, the maleate salt form B has an XRPD pattern substantially as shown in Figure 3, and the target used in the XRPD is a Cu target.

[0024] The differential scanning calorimetry (DSC) graph of the maleate salt form B has two weak endothermic peaks with peak temperatures of about 74.6°C and about 236.8°C, respectively, and a sharp endothermic peak with an onset temperature of about 225.5°C. In particular, the maleate salt form B has a DSC graph substantially as shown in Figure 4.

[0025] The thermogravimetric analysis (TGA) graph of the maleate salt Form B shows that the sample loses 6.4% of its weight when heated to approximately 200°C, and the total weight loss in the range of approximately 200-290°C is approximately 19.1%, which is presumably caused by deacidification (the theoretical weight loss due to deacidification is approximately 18.7%). In particular, the maleate salt Form B has a TGA graph substantially as shown in FIG4 .

[0026] through 1 H NMR detection shows that in the maleate salt crystalline form B, the molar ratio of maleic acid to free base is about 1:1, and contains a small amount of anti-solvent, such as acetone or toluene.

[0027] The X-ray powder diffraction (XRPD) pattern of the maleate salt form C has characteristic peaks at diffraction angles 2θ of approximately 5.51±0.2°, 6.31±0.2°, 8.91±0.2°, 9.62±0.2°, 10.59±0.2°, 11.05±0.2°, 12.17±0.2°, 14.99±0.2°, 15.73±0.2°, 16.65±0.2°, 21.40±0.2°, 22.94±0.2°, 24.71±0.2°, 26.72±0.2°, 28.22±0.2°, 32.36±0.2°, and 38.52±0.2°. In particular, the maleate salt form C has an XRPD pattern substantially as shown in Figure 5, and the target used in the XRPD is a Cu target.

[0028] The differential scanning calorimetry (DSC) graph of the maleate salt form C has an exothermic peak with a peak temperature of about 142.8° C. and a sharp endothermic peak with an onset temperature of about 222.0° C., particularly, the maleate salt form C has a DSC graph substantially as shown in FIG6 .

[0029] The thermogravimetric analysis (TGA) graph of the maleate salt Form C shows that the sample loses 6.3% of its weight when heated to approximately 200°C, and the total weight loss in the range of approximately 200-290°C is approximately 17.5%, which is presumably caused by deacidification (the theoretical weight loss due to deacidification is approximately 18.7%). In particular, the maleate salt Form C has a TGA graph substantially as shown in FIG6 .

[0030] through 1 H NMR analysis revealed that the maleate salt Form C had a molar ratio of maleic acid to free base of approximately 1:1, with no residual solvent. VT-XRPD analysis revealed that the maleate salt Form C remained unchanged when heated to approximately 110°C under nitrogen protection. Therefore, it is speculated that the maleate salt Form C is an anhydrous form.

[0031] Maleate Form B transforms into maleate Form C after N2 purge at about 30°C, and it is speculated that maleate Form B is a hydrate. Maleate Forms B and C can also transform into maleate Form A.

[0032] The present invention also provides a method for preparing the maleate salt form A, which is one of the following methods:

[0033] Method 1:

[0034] (1) reacting the free base of Compound I with maleic acid in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), an alcohol solvent (e.g., methanol (MeOH)), and an ester solvent (e.g., ethyl acetate (EtOA));

[0035] Method 2:

[0036] (2) Obtained by transformation from maleate crystal form B or C.

[0037] Maleate salt crystal form B or C is a thermodynamically unstable crystal and will eventually transform into maleate salt crystal form A. Therefore, there is no particular limitation on the method for converting maleate salt crystal form B or C to obtain maleate salt crystal form A. For example, maleate salt crystal form B or C can be converted into maleate salt crystal form A after being suspended and stirred in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), and an ester solvent (e.g., ethyl acetate (EtOA)), but the present invention is not limited thereto.

[0038] The present invention also provides a method for preparing the maleate salt form B, which comprises: adding an antisolvent (such as acetone and toluene) dropwise to a mixed solution of the maleate salt of compound I in methanol (MeOH) / dichloromethane (DCM) (1:1, v / v) for recrystallization, and placing the resulting solid at room temperature under low humidity.

[0039] The present invention also provides a method for preparing the maleate salt form C, which comprises: purging the maleate salt form B with an inert gas (such as N2) to obtain the maleate salt form C.

[0040] In one embodiment, the salt of Compound 1 is a hydrochloride salt.

[0041] In one embodiment, the hydrochloride salt of Compound 1 exists in the form of Form A or Form B.

[0042] The X-ray powder diffraction (XRPD) pattern of the hydrochloride salt form A has characteristic peaks at diffraction angles 2θ of approximately 4.41±0.2°, 5.34±0.2°, 8.90±0.2°, 9.16±0.2°, 10.69±0.2°, 11.07±0.2°, 13.16±0.2°, 15.63±0.2°, 18.49±0.2°, 19.25±0.2°, 21.28±0.2°, 24.60±0.2°, and 26.85±0.2°. In particular, the XRPD pattern of the hydrochloride salt form A is substantially as shown in Figure 7, and the target used for the XRPD is a Cu target.

[0043] The differential scanning calorimetry (DSC) chart of the hydrochloride salt form A has endothermic peaks with peak temperatures of about 94.6° C., about 237.4° C., and about 266.9° C., respectively. In particular, the hydrochloride salt form A has a DSC chart substantially as shown in FIG. 8 .

[0044] The thermogravimetric analysis (TGA) graph of the hydrochloride salt form A shows that the sample loses about 3.5% of weight when heated to about 100° C. Specifically, the hydrochloride salt form A has a TGA graph substantially as shown in FIG. 8 .

[0045] through 1 H NMR detection showed that in the hydrochloride salt form A, the molar ratio of hydrochloric acid to free base was about 1:1.

[0046] The present invention also provides a method for preparing the hydrochloride salt form A, comprising reacting a free base of Compound I and hydrochloric acid in a molar ratio of about 1:1 in a solvent selected from an ether solvent (e.g., tetrahydrofuran (THF)) and an ester solvent (e.g., ethyl acetate (EtOA)).

[0047] The X-ray powder diffraction (XRPD) pattern of the hydrochloride salt form B has characteristic peaks at diffraction angles 2θ of approximately 3.73±0.2°, 4.96±0.2°, 7.24±0.2°, 10.26±0.2°, and 15.47±0.2°. In particular, the XRPD pattern of the hydrochloride salt form B is substantially as shown in Figure 7, and the target type used for the XRPD is a Cu target.

[0048] The differential scanning calorimetry (DSC) chart of the hydrochloride salt form B has endothermic peaks with peak temperatures of about 109.9° C., about 160.3° C., and about 266.9° C., respectively. In particular, the hydrochloride salt form B has a DSC chart substantially as shown in FIG. 9 .

[0049] The thermogravimetric analysis (TGA) graph of the hydrochloride salt Form B shows that the sample loses about 9.1% of weight when heated to about 130° C. Specifically, the hydrochloride salt Form B has a TGA graph substantially as shown in FIG. 9 .

[0050] through 1 H NMR detection showed that in the hydrochloride salt form B, the molar ratio of hydrochloric acid to free base was about 3:1.

[0051] The present invention also provides a method for preparing the hydrochloride salt form B, comprising reacting a free base of Compound I and hydrochloric acid at a molar ratio of about 3:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), an ester solvent (e.g., ethyl acetate (EtOA)), and a mixed solvent (e.g., a halogenated alkane and an alcohol solvent, such as dichloromethane / MeOH).

[0052] In one embodiment, the salt of Compound 1 is a phosphate salt.

[0053] In one embodiment, the phosphate salt of Compound 1 exists in the form of Form A.

[0054] The X-ray powder diffraction (XRPD) pattern of the phosphate crystalline form A has characteristic peaks at diffraction angles 2θ of approximately 5.63±0.2°, 7.86±0.2°, 9.88±0.2°, 12.43±0.2°, 15.86±0.2°, 19.64±0.2°, 21.26±0.2°, 22.72±0.2°, 25.42±0.2°, and 27.32±0.2°. In particular, the phosphate crystalline form A has an XRPD pattern substantially as shown in Figure 10, and the target used for the XRPD is a Cu target.

[0055] The differential scanning calorimetry (DSC) chart of the phosphate salt crystal form A has endothermic peaks with onset temperatures of about 48.0° C. and about 228.3° C., respectively. Specifically, the phosphate salt crystal form A has a DSC chart substantially as shown in FIG. 11 .

[0056] The thermogravimetric analysis (TGA) graph of the phosphate salt crystal form A shows that the sample loses about 3.6% of weight when heated to about 130° C. Specifically, the phosphate salt crystal form A has a TGA graph substantially as shown in FIG. 11 .

[0057] through 1 H NMR detection showed that in the phosphate crystal form A, the molar ratio of phosphoric acid to free base was about 1:1.

[0058] The present invention also provides a method for preparing the above-mentioned phosphate salt form A, which comprises reacting the free base of Compound I and phosphoric acid in a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), an ester solvent (e.g., ethyl acetate (EtOA)), and a mixed solvent (e.g., a halogenated alkane and an alcohol solvent, such as dichloromethane / MeOH).

[0059] In one embodiment, the salt of Compound 1 is a lactate salt.

[0060] In one embodiment, the lactic acid salt of Compound 1 exists in the form of Form A.

[0061] The X-ray powder diffraction (XRPD) pattern of the lactate salt crystalline form A has characteristic peaks at diffraction angles 2θ of approximately 4.52±0.2°, 5.12±0.2°, 6.94±0.2°, 8.97±0.2°, 10.16±0.2°, 10.49±0.2°, 11.30±0.2°, 13.35±0.2°, 13.86±0.2°, 17.51±0.2°, 18.52±0.2°, 21.02±0.2°, 21.97±0.2°, 25.10±0.2°, 26.05±0.2°, and 27.04±0.2°. In particular, the lactate salt crystalline form A has an XRPD pattern substantially as shown in Figure 12, and the target used for the XRPD is a Cu target.

[0062] The differential scanning calorimetry (DSC) chart of the lactate salt crystalline form A has endothermic peaks with peak temperatures of about 99.0° C. and about 183.3° C., respectively. In particular, the lactate salt crystalline form A has a DSC chart substantially as shown in FIG. 13 .

[0063] The thermogravimetric analysis (TGA) of the lactate salt crystalline form A shows that the sample loses about 4.0% of weight when heated to about 130° C. Specifically, the lactate salt crystalline form A has a TGA graph substantially as shown in FIG. 13 .

