WO2022171117A1 - 含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途 - Google Patents

含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途 Download PDF

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WO2022171117A1
WO2022171117A1 PCT/CN2022/075631 CN2022075631W WO2022171117A1 WO 2022171117 A1 WO2022171117 A1 WO 2022171117A1 CN 2022075631 W CN2022075631 W CN 2022075631W WO 2022171117 A1 WO2022171117 A1 WO 2022171117A1
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salt
crystal form
compound
xrpd
pattern
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PCT/CN2022/075631
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English (en)
French (fr)
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陈辉
夏广新
王倩
刘俊耀
韩雅男
柯樱
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上海医药集团股份有限公司
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Priority to JP2023547372A priority Critical patent/JP2024505670A/ja
Priority to US18/276,569 priority patent/US20240116925A1/en
Priority to EP22752277.8A priority patent/EP4293021A1/en
Publication of WO2022171117A1 publication Critical patent/WO2022171117A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • 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, in particular, to the salt, crystal form, preparation method and pharmaceutical combination of the compound objects and uses.
  • Compound 1 has been disclosed in CN106928219A and WO2017114512A1 (their disclosures are incorporated herein by reference in their entirety as if described herein), which are at the molecular level cyclin-dependent kinase 4 (CDK4) and cyclin-dependent Kinase 6 (CDK6) has high selectivity and high inhibitory activity on CDK4 and CDK6. It has a significant inhibitory effect on tumor cells related to cyclin-dependent kinase activity at the cellular and animal levels, and can be used for breast cancer.
  • CDK4 cyclin-dependent kinase 4
  • CDK6 cyclin-dependent Kinase 6
  • 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
  • malignant tumors such as glioblastoma and prostate adenocarcinoma, and its good stability to liver microsomes in humans and mice, no obvious inhibition of metabolic enzymes, good absorption properties in rats and mice, high bioavailability, and high bioavailability. Good medicinal properties.
  • the present invention provides salts, crystal forms of compound I, and preparation methods, pharmaceutical compositions and uses thereof.
  • the compound I salt or its crystalline form exhibits at least one of the following advantages: improved bioavailability, good mechanical properties, improved chemical stability, excellent flow properties, good compressibility and improved dissolution characteristics .
  • the present invention provides a salt of Compound I, as shown below, selected from the group consisting of maleate, hydrochloride, phosphate, lactate, fumarate, succinate, malate, hexamethylene Diacids, hippurates, glycolates, benzoates and nicotinates,
  • the salt of the compound I can be obtained by conventional methods for preparing salt compounds in the art, for example, by reacting the free base of the compound I with the corresponding acid, or by the substitution reaction of the acid, or it can be obtained according to the following description of the application.
  • the methods and methods disclosed in the examples are prepared in combination with common technical knowledge in the art.
  • the salt can be selected from the maleate crystal form A, maleate crystal form B, maleate crystal form C, hydrochloride salt form A, hydrochloride salt form B, phosphate salt of Compound I Form A, lactate form A, fumarate form A, succinate form A, malate form A, adipate form A, hippurate form A, ethanol One or more of salt crystal form A, benzoate crystal form A and nicotinate crystal form A.
  • the salt may be one selected from the group consisting of maleate salt form A, fumarate salt form A, adipate salt form A and benzoate form A of Compound I or variety.
  • the salt may be Form A of the maleate salt of Compound I.
  • the salt may be Form A of the fumarate salt of Compound I.
  • the salt may be Form A of the adipate salt of Compound I.
  • the salt may be the benzoate salt form A of Compound I.
  • the salt of Compound I is the maleate salt.
  • the maleate salt of Compound I exists in Form A, Form B or Form C.
  • the X-ray powder diffraction (XRPD) pattern of the maleate salt crystal form A at diffraction angles 2 ⁇ is about 5.48 ⁇ 0.2°, 8.55 ⁇ 0.2°, 10.92 ⁇ 0.2°, 12.04 ⁇ 0.2°, 12.98 ⁇ 0.2°, There are characteristic peaks at 13.81 ⁇ 0.2°, 16.40 ⁇ 0.2°, 19.59 ⁇ 0.2°, 27.46 ⁇ 0.2°, preferably 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°, 25.62 ⁇ 0.2°, 26.07 ⁇ 0.2°, 28.23 ⁇ 0.2°, 28.68 ⁇ 0.2°, 33.08 ⁇ 0.2° and 38.76 There are diffraction peaks at one or more locations within ⁇ 0.2°, preferably at diffraction angles 2 ⁇ of about 5.48 ⁇ 0.2°, 6.11 ⁇ 0.2°, 7.84 ⁇ 0.2°, 8.55 ⁇ 0.2°, 10.92
  • the differential scanning calorimetry (DSC) pattern of the maleate salt 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, in particular, the maleic acid Salt Form A has a DSC pattern substantially as shown in FIG. 2 .
  • thermogravimetric (TGA) diagram of the maleate salt form A shows that the sample loses about 4.1% in weight at about 200°C, and the total weight loss in the range of about 200-290°C is about 17.5%, which is presumed to be caused by deacidification (deacidification). The theoretical weight loss is about 18.7%), in particular, the maleate salt Form A has a TGA diagram substantially as shown in FIG. 2 .
  • the molar ratio of maleic acid to free base is about 1:1.
  • VT-XRPD temperature-variable XRPD
  • the X-ray powder diffraction (XRPD) pattern of the maleate salt crystal form B at diffraction angles 2 ⁇ is about 5.75 ⁇ 0.2°, 9.72 ⁇ 0.2°, 14.91 ⁇ 0.2°, 15.76 ⁇ 0.2°, 17.43 ⁇ 0.2°, There are characteristic peaks at 18.09 ⁇ 0.2°, 22.20 ⁇ 0.2°, 23.23 ⁇ 0.2°, 25.17 ⁇ 0.2°, and 27.96 ⁇ 0.2°.
  • XRPD diagram the target type used in the XRPD is Cu target.
  • the differential scanning calorimetry (DSC) pattern 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.
  • Thermal peaks, in particular, the maleate salt Form B has a DSC pattern substantially as shown in FIG. 4 .
  • thermogravimetric (TGA) diagram of the maleate salt crystal form B shows that the sample loses 6.4% when heated to about 200°C, and the total weight loss in the range of about 200-290°C is about 19.1%, which is presumed to be caused by deacidification (deacidification). The theoretical weight loss is about 18.7%), in particular, the maleate salt Form B has a TGA pattern substantially as shown in FIG. 4 .
  • the molar ratio of maleic acid to free base is about 1:1, and it contains a small amount of anti-solvent, such as acetone or toluene.
  • the X-ray powder diffraction (XRPD) pattern of the maleate salt crystal form C at diffraction angles 2 ⁇ is about 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°, There are characteristic peaks at 32.36 ⁇ 0.2° and 38.52 ⁇ 0.2°.
  • the maleate crystal form C has an XRPD pattern substantially as shown in FIG. 5 , and the target type used in the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the maleate salt crystal 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, in particular, the The maleate salt Form C has a DSC pattern substantially as shown in FIG. 6 .
  • thermogravimetric (TGA) diagram of the maleate crystal form C shows that the sample loses 6.3% when heated to about 200°C, and the total weight loss is about 17.5% in the range of about 200-290°C, which is presumed to be caused by deacidification (deacidification).
  • the theoretical weight loss is about 18.7%
  • the maleate salt Form C has a TGA pattern substantially as shown in FIG. 6 .
  • the molar ratio of maleic acid to free base is about 1:1, and no solvent remains.
  • the crystal form of maleate salt form C remains unchanged when heated to about 110°C under the protection of N 2 , so it is speculated that the maleate salt form C is an anhydrous crystal form.
  • the maleate salt form B was transformed into the maleate salt form C after N 2 purging at about 30 °C, and it was speculated that the maleate salt form B was a hydrate. Maleate salt forms B and C can also be converted to maleate salt form A.
  • the present invention also provides the preparation method of above-mentioned maleate salt crystal form A, and described method is one of the following methods:
  • Both maleate form B or C are thermodynamically unstable crystals and will eventually transform into maleate form A. Therefore, there is no particular limitation on the method for converting the maleate salt form B or C to obtain the maleate salt form A.
  • the maleate salt form B or C can be dissolved in a solvent selected from the group consisting of ketone solvents such as acetone, ether solvents such as tetrahydrofuran (THF) and ester solvents such as ethyl acetate (EtOA) After suspending and stirring, it is converted into maleate salt crystal form A, but the present invention is not limited to this.
  • the present invention also provides a method for preparing the above-mentioned maleate salt form B, the method comprising: dissolving the maleate salt of compound I in methanol (MeOH)/dichloromethane (DCM) (1:1, v/v) Anti-solvents (such as acetone and toluene) are added dropwise to the mixed solution in , for recrystallization, and the obtained solid is obtained after standing at room temperature and humidity.
  • MeOH methanol
  • DCM dichloromethane
  • Anti-solvents such as acetone and toluene
  • the present invention also provides a method for preparing the above-mentioned maleate salt crystal form C, the method comprising: obtaining the maleate salt crystal form B by purging with an inert gas (eg N 2 ).
  • an inert gas eg N 2
  • the salt of Compound I is the hydrochloride salt.
  • the hydrochloride salt of Compound I exists in the form of Form A or Form B.
  • the X-ray powder diffraction (XRPD) pattern of the hydrochloride crystal form A is about 4.41 ⁇ 0.2°, 5.34 ⁇ 0.2°, 8.90 ⁇ 0.2°, 9.16 ⁇ 0.2°, 10.69 ⁇ 0.2°, 11.07° at diffraction angles 2 ⁇ There are characteristic peaks at ⁇ 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°, 26.85 ⁇ 0.2°, in particular, the hydrochloric acid
  • the XRPD pattern of the salt crystal form A is basically as shown in FIG. 7, and the target type used for the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the hydrochloride salt crystal form A has endothermic peaks with peak temperatures of about 94.6° C., about 237.4° C. and about 266.9° C., in particular, the hydrochloride salt crystal form A has Substantially the DSC diagram as shown in FIG. 8 .
  • thermogravimetric (TGA) graph of the hydrochloride salt form A shows that the sample has about 3.5% weight loss when heated to about 100°C, in particular, the hydrochloride salt form A has substantially as shown in FIG. 8 the TGA diagram.
  • the molar ratio of hydrochloric acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned hydrochloride salt crystal form A, the method comprising: compound I free base and hydrochloric acid in a molar ratio of about 1:1 in a solvent selected from ethers (such as tetrahydrofuran (THF)) and esters It can be obtained by reaction in a solvent like ethyl acetate (EtOA).
  • a solvent selected from ethers (such as tetrahydrofuran (THF)) and esters It can be obtained by reaction in a solvent like ethyl acetate (EtOA).
  • the X-ray powder diffraction (XRPD) pattern of the hydrochloride salt crystal form B has at diffraction angles 2 ⁇ of about 3.73 ⁇ 0.2°, 4.96 ⁇ 0.2°, 7.24 ⁇ 0.2°, 10.26 ⁇ 0.2°, and 15.47 ⁇ 0.2°. Characteristic peaks, in particular, the XRPD pattern of the hydrochloride salt crystal form B is substantially as shown in FIG. 7 , and the target type used for the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the hydrochloride salt crystal form B has endothermic peaks with peak temperatures of about 109.9° C., about 160.3° C. and about 266.9° C., in particular, the hydrochloride salt crystal form B has Substantially the DSC diagram as shown in FIG. 9 .
  • thermogravimetric (TGA) graph of the hydrochloride salt form B shows that the sample has about 9.1% weight loss when heated to about 130°C, in particular, the hydrochloride salt form B has substantially as shown in FIG. 9 .
  • TGA diagram The thermogravimetric (TGA) graph of the hydrochloride salt form B shows that the sample has about 9.1% weight loss when heated to about 130°C, in particular, the hydrochloride salt form B has substantially as shown in FIG. 9 . the TGA diagram.
  • the molar ratio of hydrochloric acid to free base is about 3:1.
  • the present invention also provides a method for preparing the above-mentioned hydrochloride salt crystal form B, the method comprising: mixing the free base of compound I and hydrochloric acid with a molar ratio of about 3:1 in a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvents (such as ethyl acetate (EtOA)), and mixed solvents (such as halogenated alkanes and alcohol solvents, such as dichloromethane/MeOH) are obtained by reaction.
  • a solvent selected from ketones (such as acetone), ethers ( For example, tetrahydrofuran (THF)), ester solvents (such as ethyl acetate (EtOA)), and mixed solvents (such as halogenated alkanes and alcohol solvents, such as dichloromethane/MeOH) are obtained by reaction.
  • the salt of Compound I is a phosphate.
  • the phosphate of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the phosphate crystal form A at diffraction angles 2 ⁇ is about 5.63 ⁇ 0.2°, 7.86 ⁇ 0.2°, 9.88 ⁇ 0.2°, 12.43 ⁇ 0.2°, 15.86 ⁇ 0.2°, 19.64 ⁇
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry (DSC) pattern of the phosphate crystal form A has endothermic peaks with onset temperatures of about 48.0° C. and about 228.3° C., respectively, and in particular, the phosphate crystal form A has substantially as shown in FIG. 11 . DSC diagram shown.
  • thermogravimetric (TGA) plot of the Phosphate Form A shows that the sample has a weight loss of about 3.6% when heated to about 130°C.
  • the Phosphate Form A has a TGA substantially as shown in FIG. 11 picture.
  • the molar ratio of phosphoric acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned phosphate crystal form A, the method comprising: mixing the free base of compound I and phosphoric acid in a molar ratio of about 1:1 in a solvent selected from ketones (eg acetone), ether solvents (eg Tetrahydrofuran (THF)), ester solvents (such as ethyl acetate (EtOA)), and mixed solvents (such as halogenated alkanes and alcohol solvents, such as dichloromethane/MeOH) are obtained by reaction.
