Therapeutically active compounds and their methods of use

1. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.8, 10.6, 13.6, 14.2, and 19.2°±0.2°.

2. The pharmaceutical composition of claim 1 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 34 .

3. The pharmaceutical composition of claim 1 for oral administration.

4. The pharmaceutical composition of claim 3 , wherein the composition is a tablet.

5. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 8.9, 13.0, 18.9, 23.8, and 28.1°±0.2°.

6. The pharmaceutical composition of claim 5 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1 .

7. The pharmaceutical composition of claim 5 for oral administration.

8. The pharmaceutical composition of claim 7 , wherein the composition is a tablet.

9. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 12.7, 17.1, 19.2, 23.0, and 24.2°±0.2°.

10. The pharmaceutical composition of claim 9 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 2 .

11. The pharmaceutical composition of claim 9 for oral administration.

12. The pharmaceutical composition of claim 11 , wherein the composition is a tablet.

13. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 7.5, 9.3, 14.5, 18.8, 21.3, and 24.8°±0.2°.

14. The pharmaceutical composition of claim 13 for oral administration.

15. The pharmaceutical composition of claim 14 , wherein the composition is a tablet.

16. The pharmaceutical composition of claim 13 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5 .

17. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 14.1, 19.1, 21.8, 23.5, and 25.7°±0.2°.

18. The pharmaceutical composition of claim 17 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 15 .

19. The pharmaceutical composition of claim 17 for oral administration.

20. The pharmaceutical composition of claim 19 , wherein the composition is a tablet.

21. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 9.0, 9.2, 21.9, 22.1, 24.2, and 24.6°±0.2°.

22. The pharmaceutical composition of claim 21 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17 .

23. The pharmaceutical composition of claim 21 for oral administration.

24. The pharmaceutical composition of claim 23 , wherein the composition is a tablet.

25. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.5, 19.6, 20.1, and 21.6°±0.2°.

26. The pharmaceutical composition of claim 25 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19 .

27. The pharmaceutical composition of claim 25 for oral administration.

28. The pharmaceutical composition of claim 27 , wherein the composition is a tablet.

29. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 7.2, 13.6, 18.5, 19.3, 21.9, and 23.5°±0.2°.

30. The pharmaceutical composition of claim 29 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 37 .

31. The pharmaceutical composition of claim 29 for oral administration.

32. The pharmaceutical composition of claim 31 , wherein the composition is a tablet.

33. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.4, 8.4, 9.8, 17.8, and 19.7°±0.2°.

34. The pharmaceutical composition of claim 33 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 38 .

35. The pharmaceutical composition of claim 33 for oral administration.

36. The pharmaceutical composition of claim 35 , wherein the composition is a tablet.

37. A pharmaceutical composition comprising a crystalline form of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl] amino}-1,3,5-triazin-2-yl)amino]propan-2-ol and at least one pharmaceutically acceptable carrier or adjuvant, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 8.1, 14.1, 16.4, 17.3, 20.5, and 24.1°±0.2°.

38. The pharmaceutical composition of claim 37 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 39 .

39. The pharmaceutical composition of claim 38 for oral administration.

40. The pharmaceutical composition of claim 39 , wherein the composition is a tablet.

41. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 1 .

42. The method of claim 41 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

43. The method of claim 42 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

44. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 5 .

45. The method of claim 44 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

46. The method of claim 45 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

47. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 9 .

48. The method of claim 47 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

49. The method of claim 48 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

50. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 13 .

51. The method of claim 50 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

52. The method of claim 51 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

53. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 17 .

54. The method of claim 53 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

55. The method of claim 54 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

56. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 21 .

57. The method of claim 56 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

58. The method of claim 57 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

59. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 25 .

60. The method of claim 59 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

61. The method of claim 60 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

62. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 29 .

63. The method of claim 62 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

64. The method of claim 63 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

65. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 33 .

66. The method of claim 65 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

67. The method of claim 66 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

68. A method of treating an advanced hematologic malignancy selected from acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), myeloid sarcoma, multiple myeloma, and lymphoma, each characterized by the presence of a mutant allele of IDH2, comprising administering to subject in need thereof the pharmaceutical composition of claim 37 .

69. The method of claim 68 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

70. The method of claim 69 , wherein the acute myelogenous leukemia is relapsed or primary refractory.