[0064] through 1 H NMR detection showed that in the lactate salt crystalline form A, the molar ratio of lactic acid to free base was about 1:1.

[0065] The present invention also provides a method for preparing the above-mentioned lactate salt form A, which comprises: reacting the free base of Compound I and lactic acid in a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), or an ester solvent (e.g., ethyl acetate (EtOA)).

[0066] In one embodiment, the salt of Compound 1 is a fumarate salt.

[0067] In one embodiment, the fumarate salt of Compound 1 exists in the form of Form A.

[0068] The X-ray powder diffraction (XRPD) pattern of the fumarate salt form A has a diffraction angle 2θ of approximately 5.73±0.2°, 6.29±0.2°, 8.04±0.2°, 10.28±0.2°, 11.27±0.2°, 12.79±0.2°, 14.17±0.2°, 14.99±0.2°, 16.07±0.2°, 17.28±0.2°, There are characteristic peaks at 18.16±0.2°, 19.90±0.2°, 20.62±0.2°, 22.13±0.2°, 23.10±0.2°, 23.82±0.2°, 24.52±0.2°, and 27.03±0.2°. In particular, the fumarate salt form A has an XRPD pattern substantially as shown in Figure 14, and the target type used in the XRPD is a Cu target.

[0069] The differential scanning calorimetry (DSC) chart of the fumarate salt form A has an exothermic peak with a peak temperature of about 163.5° C. and an endothermic peak with an onset temperature of about 248.9° C. Specifically, the fumarate salt form A has a DSC chart substantially as shown in FIG. 15 .

[0070] The thermogravimetric analysis (TGA) of the fumarate salt crystalline form A shows that the sample loses about 2.26% of weight when heated to about 130° C. Specifically, the fumarate salt crystalline form A has a TGA graph substantially as shown in FIG. 15 .

[0071] through 1 H NMR detection showed that in the fumarate salt crystalline form A, the molar ratio of fumaric acid to free base was about 1:1.

[0072] The present invention also provides a method for preparing the above-mentioned fumarate salt form A, which comprises reacting the free base of Compound I and fumaric acid in a molar ratio of about 1:1 in a solvent selected from an ether solvent (e.g., tetrahydrofuran (THF)), an ester solvent (e.g., ethyl acetate (EtOA)), and a mixed solvent (e.g., a halogenated alkane and an alcohol solvent, such as dichloromethane / MeOH).

[0073] In one embodiment, the salt of Compound 1 is succinate.

[0074] In one embodiment, the succinate salt of Compound 1 exists in the form of Form A.

[0075] The X-ray powder diffraction (XRPD) pattern of the succinate salt form A has characteristic peaks at diffraction angles 2θ of approximately 4.18±0.2°, 5.33±0.2°, 6.82±0.2°, 8.35±0.2°, 11.56±0.2°, 13.67±0.2°, 16.44±0.2°, 17.74±0.2°, 20.47±0.2°, and 23.15±0.2°. In particular, the succinate salt form A has an XRPD pattern substantially as shown in Figure 16, and the target used in the XRPD is a Cu target.

[0076] The differential scanning calorimetry (DSC) chart of the succinate salt form A has endothermic peaks with onset temperatures of about 51.6° C. and about 182.1° C., respectively. In particular, the succinate salt form A has a DSC chart substantially as shown in FIG. 17 .

[0077] The thermogravimetric analysis (TGA) graph of the succinate salt Form A shows that the sample loses about 3.2% of weight when heated to about 130° C. Specifically, the succinate salt Form A has a TGA graph substantially as shown in FIG. 17 .

[0078] through 1 H NMR detection showed that in the succinate salt crystal form A, the molar ratio of succinic acid to free base was about 1:1.

[0079] The present invention also provides a method for preparing the above-mentioned succinate salt form A, which comprises reacting the free base of Compound I and succinic acid in a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), or an ester solvent (e.g., ethyl acetate (EtOA)).

[0080] In one embodiment, the salt of Compound 1 is a malate salt.

[0081] In one embodiment, the malate salt of Compound 1 exists in the form of Form A.

[0082] The X-ray powder diffraction (XRPD) pattern of the malate salt form A has characteristic peaks at diffraction angles 2θ of approximately 4.49±0.2°, 6.10±0.2°, 7.16±0.2°, 9.00±0.2°, 10.99±0.2°, 14.87±0.2°, 16.65±0.2°, 19.73±0.2°, 20.55±0.2°, 21.96±0.2°, 23.12±0.2°, 24.03±0.2°, 25.87±0.2°, and 26.58±0.2°. In particular, the malate salt form A has an XRPD pattern substantially as shown in Figure 18, and the target used in the XRPD is a Cu target.

[0083] The differential scanning calorimetry (DSC) chart of the malate crystalline form A has endothermic peaks with peak temperatures of about 100.4° C., about 175.9° C., and about 185.6° C., respectively. In particular, the malate crystalline form A has a DSC chart substantially as shown in FIG. 19 .

[0084] The thermogravimetric analysis (TGA) graph of the malate crystalline Form A shows that the sample loses about 4.0% of its weight when heated to about 130° C. Specifically, the malate crystalline Form A has a TGA graph substantially as shown in FIG. 19 .

[0085] through 1 H NMR detection showed that in the malate salt crystalline form A, the molar ratio of malic acid to free base was about 1:1.

[0086] The present invention also provides a method for preparing the above-mentioned malate salt form A, which comprises: reacting the free base of Compound I and malic acid in a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), or an ester solvent (e.g., ethyl acetate (EtOA)).

[0087] In one embodiment, the salt of Compound 1 is an adipate salt.

[0088] In one embodiment, the adipate salt of Compound 1 exists in the form of Form A.

[0089] The X-ray powder diffraction (XRPD) pattern of the adipate salt crystalline form A has characteristic peaks at diffraction angles 2θ of approximately 4.53±0.2°, 4.85±0.2°, 6.03±0.2°, 7.15±0.2°, 9.05±0.2°, 9.56±0.2°, 10.94±0.2°, 12.18±0.2°, 13.66±0.2°, 14.61±0.2°, 18.23±0.2°, 20.12±0.2°, 24.05±0.2°, 25.77±0.2°, 26.25±0.2°, and 27.50±0.2°. In particular, the adipate salt crystalline form A has an XRPD pattern substantially as shown in Figure 20, and the target used in the XRPD is a Cu target.

[0090] The differential scanning calorimetry (DSC) chart of the adipate salt crystalline form A has an endothermic peak with an onset temperature of about 182.0° C., specifically, the adipate salt crystalline form A has a DSC chart substantially as shown in FIG. 21 .

[0091] The thermogravimetric analysis (TGA) of the adipate salt crystalline form A shows that the sample loses about 2.5% of weight when heated to about 130° C. Specifically, the adipate salt crystalline form A has a TGA graph substantially as shown in FIG. 21 .

[0092] through 1 H NMR detection showed that in the adipate salt crystalline form A, the molar ratio of adipic acid to free base was about 1:1.

[0093] The present invention also provides a method for preparing the above-mentioned adipate salt form A, which comprises reacting the free base of Compound I and adipic acid in a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), or an ester solvent (e.g., ethyl acetate (EtOA)).

[0094] In one embodiment, the salt of Compound 1 is hippurate.

[0095] In one embodiment, the hippurate salt of Compound I exists in the form of Form A.

[0096] The X-ray powder diffraction (XRPD) pattern of the hippurate salt form A has characteristic peaks at diffraction angles 2θ of approximately 4.45±0.2°, 5.50±0.2°, 9.17±0.2°, 18.79±0.2°, 23.20±0.2°, and 25.42±0.2°. In particular, the hippurate salt form A has an XRPD pattern substantially as shown in Figure 22, and the target type used for the XRPD is a Cu target.

[0097] The differential scanning calorimetry (DSC) graph of the hippurate salt form A has endothermic peaks with peak temperatures of about 124.2°C, about 141.0°C, about 154.6°C, about 178.0°C and about 217.2°C, respectively. In particular, the hippurate salt form A has a DSC graph substantially as shown in Figure 23.

[0098] The thermogravimetric analysis (TGA) of the hippurate salt crystal form A shows that the sample loses about 4.2% of its weight when heated to about 130° C. Specifically, the hippurate salt crystal form A has a TGA graph substantially as shown in FIG. 23 .

[0099] through 1 H NMR detection shows that in the hippurate salt crystal form A, the molar ratio of hippuric acid to free base is about 1:1.

[0100] The present invention also provides a method for preparing the hippurate salt form A, which comprises reacting the free base of Compound I and hippuric acid in a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone) or an ester solvent (e.g., ethyl acetate (EtOA)).

[0101] In one embodiment, the salt of Compound 1 is a glycolate salt.

[0102] In one embodiment, the glycolic acid salt of Compound 1 exists in the form of Form A.

[0103] The X-ray powder diffraction (XRPD) pattern of the glycolate salt crystalline form A has characteristic peaks at diffraction angles 2θ of approximately 4.50±0.2°, 5.19±0.2°, 6.90±0.2°, 9.00±0.2°, 10.42±0.2°, 11.35±0.2°, 13.74±0.2°, 15.60±0.2°, 16.24±0.2°, 17.97±0.2°, 20.77±0.2°, 22.68±0.2°, 25.12±0.2°, 26.61±0.2°, 27.69±0.2°, and 31.73±0.2°. In particular, the glycolate salt crystalline form A has an XRPD pattern substantially as shown in Figure 24, and the target used for the XRPD is a Cu target.

[0104] The differential scanning calorimetry (DSC) chart of the glycolate salt crystalline form A has endothermic peaks with onset temperatures of about 54.1° C. and about 183.2° C., respectively. In particular, the glycolate salt crystalline form A has a DSC chart substantially as shown in FIG. 25 .

[0105] The thermogravimetric analysis (TGA) of the glycolate salt Form A shows that the sample loses about 4.8% of its weight when heated to about 130° C. Specifically, the glycolate salt Form A has a TGA graph substantially as shown in FIG. 25 .

[0106] through 1 H NMR detection showed that in the glycolate salt crystalline form A, the molar ratio of glycolic acid to free base was about 1:1.

[0107] The present invention also provides a method for preparing the glycolate salt form A, comprising reacting a free base of Compound I and glycolic acid at a molar ratio of about 1:1 in a solvent selected from a ketone solvent (e.g., acetone), an ether solvent (e.g., tetrahydrofuran (THF)), or an ester solvent (e.g., ethyl acetate (EtOA)).