  • a solvent selected from ketones (eg acetone), ether solvents (eg Tetrahydrofuran (THF)), ester solvents (such as ethyl acetate (EtOA)
  • mixed solvents such as halogenated alkanes and alcohol solvents, such as dichloromethane/MeOH
  • the salt of Compound I is the lactate salt.
  • the lactate salt of Compound I exists as Form A.
  • the X-ray powder diffraction (XRPD) pattern of the lactate crystal form A at diffraction angles 2 ⁇ is about 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°, 27.04
  • the lactate crystal form A has an XRPD pattern substantially as shown in FIG. 12 , and the target type used in the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the lactate salt form A has endothermic peaks with peak temperatures of about 99.0°C and about 183.3°C, respectively, and in particular, the lactate salt form A has substantially as shown in the figure. DSC diagram shown in 13.
  • thermogravimetric (TGA) graph of the lactate salt form A shows that the sample has a weight loss of about 4.0% when heated to about 130°C, in particular, the lactate salt form A has substantially as shown in FIG. 13 . the TGA diagram.
  • the molar ratio of lactic acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned lactate crystal form A, the method comprising: mixing the free base of Compound I and lactic acid in a molar ratio of about 1:1 in a solvent selected from ketones (such as acetone), ethers (such as tetrahydrofuran (THF)), ester solvent (such as ethyl acetate (EtOA)) in the solvent to obtain.
  • ketones such as acetone
  • ethers such as tetrahydrofuran (THF)
  • ester solvent such as ethyl acetate (EtOA)
  • the salt of Compound I is a fumarate salt.
  • the fumarate salt of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the fumarate salt crystal form A is about 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°, 22.13 ⁇ 0.2°, 23.10 ⁇ 0.2°, There are characteristic peaks at 23.82 ⁇ 0.2°, 24.52 ⁇ 0.2°, 27.03 ⁇ 0.2°, in particular, the fumarate crystal form A has an XRPD pattern substantially as shown in FIG. 14 , the target used in the XRPD Type is Cu target.
  • the differential scanning calorimetry (DSC) pattern 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, in particular, the fumarate Salt Form A has a DSC pattern substantially as shown in FIG. 15 .
  • thermogravimetric (TGA) graph of the fumarate salt form A shows that the sample has a weight loss of about 2.26% when heated to about 130°C.
  • the fumarate salt form A has substantially as shown in FIG. 15 . TGA plot shown.
  • the molar ratio of fumaric acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned fumarate salt crystal form A, the method comprising: compound I free base and fumaric acid in a molar ratio of about 1:1 in an ether solvent (such as tetrahydrofuran (THF)) ), ester solvents (such as ethyl acetate (EtOA)), and mixed solvents (such as halogenated alkanes and alcohol solvents, such as dichloromethane/MeOH).
  • an ether solvent such as tetrahydrofuran (THF)
  • ester solvents such as ethyl acetate (EtOA)
  • mixed solvents such as halogenated alkanes and alcohol solvents, such as dichloromethane/MeOH.
  • the salt of Compound I is the succinate salt.
  • the succinate salt of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the succinate form A at diffraction angles 2 ⁇ is about 4.18 ⁇ 0.2°, 5.33 ⁇ 0.2°, 6.82 ⁇ 0.2°, 8.35 ⁇ 0.2°, 11.56 ⁇ 0.2°, 13.67
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry (DSC) pattern of the succinate form A has endothermic peaks with onset temperatures of about 51.6°C and about 182.1°C, respectively, and in particular, the succinate form A has substantially as shown in the figure. DSC diagram shown in 17.
  • thermogravimetric (TGA) graph of the succinate Form A shows that the sample has a weight loss of about 3.2% when heated to about 130°C.
  • the succinate Form A has substantially as shown in FIG. 17 . the TGA diagram.
  • the molar ratio of succinic acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned succinate crystal form A, the method comprising: mixing the free base of compound I and succinic acid in a molar ratio of about 1:1 in a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvent (for example, ethyl acetate (EtOA)) solvent.
  • a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvent (for example, ethyl acetate (EtOA)) solvent.
  • the salt of Compound I is malate.
  • the malate salt of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the malate crystal form A at diffraction angles 2 ⁇ is about 4.49 ⁇ 0.2°, 6.10 ⁇ 0.2°, 7.16 ⁇ 0.2°, 9.00 ⁇ 0.2°, 10.99 ⁇ 0.2°, 14.87
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry (DSC) pattern of the malate salt form A has endothermic peaks with peak temperatures of about 100.4°C, about 175.9°C and about 185.6°C, respectively, and in particular, the malate salt form A has Substantially the DSC diagram as shown in FIG. 19 .
  • thermogravimetric (TGA) graph of the malate salt form A shows that the sample has a weight loss of about 4.0% when heated to about 130°C.
  • the malate salt form A has substantially as shown in FIG. 19 . the TGA diagram.
  • the molar ratio of malic acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned malate salt crystal form A, the method comprising: mixing the free base of compound I and malic acid in a molar ratio of about 1:1 in a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvent (for example, ethyl acetate (EtOA)) solvent.
  • a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvent (for example, ethyl acetate (EtOA)) solvent.
  • the salt of Compound I is an adipate salt.
  • the adipate salt of Compound I exists as Form A.
  • the X-ray powder diffraction (XRPD) pattern of the adipate crystal form A at diffraction angles 2 ⁇ is about 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°, There is a characteristic peak at 27.50 ⁇ 0.2°, in particular, the adipate crystal form A has an XRPD pattern substantially as shown in FIG. 20 , and the target type used in the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the adipate salt form A has an endothermic peak with an onset temperature of about 182.0°C, in particular, the adipate salt form A has substantially as shown in FIG. 21 . DSC diagram shown.
  • thermogravimetric (TGA) graph of the adipate salt form A shows that the sample has a weight loss of about 2.5% when heated to about 130°C.
  • the adipate salt form A has substantially as shown in FIG. 21 . TGA plot shown.
  • the molar ratio of adipic acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned adipate crystal form A, the method comprising: mixing the free base of compound I and adipic acid in a molar ratio of about 1:1 in a solvent selected from ketones (such as acetone), ethers Solvents (such as tetrahydrofuran (THF)) and ester solvents (such as ethyl acetate (EtOA)) are obtained by reaction.
  • ketones such as acetone
  • ethers Solvents such as tetrahydrofuran (THF)
  • ester solvents such as ethyl acetate (EtOA)
  • the salt of Compound I is hippurate.
  • the hippurate salt of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the hippurate crystal form A at diffraction angles 2 ⁇ is about 4.45 ⁇ 0.2°, 5.50 ⁇ 0.2°, 9.17 ⁇ 0.2°, 18.79 ⁇ 0.2°, 23.20 ⁇ 0.2°, There is a characteristic peak at 25.42 ⁇ 0.2°, in particular, the hippurate crystal form A has an XRPD pattern substantially as shown in FIG. 22 , and the target type used in the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the hippurate crystal 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 Form A has a DSC pattern substantially as shown in FIG. 23 .
  • thermogravimetric (TGA) graph of the hippurate crystal form A shows that the sample has about 4.2% weight loss when heated to about 130°C.
  • the hippurate crystal form A has substantially as shown in FIG. 23 . TGA plot shown.
  • the molar ratio of hippuric acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above hippurate crystal form A, the method comprising: compound I free base and hippuric acid in a molar ratio of about 1:1 in a solvent selected from ketones (such as acetone), esters It can be obtained by reaction in a solvent such as ethyl acetate (EtOA).
  • a solvent selected from ketones (such as acetone), esters It can be obtained by reaction in a solvent such as ethyl acetate (EtOA).
  • the salt of Compound I is glycolate.
  • the glycolate salt of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the glycolate crystal form A at diffraction angles 2 ⁇ is about 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°, 31.73
  • the glycolate crystal form A has an XRPD pattern substantially as shown in FIG. 24 , and the target type used in the XRPD is a Cu target.
  • the differential scanning calorimetry (DSC) pattern of the glycolate crystal form A has endothermic peaks with onset temperatures of about 54.1°C and about 183.2°C, respectively, and in particular, the glycolate crystal form A has substantially as shown in the figure. DSC diagram shown in 25.
  • thermogravimetric (TGA) graph of the glycolate salt form A shows that the sample has a weight loss of about 4.8% when heated to about 130°C.
  • the glycolate salt form A has substantially as shown in FIG. 25 . the TGA diagram.
  • the molar ratio of glycolic acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned glycolate crystal form A, the method comprising: mixing the free base of compound I and glycolic acid in a molar ratio of about 1:1 in a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvent (for example, ethyl acetate (EtOA)) solvent.
  • a solvent selected from ketones (such as acetone), ethers (for example, tetrahydrofuran (THF)), ester solvent (for example, ethyl acetate (EtOA)) solvent.
  • the salt of Compound I is a benzoate salt.
  • the benzoate salt of Compound I exists as Form A.
  • the X-ray powder diffraction (XRPD) pattern of the benzoate crystal form A at diffraction angles 2 ⁇ is about 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°, 23.58 ⁇ 0.2°, 25.01 ⁇ 0.2°, There are characteristic peaks at 26.31 ⁇ 0.2°, 27.11 ⁇ 0.2°, 29.33 ⁇ 0.2°, in particular, the benzoate crystal form A has an XRPD pattern substantially as shown in FIG. 26 , the target used in the XRPD Type is Cu target.
  • the differential scanning calorimetry (DSC) pattern of the benzoate form A has an endothermic peak with an onset temperature of about 169.5°C, in particular, the benzoate form A has substantially as shown in FIG. 27 . DSC diagram shown.
  • thermogravimetric (TGA) graph of the benzoate form A shows that the sample has a weight loss of about 2.7% when heated to about 130° C.
  • the benzoate form A has substantially as shown in FIG. 27 . TGA plot shown.
  • the molar ratio of benzoic acid to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned benzoate crystal form A, the method comprising: reacting the free base of compound I and benzoic acid with a molar ratio of about 1:1 in a ketone solvent (eg, acetone).
  • a ketone solvent eg, acetone
  • the salt of Compound I is nicotinate.
  • the nicotinate salt of Compound I exists in Form A.
  • the X-ray powder diffraction (XRPD) pattern of the nicotinate crystal form A at diffraction angles 2 ⁇ is about 4.54 ⁇ 0.2°, 6.46 ⁇ 0.2°, 10.14 ⁇ 0.2°, 13.41 ⁇ 0.2°, 14.66 ⁇ 0.2°, 17.14
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry (DSC) graph of the nicotinate crystal form A has endothermic peaks with peak temperatures of about 103.9° C., about 160.3° C. and about 212.5° C., in particular, the nicotinate salt crystal form A has Substantially the DSC diagram as shown in FIG. 29 .
  • thermogravimetric (TGA) plot of the nicotinate salt form A shows that the sample has about 4.9% weight loss when heated to about 130°C, in particular, the nicotinate salt form A has substantially as shown in FIG. 29 . the TGA diagram.
  • the molar ratio of niacin to free base is about 1:1.
  • the present invention also provides a method for preparing the above-mentioned nicotinate crystal form A, the method comprising: mixing the free base of compound I and nicotinic acid in a molar ratio of about 1:1 in an ether solvent (such as tetrahydrofuran (THF)), It can be obtained by reacting in a solvent of ester type solvent (such as ethyl acetate (EtOA)).
  • ether solvent such as tetrahydrofuran (THF)
  • EtOA ethyl acetate
  • a seed crystal can also be used.
  • the seed crystals can be used in the preparation method of each crystal form of the present application according to methods well known in the art.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more selected from the salts of Compound I above, the salts being selected from maleate, hydrochloride, phosphate, lactic acid salts, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate.
  • the pharmaceutical composition may also include a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier varies due to the route of administration and the characteristics of the action, and usually can be a conventional filler, diluent, binder, wetting agent, disintegrating agent, lubricant, and emulsifier in the field. , suspending agent, etc.
  • compositions can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingually, buccally, rectally, urethraally, vaginally, nasally, by inhalation or topically, the preferred route is oral.
  • the pharmaceutical composition can be used to prevent or treat diseases related to abnormal cell cycle regulation.
  • the "disease associated with abnormal cell cycle regulation” may be “disease associated with abnormal cyclin-dependent kinases (preferably CDK4 and/or CDK6)", particularly tumors, more particularly malignant tumors (such as breast cancer).
  • carcinoma including but not limited to breast cancer, central nervous system primary/metastatic tumors, etc.
  • 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
  • advanced solid tumors including but not limited to breast cancer, central nervous system primary/metastatic tumors, etc.
  • the pharmaceutical composition can be used as a cyclin-dependent kinase (preferably CDK4 and/or CDK6) inhibitor.
  • a cyclin-dependent kinase preferably CDK4 and/or CDK6 inhibitor.
  • 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, brain astrocytoma cells, chronic myeloid leukemia cells, pancreatic cancer cells, acute mononuclear cells Cell leukemia cells, liver cancer cells (including hepatocellular carcinoma cells, liver adenocarcinoma cells), gastric cancer cells, non-small cell lung cancer cells, glioblastoma cells and prostate adenocarcinoma cells; the breast cancer cells are preferably breast cancer cells One or more of cells MCF-7, T-47D and ZR-75-1.
  • the present invention provides the use of the above-mentioned salt of Compound I for the preparation of a medicament
  • the salt is selected from the group consisting of maleate, hydrochloride, phosphate, lactate, fumarate, succinate, Malate, adipate, hippurate, glycolate, benzoate and nicotinate for the prevention or treatment of diseases associated with abnormal cell cycle regulation.
  • the "diseases associated with abnormal cell cycle regulation” may be “diseases associated with abnormalities in cyclin-dependent kinases (preferably CDK4 and/or CDK6)", particularly tumors, more particularly malignant tumors (eg 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 carcinoma 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.).
  • cyclin-dependent kinases preferably CDK4 and/or CDK6
  • tumors eg breast cancer, colon cancer, non-small cell carcinoma, brain astrocytoma, chronic myeloid leukemia, pancreatic cancer, acute monocytic
  • the present invention provides the use of a salt of the above-mentioned compound I, selected from the group consisting of maleate, hydrochloride, phosphate, for the preparation of a cyclin-dependent kinase (preferably CDK4 and/or CDK6) inhibitor , lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate.
