Crystal form targeting CDK

1. Crystal form A of a compound of formula (I), characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 6.6±0.2°, 10.0±0.2°, 13.2±0.2°, 17.4±0.2°, 20.1±0.2°, and 20.6±0.2° expressed as 2θ angles using Cu-Kα radiation,

2. The crystal form A of claim 1 , characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 6.6±0.2°, 8.7±0.2°, 10.0±0.2°, 10.9±0.2°, 13.2±0.2°, 15.7±0.2°, 16.4±0.2°, 17.4±0.2°, 20.1±0.2°, 20.6±0.2°, and 30.4±0.2° expressed as 2θ angles using Cu-Kα radiation.

3. The crystal form A of claim 1 , characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 6.6±0.2°, 8.7±0.2°, 10.0±0.2°, 10.9±0.2°, 13.2±0.2°, 15.7±0.2°, 16.4±0.2°, 16.7±0.2°, 17.4±0.2°, 19.3±0.2°, 20.1±0.2°, 20.6±0.2°, 22.2±0.2°, 23.3±0.2°, 24.0±0.2°, 25.9±0.2°, 28.1±0.2°, and 30.4±0.2° expressed as 2θ angles using Cu-Kα radiation.

4. The crystal form A of claim 1 , characterized by an X-ray powder diffraction pattern obtained using Cu-Kα radiation substantially as shown in FIG. 1 .

5. The crystal form A of claim 1 , characterized by a differential scanning calorimetry (DSC) diagram comprising an endothermic peak at about 195° C.-215° C.

6. The crystal form A of claim 1 , characterized by a differential scanning calorimetry (DSC) diagram comprising an endothermic peak at 205±3° C.

7. The crystal form A of claim 1 , characterized by a differential scanning calorimetry (DSC) diagram substantially as shown in FIG. 2 .

8. A method for preparing the crystal form A of the compound of formula (I) of claim 1 , comprising:

dissolving the compound of formula (I) in an organic solvent, and heating the same to 60° C.-100° C. with stirring until the compound is dissolved;

cooling to a temperature between 30° C.-55° C. to precipitate out a solid;

cooling to a temperature between 0° C.-25° C., and stirring at the temperature for 1-24 h; and

collecting the precipitated solid, and drying to obtain the crystal form A.

9. A method for preparing the crystal form A of the compound of formula (I) of claim 1 , comprising:

dissolving the compound of formula (I) in an organic solvent, and heating the same to 70° C.-100° C.;

after the compound is dissolved, cooling to a temperature between 50° C.-75° C., adding a seed crystal, and keeping at the temperature to precipitate out a solid; and

cooling to 0° C.-25° C., keeping at the temperature, collecting the precipitated solid, and drying to obtain the crystal form A,

wherein the seed crystal is the crystal form A of the compound of formula (I) or a solid precipitated during the preparation of the crystal form A of the compound of formula (I), and

wherein the amount of the seed crystal added is 0.1%-3% of the mass of the compound of formula (I).

10. The method of claim 9 , wherein

the organic solvent is selected from one of or any combination of two or more of the following solvents:

(1) alcohol solvents selected from fatty alcohol solvents, alicyclic alcohol solvents and aromatic alcohol solvents, wherein the fatty alcohol solvents are selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol or glycerol; the alicyclic alcohol solvents are selected from cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol or cyclohexylethanol; and the aromatic alcohol solvents are selected from benzyl alcohol, phenylethanol or phenylpropanol;

(2) ketone solvents selected from fatty ketone solvents and cyclic ketone solvents, wherein the fatty ketone solvents are selected from methyl ethyl ketone, methyl isopropyl ketone, acetone, methyl butanone or methyl isobutyl ketone; and the cyclic ketone solvents are selected from cyclopropanone, cyclohexanone, isophorone or N-methylpyrrolidone;

(3) nitrile solvents selected from acetonitrile or propionitrile;

(4) ether solvents selected from fatty ether solvents and cyclic ether solvents, wherein the fatty ether solvents are selected from diethyl ether, dipropyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl butyl ether, ethyl tert-butyl ether, dibutyl ether or dipentyl ether, and the cyclic ether solvents are selected from ethylene oxide, 1,2-propylene oxide, tetrahydrofuran, 2-methylfuran, dioxolane or 1,4-dioxane;

(5) amide solvents selected from formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide or N,N-diethylpropionamide; and

(6) sulfoxide solvents selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl phenyl sulfoxide.