[0108] In one embodiment, the salt of Compound 1 is a benzoate salt.

[0109] In one embodiment, the benzoate salt of Compound 1 exists in the form of Form A.

[0110] The X-ray powder diffraction (XRPD) pattern of the benzoate salt form A has diffraction angles 2θ of approximately 4.47±0.2°, 4.80±0.2°, 6.74±0.2°, 8.96±0.2°, 9.94±0.2°, 10.40±0.2°, 12.78±0.2°, 13.50±0.2°, 14.88±0.2°, 17.41±0.2°, 1 There are characteristic peaks at 8.32±0.2°, 19.54±0.2°, 20.84±0.2°, 23.58±0.2°, 25.01±0.2°, 26.31±0.2°, 27.11±0.2°, and 29.33±0.2°. In particular, the benzoate salt form A has an XRPD pattern substantially as shown in Figure 26, and the target type used in the XRPD is a Cu target.

[0111] The differential scanning calorimetry (DSC) chart of the benzoate salt form A has an endothermic peak with an onset temperature of about 169.5° C., particularly, the benzoate salt form A has a DSC chart substantially as shown in FIG. 27 .

[0112] The thermogravimetric analysis (TGA) graph of the benzoate salt Form A shows that the sample loses about 2.7% of weight when heated to about 130° C. Specifically, the benzoate salt Form A has a TGA graph substantially as shown in FIG. 27 .

[0113] through 1 H NMR detection showed that in the benzoate salt form A, the molar ratio of benzoic acid to free base was about 1:1.

[0114] The present invention also provides a method for preparing the above-mentioned benzoate salt form A, which comprises reacting the free base of Compound I and benzoic acid in a molar ratio of about 1:1 in a ketone solvent (such as acetone) to obtain.

[0115] In one embodiment, the salt of Compound 1 is a nicotinate salt.

[0116] In one embodiment, the nicotinate salt of Compound I exists in the form of Form A.

[0117] The X-ray powder diffraction (XRPD) pattern of the nicotinate salt form A has characteristic peaks at diffraction angles 2θ of approximately 4.54±0.2°, 6.46±0.2°, 10.14±0.2°, 13.41±0.2°, 14.66±0.2°, 17.14±0.2°, 18.83±0.2°, 21.36±0.2°, 24.83±0.2°, and 26.27±0.2°. In particular, the nicotinate salt form A has an XRPD pattern substantially as shown in FIG. 28 , and the target used for the XRPD is a Cu target.

[0118] The differential scanning calorimetry (DSC) chart of the nicotinate salt form A has endothermic peaks with peak temperatures of about 103.9° C., about 160.3° C., and about 212.5° C., respectively. Specifically, the nicotinate salt form A has a DSC chart substantially as shown in FIG. 29 .

[0119] The thermogravimetric analysis (TGA) graph of the nicotinate salt Form A shows that the sample loses about 4.9% of weight when heated to about 130° C. Specifically, the nicotinate salt Form A has a TGA graph substantially as shown in FIG. 29 .

[0120] through 1 H NMR detection showed that in the nicotinate salt crystal form A, the molar ratio of nicotinic acid to free base was about 1:1.

[0121] The present invention also provides a method for preparing the above-mentioned nicotinate salt form A, comprising reacting a free base of Compound I and nicotinic acid at a molar ratio of about 1:1 in a solvent selected from an ether solvent (e.g., tetrahydrofuran (THF)) or an ester solvent (e.g., ethyl acetate (EtOA)).

[0122] In the preparation method of the crystal form of the present invention, seed crystals may also be used. Seed crystals may be used in the preparation method of each crystal form of the present application according to methods known in the art.

[0123] In another aspect, the present invention provides a pharmaceutical composition comprising one or more salts selected from the above-mentioned Compound I, wherein the salt is selected from maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate.

[0124] In addition, the pharmaceutical composition may further include a pharmaceutically acceptable carrier. The choice of the pharmaceutically acceptable carrier varies depending on the route of administration and the characteristics of the action, and may generally be a filler, diluent, binder, wetting agent, disintegrant, lubricant, emulsifier, suspending agent, etc. conventional in the art.

[0125] The pharmaceutical composition can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingually, buccally, rectally, urethrally, vaginally, nasally, by inhalation or topically, with oral administration being preferred.

[0126] The pharmaceutical composition can be used to prevent or treat diseases associated with abnormal cell cycle regulation. The "disease associated with abnormal cell cycle regulation" can be a "disease associated with abnormal cyclin-dependent kinases (preferably CDK4 and / or CDK6)", particularly a tumor, more particularly a malignant tumor (such as breast cancer, colon cancer, non-small cell carcinoma, astrocytoma, chronic myeloid leukemia, pancreatic cancer, acute monocytic leukemia, liver cancer (including hepatocellular carcinoma, hepatic adenocarcinoma), gastric cancer, non-small cell lung cancer, malignant glioblastoma and prostate adenocarcinoma), advanced solid tumors (including but not limited to breast cancer, central nervous system primary tumors / metastatic tumors, etc.).

[0127] The pharmaceutical composition can be used as a cyclin-dependent kinase (preferably CDK4 and / or CDK6) inhibitor.

[0128] The pharmaceutical composition can be used to inhibit the proliferation of tumor cells. The tumor cells are preferably cancer cells; the cancer cells are preferably breast cancer cells, colon cancer cells, non-small cell cancer cells, astrocytoma cells, chronic myeloid leukemia cells, pancreatic cancer cells, acute monocytic leukemia cells, liver cancer cells (including hepatocellular carcinoma cells and hepatoadenocarcinoma cells), gastric cancer cells, non-small cell lung cancer cells, glioblastoma cells, and prostate adenocarcinoma cells; the breast cancer cells are preferably one or more of MCF-7, T-47D, and ZR-75-1 breast cancer cells.

[0129] In another aspect, the present invention provides a salt of Compound I for use in the preparation of a medicament, wherein the salt is selected from maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate, and nicotinate, and the medicament is used to prevent or treat a disease associated with abnormal cell cycle regulation. In particular, the "disease associated with abnormal cell cycle regulation" can be a "disease associated with abnormal cyclin-dependent kinases (preferably CDK4 and / or CDK6)", in particular a tumor, more particularly a malignant tumor (e.g., breast cancer, colon cancer, non-small cell carcinoma, astrocytoma, chronic myeloid leukemia, pancreatic cancer, acute monocytic leukemia, liver cancer (including hepatocellular carcinoma, liver adenocarcinoma), gastric cancer, non-small cell lung cancer, malignant glioblastoma, and prostate adenocarcinoma), advanced solid tumors (including but not limited to breast cancer, central nervous system primary tumors / metastatic tumors, etc.).

[0130] On the other hand, the present invention provides the use of a salt of the above-mentioned compound I for preparing a cyclin-dependent kinase (preferably CDK4 and / or CDK6) inhibitor, wherein the salt is selected from maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate.

[0131] In another aspect, the present invention provides the use of a salt of Compound I for preparing a medicament for inhibiting tumor cell proliferation, wherein the salt is selected from maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate, and nicotinate. The tumor cells are preferably cancer cells; the cancer cells are preferably breast cancer cells; and the breast cancer cells are preferably one or more of MCF-7, T-47D, and ZR-75-1 breast cancer cells.

[0132] In the above-mentioned pharmaceutical compositions and uses, the salt may be one or more selected from the group consisting of maleate crystalline form A, maleate crystalline form B, maleate crystalline form C, hydrochloride crystalline form A, hydrochloride crystalline form B, phosphate crystalline form A, lactate crystalline form A, fumarate crystalline form A, succinate crystalline form A, malate crystalline form A, adipate crystalline form A, hippurate crystalline form A, glycolate crystalline form A, benzoate crystalline form A and nicotinate crystalline form A of Compound I.

[0133] More particularly, the salt may be one or more selected from the group consisting of maleate crystalline form A, fumarate crystalline form A, adipate crystalline form A and benzoate crystalline form A of Compound I.

[0134] More particularly, the salt may be the maleate salt form A of Compound I.

[0135] More particularly, the salt may be the fumarate crystalline form A of Compound I.

[0136] More particularly, the salt may be the adipate salt form A of Compound I.

[0137] More particularly, the salt may be the benzoate salt form A of Compound I.

[0138] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0139] FIG1 is an XRPD pattern of the maleate salt form A of Compound I according to the present invention.

[0140] FIG2 is a DSC and TGA diagram of the maleate salt form A of Compound I according to the present invention.

[0141] FIG3 is an XRPD pattern of the maleate salt form B of Compound I according to the present invention.

[0142] FIG4 is a DSC and TGA diagram of the maleate crystalline form B of Compound I according to the present invention.

[0143] FIG5 is an XRPD pattern of Form C of maleate salt of Compound 1 according to the present invention.

[0144] FIG6 is a DSC and TGA diagram of the maleate salt form C of Compound I according to the present invention.

[0145] FIG7 is an XRPD pattern of Compound I hydrochloride Form A and Form B according to the present invention.

[0146] FIG8 is a DSC and TGA diagram of Compound I hydrochloride Form A according to the present invention.

[0147] FIG9 is a DSC and TGA diagram of Compound I hydrochloride Form B according to the present invention.

[0148] FIG10 is an XRPD pattern of Form A of the phosphate salt of Compound I according to the present invention.

[0149] FIG11 is a DSC and TGA diagram of the phosphate crystal form A of Compound I according to the present invention.

[0150] FIG12 is an XRPD pattern of Form A of the lactate salt of Compound 1 according to the present invention.

[0151] FIG13 is a DSC and TGA diagram of Form A of the lactate salt of Compound 1 according to the present invention.

[0152] FIG14 is an XRPD pattern of Form A of the fumarate salt of Compound 1 according to the present invention.

[0153] FIG15 is a DSC and TGA diagram of Form A of the fumarate salt of Compound I according to the present invention.

[0154] FIG16 is an XRPD pattern of Compound 1 succinate salt Form A according to the present invention.

[0155] FIG17 is a DSC and TGA diagram of Form A of the succinate salt of Compound 1 according to the present invention.

[0156] FIG18 is an XRPD pattern of Compound 1 malate Form A according to the present invention.

[0157] FIG19 is a DSC and TGA diagram of Compound 1 malate Form A according to the present invention.

[0158] FIG20 is an XRPD pattern of Compound 1 adipate salt Form A according to the present invention.

[0159] FIG21 is a DSC and TGA diagram of Compound 1 adipate salt Form A according to the present invention.