  • a salt of the above-mentioned compound I selected from the group consisting of maleate, hydrochloride, phosphate, for the preparation of a cyclin-dependent kinase (preferably CDK4 and/or CDK6) inhibitor , lactate, fumarate, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate.
  • a salt of the above-mentioned compound I selected from the group consisting of maleate, hydrochloride, phosphate, for the preparation of a cyclin-dependent kinase
  • the present invention provides the use of the above-mentioned salt of compound I for preparing a medicament for inhibiting the proliferation of tumor cells
  • the salt is selected from maleate, hydrochloride, phosphate, lactate, fumaric acid Salt, succinate, malate, adipate, hippurate, glycolate, benzoate and nicotinate.
  • the tumor cells are preferably cancer cells; the cancer cells are preferably breast cancer cells; the breast cancer cells are preferably one or more of breast cancer cells MCF-7, T-47D and ZR-75-1.
  • the salt can be selected from the maleate crystal form A, maleate crystal form B, maleate crystal form C, hydrochloride salt crystal form A, Hydrochloride Form B, Phosphate Form A, Lactate Form A, Fumarate Form A, Succinate Form A, Malate Form A, Adipate Form A, One or more of hippurate crystal form A, glycolate crystal form A, benzoate crystal form A and nicotinate crystal form A.
  • the salt may be one selected from the group consisting of maleate salt form A, fumarate salt form A, adipate salt form A and benzoate form A of Compound I or variety.
  • the salt may be Form A of the maleate salt of Compound I.
  • the salt may be Form A of the fumarate salt of Compound I.
  • the salt may be Form A of the adipate salt of Compound I.
  • the salt may be the benzoate salt form A of Compound I.
  • Figure 1 is an XRPD pattern of Compound I maleate salt Form A according to the present invention.
  • Figure 2 is a DSC and TGA graph of Compound I maleate salt Form A according to the present invention.
  • Figure 3 is an XRPD pattern of Compound I maleate salt Form B according to the present invention.
  • Figure 4 is a DSC and TGA graph of Compound I maleate salt Form B according to the present invention.
  • Figure 5 is an XRPD pattern of Compound I maleate salt Form C according to the present invention.
  • Figure 6 is a DSC and TGA graph of Compound I maleate salt Form C according to the present invention.
  • Figure 7 is an XRPD pattern of Compound I hydrochloride Form A and Form B according to the present invention.
  • Figure 8 is a DSC and TGA graph of Compound I hydrochloride salt form A according to the present invention.
  • Figure 9 is a DSC and TGA graph of Compound I hydrochloride salt form B according to the present invention.
  • Figure 10 is an XRPD pattern of Compound I Phosphate Form A according to the present invention.
  • Figure 11 is a DSC and TGA graph of Compound I Phosphate Form A according to the present invention.
  • Figure 12 is an XRPD pattern of Compound I lactate salt Form A according to the present invention.
  • Figure 13 is a DSC and TGA graph of Compound I lactate salt form A according to the present invention.
  • Figure 14 is an XRPD pattern of Compound I Fumarate Form A according to the present invention.
  • Figure 15 is a DSC and TGA graph of Compound I Fumarate Form A according to the present invention.
  • Figure 16 is an XRPD pattern of Compound I succinate salt form A according to the present invention.
  • Figure 17 is a DSC and TGA graph of Compound I succinate salt form A according to the present invention.
  • Figure 18 is an XRPD pattern of Compound I malate salt Form A according to the present invention.
  • Figure 19 is a DSC and TGA graph of Compound I malate salt Form A according to the present invention.
  • Figure 20 is an XRPD pattern of Compound I adipate Form A according to the present invention.
  • Figure 21 is a DSC and TGA graph of Compound I adipate Form A according to the present invention.
  • Figure 22 is an XRPD pattern of Compound I hippurate Form A according to the present invention.
  • Figure 23 is a DSC and TGA graph of Compound I hippurate Form A according to the present invention.
  • Figure 24 is an XRPD pattern of Compound I glycolate, Form A, according to the present invention.
  • Figure 25 is a DSC and TGA graph of Compound I glycolate, Form A, according to the present invention.
  • Figure 26 is an XRPD pattern of Compound I benzoate Form A according to the present invention.
  • Figure 27 is a DSC and TGA graph of Compound I benzoate Form A according to the present invention.
  • Figure 28 is an XRPD pattern of Compound I Nicotinate Form A according to the present invention.
  • Figure 29 is a DSC and TGA graph of Compound I Nicotinate Form A according to the present invention.
  • X-ray powder diffraction (XRPD): The XRPD pattern was collected on a PANalytacal Empyrean X-ray powder diffraction analyzer, and the XRPD parameters are shown in Table 1.
  • TGA and DSC spectra were collected on TAQ500/5000 thermogravimetric analyzer and TAQ200/2000 differential scanning calorimeter, respectively. The test parameters are shown in Table 2. .
  • HPLC High performance liquid chromatography
  • Ion chromatography The negative ion content was measured on an ion chromatography (IC) Thermo ICS1100, and the molar ratio was determined by combining with the HPLC data.
  • the specific instrument parameters are listed in Table 4.
  • Dynamic Moisture Sorption (DVS) curves were collected on DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2 and KCl. DVS test parameters are listed in Table 5.
  • Liquid NMR Solid NMR spectra were acquired on a Bruker 400M NMR instrument with DMSO-d 6 as the solvent.
  • the heating test was carried out as follows:
  • the samples were carried out under nitrogen protection, heated to the target temperature and then cooled to room temperature. The samples were taken out and exposed to air, and the test XRPD was collected.
  • the free base of compound 1 was prepared according to the method disclosed in CN106928219A. Only a few diffraction peaks were observed in its XRPD results. HPLC purity was 95.2 area %. The TGA results showed that the sample lost 4.8% weight when heated to 200°C. The DSC results showed that the sample had one endothermic and two exothermic signals before melting at 233.6°C (onset temperature). The heating test results showed that no change was observed in XPRD results when the starting sample was heated to 80°C; the diffraction peaks at 2 ⁇ of about 4.7° disappeared when heated to 135°C and 175°C, and the crystallinity was enhanced.
  • the crystal forms were prepared using the following methods:
  • 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 are shown in the TGA curve in Figure 2, indicating that the maleate form A loses 4.05% in weight when heated to about 200 °C, and the DSC results are shown in the DSC curve in Figure 2, indicating that it melts at about 222.8 °C (starting temperature) and with decomposition.
  • the HPLC/IC results showed that the molar ratio of the sample was 1.03 (acid/base), and it was speculated that the maleate salt form A was an anhydrous crystal form of a maleate salt.
  • the XRPD results of the fumarate salt form A are shown in FIG. 14 .
  • the TGA results, as shown in the TGA curve in Figure 15, indicate that the fumarate Form A sample has a weight loss of 2.3% when heated to about 130°C.
  • DSC results The DSC curve in Figure 15 shows an exothermic peak at about 163.5°C (peak temperature) and an endothermic peak at about 248.9°C (onset temperature).
  • the results of the heating test show that the sample is heated to about 170 °C without changing the crystal form, and the crystallinity is significantly improved. It is speculated that the exothermic signal is amorphous transformation.
  • the HPLC/IC results showed that the molar ratio of the fumarate form A was 1.07 (acid/base), and it was speculated that the fumarate form A was an anhydrous fumarate.
  • the XRPD characterization results of the adipate crystal form A are shown in Figure 20.
  • the TGA results show that the adipate Form A sample has a weight loss of about 2.5% when heated to about 130°C.
  • the DSC results show that there is an endothermic peak at about 182.0°C (starting temperature), and it is presumed that the adipate crystal form A is an anhydrous crystal form.
  • HPLC/IC results indicated that the molar ratio of adipate Form A was 0.88 (acid/base).
  • the XRPD results of the benzoate Form A are shown in FIG. 26 .
  • the TGA results, as shown in the TGA curve in Figure 27, show that the benzoate Form A loses about 2.7% in weight when heated to about 130°C.
  • the DSC results, as shown in the DSC curve in Figure 27, show that there is an endothermic peak at about 169.5 °C (starting temperature), and it is speculated that the benzoate crystal form A is an anhydrous crystal form.
  • the XRPD results of the hydrochloride salt Form A are shown in FIG. 7 .
  • the TGA results are shown in the TGA curve in Figure 8, indicating that the sample has a weight loss of about 3.5% when heated to about 100 °C
  • the DSC results are shown in the DSC curve in Figure 8, indicating that there are multiple endothermic and exothermic peaks on the DSC chart, especially , with endothermic peaks with peak temperatures of about 94.6 °C, about 237.4 °C and about 266.9 °C, respectively, and exothermic peaks with peak temperatures of about 156.2 °C and 203.0 °C, respectively.
  • the onset temperatures of the endothermic peaks whose peak temperatures are about 237.4°C and about 266.9°C, respectively are about 233.7°C and about 261.9°C, respectively.
  • the XRPD results of the hydrochloride salt Form B sample are shown in FIG. 7 .
  • the TGA results are shown in the TGA curve in Figure 9, indicating that the sample has a weight loss of about 9.1% when heated to about 130 °C, and the DSC results are shown in the DSC curve in Figure 9. There is an endothermic peak.
  • the XRPD results of the phosphate crystal form A are shown in FIG. 10 .
  • the TGA results are shown in the TGA curve in Figure 11, indicating that the phosphate crystal form A sample has a weight loss of about 3.6% when heated to about 130 °C, and the DSC results are shown in the DSC curve in Figure 11. ) has an endothermic peak.
  • the XRPD results of the lactate Form A are shown in FIG. 12 .
  • the TGA results are shown in the TGA curve in Figure 13, indicating that the lactate crystal form A sample has a weight loss of about 4.0% when heated to about 130 °C, and the DSC results are shown in the DSC curve in Figure 13, indicating that at about 99.0 °C and about 183.3 °C (peak temperature) has an endothermic peak.
  • the XRPD results of the succinate Form A are shown in FIG. 16 .
  • the TGA results are the TGA curves in Figure 17, showing that the succinate Form A sample has a weight loss of about 3.2% when heated to about 130°C, and the DSC results, as the DSC curves in Figure 17, show that at about 51.6°C and about 182.1°C (the onset temperature) has an endothermic peak.
  • the results of the heating test show that the crystal form of the sample remains unchanged when heated to 100°C.
  • the XRPD results of the malate Form A are shown in FIG. 18 .
  • the TGA results are shown in the TGA curve in Figure 19, showing that the malate crystal form A sample has a weight loss of about 4.0% when heated to about 130 °C.
  • the DSC results are shown in the DSC curve in Figure 19, indicating that there are multiple endothermic peaks before decomposition .
  • the XRPD characterization results of the hippurate crystal form A are shown in Figure 22.
  • the TGA results are shown in the TGA curve in Figure 23, indicating that the hippurate crystal form A sample has a weight loss of about 4.2% 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 the 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.
  • the XRPD results of the glycolate crystal form A are shown in FIG. 24 .
  • the TGA results are shown in the TGA curve in Figure 25, indicating that the glycolate crystal form A sample has a weight loss of about 4.8% when heated to about 130 °C, and the DSC results are shown in the DSC curve in Figure 25. temperature) has an endothermic peak.
  • the results of the heating test show that the crystal form of the sample remains unchanged when heated to 130°C.
  • 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 shows that the nicotinate crystal form A sample has a weight loss of about 4.9% when heated to about 130 °C.
  • the DSC results are shown in the DSC curve in Figure 29, indicating that there are multiple endothermic peaks before decomposition , especially the endothermic peaks with peak temperatures of about 103.9°C, about 160.3°C, and about 212.5°C, respectively.
  • maleate salt form A fumarate salt form A, adipate salt form A and benzoate form A
  • solubility at 37°C solid-state stability, and hygroscopicity of the samples were evaluated, respectively.
  • Dynamic solubility tests were performed in four vehicles: water, simulated gastric fluid (SGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) to evaluate maleate form A, fumarate form A , Solubility and disproportionation risk of adipate form A and benzoate form A.
  • SGF gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated fed intestinal fluid
  • HPLC HPLC was collected on an Agilent 1100HPLC, and the solubility test parameters were as follows in Table 9.
  • Table 10 summarizes the dynamic solubility test results of Form A and free base Form A of the four salts at 37°C.
  • Free Base Free Base Form A
  • Maleate Maleate Form A
  • Fumarate Fumarate Form A
  • Adipate Adipate Form A
  • Benzyl Acid salt benzoate form A.
  • DVS was used to test maleate form A, fumarate form A, adipate form A, and benzoate form A. . All samples were pre-dried at 0% RH to remove the adsorbed solvent or water before testing.
  • the solubility of maleate form A, fumarate form A, adipate form A and benzoate form A in water and biological solvents is similar to that of free base form A. or increase; except for adipate and benzoate, which were observed to decrease in HPLC purity, the other salt forms and free base crystal form A showed better physical and chemical stability in the solid-state stability evaluation; according to the results of water adsorption, horse The acetic acid salt form A and the fumarate form A samples have slight hygroscopicity, and the other salt form samples and the free base form A are all hygroscopic.
  • the maleate crystal form A has better properties, mainly as follows:
  • sample of maleate crystal form A has no change in crystal form or HPLC purity after being placed under the conditions of 25°C/60%RH and 40°C/75%RH for one week, showing good physical and chemical stability;
  • the crystal forms were prepared using the following general method:
  • the maleate crystal form, fumarate salt crystal form, adipate crystal form and benzoate crystal form were prepared by the above method. XRPD and DSC test results show that they are consistent with the above-mentioned maleate crystal form A, fumarate crystal form A, adipate crystal form A and benzoate crystal form A reference respectively.
  • the maleate salt form A of compound I was suspended in CHCl3 /n-hexane (1:1, v/v) under magnetic stirring ( ⁇ 1000 rpm) at 50°C for about 4 days, and centrifuged ( ⁇ 1000 rpm). 10,000 rpm, 3 minutes) to collect the solids and perform XRPD testing.