11. A pharmaceutical composition comprising the crystal form A of the compound of formula (I) of claim 1 , and optionally one or more pharmaceutical carriers and/or diluents.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition further comprises one or more additional anti-tumor agents and/or immunosuppressive agents selected from one or more of methotrexate, capecitabine, gemcitabine, doxifluridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, trastuzumab, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, triptorelin, flutamide, leuprorelin, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, melphalan, chlorambucil, carboplatin, cisplatin, oxaliplatin, lobaplatin, topotecan, camptothecin, hycamtin, everolimus, sirolimus, temsirolimus, 6-mercaptopurine, 6-thioguanine, azathioprine, mycin D, daunorubicin, amycin, mitoxantrone, plicamycin and aminoglutethimide.

13. A method for treating a disease associated with CDK4/6 kinase-mediated cancers in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of the crystal form A of the compound of formula (I) of claim 1 .

14. The method of claim 13 , wherein the disease associated with CDK4/6 kinase-mediated cancers is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostatic cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma.

15. The method of claim 8 , wherein

the organic solvent is selected from one of or any combination of two or more of the following solvents:

(1) alcohol solvents selected from fatty alcohol solvents, alicyclic alcohol solvents and aromatic alcohol solvents, wherein the fatty alcohol solvents are selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol or glycerol; the alicyclic alcohol solvents are selected from cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol or cyclohexylethanol; and the aromatic alcohol solvents are selected from benzyl alcohol, phenylethanol or phenylpropanol;

(2) ketone solvents selected from fatty ketone solvents and cyclic ketone solvents, wherein the fatty ketone solvents are selected from methyl ethyl ketone, methyl isopropyl ketone, acetone, methyl butanone or methyl isobutyl ketone; and the cyclic ketone solvents are selected from cyclopropanone, cyclohexanone, isophorone or N-methylpyrrolidone;

(3) nitrile solvents selected from acetonitrile or propionitrile;

(4) ether solvents selected from fatty ether solvents and cyclic ether solvents, wherein the fatty ether solvents are selected from diethyl ether, dipropyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl butyl ether, ethyl tert-butyl ether, dibutyl ether or dipentyl ether, and the cyclic ether solvents are selected from ethylene oxide, 1,2-propylene oxide, tetrahydrofuran, 2-methylfuran, dioxolane or 1,4-dioxane;

(5) amide solvents selected from formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide or N,N-diethylpropionamide; and

(6) sulfoxide solvents selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl phenyl sulfoxide.

16. A method for preparing the crystal form A of the compound of formula (I) of claim 1 , comprising:

dissolving the compound of formula (I) in an organic solvent to form a mixture, heating the mixture to a temperature between 60° C.-100° C. and stirring until the compound is dissolved, further stirring and cooling resultant solution to a temperature between 0° C.-25° C. to precipitate out a solid, keeping at the temperature and stirring for 1-24 h, filtering with suction, and drying to obtain the crystal form A.

17. The method of claim 16 , wherein

the organic solvent is selected from one of or any combination of two or more of the following solvents:

(1) alcohol solvents selected from fatty alcohol solvents, alicyclic alcohol solvents and aromatic alcohol solvents, wherein the fatty alcohol solvents are selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol or glycerol; the alicyclic alcohol solvents are selected from cyclopentanol, cyclopentylmethanol, cyclohexanol, cyclohexylmethanol or cyclohexylethanol; and the aromatic alcohol solvents are selected from benzyl alcohol, phenylethanol or phenylpropanol;

(2) ketone solvents selected from fatty ketone solvents and cyclic ketone solvents, wherein the fatty ketone solvents are selected from methyl ethyl ketone, methyl isopropyl ketone, acetone, methyl butanone or methyl isobutyl ketone; and the cyclic ketone solvents are selected from cyclopropanone, cyclohexanone, isophorone or N-methylpyrrolidone;

(3) nitrile solvents selected from acetonitrile or propionitrile;

(4) ether solvents selected from fatty ether solvents and cyclic ether solvents, wherein the fatty ether solvents are selected from diethyl ether, dipropyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl butyl ether, ethyl tert-butyl ether, dibutyl ether or dipentyl ether, and the cyclic ether solvents are selected from ethylene oxide, 1,2-propylene oxide, tetrahydrofuran, 2-methylfuran, dioxolane or 1,4-dioxane;

(5) amide solvents selected from formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide or N,N-diethylpropionamide; and

(6) sulfoxide solvents selected from dimethyl sulfoxide, diethyl sulfoxide or benzyl phenyl sulfoxide.

18. The method of claim 16 , wherein the organic solvent is selected from acetone, isopropanol, butanol and n-pentanol.

19. The method of claim 8 , wherein the organic solvent is selected from acetone, isopropanol, butanol and n-pentanol.

20. The method of claim 9 , wherein the organic solvent is selected from acetone, isopropanol, butanol and n-pentanol.