[0160] FIG22 is an XRPD pattern of Form A of the hippurate salt of Compound 1 according to the present invention.

[0161] FIG23 is a DSC and TGA diagram of Form A of the hippurate salt of Compound 1 according to the present invention.

[0162] FIG24 is an XRPD pattern of Form A of Compound 1 glycolate according to the present invention.

[0163] FIG25 is a DSC and TGA diagram of Form A of the glycolate salt of Compound 1 according to the present invention.

[0164] FIG26 is an XRPD pattern of Compound 1 benzoate Form A according to the present invention.

[0165] FIG27 is a DSC and TGA diagram of Compound 1 benzoate Form A according to the present invention.

[0166] FIG28 is an XRPD pattern of Form A of the nicotinate salt of Compound 1 according to the present invention.

[0167] FIG29 is a DSC and TGA chart of Form A of the nicotinate salt of Compound 1 according to the present invention. DETAILED DESCRIPTION

[0168] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0169] Unless otherwise stated, the devices and testing methods involved in the embodiments of the present invention are as follows:

[0170] X-ray powder diffraction (XRPD): XRPD patterns were collected on a PANalytacal Empyrean X-ray powder diffraction analyzer. The XRPD parameters are shown in Table 1.

[0171] Table 1

[0172]

[0173] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): TGA and DSC spectra were collected on a TA Q500 / 5000 thermogravimetric analyzer and a TAQ200 / 2000 differential scanning calorimeter, respectively. The test parameters are shown in Table 2.

[0174] Table 2: DSC and TGA test parameters

[0175]

[0176] High performance liquid chromatography (HPLC): HPLC was collected on an Agilent 1100 HPLC. Specific HPLC purity test parameters are shown in Table 3 below.

[0177] Table 3

[0178]

[0179]

[0180] Ion chromatography (IC): The anion content was measured on an ion chromatograph (IC) Thermo ICS1100 and the molar ratio was determined by coupling with HPLC data. The specific instrument parameters are listed in Table 4.

[0181] Table 4

[0182] Parameter settings: Column: IonPac AS18 Analytical Column (4 × 250 mm); Mobile phase: 25 mM NaOH; Injection volume: 25 μL; Flow rate: 1.0 mL / min; Sample compartment temperature: 35°C; Column temperature: 35°C; Current: 80 mA; Run time: 10 min (maleic acid, adipic acid), 14 min (fumaric acid), 18 min (benzoic acid)

[0183] Dynamic moisture sorption (DVS): Dynamic moisture sorption (DVS) curves were collected on an SMS (Surface Measurement Systems) DVS Intrinsic. Relative humidity at 25°C was calibrated using the deliquescent points of LiCl, Mg(NO₃)₂, and KCl. DVS test parameters are listed in Table 5.

[0184] Table 5

[0185]

[0186] Solution NMR: Solution NMR spectra were collected on a Bruker 400M NMR spectrometer using DMSO-d6 as the solvent.

[0187] The heating test was carried out as follows:

[0188] The sample was tested under nitrogen protection, heated to the target temperature and then cooled to room temperature. The sample was taken out and exposed to the air, and XRPD was collected for testing.

[0189] The free base of compound 1 was prepared according to the method disclosed in CN106928219A. Its XRPD results showed only a few diffraction peaks. HPLC purity was 95.2 area%. TGA results showed that the sample lost 4.8% of its weight when heated to 200°C. DSC results showed that the sample had one endotherm and two exotherm signals before melting at 233.6°C (starting point temperature). Heating test results showed that the XPRD results did not change when the starting sample was heated to 80°C; the diffraction peak at approximately 4.7° 2θ disappeared when heated to 135°C and 175°C, indicating enhanced crystallinity.

[0190] Preparation Example 1

[0191] The crystalline form was prepared using the following method:

[0192] Acetone, tetrahydrofuran (THF), ethyl acetate (EtOA) and dichloromethane (DCM) / methanol (MeOH) (10:1, v / v) were used as solvents, respectively.

[0193] Approximately 20 mg of Compound I free base was weighed and the corresponding acid was added according to the molar ratios shown in Table 6. 0.3-0.5 mL of solvent was added. After stirring at room temperature for 2 days, the solid was isolated by centrifugation and dried at 50°C for 2 hours for purity characterization by XRPD, TGA, DSC, and HPLC. Blank indicates no acid was added.

[0194] The results of crystal preparation screening are shown in Table 6.

[0195] Table 6

[0196]

[0197]

[0198] XRPD results of the free base Form A showed a small number of diffraction peaks, and HPLC purity was 98.2 area%. TGA results showed a 1.2% weight loss when heated to 130°C. DSC results revealed an endothermic peak at 239.9°C (onset temperature) before melting. DVS results showed a water adsorption of 2.9% at 25°C / 80% RH. XRPD results of the sample before and after DVS testing showed no change in the crystalline form.

[0199] After repeated crystal preparation, it was found that the crystallinity of samples in tartaric acid, citric acid, gentisic acid and methanesulfonic acid systems was weak.

[0200] The safety level and crystallinity data of the acid used in each crystalline sample are summarized in Table 7 below.

[0201] Table 7

[0202]

[0203]

[0204] Note: +: Data not collected due to small sample quantity; -: Data not collected due to consideration of sample crystallinity and acid safety level.

[0205] The XRPD characterization results of the maleate salt Form A are shown in Figure 1, and the XRPD diffraction peak data are shown in Table 8. The TGA results, as shown in the TGA curve in Figure 2, indicate that the maleate salt Form A loses 4.05% weight when heated to approximately 200°C. The DSC results, as shown in the DSC curve in Figure 2, indicate that it melts at approximately 222.8°C (onset temperature) with accompanying decomposition. HPLC / IC results indicate a molar ratio of 1.03 (acid / base), suggesting that the maleate salt Form A is an anhydrous form of the maleate salt.

[0206] Table 8: XRPD diffraction peak data of maleate salt form A

[0207]

[0208] The XRPD results of the fumarate salt crystal form A are shown in Figure 14. The TGA results are shown in the TGA curve in Figure 15, indicating that the fumarate salt crystal form A sample loses 2.3% weight when heated to about 130°C. The DSC results are shown in the DSC curve in Figure 15, indicating that there is an exothermic peak at about 163.5°C (peak temperature) and an endothermic peak at about 248.9°C (starting temperature). The heating test results show that the crystal form of the sample remains unchanged when heated to about 170°C, and the crystallinity is significantly improved. It is speculated that the exothermic signal is an amorphous transformation. The HPLC / IC results show that the molar ratio of the fumarate salt crystal form A is 1.07 (acid / base), and it is speculated that the fumarate salt crystal form A is a crystalline form of a fumarate salt.

[0209] The XRPD characterization results of the adipate salt Form A are shown in Figure 20. The TGA results, as shown in the TGA curve in Figure 21, show that the adipate salt Form A sample loses approximately 2.5% weight upon heating to approximately 130°C. The DSC results, as shown in the DSC curve in Figure 21, indicate an endothermic peak at approximately 182.0°C (starting point temperature), suggesting that the adipate salt Form A is an anhydrous form. HPLC / IC results indicate that the molar ratio of the adipate salt Form A is 0.88 (acid / base).

[0210] The XRPD results of the benzoate salt Form A are shown in Figure 26. The TGA results, as shown in the TGA curve in Figure 27, show that the benzoate salt Form A loses approximately 2.7% weight when heated to approximately 130°C. The DSC results, as shown in the DSC curve in Figure 27, show an endothermic peak at approximately 169.5°C (starting point temperature), suggesting that the benzoate salt Form A is an anhydrous form. HPLC / IC results indicate that the molar ratio of the benzoate salt Form A is 0.81 (acid / base).

[0211] The XRPD results of the hydrochloride salt form A are shown in Figure 7. The TGA results, as shown in the TGA curve in Figure 8, indicate that the sample loses approximately 3.5% weight when heated to approximately 100°C. The DSC results, as shown in the DSC curve in Figure 8, indicate that the DSC graph has multiple endothermic and exothermic peaks, particularly endothermic peaks with peak temperatures of approximately 94.6°C, approximately 237.4°C, and approximately 266.9°C, and exothermic peaks with peak temperatures of approximately 156.2°C and 203.0°C. In addition, the endothermic peaks with peak temperatures of approximately 237.4°C and approximately 266.9°C have starting points of approximately 233.7°C and approximately 261.9°C, respectively.

[0212] The XRPD results of the hydrochloride Form B sample are shown in Figure 7. The TGA results are shown in the TGA curve in Figure 9, indicating that the sample loses about 9.1% weight when heated to about 130°C. The DSC results are shown in the DSC curve in Figure 9, indicating endothermic peaks at about 109.9°C, about 160.3°C, and about 266.9°C (peak temperature).

[0213] The XRPD results of the phosphate crystal form A are shown in Figure 10. The TGA results are shown in the TGA curve in Figure 11, indicating that the phosphate crystal form A sample loses about 3.6% weight when heated to about 130°C. The DSC results are shown in the DSC curve in Figure 11, indicating endothermic peaks at about 48.0°C and about 228.3°C (starting temperature).

[0214] The XRPD results of the lactate salt Form A are shown in Figure 12. The TGA results are shown in the TGA curve in Figure 13, indicating that the lactate salt Form A sample loses about 4.0% weight when heated to about 130°C. The DSC results are shown in the DSC curve in Figure 13, indicating endothermic peaks at about 99.0°C and about 183.3°C (peak temperature).

[0215] The XRPD results for the succinate Form A are shown in Figure 16. The TGA results, as shown in the TGA curve in Figure 17, show that the succinate Form A sample loses approximately 3.2% weight when heated to approximately 130°C. The DSC results, as shown in the DSC curve in Figure 17, show endothermic peaks at approximately 51.6°C and approximately 182.1°C (onset temperature). The heating test results show that the sample maintains its crystalline form when heated to 100°C.

[0216] The XRPD results of the malate Form A are shown in Figure 18. The TGA results are shown in the TGA curve in Figure 19, which show that the malate Form A sample loses about 4.0% weight when heated to about 130°C. The DSC results are shown in the DSC curve in Figure 19, which show multiple endothermic peaks before decomposition.

[0217] The XRPD characterization results of the hippurate salt form A are shown in Figure 22. The TGA results are shown in the TGA curve in Figure 23, indicating that the hippurate salt form A sample loses about 4.2% of its weight when heated to about 130°C. The DSC results are shown in the DSC curve in Figure 23, indicating that there are multiple endothermic peaks before decomposition, especially endothermic peaks with peak temperatures of about 124.2°C, about 141.0°C, about 154.6°C, about 178.0°C, and about 217.2°C, respectively.