  • Form B of the maleate salt was also obtained.
  • the XRPD results of maleate 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 about 6.4% of the weight when heated to about 200°C (about 19.1% of the weight loss at 200-290°C is presumed to be caused by deacidification, and the theoretical weight loss of deacidification is about 18.7%).
  • DSC characterization results The DSC curve in Figure 4 shows two weak endothermic peaks at about 74.6 °C and about 236.8 °C (peak temperature), and a sharp endothermic peak at about 225.5 °C (starting temperature). 1 H NMR results showed that the molar ratio of maleic acid to free base was 1:1.
  • the maleate salt form B was transformed into the maleate salt form C after a N purge at 30 °C for 20 min.
  • the XRPD results of maleate 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 about 6.3% weight when heated to about 200°C (about 17.5% of the weight loss at 200-290°C is presumed to be caused by deacidification, and the theoretical weight loss of deacidification is about 18.7%).
  • DSC characterization results The DSC curve in Figure 6 shows an exothermic peak at about 142.8°C (peak temperature) and a sharp endothermic peak at about 222.0°C (onset temperature).
  • 1 H NMR results showed that the molar ratio of maleic acid to free base was 1:1.
  • VT-XRPD results show that the maleate salt form C does not change when heated to about 110 °C under the protection of N2 . Based on the above results, it is presumed that the maleate salt form C is an anhydrous form.
  • the maleate salt form C is transformed into the maleate salt form A after heating to about 170 °C under the protection of N2 .
  • the maleate salt form B is a hydrate, and after being purged with N 2 , the bound water is removed and transformed into an anhydrous crystal form.
  • the clear solution containing the maleate salt of compound I in the solvent listed in Table 14 below was placed in a biochemical incubator, and the temperature was lowered from 50°C to 5°C at a cooling rate of 0.1°C/min. It evaporated at room temperature and the resulting solid was collected and tested by XRPD.
  • the specific steps are as follows: 1) prepare saturated solutions of maleate anhydrous crystal form A in different solvents at a specific temperature; 2) add equal mass samples of crystal form A and B or C (about 4 mg each) to 0.5 mL of A suspension was formed in the saturated solution; 3) Suspended and stirred at room temperature and 50° C. for about 5 days ( ⁇ 800 rpm); 4) The remaining solid was separated and tested by XRPD.
  • the suspensions of each crystal form were prepared, magnetically stirred at room temperature for 24 hours (rotation speed ⁇ 800rpm), centrifuged (10000rpm, 5min), and the supernatant was filtered (0.22 ⁇ m PTFE membrane), and then the solubility and pH were measured. XRPD.
  • Table 16 summarizes the results of the equilibrium solubility in water of the maleate salt forms A, B, and C.
  • This test is used to evaluate the solid state stability of the maleate salt Form A.
  • High temperature (60°C) and light (1.2*10 6 Lux*hr) were carried out on the free base crystal form A and the maleate crystal form A obtained therefrom for a period of 5 days, and the detection items were related substances.
  • Test solution Take about 25mg of this product, put it in a 100ml volumetric flask, add methanol to dissolve and dilute to the mark, shake well, and use it as the test solution.
  • Test solution take about 30mg of this product, put it in a 100ml volumetric flask, add diluent to dissolve and dilute to the mark, shake well, and use it as the test solution.

Abstract

含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途，特别是涉及如下所示的化合物I的盐、晶型及制备方法、药物组合物和用途。所述的化合物I盐或其晶型表现出了以下至少一方面优势：改善的生物利用率，良好的力学性质、改善的化学稳定性，优秀的流动性质，良好的压缩性和改善的溶解特征。

Description

含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途 技术领域
本发明涉及N-(4-(1-环丙基-4-氟-2-甲基-1H-苯并咪唑-6-基)-5-氟嘧啶-2-基)-6-(2-(二甲胺基)乙基)-5,6,7,8-四氢-1,6-萘啶-2-胺，具体而言，涉及该化合物的盐、晶型及制备方法、药物组合物和用途。
背景技术
化合物I，N-(4-(1-环丙基-4-氟-2-甲基-1H-苯并咪唑-6-基)-5-氟嘧啶-2-基)-6-(2-(二甲胺基)乙基)-5,6,7,8-四氢-1,6-萘啶-2-胺，结构如下式所示：
Figure PCTCN2022075631-appb-000001
化合物I已经公开于CN106928219A和WO2017114512A1(它们公开的全部内容通过引用并入本文，如同记载在本文中一样)中，其在分子水平对细胞周期蛋白依赖性激酶4(CDK4)和细胞周期蛋白依赖性激酶6(CDK6)的选择性高，且对CDK4和CDK6的抑制活性高，在细胞水平和动物水平对与周期蛋白依赖性激酶活性相关的肿瘤细胞具有显著的抑制增殖作用，可以用于乳腺癌，结肠癌，非小细胞癌，脑星形细胞瘤，慢性粒细胞性白血病，胰腺癌，急性单核细胞白血病，肝癌(包括肝细胞癌，肝腺癌)，胃癌，非小细胞肺癌，恶性胶质母细胞瘤和***腺癌等恶性肿瘤的治疗，而且其对于人、鼠等的肝微粒体稳定性良好，代谢酶无明显抑制，大小鼠体内吸收性质好，生物利用度高，具有较好的成药性。
但是仍然需要能够提供具有合意加工性质的化合物I以改进药物的性能特征，所述的合意处理性质如易于处理、易于加工、改善的溶解特征、改善的储存期限、易于提纯等。
发明内容
本发明提供化合物I的盐、晶型及其制备方法、药物组合物和用途。所述的化合物I 盐或其晶型表现出了以下至少一方面优势：改善的生物利用率，良好的力学性质、改善的化学稳定性，优秀的流动性质，良好的压缩性和改善的溶解特征。
一方面，本发明提供如下所示的化合物I的盐，所述盐选自马来酸盐、盐酸盐、磷酸盐、乳酸盐、富马酸盐、琥珀酸盐、苹果酸盐、己二酸盐、马尿酸盐、乙醇酸盐、苯甲酸盐和烟酸盐，
Figure PCTCN2022075631-appb-000002
所述化合物I的盐可以通过本领域中的常规制备盐化合物的方法得到，例如将化合物I的游离碱与相应的酸反应得到，或者通过酸的置换反应得到，或者可以根据本申请下面描述的方法以及实施例公开的方法，结合本领域技术常识制备得到。
所述盐可以为选自化合物I的马来酸盐晶型A、马来酸盐晶型B、马来酸盐晶型C、盐酸盐晶型A、盐酸盐晶型B、磷酸盐晶型A、乳酸盐晶型A、富马酸盐晶型A、琥珀酸盐晶型A、苹果酸盐晶型A、己二酸盐晶型A、马尿酸盐晶型A、乙醇酸盐晶型A、苯甲酸盐晶型A和烟酸盐晶型A中的一种或多种。
更特别地，所述盐可以为选自化合物I的马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A中的一种或多种。
更特别地，所述盐可以为化合物I的马来酸盐晶型A。
更特别地，所述盐可以为化合物I的富马酸盐晶型A。
更特别地，所述盐可以为化合物I的己二酸盐晶型A。
更特别地，所述盐可以为化合物I的苯甲酸盐晶型A。
在一个实施方式中，所述化合物I的盐是马来酸盐。
在一个实施方式中，所述化合物I的马来酸盐以晶型A、晶型B或晶型C的形式存在。
所述马来酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、27.46±0.2°处有特征峰，优选地，还在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°、25.62±0.2°、26.07±0.2°、28.23±0.2°、28.68±0.2°、33.08±0.2°和38.76±0.2°一处或多处有衍射峰，优选在衍射角2θ约为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°和38.76±0.2°处有特征峰，特别地，所述马来酸盐晶型A具有基本上如图1所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述马来酸盐晶型A的差示扫描量热(DSC)图具有起点温度为约222.8℃的吸热峰以及峰值温度为约235.3℃的吸热峰，特别地，所述马来酸盐晶型A具有基本上如图2中所示的DSC图。
所述马来酸盐晶型A的热失重(TGA)图显示样品在约200℃失重约4.1％，在约200～290℃区间总的失重为约17.5％，推测为脱酸导致(脱酸的理论失重为约18.7％)，特别地，所述马来酸盐晶型A具有基本上如图2中所示的TGA图。
经 1H NMR检测，所述马来酸盐晶型A中，马来酸与游离碱的摩尔比为约1:1。经变温XRPD(VT-XRPD)检测，马来酸盐晶型A在N 2保护下加热至约170℃及冷却至约30℃后晶型不变，由此推测马来酸盐晶型A为无水晶型。
所述马来酸盐晶型B的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、27.96±0.2°处有特征峰，特别地，所述马来酸盐晶型B具有基本上如图3所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述马来酸盐晶型B的差示扫描量热(DSC)图具有峰值温度分别为约74.6℃和约236.8℃的两个弱的吸热峰，以及起点温度为约225.5℃的尖锐的吸热峰，特别地，所述马来酸盐晶型B具有基本上如图4中所示的DSC图。
所述马来酸盐晶型B的热失重(TGA)图显示样品加热至约200℃失重6.4％，在约200～290℃区间总的失重约19.1％，推测为脱酸导致(脱酸的理论失重为约18.7％)，特别地，所述马来酸盐晶型B具有基本上如图4中所示的TGA图。
经 1H NMR检测，所述马来酸盐晶型B中，马来酸与游离碱的摩尔比为约1:1，含有少量的反溶剂，例如丙酮或甲苯。
所述马来酸盐晶型C的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、38.52±0.2°处有特征峰，特别地，所述马来酸盐晶型C具有基本上如图5所示的XRPD图，所述的 XRPD使用的靶型为Cu靶。
所述马来酸盐晶型C的差示扫描量热(DSC)图具有峰值温度为约142.8℃的放热峰，和起点温度为约222.0℃的尖锐的吸热峰，特别地，所述马来酸盐晶型C具有基本上如图6中所示的DSC图。
所述马来酸盐晶型C的热失重(TGA)图显示样品加热至约200℃失重6.3％，在约200～290℃区间总的失重约17.5％，推测为脱酸导致(脱酸的理论失重为约18.7％)，特别地，所述马来酸盐晶型C具有基本上如图6中所示的TGA图。
经 1H NMR检测，所述马来酸盐晶型C中，马来酸与游离碱的摩尔比为约1:1，无溶剂残留。经VT-XRPD检测，马来酸盐晶型C在N 2保护下加热至约110℃时晶型不变，由此推测马来酸盐晶型C为无水晶型。
马来酸盐晶型B在约30℃下N 2吹扫后即转变为马来酸盐晶型C，推测马来酸盐晶型B为水合物。马来酸盐晶型B和C也可以转变为马来酸盐晶型A。
本发明还提供上述马来酸盐晶型A的制备方法，所述方法为以下方法之一：
方法一：
(1)将化合物I的游离碱和马来酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、醇类溶剂(例如甲醇(MeOH))和酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到；
方法二：
(2)由马来酸盐晶型B或C转化得到。
