CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer

1. A crystalline form of a compound having the following structure (I):

or a tautomer or zwitterionic form thereof, the crystalline form being Form B and characterized by an x-ray powder diffraction pattern comprising at least three peaks at 2-theta angles selected from the group consisting of 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2°, 20.0±0.2° and 24.6±0.2°.

2. The crystalline form of claim 1 , wherein the crystalline form is substantially pure.

3. The crystalline form of claim 1 , characterized by an x-ray powder diffraction pattern comprising at least four peaks at 2-theta angles selected from the group consisting of 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2°, 20.0±0.2° and 24.6±0.2°.

4. The crystalline form of claim 3 , characterized by an x-ray powder diffraction pattern comprising at least five peaks at 2-theta angles selected from the group consisting of 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2°, 20.0±0.2° and 24.6±0.2°.

5. The crystalline form of claim 1 , characterized by an x-ray powder diffraction pattern comprising peaks at the following 2-theta angles: 10.8±0.2°, 14.9±0.2° and 20.0±0.2°.

6. The crystalline form of claim 5 , characterized by an x-ray powder diffraction pattern comprising peaks at the following 2-theta angles: 4.8±0.2°, 10.8±0.2°, 14.9±0.2° and 20.0±0.2°.

7. The crystalline form of claim 6 , characterized by an x-ray powder diffraction pattern comprising peaks at the following 2-theta angles: 4.8±0.2°, 10.8±0.2°, 13.7±0.2°, 14.9±0.2° and 20.0±0.2°.

8. A crystalline form of a compound having the following structure (I):

or a tautomer or zwitterionic form thereof, having an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1 .

9. The crystalline form of claim 1 , characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at about 264° C.

10. The crystalline form of claim 1 , characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 8 .

11. The crystalline form of claim 1 , wherein the crystalline form is of a compound having structure (II):

12. A pharmaceutical composition comprising a crystalline form of claim 1 and a pharmaceutically acceptable carrier or excipient.

13. The pharmaceutical composition of claim 12 , formulated for oral administration.

14. A pharmaceutical composition comprising:

from about 0.5 weight percent to about 11.25 weight percent of a crystalline form of claim 1 ;

 and

from about 85 weight percent to about 99.5 weight percent of a pharmaceutically acceptable carrier or excipient.

15. A method for treating a cancer associated with overexpression of a cyclin-dependent kinase (CDK) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a crystalline form of claim 1 .

16. The method of claim 15 , wherein the cancer is a hematologic cancer.

17. The method of claim 16 , wherein the hematologic cancer is selected from acute myelogenous leukemia (AML), follicular lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin's lymphoma.

18. The method of claim 15 , wherein the cancer is a solid tumor.

19. The method of claim 18 , wherein the cancer is prostate cancer.

20. A method for preparing a crystalline form of claim 1 , the crystalline form being crystalline Form B of a compound having the following structure (II):

the method comprising:

contacting amorphous compound having the following structure (I):

or a tautomer or zwitterionic form thereof, with an acid in a solvent, thereby preparing the crystalline Form B of the compound having structure (II).

21. The method of claim 20 , wherein the acid has at least one pK a value that is less than about 5, and a pK a value of greater than about 1.

22. The method of claim 20 , wherein the acid is an organic acid.

23. The method of claim 20 , wherein the acid is maleic acid.

24. The method of claim 20 , wherein the solvent is tetrahydrofuran, methanol, ethanol, butanol, methyl ethyl ketone, acetone, diisopropylether, ethyl acetate or water, or a combination of any of the foregoing.

25. A method for preparing a crystalline form of claim 1 , the method comprising:

(a) contacting a compound having the following structure (IV):

or a tautomer or salt thereof, with di-tert-butylhalophosphonate in the presence of an amine base, thereby forming a compound having the following structure (V):

or a tautomer or salt thereof; and

(b) contacting the compound having structure (V), or a tautomer or salt thereof, with an acid, thereby preparing a compound having structure (I), or a salt, tautomer or zwitterionic form thereof.

26. A method for preparing a crystalline form of claim 1 , the crystalline form being crystalline Form B of a compound having the following structure (II):

the method comprising:

(a) contacting a compound having the following structure (IV):

or a tautomer or salt thereof, with di-tert-butylhalophosphonate in the presence of an amine base, thereby forming a compound having the following structure (V):

or a tautomer or salt thereof;

(b) contacting the compound having structure (V), or a tautomer or salt thereof, with an acid having a pK a value of less than about 1, thereby forming a salt of a compound having the following structure (I):

(c) contacting the salt of a compound having structure (I) with a base, thereby forming amorphous compound having structure (I); and

(d) contacting the amorphous compound having structure (I), in an organic solvent, with an acid having at least one pK a value that is less than about 5 and a pK a value of greater than about 1,

thereby preparing crystalline Form B of the compound having structure (II).

27. The method of claim 18 , wherein the cancer is a sarcoma.

28. The method of claim 27 , wherein the sarcoma is Kaposi sarcoma, Ewing sarcoma, osteosarcoma, Soft Tissue Sarcoma, Uterine Sarcoma, or Rhabdomyosarcoma.