[0218] The XRPD results for the glycolate Form A are shown in Figure 24. The TGA results, as shown in the TGA curve in Figure 25, indicate that the glycolate Form A sample loses approximately 4.8% weight upon heating to approximately 130°C. The DSC results, as shown in the DSC curve in Figure 25, demonstrate endothermic peaks at approximately 54.1°C and approximately 183.2°C (onset temperature). The heating test results indicate that the sample maintains its crystalline form upon heating to 130°C.

[0219] The XRPD results of the nicotinate Form A are shown in Figure 28. The TGA results are shown in the TGA curve in Figure 29, which show that the nicotinate Form A sample loses approximately 4.9% weight when heated to approximately 130°C. The DSC results, shown in the DSC curve in Figure 29, indicate that there are multiple endothermic peaks before decomposition, particularly endothermic peaks with peak temperatures of approximately 103.9°C, approximately 160.3°C, and approximately 212.5°C.

[0220] Taking into account 1) the safety level of the selected acid (Level I > Level II > Level III); 2) sharp diffraction peaks in the XRPD pattern (at the same time, to ensure the representativeness of the sample and the collected data, the absence of obvious amorphous peaks is preferred); 3) small and gentle TGA weight loss; 4) a single and sharp melting peak in the DSC (the absence of crystalline form and low amount of adsorbed water or solvent is preferred), it was found that maleate form A, fumarate form A, adipate form A and benzoate form A are preferred.

[0221] Experimental Example 1

[0222] The solubility at 37°C, solid-state stability, and hygroscopicity of the samples were evaluated for maleate Form A, fumarate Form A, adipate Form A, and benzoate Form A, respectively.

[0223] Dynamic solubility at 37°C

[0224] Dynamic solubility tests were conducted in four solvents: water, simulated gastric fluid (SGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) to evaluate the solubility and disproportionation risk of maleate Form A, fumarate Form A, adipate Form A, and benzoate Form A.

[0225] In the test, using Form A as the reference, approximately 32 mg of the solid was mixed with 4.0 mL of solvent in a 5 mL glass vial. The vial was sealed and fixed to a rotating disk at 25 rpm. Samples were collected after 1, 2, 4, and 24 hours of rotational mixing at 37°C. Turbid samples were centrifuged, and the filtered supernatant was analyzed for HPLC concentration and pH. The solid was then analyzed for crystalline form by XRPD. If the sample remained clear, a sample was collected after 24 hours for concentration and pH testing.

[0226] HPLC was collected on an Agilent 1100 HPLC, and the solubility test parameters are shown in Table 9 below.

[0227] Table 9 Solubility test parameters

[0228]

[0229] The dynamic solubility test results of Form A of the four salts and Form A of the free base at 37°C are summarized in Table 10.

[0230] Table 10: Summary of dynamic solubility test results

[0231]

[0232]

[0233] Note: S 1 : Solubility, μg / ml, measured data is free base concentration, pH 2 : Measured pH value at each sampling point, FC 3 : Crystal form changes after XRPD analysis. --: Sample dissolved clearly and no data was collected. NA: Unable to analyze due to small sample quantity.

[0234] Free base: free base Form A, maleate: maleate Form A, fumarate: fumarate Form A, adipate: adipate Form A, benzoate: benzoate Form A.

[0235] The results showed that 1) in water, the solubility of Form A of the four salts was significantly higher than that of the free base Form A (from a few micrograms to several milligrams per milliliter). Furthermore, the maleate salt Form A maintained its crystalline form after 24 hours of suspension in water. 2) In other solvents, the solubility of Form A of the four salts was similar to that of the free base Form A, at several milligrams per milliliter. However, all samples were observed to form oil after one hour of suspension in FeSSIF. Compared with the observations in FaSSIF, these in vitro solubility tests suggest that food effects may need to be considered to optimize absorption.

[0236] One-week solid-state stability

[0237] Appropriate amounts of samples were weighed and placed in the open at 25°C / 60% RH and 40°C / 75% RH. After one week, all samples were subjected to XRPD characterization and HPLC purity testing to detect changes in crystal form and purity.

[0238] The results of one-week stability evaluation of maleate Form A, fumarate Form A, adipate Form A, benzoate Form A and free base Form A are summarized in Table 11.

[0239] Table 11

[0240]

[0241] The results showed that the four salt forms and the free base did not undergo changes in crystal form or HPLC purity at 25°C / 60% RH, demonstrating good physicochemical stability; however, the HPLC purity of the adipate salt form A and the benzoate salt form A samples decreased after storage at 40°C / 75% RH.

[0242] Hygroscopicity

[0243] To evaluate the stability of the samples at 25°C with changes in humidity, DVS was used to test maleate Form A, fumarate Form A, adipate Form A, and benzoate Form A. The samples were dried at 0% RH to remove adsorbed solvent or water before testing.

[0244] The following conclusions were drawn from the test results:

[0245] 1) At 80% RH, the moisture adsorption (wt%) of Form A, maleate, and Form A, fumarate were 0.8% and 1.0%, respectively, indicating slight hygroscopicity. Meanwhile, the moisture adsorption of Form A, adipate, and Form A, benzoate, were 9.1% and 7.7%, respectively, indicating hygroscopicity. Furthermore, XRPD analysis was performed before and after DVS testing. The results showed that the crystalline forms of Form A, maleate, and adipate remained unchanged, while the crystallinity of Form A, fumarate, and benzoate decreased.

[0246] 2) Under RH of 80% to 95%, except for maleate crystal form A which absorbs less water, the water absorption of the other three salt forms increases rapidly.

[0247] Based on the above results, the solubility of maleate Form A, fumarate Form A, adipate Form A and benzoate Form A in water and biological solvents is similar to or higher than that of free base Form A; except for adipate and benzoate salts, which showed a decrease in HPLC purity, the other salt forms and free base Form A showed good physicochemical stability in the solid-state stability assessment; according to the water adsorption results, maleate Form A and fumarate Form A samples are slightly hygroscopic, while the other salt form samples and free base Form A are observed to be hygroscopic.

[0248] Based on the above evaluations of dynamic solubility, solid stability, and hygroscopicity, it was concluded that maleate salt form A has superior properties, mainly manifested in:

[0249] 1) Under the same operating conditions, the crystallinity of the laboratory batch samples was high, while the crystallinity of the fumarate form A, adipate form A, and benzoate form A was medium;

[0250] 2) Compared to the free base crystalline form A, the solubility of the maleate salt crystalline form A in water at 37°C was significantly increased (from a few micrograms to several milligrams / mL), and the crystalline form remained unchanged after 24 hours. The solubility in other solvents (simulated gastric fluid (SGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF)) was similar;

[0251] 3) The maleate salt Form A samples showed no change in crystal form or HPLC purity after being stored at 25°C / 60% RH and 40°C / 75% RH for one week, demonstrating good physicochemical stability.

[0252] 4) The results of dynamic moisture sorption (DVS) tests at 25°C showed that the maleate salt form A sample was slightly hygroscopic and had a lower moisture adsorption capacity than other candidate salts and the free base under high humidity conditions (95% RH).

[0253] Preparation Example 2

[0254] The crystalline forms were prepared using the following general method:

[0255] Weigh approximately 200 mg of the free base and add the corresponding acid and 5 mL of EtOAc in a 1:1 molar ratio to obtain a suspension. Stir at room temperature for 30 minutes. Add ~2 mg of seed crystals and magnetically stir overnight under temperature cycling (50-20°C, 0.1°C / min, 3 times; 500 rpm). Isolate the solid by centrifugation and dry under vacuum at room temperature for 5 hours. Collect a crystalline sample for XRPD and DSC analysis.

[0256] The maleate, fumarate, adipate, and benzoate crystals were prepared using the above-mentioned method. XRPD and DSC test results showed that they were consistent with the maleate crystal form A, fumarate crystal form A, adipate crystal form A, and benzoate crystal form A references, respectively.

[0257] Preparation Example 3

[0258] 3.1 Preparation of Maleate Form B

[0259] To a clear solution of the maleate salt of Compound I in the solvent, add the antisolvent dropwise with stirring (~1000 rpm) until solid precipitates. If no solid precipitates after adding approximately 10 mL of antisolvent, stop the process. Isolate the precipitated solid by centrifugation (~10,000 rpm, 2 minutes) and perform XRPD analysis.

[0260] The results are shown in Table 12, and maleate salt crystal forms A, B, amorphous and oil were obtained.

[0261] Table 12

[0262]

[0263] In addition, the maleate salt of Compound I, Form A, was suspended in CHCl / n-hexane (1:1, v / v) at 50°C with magnetic stirring (~1000 rpm) for approximately 4 days. The solid was then collected by centrifugation (~10,000 rpm, 3 minutes) and subjected to XRPD analysis. Form B, a maleate salt, was also obtained.

[0264] The XRPD results of maleate salt Form B are shown in Figure 3. The TGA characterization results are shown in the TGA curve in Figure 4, which shows that the sample loses approximately 6.4% weight when heated to approximately 200°C (the weight loss of approximately 19.1% between 200°C and 290°C is presumably due to deacidification, with the theoretical weight loss for deacidification being approximately 18.7%). The DSC characterization results are shown in the DSC curve in Figure 4, which shows two weak endothermic peaks at approximately 74.6°C and approximately 236.8°C (peak temperatures), and a sharp endothermic peak at approximately 225.5°C (starting point temperature). 1 H NMR results showed that the molar ratio of maleic acid to free base was 1:1.

[0265] 3.2 Preparation of Maleate Form C

[0266] The maleate salt form B was converted into the maleate salt form C after N2 purging at 30°C for 20 min.

[0267] The XRPD results of maleate salt Form C are shown in Figure 5. The TGA characterization results are shown in the TGA curve in Figure 6, which shows that the sample loses approximately 6.3% weight when heated to approximately 200°C (the weight loss of approximately 17.5% between 200°C and 290°C is presumably due to deacidification, with the theoretical weight loss for deacidification being approximately 18.7%). The DSC characterization results are shown in the DSC curve in Figure 6, which shows an exothermic peak at approximately 142.8°C (peak temperature) and a sharp endothermic peak at approximately 222.0°C (starting temperature). 1 H NMR results indicated a 1:1 molar ratio of maleic acid to free base. VT-XRPD results showed that maleate Form C remained unchanged when heated to approximately 110°C under nitrogen. Based on these results, it is speculated that maleate Form C is an anhydrous form.