马来酸盐晶型B或C均为热力学不稳定晶体，最终都会转变为马来酸盐晶型A。因此，对于将由马来酸盐晶型B或C转化得到马来酸盐晶型A的方法没有特别限制。例如，可以将马来酸盐晶型B或C在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))和酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中悬浮搅拌后转变为马来酸盐晶型A，但是本发明不限于此。
本发明还提供上述马来酸盐晶型B的制备方法，所述方法包括：将化合物I的马来酸盐在甲醇(MeOH)/二氯甲烷(DCM)(1:1,v/v)中的混合溶液中滴加反溶剂(例如丙酮和甲苯)进行重结晶，所得固体在室温室湿下放置后得到。
本发明还提供上述马来酸盐晶型C的制备方法，所述方法包括：将马来酸盐晶型B用惰性气体(例如N 2)吹扫得到。
在一个实施方式中，所述化合物I的盐是盐酸盐。
在一个实施方式中，所述化合物I的盐酸盐以晶型A或晶型B的形式存在。
所述盐酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、26.85±0.2°处有特征峰，特别地，所述盐酸盐晶型A的XRPD图基本上如图7中所示，所述的XRPD使用的靶型为Cu靶。
所述盐酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为约94.6℃、约237.4℃和约266.9℃的吸热峰，特别地，所述盐酸盐晶型A具有基本上如图8中所示的DSC图。
所述盐酸盐晶型A的热失重(TGA)图显示样品在加热至约100℃有约3.5％的失重，特别地，所述盐酸盐晶型A具有基本上如图8中所示的TGA图。
经 1H NMR检测，所述盐酸盐晶型A中，盐酸与游离碱的摩尔比为约1:1。
本发明还提供上述盐酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和盐酸在选自醚类溶剂(例如四氢呋喃(THF))和酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
所述盐酸盐晶型B的X-射线粉末衍射(XRPD)图在衍射角2θ约为3.73±0.2°、4.96±0.2°、7.24±0.2°、10.26±0.2°、15.47±0.2°处有特征峰，特别地，所述盐酸盐晶型B的XRPD图基本上如图7中所示，所述的XRPD使用的靶型为Cu靶。
所述盐酸盐晶型B的差示扫描量热(DSC)图具有峰值温度分别为约109.9℃、约160.3℃和约266.9℃的吸热峰，特别地，所述盐酸盐晶型B具有基本上如图9中所示的DSC图。
所述盐酸盐晶型B的热失重(TGA)图显示样品在加热至约130℃有约9.1％的失重，特别地，所述盐酸盐晶型B具有基本上如图9中所示的TGA图。
经 1H NMR检测，所述盐酸盐晶型B中，盐酸与游离碱的摩尔比为约3:1。
本发明还提供上述盐酸盐晶型B的制备方法，所述方法包括：将摩尔比为约3:1的化合物I游离碱和盐酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))、以及混合溶剂(例如卤代烷烃和醇类溶剂，例如二氯甲烷/MeOH)的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是磷酸盐。
在一个实施方式中，所述化合物I的磷酸盐以晶型A的形式存在。
所述磷酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、27.32±0.2°处有特征峰，特别地，所述磷酸盐晶型A具有基本上如图10所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述磷酸盐晶型A的差示扫描量热(DSC)图具有起点温度分别为约48.0℃和约228.3℃的吸热峰，特别地，所述磷酸盐晶型A具有基本上如图11中所示的DSC图。
所述磷酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约3.6％的失重，特别地，所述磷酸盐晶型A具有基本上如图11中所示的TGA图。
经 1H NMR检测，所述磷酸盐晶型A中，磷酸与游离碱的摩尔比为约1:1。
本发明还提供上述磷酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和磷酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))、以及混合溶剂(例如卤代烷烃和醇类溶剂，例如二氯甲烷/MeOH)的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是乳酸盐。
在一个实施方式中，所述化合物I的乳酸盐以晶型A的形式存在。
所述乳酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、27.04±0.2°处有特征峰，特别地，所述乳酸盐晶型A具有基本上如图12所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述乳酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为约99.0℃和约183.3℃的吸热峰，特别地，所述乳酸盐晶型A具有基本上如图13中所示的DSC图。
所述乳酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约4.0％的失重，特别地，所述乳酸盐晶型A具有基本上如图13中所示的TGA图。
经 1H NMR检测，所述乳酸盐晶型A中，乳酸与游离碱的摩尔比为约1:1。
本发明还提供上述乳酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和乳酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是富马酸盐。
在一个实施方式中，所述化合物I的富马酸盐以晶型A的形式存在。
所述富马酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、22.13±0.2°、23.10±0.2°、23.82±0.2°、24.52±0.2°、27.03±0.2°处有特征峰，特别地，所述富马酸盐晶型A具有基本上如图14所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述富马酸盐晶型A的差示扫描量热(DSC)图具有峰值温度为约163.5℃的放热峰， 和起点温度为约248.9℃的吸热峰，特别地，所述富马酸盐晶型A具有基本上如图15中所示的DSC图。
所述富马酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约2.26％的失重，特别地，所述富马酸盐晶型A具有基本上如图15中所示的TGA图。
经 1H NMR检测，所述富马酸盐晶型A中，富马酸与游离碱的摩尔比为约1:1。
本发明还提供上述富马酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和富马酸在选自醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))、以及混合溶剂(例如卤代烷烃和醇类溶剂，例如二氯甲烷/MeOH)的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是琥珀酸盐。
在一个实施方式中，所述化合物I的琥珀酸盐以晶型A的形式存在。
所述琥珀酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、23.15±0.2°处有特征峰，特别地，所述琥珀酸盐晶型A具有基本上如图16所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述琥珀酸盐晶型A的差示扫描量热(DSC)图具有起点温度分别为约51.6℃和约182.1℃的吸热峰，特别地，所述琥珀酸盐晶型A具有基本上如图17中所示的DSC图。
所述琥珀酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约3.2％的失重，特别地，所述琥珀酸盐晶型A具有基本上如图17中所示的TGA图。
经 1H NMR检测，所述琥珀酸盐晶型A中，琥珀酸与游离碱的摩尔比为约1:1。
本发明还提供上述琥珀酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和琥珀酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是苹果酸盐。
在一个实施方式中，所述化合物I的苹果酸盐以晶型A的形式存在。
所述苹果酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、26.58±0.2°处有特征峰，特别地，所述苹果酸盐晶型A具有基本上如图18所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述苹果酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为约100.4℃、约175.9℃和约185.6℃的吸热峰，特别地，所述苹果酸盐晶型A具有基本上如图19中所示的DSC图。
所述苹果酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约4.0％的失重，特别地，所述苹果酸盐晶型A具有基本上如图19中所示的TGA图。
经 1H NMR检测，所述苹果酸盐晶型A中，苹果酸与游离碱的摩尔比为约1:1。
本发明还提供上述苹果酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和苹果酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是己二酸盐。
在一个实施方式中，所述化合物I的己二酸盐以晶型A的形式存在。
所述己二酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、27.50±0.2°处有特征峰，特别地，所述己二酸盐晶型A具有基本上如图20所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述己二酸盐晶型A的差示扫描量热(DSC)图具有起点温度为约182.0℃的吸热峰，特别地，所述己二酸盐晶型A具有基本上如图21中所示的DSC图。
所述己二酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约2.5％的失重，特别地，所述己二酸盐晶型A具有基本上如图21中所示的TGA图。
经 1H NMR检测，所述己二酸盐晶型A中，己二酸与游离碱的摩尔比为约1:1。
本发明还提供上述己二酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和己二酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是马尿酸盐。
在一个实施方式中，所述化合物I的马尿酸盐以晶型A的形式存在。
所述马尿酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为4.45±0.2°、5.50±0.2°、9.17±0.2°、18.79±0.2°、23.20±0.2°、25.42±0.2°处有特征峰，特别地，所述马尿酸盐晶型A具有基本上如图22所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述马尿酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为约124.2℃、约141.0℃、约154.6℃、约178.0℃和约217.2℃的吸热峰，特别地，所述马尿酸盐晶型A具有基本上如图23中所示的DSC图。
所述马尿酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约4.2％的失重，特别地，所述马尿酸盐晶型A具有基本上如图23中所示的TGA图。
经 1H NMR检测，所述马尿酸盐晶型A中，马尿酸与游离碱的摩尔比为约1:1。
本发明还提供上述马尿酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和马尿酸在选自酮类溶剂(例如丙酮)、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是乙醇酸盐。
在一个实施方式中，所述化合物I的乙醇酸盐以晶型A的形式存在。
所述乙醇酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、31.73±0.2°处有特征峰，特别地，所述乙醇酸盐晶型A具有基本上如图24所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述乙醇酸盐晶型A的差示扫描量热(DSC)图具有起点温度分别为约54.1℃和约183.2℃的吸热峰，特别地，所述乙醇酸盐晶型A具有基本上如图25中所示的DSC图。
所述乙醇酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约4.8％的失重，特别地，所述乙醇酸盐晶型A具有基本上如图25中所示的TGA图。
经 1H NMR检测，所述乙醇酸盐晶型A中，乙醇酸与游离碱的摩尔比为约1:1。
本发明还提供上述乙醇酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和乙醇酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在一个实施方式中，所述化合物I的盐是苯甲酸盐。
在一个实施方式中，所述化合物I的苯甲酸盐以晶型A的形式存在。
所述苯甲酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、23.58±0.2°、25.01±0.2°、26.31±0.2°、27.11±0.2°、29.33±0.2°处有特征峰，特别地，所述苯甲酸盐晶型A具有基本上如图26所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述苯甲酸盐晶型A的差示扫描量热(DSC)图具有起点温度为约169.5℃的吸热峰，特别地，所述苯甲酸盐晶型A具有基本上如图27中所示的DSC图。
所述苯甲酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约2.7％的失重，特别地，所述苯甲酸盐晶型A具有基本上如图27中所示的TGA图。
经 1H NMR检测，所述苯甲酸盐晶型A中，苯甲酸与游离碱的摩尔比为约1:1。
本发明还提供上述苯甲酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和苯甲酸在酮类溶剂(例如丙酮)中反应得到。
在一个实施方式中，所述化合物I的盐是烟酸盐。
在一个实施方式中，所述化合物I的烟酸盐以晶型A的形式存在。
所述烟酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ约为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°、26.27±0.2°处有特征峰，特别地，所述烟酸盐晶型A具有基本上如图28所示的XRPD图，所述的XRPD使用的靶型为Cu靶。
所述烟酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为约103.9℃、约160.3℃和约212.5℃的吸热峰，特别地，所述烟酸盐晶型A具有基本上如图29中所示的DSC图。
所述烟酸盐晶型A的热失重(TGA)图显示样品在加热至约130℃有约4.9％的失重，特别地，所述烟酸盐晶型A具有基本上如图29中所示的TGA图。
经 1H NMR检测，所述烟酸盐晶型A中，烟酸与游离碱的摩尔比为约1:1。
