N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide

1. A compound selected from the group consisting of:

N-(cyanomethyl)-4-(2-(4-morpholinoohenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;

N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrirnidin-4-yl)benzarnide monohydrochloride anhydrous Form I; and

N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III.

2. The compound of claim 1 in a crystalline form.

3. The crystalline form of claim 2 , wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylarnino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.

4. The crystalline form of claim 3 , wherein the crystals have unit cell parameters at T=100° K of: a=10.2837(6) Å, b=10.4981(6) Å, c=11.5143 (7) Å, α=83.297(2)° ,β=87.649 (2)° , y=67.445(2)° , and a triclinic P-1 space group.

5. The crystalline form of claim 3 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5 .

6. The crystalline form of claim 3 , characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 7.7° , 19.3° , 24.0° , 25.7° , and 29.6°2−θ±0.2° 2−θ.

7. The crystalline form of claim 3 , characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8 .

8. The crystalline form of claim 3 , characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 14 .

9. The crystalline form of claim 2 , wherein the crystalline form is Crystalline N-(cyanomethyI)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I.

10. The crystalline form of claim 9 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 6 .

11. The crystalline form of claim 9 , characterized by an X-ray powder diffraction (“XRPD”) pattern having peaks at about 13.5° , 20.9° , 26.1° , 26.6° , and 28.3° 2−θ±0.2° 2−θ.

12. The crystalline form of claim 9 , characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 9 .

13. The crystalline form of claim 2 , wherein the crystalline form is crystalline N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrirnidin-4-yl)benzamide monohydrochloride anhydrous Form III.

14. The crystalline form of claim 13 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 7 .

15. The crystalline form of claim 13 , characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 12.7° , 14.6° , 17,8° , 19.7° , and 23.3° 2−θ±0.2° 2−θ.

16. The crystalline form of claim 13 , characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 10 .

17. A pharmaceutical composition comprising a compound of claim 1 , wherein the pharmaceutical composition is in a solid form.

18. The pharmaceutical composition of claim 17 , wherein the compound of claim 1 is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.

19. The pharmaceutical composition of claim 17 wherein N-(cyanornethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is present at an amount equivalent to 50 mg, 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinaphenybmino)pyrimidin-4-yl)benzamide.

20. The pharmaceutical composition of claim 17 in the form of a tablet.

21. The pharmaceutical composition of claim 17 , wherein after a single oral administration said composition provides:

a C max in the range of 260 to 405 ng/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4yl)benzamide,

an AUC inf in the range of 2,057 to 3,214 ng·hr/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide, or

both a C max in the range of 260 to 405 ng/ml of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide and an AUC inf in the range of 2,057 to 3,214 ng·hr/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

22. The pharmaceutical composition of claim 21 , wherein after a single oral administration said composition provides a pharmacokinetic profile substantially similar to that of a dosage form comprising N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride anhydrous Form I in an amount equivalent to 300 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

23. A method for the treatment of a disease associated with Janus Kinase (JAK) which comprises administering to a subject in need an effective amount of the pharmaceutical composition of claim 18 , wherein the disease is a myeloproliferative disease selected from the group consisting of thrombocythemia, idiopathic myelofibrosis, systemic mastocystosis (SM), myelodispiastic syndrome (MDS) and systemic mast cell disease (SMCD).

24. A pharmaceutical composition comprising a compound having the formula

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent;

wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by a deuterium atom.

25. A pharmaceutical composition comprising a compound having the formula

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent;

wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.

26. A pharmaceutical composition comprising a compound having the formula

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent;

wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.

27. A compound selected from the group consisting of:

N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;

N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I; and

N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III;

wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.

28. The compound of claim 27 in a crystalline form.

29. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.

30. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and the crystals have unit cell parameters at T=100° K of: a =10.2837(6) Å, b=10.4981(6) Å, c=11.5143(7) Å, α=83.297(2)°, β=87.649(2)°, y=67.445(2)°, and a triclinic P-1 space group.

31. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5.

32. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 7.7°, 19.3°, 24.0°, 25.7°, and 29.6° 2−θ±0.2° −θ.

33. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8.

34. The crystalline form of claim 28, wherein the crystalline form is N-cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 14.

35. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I.

36. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I and is characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 6.

37. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I and is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 13.5°, 20.9°, 26.1°, 26.6°, and 28.3° 2−θ±0.2° 2−θ.

38. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I and is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 9.

39. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III.

40. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III and is characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 7.

41. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III and is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 12.7°, 14.6°, 17.8°, 19.7°, and 23.3° 2−θ±0.2° 2−θ.

42. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III and is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 10.

43. A pharmaceutical composition comprising a compound of claim 27, wherein the pharmaceutical composition is in a solid form.

44. The pharmaceutical composition of claim 43, wherein the compound is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.

45. The pharmaceutical composition of claim 43, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is present in an amount equivalent to 50 mg, 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

46. The pharmaceutical composition of claim 43, wherein the compound is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I.

47. The pharmaceutical composition of claim 43, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I is present in an amount equivalent to 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

48. The pharmaceutical composition of claim 43, wherein the compound is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III.

49. The pharmaceutical composition of claim 43, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III is present in an amount equivalent to 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

50. The pharmaceutical composition of claim 43 in the form of a tablet.

51. The pharmaceutical composition of claim 43, wherein after a single oral administration said composition provides:

a C max in the range of 260 to 405 ng/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide,

an AUC inf in the range of 2,057 to 3,214 ng·hr/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide, or

both a C max in the range of 260 to 405 ng/ml of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide and an AUC inf in the range of 2,057 to 3,214 ng·hr/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

52. The pharmaceutical composition of claim 51, wherein after a single oral administration said composition provides a pharmacokinetic profile substantially similar to that of a dosage form comprising N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride anhydrous Form I in an amount equivalent to 300 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

53. A method for the treatment of a disease associated with Janus Kinase (JAK) which comprises administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 51, wherein the disease is a myeloproliferative disease selected from the group consisting of thrombocythemia, idiopathic myelofibrosis, systemic mastocystosis (SM), myelodysplastic syndrome (MDS) and systemic mast cell disease (SMCD).

54. A method for the treatment of a disease associated with Janus Kinase (JAK) which comprises administering to a subject in need thereof:

an effective amount of a therapeutic agent that inhibits or modulates the activity of a bromodomain-containing protein; and

an effective amount of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.

55. The method of claim 54, wherein the therapeutic agent is a bromodomain-containing protein (BRD) inhibitor.

56. The method of claim 55, wherein the therapeutic agent is a BRD4 inhibitor.

57. The method of claim 54, wherein the N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is crystalline.

58. The method of claim 54, wherein the N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is crystalline and

(a) the crystals have unit cell parameters at T=100° K of: a=10.2837(6) Å, b=10.4981(6) Å, c=11.5143(7) Å, α=83.297(2)°, β=87.649(2)°, y=67.445(2)°, and a triclinic P-1 space group;

(b) is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5;

(c) is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8; or

(d) is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 14.

59. The method of claim 54, wherein the disease is a myeloproliferative disease selected from the group consisting of thrombocythemia, idiopathic myelofibrosis, systemic mastocystosis (SM), myelodysplastic syndrome (MDS) and systemic mast cell disease (SMCD).

60. The method of claim 54, wherein the N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is provided in a pharmaceutical composition that is in a solid form.

61. The method of claim 60, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is present in an amount equivalent to 50 mg, 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

62. The method of claim 61, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is in the form of a tablet.