[0268] The maleate salt form C is heated to about 170°C under N2 protection and then transformed into the maleate salt form A.

[0269] Based on the above results, it is speculated that maleate crystal form B is a hydrate, which is converted into an anhydrous crystal form after removing bound water by N2 purging.

[0270] 3.3 Slow evaporation preparation test

[0271] A vial containing a clear solution of the maleate salt of Compound 1 in a solvent listed in Table 13 below was sealed with a sealing film and pierced with five small holes, and allowed to evaporate slowly at room temperature. After the solvent was completely evaporated, the resulting solid was collected and subjected to XRPD analysis.

[0272] The test results are shown in Table 13. In the slow volatilization test, Form A and amorphous form were obtained.

[0273] Table 13

[0274] Solvent (v / v) Solid Crystalline Form MeOH / DCM (1:1) Crystalline Form A Acetonitrile (CAN) / H2O (1:1) Amorphous Form MeOH / THF (2:1) Crystalline Form A

[0275] 3.4 Slow cooling preparation test

[0276] A clear solution of the maleate salt of Compound I in the solvent listed in Table 14 below was placed in a biochemical incubator and cooled from 50°C to 5°C at a cooling rate of 0.1°C / min. The solid that did not precipitate was transferred to room temperature for volatilization, and the resulting solid was collected and subjected to XRPD analysis.

[0277] The test results are shown in Table 14. The slow cooling test resulted in an amorphous state.

[0278] Table 14

[0279] Solvent (v / v)Solid Crystalline FormMeOH / DCM (1:1)AmorphousMeOH / THF (2:1)AmorphousDimethylacetamide (DMAc)Amorphous*

[0280] Note: *: obtained by vacuum drying at room temperature.

[0281] Experimental Example 2

[0282] 1. Suspension Competition Test

[0283] To further investigate the stability relationship between maleate anhydrous crystalline forms A and C and hydrated crystalline form B, suspension competition tests were conducted between the crystalline forms. Specifically, suspension competitions between crystalline forms A and C in acetone and EtOAc at room temperature and 50°C, and suspension competitions between anhydrous crystalline form A and hydrated crystalline form B in MeOH / H2O (water activity a) at room temperature were conducted. w =0~1) in the suspension competition test.

[0284] The specific steps are as follows: 1) preparing saturated solutions of the maleate anhydrous crystalline Form A in different solvents at specific temperatures; 2) adding equal masses of Form A and Form B or C samples (approximately 4 mg each) to 0.5 mL of the saturated solution to form a suspension; 3) suspending and stirring the suspension at room temperature and 50°C for approximately 5 days (~800 rpm); 4) separating the remaining solid and performing XRPD analysis.

[0285] The results of the suspension competition test are summarized in Table 18.

[0286] Table 15

[0287]

[0288] The results showed that at room temperature and 50 ° C, the physical mixture of Forms A and C transformed into Form A after suspension and stirring in acetone and EtOAc; at room temperature, the physical mixture of Forms A and B transformed into Form A after suspension and stirring in MeOH / H2O (a w =0~1) and then suspended and stirred to transform into crystal form A. Based on this, it is speculated that the water activity a at room temperature to 50 ° C and room temperature w =0-1, Form A is a thermodynamically stable form.

[0289] 2. Equilibrium Solubility Test

[0290] The equilibrium solubility of maleate salt forms A, B and C in water was tested at room temperature.

[0291] In the experiment, suspensions of each crystal form were prepared, magnetically stirred at room temperature for 24 hours (speed ~800 rpm) and then centrifuged (10000 rpm, 5 min). The supernatant was filtered (0.22 μm PTFE filter membrane) and the solubility and pH were measured. The solid was measured by XRPD.

[0292] The equilibrium solubility results of maleate salt forms A, B, and C in water are summarized in Table 16.

[0293] Table 16

[0294] Initial crystal solubility (mg / mL)*pH Crystal form conversion Crystal form A 4.14.5 No Crystal form B 4.54.4 No Crystal form C 13.14.7 NA

[0295] Note: *: Calculated based on free base equivalent. NA: Little residual solid, not tested.

[0296] 3. Solid-state stability test

[0297] This test is used to evaluate the solid-state stability of maleate salt Form A.

[0298] An appropriate amount of maleate salt Form A was weighed and stored at 80°C with a closed container for one day, and then at 25°C / 60% RH and 40°C / 75% RH, respectively, for one week. Solid samples isolated under different conditions were tested for purity and chemical stability by HPLC, and for physical stability by XRPD analysis of the crystal form.

[0299] The results of the solid state stability evaluation of maleate salt Form A are summarized in Table 17.

[0300] Table 17

[0301]

[0302] No crystal transformation and HPLC purity reduction occurred under the three test conditions, indicating that maleate crystal form A has good physical and chemical stability under the selected test conditions.

[0303] 4. Stability in solvent

[0304] This test is used to evaluate the stability of the maleate salt of Compound I in solvents.

[0305] The stability of the maleate salt of Compound I in solvents was evaluated by suspension stirring tests in dichloromethane (DCM), methanol (MeOH), ethyl acetate (EtOAc), dimethylformamide (DMF), tetrahydrofuran (THF), MTBE, and 1,4-dioxane.

[0306] The specific steps are as follows: weigh ~15 mg of each portion of Compound I maleate salt Form A, add it to different solvents, suspend and stir at room temperature for 6 hours, then transfer to 60°C and stir for 5 hours, centrifuge to separate the solid and measure XRPD, and use the solution for HPLC purity analysis.

[0307] The results showed that the maleate salt form A remained unchanged after suspension and stirring in DCM, EtOAc, THF, and MTBE, and the purity did not decrease significantly; the maleate salt form A remained unchanged after suspension and stirring in MeOH and DMF, and the purity increased slightly; the maleate salt form A remained unchanged after suspension and stirring in 1,4-dioxane, and the purity decreased slightly.

[0308] The results of the stability evaluation of maleate salt form A in solvents are summarized in Tables 18 and 19.

[0309] Table 18

[0310]

[0311] Table 19

[0312]

[0313] Experimental Example 3 Comparison of the stability of free base crystal form A and maleate crystal form A

[0314] The free base crystal form A and the maleate crystal form A obtained therefrom were subjected to high temperature (60°C), light (1.2*10 6 Lux*hr) conducted a 5-day inspection, and the testing items were related substances.

[0315] Analysis method for related substances of free base

[0316] Instrument: High Performance Liquid Chromatography

[0317] Column: Waters XBridge C18, 150*4.6mm, 3.5μm

[0318] Mobile phase A: 10 mmol ammonium dihydrogen phosphate (containing 0.1% triethylamine): methanol (80:20)

[0319] Mobile phase B: methanol

[0320] Gradient table:

[0321] Time (min) Mobile phase A (%) Mobile phase B (%) 0752515445620376325257540257540.017525457525

[0322] Detection wavelength: 230nm

[0323] Flow rate: 1.0 mL / min

[0324] Injection volume: 20 μl

[0325] Column temperature: 45°C

[0326] Run time: 45 minutes

[0327] Test solution: Take about 25 mg of this product, place it in a 100 ml volumetric flask, add methanol to dissolve and dilute to the scale, shake well, and use it as the test solution.

[0328] Analysis method for related substances of maleate crystal form A

[0329] Instrument: High Performance Liquid Chromatography

[0330] Column: Waters Xbridge C18, 4.6×150 mm, 3.5 μm

[0331] Mobile phase A: 0.01M ammonium dihydrogen phosphate aqueous solution (containing 0.1% triethylamine): methanol = 80:20

[0332] Mobile phase B: methanol

[0333] Gradient table:

[0334] Time (min) Mobile phase A (%) Mobile phase B (%) 0752515445620376325257540257540.017525457525

[0335] Detection wavelength: 230nm

[0336] Flow rate: 1.0ml / min

[0337] Injection volume: 20 μl

[0338] Column temperature: 45°C

[0339] Run time: 45 minutes

[0340] Diluent: 0.01M ammonium dihydrogen phosphate aqueous solution (containing 0.1% triethylamine): methanol = 30:70

[0341] Test solution: Take about 30 mg of this product, place it in a 100 ml volumetric flask, add diluent to dissolve and dilute to the scale, shake well, and use it as the test solution.

[0342] The data obtained is as follows:

[0343] High temperature and light related substance data of free base form A / maleate salt form A

[0344]

[0345] From the table above, we can see that the free alkali is 6 Lux·hr) for 5 days, it showed instability. However, the maleate salt form was more stable than the free base form under the same conditions.

Claims

1. A salt of compound I as shown below, wherein, The salt is selected from maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate, and nicotinate.

2. The salt of compound I according to claim 1, wherein, The salt is selected from one or more of the following crystal forms of compound I: maleate crystal form A, maleate crystal form B, maleate crystal form C, hydrochloride crystal form A, hydrochloride crystal form B, phosphate crystal form A, lactate crystal form A, fumarate crystal form A, succinate crystal form A, malate crystal form A, adipate crystal form A, hippurate crystal form A, glycolate crystal form A, benzoate crystal form A, and nicotinate crystal form A. Specifically, the salt is one or more selected from maleate crystal form A, fumarate crystal form A, adipate crystal form A, and benzoate crystal form A of compound I. More specifically, the salt is maleate crystal form A of compound I. More specifically, the salt is the fumarate crystal form A of compound I. More specifically, the salt is the adipate crystal form A of compound I. More specifically, the salt is the benzoate crystal form A of compound I.