本发明还提供上述烟酸盐晶型A的制备方法，所述方法包括：将摩尔比为约1:1的化合物I游离碱和烟酸在选自醚类溶剂(例如四氢呋喃(THF))、酯类溶剂(例如乙酸乙酯(EtOA))的溶剂中反应得到。
在本发明的晶型的制备方法中，还可以使用晶种。晶种可以按照本领域中公知的方法在本申请各晶型的制备方法中使用。
在另一方面，本发明提供一种药物组合物，其包括选自上述化合物I的盐中的一种或多种，所述盐选自马来酸盐、盐酸盐、磷酸盐、乳酸盐、富马酸盐、琥珀酸盐、苹果酸盐、己二酸盐、马尿酸盐、乙醇酸盐、苯甲酸盐和烟酸盐。
此外，所述药物组合物还可以包括药学上可接受的载体。所述的药学上可接受的载体的选择因施用途径和作用特点而异，通常可为本领域常规的填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂、助悬剂等。
所述的药物组合物可以通过口服、注射(静脉、肌肉、皮下和冠状动脉内)、舌下、经颊、经直肠、经尿道、经***、经鼻、吸入或局部途径施用，优选途径是口服。
所述药物组合物可以用于预防或治疗与细胞周期调控异常相关的疾病。所述的“与细胞周期调控异常相关的疾病”可以为“与周期蛋白依赖性激酶(优选CDK4和/或CDK6)异常相关的疾病”，特别地为肿瘤，更特别地为恶性肿瘤(例如乳腺癌，结肠癌，非小细胞癌，脑星形细胞瘤，慢性粒细胞性白血病，胰腺癌，急性单核细胞白血病，肝癌(包括肝细胞癌，肝腺癌)，胃癌，非小细胞肺癌，恶性胶质母细胞瘤和***腺癌)，晚期实体瘤(包括但不限于乳腺癌、中枢神经原发性肿瘤/转移性肿瘤等)。
所述药物组合物可以用作周期蛋白依赖性激酶(优选CDK4和/或CDK6)抑制剂。
所述药物组合物可以用于抑制肿瘤细胞的增殖。所述的肿瘤细胞优选癌细胞；所述的癌细胞优选乳腺癌细胞，结肠癌细胞，非小细胞癌细胞，脑星形细胞瘤细胞，慢性粒细胞性白血病细胞，胰腺癌细胞，急性单核细胞白血病细胞，肝癌细胞(包括肝细胞癌细胞，肝腺癌细胞)，胃癌细胞，非小细胞肺癌细胞，恶性胶质母细胞瘤细胞和***腺癌细胞；所述的乳腺癌细胞优选乳腺癌细胞MCF-7、T-47D和ZR-75-1中的一种或多种。
在另一方面，本发明提供上述化合物I的盐用于制备药物的用途，所述盐选自马来酸盐、盐酸盐、磷酸盐、乳酸盐、富马酸盐、琥珀酸盐、苹果酸盐、己二酸盐、马尿酸盐、乙醇酸盐、苯甲酸盐和烟酸盐，所述药物用于预防或治疗与细胞周期调控异常相关的疾病。特别地，所述的“与细胞周期调控异常相关的疾病”可以为“与周期蛋白依赖性激酶(优选CDK4和/或CDK6)异常相关的疾病”，特别地为肿瘤，更特别地为恶性肿瘤(例如乳腺癌，结肠癌，非小细胞癌，脑星形细胞瘤，慢性粒细胞性白血病，胰腺癌，急性单核细胞白血病，肝癌(包括肝细胞癌，肝腺癌)，胃癌，非小细胞肺癌，恶性胶质母细胞瘤和***腺癌)，晚期实体瘤(包括但不限于乳腺癌、中枢神经原发性肿瘤/转移性肿瘤等)。
在另一方面，本发明提供上述化合物I的盐用于制备周期蛋白依赖性激酶(优选CDK4和/或CDK6)抑制剂的用途，所述盐选自马来酸盐、盐酸盐、磷酸盐、乳酸盐、富马酸盐、琥珀酸盐、苹果酸盐、己二酸盐、马尿酸盐、乙醇酸盐、苯甲酸盐和烟酸盐。
在另一方面，本发明提供上述化合物I的盐用于制备抑制肿瘤细胞的增殖的药物的用途，所述盐选自马来酸盐、盐酸盐、磷酸盐、乳酸盐、富马酸盐、琥珀酸盐、苹果酸盐、己二酸盐、马尿酸盐、乙醇酸盐、苯甲酸盐和烟酸盐。所述的肿瘤细胞优选癌细胞；所述的癌细胞优选乳腺癌细胞；所述的乳腺癌细胞优选乳腺癌细胞MCF-7、T-47D和ZR-75-1中的一种或多种。
在上述药物组合物和用途中，所述盐可以为选自化合物I的马来酸盐晶型A、马来酸盐晶型B、马来酸盐晶型C、盐酸盐晶型A、盐酸盐晶型B、磷酸盐晶型A、乳酸盐晶型A、富马酸盐晶型A、琥珀酸盐晶型A、苹果酸盐晶型A、己二酸盐晶型A、马尿酸盐晶型A、乙醇酸盐晶型A、苯甲酸盐晶型A和烟酸盐晶型A中的一种或多种。
更特别地，所述盐可以为选自化合物I的马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A中的一种或多种。
更特别地，所述盐可以为化合物I的马来酸盐晶型A。
更特别地，所述盐可以为化合物I的富马酸盐晶型A。
更特别地，所述盐可以为化合物I的己二酸盐晶型A。
更特别地，所述盐可以为化合物I的苯甲酸盐晶型A。
应理解，在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是根据本发明的化合物I马来酸盐晶型A的XRPD图。
图2是根据本发明的化合物I马来酸盐晶型A的DSC和TGA图。
图3是根据本发明的化合物I马来酸盐晶型B的XRPD图。
图4是根据本发明的化合物I马来酸盐晶型B的DSC和TGA图。
图5是根据本发明的化合物I马来酸盐晶型C的XRPD图。
图6是根据本发明的化合物I马来酸盐晶型C的DSC和TGA图。
图7是根据本发明的化合物I盐酸盐晶型A和晶型B的XRPD图。
图8是根据本发明的化合物I盐酸盐晶型A的DSC和TGA图。
图9是根据本发明的化合物I盐酸盐晶型B的DSC和TGA图。
图10是根据本发明的化合物I磷酸盐晶型A的XRPD图。
图11是根据本发明的化合物I磷酸盐晶型A的DSC和TGA图。
图12是根据本发明的化合物I乳酸盐晶型A的XRPD图。
图13是根据本发明的化合物I乳酸盐晶型A的DSC和TGA图。
图14是根据本发明的化合物I富马酸盐晶型A的XRPD图。
图15是根据本发明的化合物I富马酸盐晶型A的DSC和TGA图。
图16是根据本发明的化合物I琥珀酸盐晶型A的XRPD图。
图17是根据本发明的化合物I琥珀酸盐晶型A的DSC和TGA图。
图18是根据本发明的化合物I苹果酸盐晶型A的XRPD图。
图19是根据本发明的化合物I苹果酸盐晶型A的DSC和TGA图。
图20是根据本发明的化合物I己二酸盐晶型A的XRPD图。
图21是根据本发明的化合物I己二酸盐晶型A的DSC和TGA图。
图22是根据本发明的化合物I马尿酸盐晶型A的XRPD图。
图23是根据本发明的化合物I马尿酸盐晶型A的DSC和TGA图。
图24是根据本发明的化合物I乙醇酸盐晶型A的XRPD图。
图25是根据本发明的化合物I乙醇酸盐晶型A的DSC和TGA图。
图26是根据本发明的化合物I苯甲酸盐晶型A的XRPD图。
图27是根据本发明的化合物I苯甲酸盐晶型A的DSC和TGA图。
图28是根据本发明的化合物I烟酸盐晶型A的XRPD图。
图29是根据本发明的化合物I烟酸盐晶型A的DSC和TGA图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
除了特别声明，本发明中实施例涉及的设备及测试方法如下：
X射线粉末衍射(XRPD)：XRPD图谱在PANalytacal Empyrean X射线粉末衍射分析仪上采集，XRPD参数如表1所示。
表1
Figure PCTCN2022075631-appb-000003
热重分析(TGA)和差示扫描量热(DSC)：TGA和DSC图谱分别在TA Q500/5000热重分析仪和TAQ200/2000差示扫描量热仪上采集，测试参数如表2所示。
表2：DSC和TGA测试参数
Figure PCTCN2022075631-appb-000004
高效液相色谱(HPLC)：高效液相色谱在Agilent 1100HPLC上采集，具体HPLC纯度测试参数见下表3。
表3
Figure PCTCN2022075631-appb-000005
Figure PCTCN2022075631-appb-000006
离子色谱(IC)：在离子色谱(IC)Thermo ICS1100上测量负离子含量，与HPLC数据联用确定摩尔比，具体仪器参数列于表4。
表4
参数 设定值
色谱柱 IonPac AS18 Analytical Column(4×250毫米)
流动相 25毫摩尔NaOH
进样量 25微升
流速 1.0毫升/分钟
样品室温度 35℃
柱温 35℃
电流 80毫安
运行时间 10分钟(马来酸，己二酸)，14分钟(富马酸)，18分钟(苯甲酸)
动态水分吸附(DVS)：动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl,Mg(NO3)2和KCl的潮解点校正。DVS测试参数列于表5。
表5
Figure PCTCN2022075631-appb-000007
液态核磁(Solution NMR)：液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d 6作为溶剂。
加热试验如下进行：
将样品在氮气保护下进行，加热至目标温度后降至室温，取出样品暴露在空气中，收集测试XRPD。
化合物1的游离碱按照CN106928219A中公开的方法制备。其XRPD结果仅观察到少量衍射峰。HPLC纯度为95.2面积％。TGA结果显示样品加热至200℃时失重4.8％。DSC结果显示该样品在233.6℃(起点温度)熔化前有一个吸热和两个放热信号。加热试验结果显示起始样品加热至80℃时XPRD结果未观察到变化；加热至135℃和175℃时在2θ为约4.7°处的衍射峰消失，结晶度增强。
制备例1
使用以下方法制备晶型：
分别采用丙酮(acetone)、四氢呋喃(THF)、乙酸乙酯(EtOA)和二氯甲烷(DCM)/甲醇(MeOH)(10:1，v/v)作为溶剂。
称取约20毫克化合物I游离碱，并按照表6中的相应摩尔比加入相应的酸，加入0.3～0.5毫升溶剂，室温搅拌2天后离心分离固体，50℃干燥2小时用于XRPD、TGA、DSC和HPLC纯度表征。空白表示未加入酸。
晶型制备筛选结果见表6。
表6
Figure PCTCN2022075631-appb-000008
Figure PCTCN2022075631-appb-000009
游离碱晶型A的XRPD结果观察到少量衍射峰，HPLC纯度为98.2面积％。TGA结果显示样品加热至130℃时失重1.2％。DSC结果显示该样品在239.9℃(起点温度)熔化前有一个吸热峰。DVS结果显示在25℃/80％RH条件下，样品水分吸附量为2.9％，且DVS测试前后样品的XRPD结果显示晶型未发生改变。
经重复进行晶型制备，发现酒石酸、柠檬酸、龙胆酸及甲磺酸体系中样品结晶度较弱。
所得各晶型样品所用酸的安全级别和结晶度数据汇总见下表7。
表7
Figure PCTCN2022075631-appb-000010
Figure PCTCN2022075631-appb-000011
备注：+：样品量少数据未收集；--：考虑到样品结晶度及酸的安全级别未收集数据。
所述马来酸盐晶型A的XRPD表征结果如图1，XRPD衍射峰数据见表8。TGA结果如图2中的TGA曲线，表明马来酸盐晶型A加热至约200℃时失重为4.05％，DSC结果如图2中的DSC曲线，表明在约222.8℃(起点温度)熔化并伴随着分解。HPLC/IC结果表明样品的摩尔比为1.03(酸/碱)，推测马来酸盐晶型A为一马来酸盐的无水晶型。
表8：马来酸盐晶型A的XRPD衍射峰数据
Figure PCTCN2022075631-appb-000012
所述富马酸盐晶型A的XRPD结果如图14所示。TGA结果如图15中的TGA曲线，表明富马酸盐晶型A样品加热至约130℃有2.3％的失重。DSC结果如图15中的DSC曲线，表明在约163.5℃(峰值温度)有放热峰，在约248.9℃(起点温度)有吸热峰。加热试验结果显示样品加热至约170℃晶型不变，结晶度明显提高，推测放热信号为无定形转晶。HPLC/IC结果表明富马酸盐晶型A的摩尔比为1.07(酸/碱)，推测富马酸盐晶型A为一富马酸盐的无水晶型。
所述己二酸盐晶型A的XRPD表征结果如图20。TGA结果如图21中的TGA曲线，显示己二酸盐晶型A样品加热至约130℃失重为约2.5％。DSC结果如图21中的DSC曲线，表明在约182.0℃(起点温度)有吸热峰，推测己二酸盐晶型A为无水晶型。HPLC/IC结果表明己二酸盐晶型A的摩尔比为0.88(酸/碱)。
所述苯甲酸盐晶型A的XRPD结果如图26所示。TGA结果如图27中的TGA曲线，显示苯甲酸盐晶型A加热至约130℃时失重为约2.7％。DSC结果如图27中的DSC曲线，表明在约169.5℃(起点温度)有吸热峰，推测苯甲酸盐晶型A为无水晶型。HPLC/IC结果表明苯甲酸盐晶型A的摩尔比为0.81(酸/碱)。
所述盐酸盐晶型A的XRPD结果如图7中所示。TGA结果如图8中的TGA曲线，表明样品加热至约100℃有约3.5％的失重，DSC结果如图8的DSC曲线，表明DSC图上有多个吸热峰和放热峰，特别地，具有峰值温度分别为约94.6℃、约237.4℃和约266.9℃的吸热峰，峰值温度分别为约156.2℃和203.0℃的放热峰。此外，峰值温度分别为约237.4℃和约266.9℃的吸热峰的起点温度分别为约233.7℃和约261.9℃。
所述盐酸盐晶型B样品的XRPD结果如图7中所示。TGA结果如图9中的TGA曲线，表明样品加热至约130℃有约9.1％的失重，DSC结果如图9中的DSC曲线，表明在约109.9℃、约160.3℃和约266.9℃(峰值温度)有吸热峰。
所述磷酸盐晶型A的XRPD结果如图10所示。TGA结果如图11中的TGA曲线，表明磷酸盐晶型A样品加热至约130℃有约3.6％的失重，DSC结果如图11中的DSC曲线，表明在约48.0℃和约228.3℃(起点温度)有吸热峰。
所述乳酸盐晶型A的XRPD结果如图12所示。TGA结果如图13中的TGA曲线，表明乳酸盐晶型A样品加热至约130℃有约4.0％的失重，DSC结果如图13中的DSC曲线，表明在约99.0℃和约183.3℃(峰值温度)有吸热峰。
所述琥珀酸盐晶型A的XRPD结果如图16所示。TGA结果如图17中的TGA曲线，显示琥珀酸盐晶型A样品加热至约130℃时失重为约3.2％，DSC结果如图17中的DSC曲线，表明在约51.6℃和约182.1℃(起点温度)有吸热峰。加热试验结果显示样品加热至100℃晶型不变。
所述苹果酸盐晶型A的XRPD结果如图18所示。TGA结果如图19中的TGA曲线，显示苹果酸盐晶型A样品加热至约130℃有约4.0％的失重，DSC结果如图19中的DSC曲线，表明在分解前有多个吸热峰。
所述马尿酸盐晶型A的XRPD表征结果如图22。TGA结果如图23中的TGA曲线，表明马尿酸盐晶型A样品加热至约130℃失重为约4.2％，DSC结果如图23中的DSC曲线，表明在分解前有多个吸热峰，特别是峰值温度分别为约124.2℃、约141.0℃、约154.6℃、约178.0℃和约217.2℃的吸热峰。
所述乙醇酸盐晶型A的XRPD结果如图24。TGA结果如图25中的TGA曲线，表明乙醇酸盐晶型A样品加热至约130℃有约4.8％的失重，DSC结果如图25中的DSC曲线，表明在约54.1℃和约183.2℃(起点温度)有吸热峰。加热试验结果显示样品加热至130℃晶型不变。
所述烟酸盐晶型A的XRPD结果如图28。TGA结果如图29中的TGA曲线，显示烟酸盐晶型A样品加热至约130℃有约4.9％的失重，DSC结果如图29中的DSC曲线，表明在分解前有多个吸热峰，特别是峰值温度分别为约103.9℃、约160.3℃和约212.5℃的吸热峰。
综合考虑1)所选用酸的安全级别(I级>II级>III级)；2)XRPD图中有尖锐的衍射峰(同时，为保障样品及收集到的数据的代表性，无明显的无定形峰包优先考虑)；3)TGA失重较小且平缓；4)DSC上有单一且较尖锐的熔化峰(无水晶型且吸附水或溶剂量低者优先)，发现马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A是优选地。
实验例1
对于马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A分别评估了样品的37℃态溶解度、固态稳定性、引湿性。
37℃动态溶解度
动态溶解度测试在水、模拟胃液(SGF)、模拟禁食肠液(FaSSIF)以及模拟喂食肠液(FeSSIF)四种溶媒中进行，用以评估马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A的溶解度及歧化风险。
试验中，以游离碱晶型A作为参照，分别将约32毫克固体与4.0毫升溶媒在5毫升玻璃瓶中混合，密封固定在转速为25转/分钟的旋转盘上，在37℃下旋转混合1小时、2小时、4小时和24小时后取样。对浑浊样品离心分离，取过滤后的上清液测定HPLC浓度和pH，固体用XRPD确定晶型。若样品一直澄清，则在24小时取样测试浓度和pH。
HPLC在Agilent 1100HPLC上采集，溶解度测试参数如下表9。
