Therapeutically active compounds and their methods of use

1. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.5, 19.0, 19.4, 19.9, and 24.7°±0.2°.

2. The isolated crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 9 .

3. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 7.1, 14.5, 17.1, and 21.8°±0.2°.

4. The isolated crystalline form of claim 3 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 11 .

5. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.3, 7.2, 8.1, 12.7, and 14.9°±0.2°.

6. The isolated crystalline form of claim 5 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 13 .

7. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.7, 9.1, 10.8, 19.9, and 21.9°±0.2°.

8. The isolated crystalline form of claim 7 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 21 .

9. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.3, 20.0, 20.2, 20.5, 21.2, and 26.5°±0.2°.

10. The isolated crystalline form of claim 9 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 23 .

11. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 7.2, 7.4, 8.0, 8.2, 16.5, and 18.6°±0.2°.

12. The isolated crystalline form of claim 11 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 26 .

13. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.3, 12.7, and 20.3°±0.2°.

14. The isolated crystalline form of claim 13 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 28 .

15. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.6, 17.5, 20.8 and 23.3°±0.2°.

16. The isolated crystalline form of claim 15 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 30 .

17. An isolated 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, wherein the isolated crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 2θ angles of 6.4, 12.9, 20.2, and 26.1°±0.2°.

18. The isolated crystalline form of claim 17 , characterized by an X-ray powder diffraction pattern substantially similar to FIG. 32 .

19. A pharmaceutical composition comprising the crystalline form of claim 1 and a pharmaceutically acceptable excipient.

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

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

22. A pharmaceutical composition comprising the crystalline form of claim 3 and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition of claim 22 for oral administration.

24. The pharmaceutical composition of claim 22 , wherein the composition is a tablet.

25. A pharmaceutical composition comprising the crystalline form of claim 5 and a pharmaceutically acceptable excipient.

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

27. The pharmaceutical composition of claim 25 , wherein the composition is a tablet.

28. A pharmaceutical composition comprising the crystalline form of claim 7 and a pharmaceutically acceptable excipient.

29. The pharmaceutical composition of claim 28 for oral administration.

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

31. A pharmaceutical composition comprising the crystalline form of claim 9 and a pharmaceutically acceptable excipient.

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

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

34. A pharmaceutical composition comprising the crystalline form of claim 11 and a pharmaceutically acceptable excipient.

35. The pharmaceutical composition of claim 34 for oral administration.

36. The pharmaceutical composition of claim 34 , wherein the composition is a tablet.

37. A pharmaceutical composition comprising the crystalline form of claim 13 and a pharmaceutically acceptable excipient.

38. The pharmaceutical composition of claim 37 for oral administration.

39. The pharmaceutical composition of claim 37 , wherein the composition is a tablet.

40. A pharmaceutical composition comprising the crystalline form of claim 15 and a pharmaceutically acceptable excipient.

41. The pharmaceutical composition of claim 40 for oral administration.

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

43. A pharmaceutical composition comprising the crystalline form of claim 17 and a pharmaceutically acceptable excipient.

44. The pharmaceutical composition of claim 43 for oral administration.

45. The pharmaceutical composition of claim 43 , wherein the composition is a tablet.

46. 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 a subject having the malignancy the crystalline form of claim 1 .

47. The method of claim 46 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

48. The method of claim 47 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

49. 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 a subject having the malignancy the crystalline form of claim 3 .

50. The method of claim 49 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

51. The method of claim 50 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

52. 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 a subject having the malignancy the crystalline form of claim 5 .

53. The method of claim 52 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

54. The method of claim 53 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

55. 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 a subject having the malignancy the crystalline form of claim 7 .

56. The method of claim 55 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

57. The method of claim 56 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

58. 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 a subject having the malignancy the crystalline form of claim 9 .

59. The method of claim 58 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

60. The method of claim 59 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

61. 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 a subject having the malignancy the crystalline form of claim 11 .

62. The method of claim 61 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

63. The method of claim 62 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

64. 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 a subject having the malignancy the crystalline form of claim 13 .

65. The method of claim 64 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

66. The method of claim 65 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

67. 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 a subject having the malignancy the crystalline form of claim 15 .

68. The method of claim 67 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

69. The method of claim 68 , wherein the acute myelogenous leukemia is relapsed or primary refractory.

70. 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 a subject having the malignancy the crystalline form of claim 17 .

71. The method of claim 70 , wherein the advanced hematologic malignancy is acute myelogenous leukemia.

72. The method of claim 71 , wherein the acute myelogenous leukemia is relapsed or primary refractory.