3. The salt of compound I according to claim 1 or 2, wherein, The salt of compound I is a maleate salt, and in particular, the maleate salt of compound I is selected from one or more of maleate crystal forms A, B and C; The X-ray powder diffraction (XRPD) pattern of the maleate crystal form A shows characteristic peaks at diffraction angles 2θ of 5.48±0.2°, 8.55±0.2°, 10.92±0.2°, 12.04±0.2°, 12.98±0.2°, 13.81±0.2°, 16.40±0.2°, 19.59±0.2°, and 27.46±0.2°. Preferably, characteristic peaks are also observed at 6.11±0.2°, 7.84±0.2°, 15.32±0.2°, 18.70±0.2°, 21.55±0.2°, 22.21±0.2°, 22.80±0.2°, 23.32±0.2°, 24.57±0.2°, and 25.62±0.2°. Diffraction peaks are observed at one or more locations with diffraction angles 2θ of 5.48±0.2°, 6.11±0.2°, 7.84±0.2°, 8.55±0.2°, 10.92±0.2°, 12.04±0.2°, 12.98±0.2°, 13.81±0.2°, 15.32±0.2°, 16.40±0.2°, 18.70±0.2°, 19.59±0.2°, 21.55±0.2°, 22.21±0.2°, 22.80±0.2°, and 23.32±0.2°. Characteristic peaks are present at 24.57±0.2°, 25.62±0.2°, 26.07±0.2°, 27.46±0.2°, 28.23±0.2°, 28.68±0.2°, 33.08±0.2°, and 38.76±0.2°. Specifically, the maleate crystal form A has an XRPD pattern substantially as shown in Figure 1, and the XRPD target used is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the maleate crystal form A has an endothermic peak with a starting temperature of 222.8°C and an endothermic peak with a peak temperature of 235.3°C. Specifically, the maleate crystal form A has a DSC pattern substantially as shown in Figure 2. Specifically, the maleate crystal form A has a TGA pattern substantially as shown in Figure 2. The X-ray powder diffraction (XRPD) pattern of the maleate crystal form B exhibits characteristic peaks at diffraction angles 2θ of 5.75±0.2°, 9.72±0.2°, 14.91±0.2°, 15.76±0.2°, 17.43±0.2°, 18.09±0.2°, 22.20±0.2°, 23.23±0.2°, 25.17±0.2°, and 27.96±0.2°. In particular, the maleate crystal form B has essentially the following characteristics... The XRPD plot shown in Figure 3 uses a Cu target for XRPD. Specifically, the differential scanning calorimetry (DSC) plot of maleate crystal form B has two weak endothermic peaks with peak temperatures of 74.6°C and 236.8°C, and a sharp endothermic peak with an onset temperature of 225.5°C. Furthermore, the maleate crystal form B has a DSC plot substantially as shown in Figure 4. In particular, the maleate crystal form B has a TGA plot substantially as shown in Figure 4. The X-ray powder diffraction (XRPD) patterns of the maleate crystal form C at diffraction angles 2θ of 5.51±0.2°, 6.31±0.2°, 8.91±0.2°, 9.62±0.2°, 10.59±0.2°, 11.05±0.2°, 12.17±0.2°, 14.99±0.2°, 15.73±0.2°, 16.65±0.2°, 21.40±0.2°, 22.94±0.2°, 24.71±0.2°, 26.72±0.2°, 28.22±0.2°, and 32... Characteristic peaks are present at 0.36±0.2° and 38.52±0.2°. Specifically, the maleate crystal form C has an XRPD pattern substantially as shown in Figure 5, where the XRPD target is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the maleate crystal form C has an exothermic peak with a peak temperature of 142.8°C and a sharp endothermic peak with a starting temperature of 222.0°C. Specifically, the maleate crystal form C has a DSC pattern substantially as shown in Figure 6. Specifically, the maleate crystal form C has a TGA pattern substantially as shown in Figure 6. Alternatively, the salt of compound I is a hydrochloride salt, and in particular, the hydrochloride salt of compound I is selected from one or more of hydrochloride crystal form A and crystal form B; The X-ray powder diffraction (XRPD) patterns of the hydrochloride crystal form A at diffraction angles 2θ were 4.41±0.2°, 5.34±0.2°, 8.90±0.2°, 9.16±0.2°, 10.69±0.2°, 11.07±0.2°, 13.16±0.2°, 15.63±0.2°, 18.49±0.2°, 19.25±0.2°, 21.28±0.2°, 24.60±0.2°, and 26.85±0.2°. A characteristic peak is present at °. In particular, the XRPD pattern of the hydrochloride crystal form A is substantially as shown in Figure 7, and the target used for the XRPD is a Cu target. In particular, the differential scanning calorimetry (DSC) pattern of the hydrochloride crystal form A has endothermic peaks with peak temperatures of 94.6 °C, 237.4 °C, and 266.9 °C. In particular, the DSC pattern of the hydrochloride crystal form A is substantially as shown in Figure 8. In particular, the TGA pattern of the hydrochloride crystal form A is substantially as shown in Figure 8. The X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form B has characteristic peaks at diffraction angles 2θ of 3.73±0.2°, 4.96±0.2°, 7.24±0.2°, 10.26±0.2°, and 15.47±0.2°. Specifically, the XRPD pattern of the hydrochloride crystal form B is substantially as shown in Figure 7, and the target used for the XRPD is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the hydrochloride crystal form B has endothermic peaks with peak temperatures of 109.9℃, 160.3℃, and 266.9℃. Specifically, the DSC pattern of the hydrochloride crystal form B is substantially as shown in Figure 9. Specifically, the TGA pattern of the hydrochloride crystal form B is substantially as shown in Figure 9. Alternatively, the salt of compound I is a phosphate, and in particular, the phosphate of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which is at diffraction angles 2θ of 5.63±0.2°, 7.86±0.2°, 9.88±0.2°, 12.43±0.2°, 15.86±0.2°, 19.64±0.2°, 21.26±0.2°, 22.72±0.2°, 25.42±0.2°, and 27. A characteristic peak is present at 32±0.2°. In particular, the phosphate crystal form A has an XRPD pattern substantially as shown in Figure 10, wherein the target used for XRPD is a Cu target. In particular, the differential scanning calorimetry (DSC) pattern of the phosphate crystal form A has endothermic peaks with start-point temperatures of 48.0°C and 228.3°C, respectively. In particular, the phosphate crystal form A has a DSC pattern substantially as shown in Figure 11. In particular, the phosphate crystal form A has a TGA pattern substantially as shown in Figure 11. Alternatively, the salt of compound I is a lactate; specifically, the lactate of compound I exists in crystal form A, and the X-ray powder diffraction (XRPD) pattern of crystal form A is given by diffraction angles 2θ of 4.52±0.2°, 5.12±0.2°, 6.94±0.2°, 8.97±0.2°, 10.16±0.2°, 10.49±0.2°, 11.30±0.2°, 13.35±0.2°, 13.86±0.2°, 17.51±0.2°, 18.52±0.2°, 21.02±0.2°, and 21. Characteristic peaks are present at 0.97±0.2°, 25.10±0.2°, 26.05±0.2°, and 27.04±0.2°. Specifically, the lactate crystal form A has an XRPD pattern substantially as shown in Figure 12, and the target used for the XRPD is a Cu target. The differential scanning calorimetry (DSC) pattern of the lactate crystal form A has endothermic peaks with peak temperatures of 99.0°C and 183.3°C, respectively. Specifically, the lactate crystal form A has a DSC pattern substantially as shown in Figure 13. Specifically, the lactate crystal form A has a TGA pattern substantially as shown in Figure 13. Alternatively, the salt of compound I is a fumarate, and specifically, the fumarate of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which is located at diffraction angles 2θ of 5.73±0.2°, 6.29±0.2°, 8.04±0.2°, 10.28±0.2°, 11.27±0.2°, 12.79±0.2°, 14.17±0.2°, 14.99±0.2°, 16.07±0.2°, 17.28±0.2°, 18.16±0.2°, 19.90±0.2°, 20.62±0.2°, and 22.13±0.2°. Characteristic peaks are present at 2°, 23.10±0.2°, 23.82±0.2°, 24.52±0.2°, and 27.03±0.2°. Specifically, the fumarate crystal form A has an XRPD pattern substantially as shown in Figure 14, and the target used for the XRPD is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the fumarate crystal form A has an exothermic peak with a peak temperature of 163.5°C and an endothermic peak with a starting temperature of 248.9°C. Specifically, the fumarate crystal form A has a DSC pattern substantially as shown in Figure 15. Specifically, the fumarate crystal form A has a TGA pattern substantially as shown in Figure 15. Alternatively, the salt of compound I is a succinate, and specifically, the succinate of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which succinate crystal form A has diffraction angles 2θ of 4.18±0.2°, 5.33±0.2°, 6.82±0.2°, 8.35±0.2°, 11.56±0.2°, 13.67±0.2°, 16.44±0.2°, 17.74±0.2°, and 20.47±0.2°. A characteristic peak is present at 23.15±0.2°. In particular, the succinate crystal form A has an XRPD pattern substantially as shown in Figure 16, wherein the target used for XRPD is a Cu target. The differential scanning calorimetry (DSC) pattern of the succinate crystal form A has endothermic peaks with start temperatures of 51.6°C and 182.1°C, respectively. In particular, the succinate crystal form A has a DSC pattern substantially as shown in Figure 17. In particular, the succinate crystal form A has a TGA pattern substantially as shown in Figure 17. Alternatively, the salt of compound I is a malate, and in particular, the malate of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which is at diffraction angles 2θ of 4.49±0.2°, 6.10±0.2°, 7.16±0.2°, 9.00±0.2°, 10.99±0.2°, 14.87±0.2°, 16.65±0.2°, 19.73±0.2°, 20.55±0.2°, 21.96±0.2°, 23.12±0.2°, and 24.03±0.2°. Characteristic peaks are present at 2°, 25.87±0.2°, and 26.58±0.2°. Specifically, the malate crystal form A has an XRPD pattern substantially as shown in Figure 18, where the XRPD target is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the malate crystal form A has endothermic peaks with peak temperatures of 100.4°C, 175.9°C, and 185.6°C. Specifically, the malate crystal form A has a DSC pattern substantially as shown in Figure 19. Specifically, the malate crystal form A has a TGA pattern substantially as shown in Figure 19. Alternatively, the salt of compound I is an adipic acid salt, specifically, the adipic acid salt of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which is located at diffraction angles 2θ of 4.53±0.2°, 4.85±0.2°, 6.03±0.2°, 7.15±0.2°, 9.05±0.2°, 9.56±0.2°, 10.94±0.2°, 12.18±0.2°, 13.66±0.2°, 14.61±0.2°, 18.23±0.2°, 20.12±0.2°, and 2... Characteristic peaks are present at 4.05±0.2°, 25.77±0.2°, 26.25±0.2°, and 27.50±0.2°. Specifically, the adipate crystal form A has an XRPD pattern substantially as shown in Figure 20, and the target used for the XRPD is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the adipate crystal form A has an endothermic peak with a starting temperature of 182.0°C. Specifically, the adipate crystal form A has a DSC pattern substantially as shown in Figure 21. Specifically, the adipate crystal form A has a TGA pattern substantially as shown in Figure 21. Alternatively, the salt of compound I is hippurate, and the hippurate of compound I exists in crystal form A. The X-ray powder diffraction (XRPD) pattern of hippurate crystal form A has characteristic peaks at diffraction angles 2θ of 4.45±0.2°, 5.50±0.2°, 9.17±0.2°, 18.79±0.2°, 23.20±0.2°, and 25.42±0.2°. In particular, the hippurate crystal form A has essentially the characteristics shown in Figure 22. The XRPD pattern shown is provided, wherein the target used for XRPD is a Cu target; in particular, the differential scanning calorimetry (DSC) pattern of the hippurate crystal form A has endothermic peaks with peak temperatures of 124.2℃, 141.0℃, 154.6℃, 178.0℃ and 217.2℃, respectively; in particular, the hippurate crystal form A has a DSC pattern substantially as shown in Figure 23; in particular, the hippurate crystal form A has a TGA pattern substantially as shown in Figure 23; Alternatively, the salt of compound I is a glycolate, and specifically, the glycolate of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which is shown at diffraction angles 2θ of 4.50±0.2°, 5.19±0.2°, 6.90±0.2°, 9.00±0.2°, 10.42±0.2°, 11.35±0.2°, 13.74±0.2°, 15.60±0.2°, and 16.24±0.2°. Characteristic peaks are observed at 17.97±0.2°, 20.77±0.2°, 22.68±0.2°, 25.12±0.2°, 26.61±0.2°, 27.69±0.2°, and 31.73±0.2°. Specifically, the glycolate crystal form A has an XRPD pattern substantially as shown in Figure 24, and the target used for the XRPD is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the glycolate crystal form A has endothermic peaks with starting temperatures of 54.1°C and 183.2°C, respectively. Specifically, the glycolate crystal form A has a DSC pattern substantially as shown in Figure 25. Specifically, the glycolate crystal form A has a TGA pattern substantially as shown in Figure 25. Alternatively, the salt of compound I is a benzoate, specifically, the benzoate of compound I exists in crystal form A, the X-ray powder diffraction (XRPD) pattern of which is located at diffraction angles 2θ of 4.47±0.2°, 4.80±0.2°, 6.74±0.2°, 8.96±0.2°, 9.94±0.2°, 10.40±0.2°, 12.78±0.2°, 13.50±0.2°, 14.88±0.2°, 17.41±0.2°, 18.32±0.2°, 19.54±0.2°, 20.84±0.2°, 2 Characteristic peaks are present at 3.58±0.2°, 25.01±0.2°, 26.31±0.2°, 27.11±0.2°, and 29.33±0.2°. Specifically, the benzoate crystal form A has an XRPD pattern substantially as shown in Figure 26, and the target used for the XRPD is a Cu target. Specifically, the differential scanning calorimetry (DSC) pattern of the benzoate crystal form A has an endothermic peak with a starting temperature of 169.5°C. Specifically, the benzoate crystal form A has a DSC pattern substantially as shown in Figure 27. Specifically, the benzoate crystal form A has a TGA pattern substantially as shown in Figure 27. Alternatively, the salt of compound I is a nicotinate, specifically, the nicotinate of compound I exists in crystal form A; the X-ray powder diffraction (XRPD) pattern of nicotinate crystal form A at diffraction angles 2θ of 4.54±0.2°, 6.46±0.2°, 10.14±0.2°, 13.41±0.2°, 14.66±0.2°, 17.14±0.2°, 18.83±0.2°, 21.36±0.2°, 24.83±0.2°, and 26.27±0.2°. A characteristic peak is present at 0.2°. In particular, the nicotinate crystal form A has an XRPD pattern substantially as shown in Figure 28, wherein the target used for the XRPD is a Cu target. In particular, the differential scanning calorimetry (DSC) pattern of the nicotinate crystal form A has endothermic peaks with peak temperatures of 103.9°C, 160.3°C, and 212.5°C. In particular, the nicotinate crystal form A has a DSC pattern substantially as shown in Figure 29. In particular, the nicotinate crystal form A has a TGA pattern substantially as shown in Figure 29.