表9溶解度测试参数
Figure PCTCN2022075631-appb-000013
37℃下四种盐的晶型A和游离碱晶型A的动态溶解度测试结果汇总于表10。
表10：动态溶解度测试结果汇总
Figure PCTCN2022075631-appb-000014
Figure PCTCN2022075631-appb-000015
备注：S 1：溶解度，微克/毫升，所测数据为游离碱浓度，pH 2：各取样点的实测pH值，FC 3：经XRPD检测后的晶型变化。--：样品溶清未收集数据，NA：由于样品量少无法检测。
游离碱：游离碱晶型A，马来酸盐：马来酸盐晶型A，富马酸盐：富马酸盐晶型A，己二酸盐：己二酸盐晶型A，苯甲酸盐：苯甲酸盐晶型A。
结果显示，1)在水中，四种盐的晶型A的溶解度较游离碱晶型A明显提高(从几微克提升至几毫克/毫升)，同时马来酸盐晶型A在水中悬浮24小时后晶型不变；2)在其它溶媒中，四种盐的晶型A和游离碱晶型A溶解度相近，均为几毫克/毫升。但所有样品在FeSSIF悬浮1小时后均观察到成油现象，对比FaSSIF中的观察，体外溶解度的测试结果显示为优化吸收可能需要考虑食物效应。
一周固态稳定性
分别称取适量样品在25℃/60％RH和40℃/75％RH条件下敞口放置，一周后对所有样品进行XRPD表征和HPLC纯度测试以检测晶型和纯度变化。
马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A、苯甲酸盐晶型A和游离碱晶型A的一周稳定性评估结果汇总于表11中。
表11
Figure PCTCN2022075631-appb-000016
结果表明，25℃/60％RH下四种盐型和游离碱均未发生晶型或HPLC纯度变化，体现出较好的理化稳定性；但40℃/75％RH保存后的己二酸盐晶型A和苯甲酸盐晶型A样品HPLC纯度下降。
引湿性
为了评估25℃条件下样品随湿度变化的稳定性，采用DVS对马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A、苯甲酸盐晶型A进行测试。样品均预先在0％RH条件下干燥去除吸附的溶剂或水后开始测试。
由测试结果得出如下结论：
1)80％RH下，马来酸盐晶型A和富马酸盐晶型A的水分吸附量(重量％)分别为0.8％和1.0％，具有轻微引湿性；而己二酸盐晶型A和苯甲酸盐晶型A的水分吸附量分别为9.1％和7.7％，具有引湿性。此外，DVS测试前后分别进行了XRPD测试。结果表明，马来酸盐晶型A和己二酸盐晶型A晶型不变，富马酸盐晶型A和苯甲酸盐晶型A结晶度变弱。
2)在80％RH至95％RH下，除马来酸盐晶型A吸水较少外，其余三种盐型样品的吸水量均迅速增加。
综合以上结果，马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A较游离碱晶型A在水及生物溶媒中溶解度均相近或提高；除己二酸盐和苯甲酸盐观察到HPLC纯度下降外，其余盐型和游离碱晶型A在固态稳定性评估中体现出较好的理化稳定性；根据水分吸附结果，马来酸盐晶型A和富马酸盐晶型A样品具有轻微引湿性，其余盐型样品及游离碱晶型A均观察到引湿性。
综合以上开展的动态溶解度、固体稳定性及引湿性等评估，得出马来酸盐晶型A性质较优，主要表现为：
1)相同操作条件下，实验室批次样品结晶度较高，而富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A结晶度中等；
2)对比游离碱晶型A，马来酸盐晶型A在37℃下在水中溶解度明显提高(从几微克提升至几毫克/毫升)，24小时后晶型未发生改变；在其它溶媒中(模拟胃液SGF、模拟禁食状态肠液FaSSIF和模拟喂食状态肠液FeSSIF)溶解度相近；
3)马来酸盐晶型A样品在25℃/60％RH和40℃/75％RH条件下放置一周后未发生晶型或HPLC纯度变化，体现出较好的理化稳定性；
4)25℃条件下的动态水分吸附(DVS)试验结果表明，马来酸盐晶型A样品具有轻微引湿性，在高湿度条件下(95％RH)水分吸附量较其他候选盐及游离碱低。
制备例2
使用以下通用方法制备晶型：
称取约200毫克游离碱，并1:1摩尔比加入相应的酸和5毫升EtOAc得到悬浊液，室温搅拌30分钟。加入～2毫克晶种，温度循环下磁力搅拌过夜(50-20℃，0.1℃/分，3次；转速为500rpm)。离心分离固体，室温真空干燥5小时，收集晶型样品，进行XRPD和DSC测试。
采用上述方法分别制备了马来酸盐晶型、富马酸盐晶型、己二酸盐晶型和苯甲酸盐晶型。XRPD和DSC测试结果显示与上述马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A参比分别一致。
制备例3
3.1马来酸盐晶型B的制备
在化合物I的马来酸盐在正溶剂中的澄清溶液中加入反溶剂，边滴加边搅拌(～1000转/分钟)至有固体析出，若加入约10mL反溶剂后仍无固体析出则停止。离心分离(～10000转，2分钟)析出的固体并进行XRPD测试。
所得结果见表12，得到马来酸盐晶型A、B、无定形和油。
表12
Figure PCTCN2022075631-appb-000017
此外，将化合物I的马来酸盐晶型A悬浮在CHCl 3/正己烷(1:1，v/v)中于50℃下磁力搅拌(～1000转/分)约4天后，离心(～10000转，3分钟)收集固体并进行XRPD测试。结果也得到马来酸盐晶型B。
马来酸盐晶型B的XRPD结果如图3。TGA表征结果如图4中的TGA曲线，显示样品加热至约200℃失约重6.4％(200～290℃的失重约19.1％推测为脱酸导致，脱酸的理论失重为约18.7％)。DSC表征结果如图4中的DSC曲线，显示约在74.6℃和约236.8℃(峰值温度)处有两个弱的吸热峰，在约225.5℃(起点温度)处有一个尖锐的吸热峰。 1H NMR结果显示马来酸与游离碱的摩尔比为1:1。
3.2马来酸盐晶型C的制备
马来酸盐晶型B在30℃下N 2吹扫20min后转变为马来酸盐晶型C。
马来酸盐晶型C的XRPD结果如图5。TGA表征结果如图6中的TGA曲线，显示样品加热至约200℃失重约6.3％(200～290℃的失重约17.5％推测为脱酸导致，脱酸的理论失重为约18.7％)。DSC表征结果如图6中的DSC曲线，显示在约142.8℃(峰值温度)处有一个放热峰，在约222.0℃(起点温度)处有一个尖锐的吸热峰。 1H NMR结果显示马来酸与游离碱的摩尔比为1:1。VT-XRPD结果显示马来酸盐晶型C在N 2保护下加热至约110℃时晶型不变。根据上述结果，推测马来酸盐晶型C为无水晶型。
马来酸盐晶型C在N 2保护下加热至约170℃后转变为马来酸盐晶型A。
根据上述结果，推测马来酸盐晶型B为水合物，经N 2吹扫后脱去结合水转变为无水晶型。
3.3缓慢挥发制备试验
将装有化合物I的马来酸盐在下面表13所列溶剂中的澄清溶液的小瓶用封口膜封住并在上面扎5个小孔，放置在室温下缓慢挥发。当溶剂完全挥干后，收集所得固体并进行XRPD测试。
试验结果如表13所示。缓慢挥发试验中得到晶型A和无定形。
表13
溶剂(v/v) 固体晶型
MeOH/DCM(1:1) 晶型A
乙腈(CAN)/H 2O(1:1) 无定型
MeOH/THF(2:1) 晶型A
3.4缓慢降温制备试验
将装有化合物I的马来酸盐在下面表14所列溶剂中的澄清溶液放置在生化培养箱中，以0.1℃/分钟的降温速度从50℃降温至5℃，未析出固体的转移至室温下挥发，收集所得固体并进行XRPD测试。
试验结果见表14。缓慢降温试验得到无定形。
表14
溶剂(v/v) 固体晶型
MeOH/DCM(1:1) 无定型
MeOH/THF(2:1) 无定型
二甲基乙酰胺(DMAc) 无定型*
备注：*：室温下真空干燥得到。
实验例2
1.混悬竞争试验
进一步研究马来酸盐无水晶型A、C和水合物晶型B之间的稳定性关系，设置了各晶型间的混悬竞争试验。具体包括室温和50℃下晶型A和C在丙酮和EtOAc中的混悬竞争，以及室温下无水晶型A和水合物晶型B在MeOH/H 2O(水活度a w＝0～1)中的混悬竞争试验。
具体步骤如下：1)配制特定温度下马来酸盐无水晶型A在不同溶剂中的饱和溶液；2)将等质量的晶型A和B或C样品(各约4mg)分别加入到0.5mL的饱和溶液中形成悬浊液；3)分别在室温和50℃条件下悬浮搅拌约5天(～800转/分)；4)分离出剩余固体，测试XRPD。
混悬竞争试验结果汇总于表18。
表15
Figure PCTCN2022075631-appb-000018
结果显示，室温及50℃下，晶型A和C的物理混合物在丙酮和EtOAc中悬浮搅拌后转变为晶型A；室温下，晶型A和B的物理混合物在MeOH/H 2O(a w＝0～1)中悬浮搅拌后转变为晶型A。据此推测，在室温至50℃及室温下水活度a w＝0～1时，晶型A为热力学稳定的晶型。
2.平衡溶解度试验
室温下对马来酸盐晶型A、B和C在水中的平衡溶解度进行了测试。
试验中配置各晶型的悬浊液，室温下磁力搅拌24小时(转速～800rpm)后离心(10000rpm,5min)，上清液过滤(0.22μm的PTFE滤膜)后测溶解度和pH，固体测XRPD。
马来酸盐晶型A、B、C的水中平衡溶解度结果汇总表16中。
表16
起始晶型 溶解度(mg/mL)* pH 晶型转变
晶型A 4.1 4.5 否
晶型B 4.5 4.4 否
晶型C 13.1 4.7 NA
备注：*：按游离碱当量计算。NA：剩余固体少，未测试。
3.固态稳定性试验
本试验用于评估马来酸盐晶型A的固态稳定性。
称取适量马来酸盐晶型A在80℃下闭口放置1天以及25℃/60％RH、40℃/75％RH条件下敞口下放置一周。将不同条件下分离出的固体样品，分别通过HPLC测试纯度评估化学稳定性，XRPD测试晶型评估物理稳定性。
马来酸盐晶型A的固态稳定性评估结果汇总于表17中。
表17
Figure PCTCN2022075631-appb-000019
在三种测试条件下均未发生晶型转变和HPLC纯度降低，表明马来酸盐晶型A在选定的测试条件下具有较好的物理和化学稳定性。
4.在溶剂中稳定性
本试验用于评估化合物I的马来酸盐在溶剂中的稳定性。
分别在二氯甲烷(DCM)、甲醇(MeOH)、乙酸乙酯(EtOAc)、二甲基甲酰胺(DMF)、四氢呋喃(THF)、MTBE、1,4-二噁烷中的悬浮搅拌试验评估以化合物I马来酸盐在溶剂中的稳定性。
具体步骤如下：称取～15mg每份的化合物I的马来酸盐晶型A，加入不同溶剂中，室温下悬浮搅拌6h后转移至60℃下搅拌5h，离心分离固体测XRPD，溶液用于HPLC纯度分析。
结果表明，马来酸盐晶型A在DCM、EtOAc、THF、MTBE中悬浮搅拌后晶型不变，且纯度无明显降低；在MeOH、DMF中悬浮搅拌后晶型不变，纯度稍有增加；在1,4-二噁烷中悬浮搅拌后晶型不变，纯度稍有降低。
马来酸盐晶型A在溶剂中稳定性评估结果汇总于表18和表19中。
表18
Figure PCTCN2022075631-appb-000020
表19
Figure PCTCN2022075631-appb-000021
实验例3游离碱晶型A和马来酸盐晶型A的稳定性比较
对游离碱晶型A和由其得到的马来酸盐晶型A开展高温(60℃)、光照(1.2*10 6Lux*hr)进行为期5天考察，检测项目为有关物质。
游离碱的有关物质分析方法
仪器：高效液相色谱仪
色谱柱：Waters XBridge C18，150*4.6mm，3.5μm
流动相A：10mmol磷酸二氢铵(内含0.1％三乙胺):甲醇(80:20)
流动相B：甲醇
梯度表：
时间(分钟) 流动相A(％) 流动相B(％)
0 75 25
15 44 56
20 37 63
25 25 75
40 25 75
40.01 75 25
45 75 25
检测波长：230nm
流速：1.0mL/min
进样量：20μl
柱温：45℃
运行时间：45min
供试品溶液：取本品约25mg，置100ml容量瓶中，加甲醇溶解并稀释至刻度，摇匀，作为供试品溶液。
马来酸盐晶型A的有关物质分析方法
仪器：高效液相色谱仪
色谱柱：Waters Xbridge C18,4.6×150mm,3.5μm
流动相A：0.01M磷酸二氢铵水溶液(含0.1％三乙胺)：甲醇＝80：20
流动相B：甲醇
梯度表：
时间(min) 流动相A(％) 流动相B(％)
0 75 25
15 44 56
20 37 63
25 25 75
40 25 75
40.01 75 25
45 75 25
检测波长：230nm
流速：1.0ml/min
进样量：20μl
柱温：45℃
运行时间：45min
稀释液：0.01M磷酸二氢铵水溶液(含0.1％三乙胺)：甲醇＝30：70
供试品溶液：取本品约30mg，置100ml容量瓶中，加稀释剂溶解并稀释至刻度，摇匀，作为供试品溶液。
得到的数据如下：
游离碱晶型A/马来酸盐晶型A的高温和光照有关物质数据
Figure PCTCN2022075631-appb-000022
从上表可以看出游离碱在高温(60℃)和光照(1.2*10 6Lux·hr)5天实验中，显示出不稳定性。而马来酸盐形态比游离碱形态在同等条件下稳定。

Claims (10)

  1. 如下所示的化合物I的盐，其中，所述盐选自马来酸盐、盐酸盐、磷酸盐、乳酸盐、富马酸盐、琥珀酸盐、苹果酸盐、己二酸盐、马尿酸盐、乙醇酸盐、苯甲酸盐和烟酸盐，
    Figure PCTCN2022075631-appb-100001
  2. 根据权利要求1所述的化合物I的盐，其中，所述盐为选自化合物I的马来酸盐晶型A、马来酸盐晶型B、马来酸盐晶型C、盐酸盐晶型A、盐酸盐晶型B、磷酸盐晶型A、乳酸盐晶型A、富马酸盐晶型A、琥珀酸盐晶型A、苹果酸盐晶型A、己二酸盐晶型A、马尿酸盐晶型A、乙醇酸盐晶型A、苯甲酸盐晶型A和烟酸盐晶型A中的一种或多种，
    特别地，所述盐为选自化合物I的马来酸盐晶型A、富马酸盐晶型A、己二酸盐晶型A和苯甲酸盐晶型A中的一种或多种，
    更特别地，所述盐为化合物I的马来酸盐晶型A，
    更特别地，所述盐为化合物I的富马酸盐晶型A，
    更特别地，所述盐为化合物I的己二酸盐晶型A，
    更特别地，所述盐为化合物I的苯甲酸盐晶型A。
  3. 根据权利要求1或2所述的化合物I的盐，其中，
    所述化合物I的盐是马来酸盐，特别地，所述化合物I的马来酸盐为选自马来酸盐晶型A、晶型B和晶型C中的一种或多种；
    所述马来酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、27.46±0.2°处有特征峰，优选地，还在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°、25.62±0.2°、26.07±0.2°、28.23±0.2°、28.68±0.2°、33.08±0.2°和38.76±0.2°一处或多处有衍射峰，优选在衍射角2θ为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°和38.76±0.2°处有特征峰，特别地，所述马来酸盐晶型A具有基本上如图1所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述马来酸盐晶型A的差示扫描量热(DSC)图具有起点温度为222.8℃的吸热峰以及峰值温度为235.3℃的吸热峰，特别地，所述马来酸盐晶型A具有基本上如图2中所示的DSC图；特别地，所述马来酸盐晶型A具有基本上如图2中所示的TGA图；
    所述马来酸盐晶型B的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、27.96±0.2°处有特征峰，特别地，所述马来酸盐晶型B具有基本上如图3所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述马来酸盐晶型B的差示扫描量热(DSC)图具有峰值温度分别为74.6℃和236.8℃的两个弱的吸热峰，以及起点温度为225.5℃的尖锐的吸热峰，特别地，所述马来酸盐晶型B具有基本上如图4中所示的DSC图；特别地，所述马来酸盐晶型B具有基本上如图4中所示的TGA图；