4. A method for preparing the crystal form as described in claim 2 or 3, wherein, The method for preparing the maleate crystal form A is one of the following methods: Method 1: (1) The free base of compound I and maleic acid are reacted in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), alcohol solvents (e.g., methanol) and ester solvents (e.g., ethyl acetate). Method 2: (2) Obtained by conversion of maleate crystal form B or C; The method for preparing the maleate crystal form B comprises: recrystallizing the maleate of compound I by adding an antisolvent (e.g., acetone and toluene) dropwise to a mixed solution of methanol / dichloromethane in a volume ratio of 1:1, and then placing the resulting solid under room temperature and humidity. The method for preparing the maleate crystal form C includes: purging the maleate crystal form B with an inert gas (e.g., N2); The method for preparing the hydrochloride crystal form A includes reacting a free base of compound I and hydrochloric acid in a molar ratio of 1:1 in a solvent selected from ether solvents (e.g., tetrahydrofuran) and ester solvents (e.g., ethyl acetate); The method for preparing the hydrochloride crystal form B includes reacting a free base of compound I and hydrochloric acid in a molar ratio of 3:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), ester solvents (e.g., ethyl acetate), and mixed solvents (e.g., haloalkanes and alcohol solvents, such as dichloromethane / methanol). The method for preparing the phosphate crystal form A includes reacting a free base of compound I and phosphoric acid in a molar ratio of 1:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), ester solvents (e.g., ethyl acetate), and mixed solvents (e.g., haloalkanes and alcohol solvents, such as dichloromethane / methanol). The method for preparing the lactate crystal form A includes reacting compound I free base and lactic acid in a molar ratio of 1:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), and ester solvents (e.g., ethyl acetate). The method for preparing the fumarate crystal form A includes reacting compound I free base and fumaric acid in a molar ratio of 1:1 in a solvent selected from ether solvents (e.g., tetrahydrofuran), ester solvents (e.g., ethyl acetate), and mixed solvents (e.g., haloalkanes and alcohol solvents, such as dichloromethane / methanol). The method for preparing the succinate crystal form A includes reacting a free base of compound I and succinic acid in a molar ratio of 1:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), and ester solvents (e.g., ethyl acetate). The method for preparing the malate crystal form A includes reacting a free base of compound I and malic acid in a molar ratio of 1:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), and ester solvents (e.g., ethyl acetate). The method for preparing the adipic acid salt crystal form A includes reacting a free base of compound I and adipic acid in a molar ratio of about 1:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), and ester solvents (e.g., ethyl acetate). The method for preparing the hippurate crystal form A includes reacting compound I free base and hippuric acid in a molar ratio of 1:1 in a solvent selected from ketone solvents (e.g., acetone) and ester solvents (e.g., ethyl acetate); The method for preparing the glycolate crystal form A includes reacting a free base of compound I and glycolic acid in a molar ratio of 1:1 in a solvent selected from ketone solvents (e.g., acetone), ether solvents (e.g., tetrahydrofuran), and ester solvents (e.g., ethyl acetate). The method for preparing the benzoate crystal form A includes reacting compound I (free base) and benzoic acid in a molar ratio of 1:1 in a ketone solvent (e.g., acetone). The method for preparing the nicotinate crystal form A includes reacting compound I free base and nicotinic acid in a molar ratio of 1:1 in a solvent selected from ether solvents (e.g., tetrahydrofuran) and ester solvents (e.g., ethyl acetate).

5. A pharmaceutical composition comprising one or more salts selected from compound I according to any one of claims 1-3.

6. The pharmaceutical composition according to claim 5, for the prevention or treatment of diseases related to abnormal cell cycle regulation; Specifically, the "diseases associated with abnormal cell cycle regulation" are "diseases associated with abnormalities in cyclin-dependent kinases (preferably CDK4 and / or CDK6)," particularly tumors, and more particularly malignant tumors (e.g., breast cancer, colon cancer, non-small cell carcinoma, astrocytoma, chronic myeloid leukemia, pancreatic cancer, acute monocytic leukemia, liver cancer (including hepatocellular carcinoma, hepatic adenocarcinoma), gastric cancer, non-small cell lung cancer, glioblastoma, and prostate adenocarcinoma), and advanced solid tumors (including but not limited to breast cancer, primary / metastatic tumors of the central nervous system). In particular, the pharmaceutical composition is used as a cyclin-dependent kinase (preferably CDK4 and / or CDK6) inhibitor; Specifically, the pharmaceutical composition is used to inhibit the proliferation of tumor cells, wherein the tumor cells are preferably cancer cells; wherein the cancer cells are preferably breast cancer cells, colon cancer cells, non-small cell carcinoma cells, astrocytoma cells, chronic myeloid leukemia cells, pancreatic cancer cells, acute monocytic leukemia cells, liver cancer cells (including hepatocellular carcinoma cells and hepatic adenocarcinoma cells), gastric cancer cells, non-small cell lung cancer cells, glioblastoma cells, and prostate adenocarcinoma cells; wherein the breast cancer cells are preferably selected from one or more of breast cancer cells MCF-7, T-47D, and ZR-75-1.

7. Use of the salt of compound I according to any one of claims 1-3 for the preparation of a pharmaceutical product.

8. The use according to claim 7, wherein, The drug is used to prevent or treat diseases associated with abnormal cell cycle regulation; in particular, the "diseases associated with abnormal cell cycle regulation" are "diseases associated with abnormalities in cyclin-dependent kinases (preferably CDK4 and / or CDK6)," especially tumors, and more particularly malignant tumors (e.g., breast cancer, colon cancer, non-small cell carcinoma, astrocytoma, chronic myeloid leukemia, pancreatic cancer, acute monocytic leukemia, liver cancer (including hepatocellular carcinoma, hepatic adenocarcinoma), gastric cancer, non-small cell lung cancer, malignant glioblastoma, and prostate adenocarcinoma), and advanced solid tumors (including but not limited to breast cancer, primary / metastatic tumors of the central nervous system).

9. Use of the salt of compound I according to any one of claims 1-3 for the preparation of cyclin-dependent kinase (preferably CDK4 and / or CDK6) inhibitors.

10. Use of the salt of compound I according to any one of claims 1-3 for the preparation of a drug for inhibiting the proliferation of tumor cells, wherein the tumor cells are preferably cancer cells; wherein the cancer cells are preferably breast cancer cells, colon cancer cells, non-small cell carcinoma cells, astrocytoma cells, chronic myeloid leukemia cells, pancreatic cancer cells, acute monocytic leukemia cells, liver cancer cells (including hepatocellular carcinoma cells and hepatic adenocarcinoma cells), gastric cancer cells, non-small cell lung cancer cells, glioblastoma cells, and prostate adenocarcinoma cells; wherein the breast cancer cells are preferably one or more of breast cancer cells MCF-7, T-47D, and ZR-75-1.