    所述马来酸盐晶型C的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、38.52±0.2°处有特征峰，特别地，所述马来酸盐晶型C具有基本上如图5所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述马来酸盐晶型C的差示扫描量热(DSC)图具有峰值温度为142.8℃的放热峰，和起点温度为222.0℃的尖锐的吸热峰，特别地，所述马来酸盐晶型C具有基本上如图6中所示的DSC图；特别地，所述马来酸盐晶型C具有基本上如图6中所示的TGA图；
    或者，所述化合物I的盐是盐酸盐，特别地，所述化合物I的盐酸盐为选自盐酸盐晶型A和晶型B中的一种或多种；
    所述盐酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、26.85±0.2°处有特征峰，特别地，所述盐酸盐晶型A的XRPD图基本上如图7中所示，所述的XRPD使用的靶型为Cu靶；特别地，所述盐酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为94.6℃、237.4℃和266.9℃的吸热峰，特别地，所述盐酸盐晶型A具有基本上如图8中所示的DSC图；特别地，所述盐酸盐晶型A具有基本上如图8中所示的TGA图；
    所述盐酸盐晶型B的X-射线粉末衍射(XRPD)图在衍射角2θ为3.73±0.2°、4.96±0.2°、7.24±0.2°、10.26±0.2°、15.47±0.2°处有特征峰，特别地，所述盐酸盐晶型B的XRPD图基 本上如图7中所示，所述的XRPD使用的靶型为Cu靶；特别地，所述盐酸盐晶型B的差示扫描量热(DSC)图具有峰值温度分别为109.9℃、160.3℃和266.9℃的吸热峰，特别地，所述盐酸盐晶型B具有基本上如图9中所示的DSC图；特别地，所述盐酸盐晶型B具有基本上如图9中所示的TGA图；
    或者，所述化合物I的盐是磷酸盐，特别地，所述化合物I的磷酸盐以晶型A的形式存在，所述磷酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、27.32±0.2°处有特征峰，特别地，所述磷酸盐晶型A具有基本上如图10所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述磷酸盐晶型A的差示扫描量热(DSC)图具有起点温度分别为48.0℃和228.3℃的吸热峰，特别地，所述磷酸盐晶型A具有基本上如图11中所示的DSC图；特别地，所述磷酸盐晶型A具有基本上如图11中所示的TGA图；
    或者，所述化合物I的盐是乳酸盐；特别地，所述化合物I的乳酸盐以晶型A的形式存在，所述乳酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、27.04±0.2°处有特征峰，特别地，所述乳酸盐晶型A具有基本上如图12所示的XRPD图，所述的XRPD使用的靶型为Cu靶；所述乳酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为99.0℃和183.3℃的吸热峰，特别地，所述乳酸盐晶型A具有基本上如图13中所示的DSC图；特别地，所述乳酸盐晶型A具有基本上如图13中所示的TGA图；
    或者，所述化合物I的盐是富马酸盐，特别地，所述化合物I的富马酸盐以晶型A的形式存在，所述富马酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、22.13±0.2°、23.10±0.2°、23.82±0.2°、24.52±0.2°、27.03±0.2°处有特征峰，特别地，所述富马酸盐晶型A具有基本上如图14所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述富马酸盐晶型A的差示扫描量热(DSC)图具有峰值温度为163.5℃的放热峰，和起点温度为248.9℃的吸热峰，特别地，所述富马酸盐晶型A具有基本上如图15中所示的DSC图；特别地，所述富马酸盐晶型A具有基本上如图15中所示的TGA图；
    或者，所述化合物I的盐是琥珀酸盐，特别地，所述化合物I的琥珀酸盐以晶型A的形式存在，所述琥珀酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、 23.15±0.2°处有特征峰，特别地，所述琥珀酸盐晶型A具有基本上如图16所示的XRPD图，所述的XRPD使用的靶型为Cu靶；所述琥珀酸盐晶型A的差示扫描量热(DSC)图具有起点温度分别为51.6℃和182.1℃的吸热峰，特别地，所述琥珀酸盐晶型A具有基本上如图17中所示的DSC图；特别地，所述琥珀酸盐晶型A具有基本上如图17中所示的TGA图；
    或者，所述化合物I的盐是苹果酸盐，特别地，所述化合物I的苹果酸盐以晶型A的形式存在，所述苹果酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、26.58±0.2°处有特征峰，特别地，所述苹果酸盐晶型A具有基本上如图18所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述苹果酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为100.4℃、175.9℃和185.6℃的吸热峰，特别地，所述苹果酸盐晶型A具有基本上如图19中所示的DSC图；特别地，所述苹果酸盐晶型A具有基本上如图19中所示的TGA图；
    或者，所述化合物I的盐是己二酸盐，特别地，所述化合物I的己二酸盐以晶型A的形式存在，所述己二酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、27.50±0.2°处有特征峰，特别地，所述己二酸盐晶型A具有基本上如图20所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述己二酸盐晶型A的差示扫描量热(DSC)图具有起点温度为182.0℃的吸热峰，特别地，所述己二酸盐晶型A具有基本上如图21中所示的DSC图；特别地，所述己二酸盐晶型A具有基本上如图21中所示的TGA图；
    或者，所述化合物I的盐是马尿酸盐，所述化合物I的马尿酸盐以晶型A的形式存在，所述马尿酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为4.45±0.2°、5.50±0.2°、9.17±0.2°、18.79±0.2°、23.20±0.2°、25.42±0.2°处有特征峰，特别地，所述马尿酸盐晶型A具有基本上如图22所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述马尿酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为124.2℃、141.0℃、154.6℃、178.0℃和217.2℃的吸热峰，特别地，所述马尿酸盐晶型A具有基本上如图23中所示的DSC图；特别地，所述马尿酸盐晶型A具有基本上如图23中所示的TGA图；
    或者，所述化合物I的盐是乙醇酸盐，特别地，所述化合物I的乙醇酸盐以晶型A的形式存在，所述乙醇酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、31.73±0.2°处有特征峰，特别地，所述乙醇酸盐晶型A具有基本上如图24所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述乙醇酸盐晶型A的差示扫描量热(DSC)图具有起点温度分别为54.1℃和183.2℃的吸热峰，特别地，所述乙醇酸盐晶型A具有基本上如图25中所示的DSC图；特别地，所述乙醇酸盐晶型A具有基本上如图25中所示的TGA图；
    或者，所述化合物I的盐是苯甲酸盐，特别地，所述化合物I的苯甲酸盐以晶型A的形式存在，所述苯甲酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、23.58±0.2°、25.01±0.2°、26.31±0.2°、27.11±0.2°、29.33±0.2°处有特征峰，特别地，所述苯甲酸盐晶型A具有基本上如图26所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述苯甲酸盐晶型A的差示扫描量热(DSC)图具有起点温度为169.5℃的吸热峰，特别地，所述苯甲酸盐晶型A具有基本上如图27中所示的DSC图；特别地，所述苯甲酸盐晶型A具有基本上如图27中所示的TGA图；
    或者，所述化合物I的盐是烟酸盐，特别地，所述化合物I的烟酸盐以晶型A的形式存在；所述烟酸盐晶型A的X-射线粉末衍射(XRPD)图在衍射角2θ为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°、26.27±0.2°处有特征峰，特别地，所述烟酸盐晶型A具有基本上如图28所示的XRPD图，所述的XRPD使用的靶型为Cu靶；特别地，所述烟酸盐晶型A的差示扫描量热(DSC)图具有峰值温度分别为103.9℃、160.3℃和212.5℃的吸热峰，特别地，所述烟酸盐晶型A具有基本上如图29中所示的DSC图；特别地，所述烟酸盐晶型A具有基本上如图29中所示的TGA图。
  4. 制备如权利要求2或3中所述的晶型的方法，其中，
    制备所述马来酸盐晶型A的方法为以下方法之一：
    方法一：
    (1)将化合物I的游离碱和马来酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、醇类溶剂(例如甲醇)和酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    方法二：
    (2)由马来酸盐晶型B或C转化得到；
    制备所述马来酸盐晶型B的方法包括：向化合物I的马来酸盐在体积比为1:1的甲醇/二氯甲烷中的混合溶液中滴加反溶剂(例如丙酮和甲苯)进行重结晶，所得固体在室温室湿下放置后得到；
    制备所述马来酸盐晶型C的方法包括：将马来酸盐晶型B用惰性气体(例如N 2)吹扫得到；
    制备所述盐酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和盐酸在选自醚类溶剂(例如四氢呋喃)和酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    制备所述盐酸盐晶型B的方法包括：将摩尔比为3:1的化合物I游离碱和盐酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)、以及混合溶剂(例如卤代烷烃和醇类溶剂，例如二氯甲烷/甲醇)的溶剂中反应得到；
    制备所述磷酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和磷酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)、以及混合溶剂(例如卤代烷烃和醇类溶剂，例如二氯甲烷/甲醇)的溶剂中反应得到；
    制备所述乳酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和乳酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    制备所述富马酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和富马酸在选自醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)、以及混合溶剂(例如卤代烷烃和醇类溶剂，例如二氯甲烷/甲醇)的溶剂中反应得到；
    制备所述琥珀酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和琥珀酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    制备所述苹果酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和苹果酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    制备所述己二酸盐晶型A的方法包括：将摩尔比为约1:1化合物I游离碱和己二酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    制备所述马尿酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和马尿酸在选自酮类溶剂(例如丙酮)、酯类溶剂(例如乙酸乙酯)的溶剂中反应得到；
    制备所述乙醇酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和乙醇酸在选自酮类溶剂(例如丙酮)、醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)的溶 剂中反应得到；
    制备所述苯甲酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和苯甲酸在酮类溶剂(例如丙酮)中反应得到；
    制备所述烟酸盐晶型A的方法包括：将摩尔比为1:1的化合物I游离碱和烟酸在选自醚类溶剂(例如四氢呋喃)、酯类溶剂(例如乙酸乙酯)的溶剂中反应得到。
  5. 一种药物组合物，其包括选自根据权利要求1-3中任一项所述的化合物I的盐中的一种或多种。
  6. 根据权利要求5所述的药物组合物，其用于预防或治疗与细胞周期调控异常相关的疾病；
    特别地，所述的“与细胞周期调控异常相关的疾病”为“与周期蛋白依赖性激酶(优选CDK4和/或CDK6)异常相关的疾病”，特别地为肿瘤，更特别地为恶性肿瘤(例如乳腺癌，结肠癌，非小细胞癌，脑星形细胞瘤，慢性粒细胞性白血病，胰腺癌，急性单核细胞白血病，肝癌(包括肝细胞癌，肝腺癌)，胃癌，非小细胞肺癌，恶性胶质母细胞瘤和***腺癌)，晚期实体瘤(包括但不限于乳腺癌、中枢神经原发性肿瘤/转移性肿瘤)；
    特别地，所述药物组合物用作周期蛋白依赖性激酶(优选CDK4和/或CDK6)抑制剂；
    特别地，所述药物组合物用于抑制肿瘤细胞的增殖，所述的肿瘤细胞优选癌细胞；所述的癌细胞优选乳腺癌细胞，结肠癌细胞，非小细胞癌细胞，脑星形细胞瘤细胞，慢性粒细胞性白血病细胞，胰腺癌细胞，急性单核细胞白血病细胞，肝癌细胞(包括肝细胞癌细胞，肝腺癌细胞)，胃癌细胞，非小细胞肺癌细胞，恶性胶质母细胞瘤细胞和***腺癌细胞；所述的乳腺癌细胞优选为选自乳腺癌细胞MCF-7、T-47D和ZR-75-1中的一种或多种。
  7. 根据权利要求1-3中任一项所述的化合物I的盐用于制备药物的用途。
  8. 根据权利要求7所述的用途，其中，所述药物用于预防或治疗与细胞周期调控异常相关的疾病；特别地，所述的“与细胞周期调控异常相关的疾病”为“与周期蛋白依赖性激酶(优选CDK4和/或CDK6)异常相关的疾病”，特别地为肿瘤，更特别地为恶性肿瘤(例如乳腺癌，结肠癌，非小细胞癌，脑星形细胞瘤，慢性粒细胞性白血病，胰腺癌，急性单核细胞白血病，肝癌(包括肝细胞癌，肝腺癌)，胃癌，非小细胞肺癌，恶性胶质母细胞瘤和***腺癌)，晚期实体瘤(包括但不限于乳腺癌、中枢神经原发性肿瘤/转移性肿瘤)。
  9. 根据权利要求1-3中任一项所述的化合物I的盐用于制备周期蛋白依赖性激酶(优选CDK4和/或CDK6)抑制剂的用途。
  10. 根据权利要求1-3中任一项所述的化合物I的盐用于制备抑制肿瘤细胞的增殖的药物的用途，所述的肿瘤细胞优选癌细胞；所述的癌细胞优选乳腺癌细胞，结肠癌细胞，非小细胞癌细胞，脑星形细胞瘤细胞，慢性粒细胞性白血病细胞，胰腺癌细胞，急性单核细胞白血病细胞，肝癌细胞(包括肝细胞癌细胞，肝腺癌细胞)，胃癌细胞，非小细胞肺癌细胞，恶性胶质母细胞瘤细胞和***腺癌细胞；所述的乳腺癌细胞优选乳腺癌细胞MCF-7、T-47D和ZR-75-1中的一种或多种。
PCT/CN2022/075631 2021-02-10 2022-02-09 含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途 WO2022171117A1 (zh)

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