IP Library › Granted Patent US 9,139,534
Granted Patent B2
US 9,139,534 · App. 13/451,574 · Granted Sep 22, 2015

Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith

Inventors: Brydon L. Bennett (San Diego, CA); Jan Elsner (San Diego, CA); Paul Erdman (San Diego, CA); Robert Hilgraf (San Diego, CA); Laurie Ann LeBrun (San Diego, CA); Meg McCarrick (San Diego, CA); Mehran F. Moghaddam (Carlsbad, CA); Mark A. Nagy (San Diego, CA); Stephen Norris (San Diego, CA); David A. Paisner (Portland, OR); Marianne Sloss (San Diego, CA); William J. Romanow (San Diego, CA); Yoshitaka Satoh (Poway, CA); Jayashree Tikhe (San Diego, CA); Won Hyung Yoon (San Diego, CA); Mercedes Delgado (San Diego, CA)
Assignee: Signal Pharmaceuticals, LLC
C07D239/48A61K31/505C07D401/04C07D401/12C07D403/12C07D405/12C07D409/12
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Quick Facts
Patent No.
US 9,139,534
App. No.
13/451,574
Granted
Sep 22, 2015
Kind
B2
Abstract

Provided herein are Diaminopyrimidine Compounds having the following structures: wherein R 1 , R 2 , R 3 , and R 4 are as defined herein, compositions comprising an effective amount of a Diaminopyrimidine Compound, and methods for treating or preventing liver fibrotic disorders or a condition treatable or preventable by inhibition of a JNK pathway.

Claims (108)

1. A compound selected from

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

2. A compound selected from

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

3. A compound selected from

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

4. A method of inhibiting a JNK1 or JNK2 kinase in a cell expressing said JNK1 or JNK2 kinase, comprising contacting said cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

5. A method for the treatment of a liver fibrotic disorder, or diabetes or metabolic syndrome leading to a liver fibrotic disorder, the methods comprising administering to a subject having a liver fibrotic disorder, or diabetes or metabolic syndrome leading to a liver fibrotic disorder an effective amount of a compound of claim 1 .

6. The method of claim 5 , wherein the liver fibrotic disorder is non-alcoholic steatohepatitis, steatosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, or liver fibrosis coincident with chronic or repeated alcohol ingestion, with infection, with liver transplant, or with drug induced liver injury.

7. The method of claim 5 , wherein the liver fibrotic disorder is non-alcoholic steatohepatitis, steatosis, hepatitis, or cirrhosis.

8. A method for the treatment of a liver fibrotic disorder, or diabetes or metabolic syndrome leading to a liver fibrotic disorder, the methods comprising administering to a subject having a liver fibrotic disorder, or diabetes or metabolic syndrome leading to a liver fibrotic disorder an effective amount of a compound of claim 2 .

9. The method of claim 8 , wherein the liver fibrotic disorder is non-alcoholic steatohepatitis, steatosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, or liver fibrosis coincident with chronic or repeated alcohol ingestion, with infection, with liver transplant, or with drug induced liver injury.

10. The method of claim 8 , wherein the liver fibrotic disorder is non-alcoholic steatohepatitis, steatosis, hepatitis, or cirrhosis.

11. A method for the treatment of a liver fibrotic disorder, or diabetes or metabolic syndrome leading to a liver fibrotic disorder, the methods comprising administering to a subject having a liver fibrotic disorder, or diabetes or metabolic syndrome leading to a liver fibrotic disorder an effective amount of a compound of claim 3 .

12. The method of claim 11 , wherein the liver fibrotic disorder is non-alcoholic steatohepatitis, steatosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, or liver fibrosis coincident with chronic or repeated alcohol ingestion, with infection, with liver transplant, or with drug induced liver injury.

13. The method of claim 11 , wherein the liver fibrotic disorder is non-alcoholic steatohepatitis, steatosis, hepatitis, or cirrhosis.

14. A method of inhibiting a JNK1 or JNK2 kinase in a cell expressing said JNK1 or JNK2 kinase, comprising contacting said cell with an effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

15. A method of inhibiting a JNK1 or JNK2 kinase in a cell expressing said JNK1 or JNK2 kinase, comprising contacting said cell with an effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

16. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

17. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

18. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

19. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

20. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

21. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

22. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

23. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

24. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

25. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

26. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

27. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

28. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

29. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

30. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

31. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

32. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

33. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

34. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

35. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

36. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

37. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

38. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

39. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

40. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

41. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

42. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

43. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

44. The compound of claim 2 , wherein the compound is

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof.

45. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

46. A pharmaceutical composition comprising an effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

47. A pharmaceutical composition comprising an effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

48. A pharmaceutical composition comprising an effective amount of a compound of claim 16 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

49. A pharmaceutical composition comprising an effective amount of a compound of claim 17 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

50. A pharmaceutical composition comprising an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

51. A pharmaceutical composition comprising an effective amount of a compound of claim 19 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

52. A pharmaceutical composition comprising an effective amount of a compound of claim 20 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

53. A pharmaceutical composition comprising an effective amount of a compound of claim 21 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

54. A pharmaceutical composition comprising an effective amount of a compound of claim 22 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

55. A pharmaceutical composition comprising an effective amount of a compound of claim 23 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

56. A pharmaceutical composition comprising an effective amount of a compound of claim 24 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

57. A pharmaceutical composition comprising an effective amount of a compound of claim 25 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

58. A pharmaceutical composition comprising an effective amount of a compound of claim 26 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

59. A pharmaceutical composition comprising an effective amount of a compound of claim 27 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

60. A pharmaceutical composition comprising an effective amount of a compound of claim 28 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

61. A pharmaceutical composition comprising an effective amount of a compound of claim 29 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

62. A pharmaceutical composition comprising an effective amount of a compound of claim 30 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

63. A pharmaceutical composition comprising an effective amount of a compound of claim 31 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

64. A pharmaceutical composition comprising an effective amount of a compound of claim 32 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

65. A pharmaceutical composition comprising an effective amount of a compound of claim 33 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

66. A pharmaceutical composition comprising an effective amount of a compound of claim 34 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

67. A pharmaceutical composition comprising an effective amount of a compound of claim 35 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

68. A pharmaceutical composition comprising an effective amount of a compound of claim 36 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

69. A pharmaceutical composition comprising an effective amount of a compound of claim 37 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

70. A pharmaceutical composition comprising an effective amount of a compound of claim 38 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

71. A pharmaceutical composition comprising an effective amount of a compound of claim 39 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

72. A pharmaceutical composition comprising an effective amount of a compound of claim 40 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

73. A pharmaceutical composition comprising an effective amount of a compound of claim 41 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

74. A pharmaceutical composition comprising an effective amount of a compound of claim 42 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

75. A pharmaceutical composition comprising an effective amount of a compound of claim 43 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

76. A pharmaceutical composition comprising an effective amount of a compound of claim 44 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 4, 2012
From: BENNETT, BRYDON L.; ELSNER, JAN; ERDMAN, PAUL; HILGRAF, ROBERT; LEBRUN, LAURIE ANN; MCCARRICK, MARGARET (MEG); MOGHADDAM, MEHRAN F.; NAGY, MARK A.; NORRIS, STEPHEN; PAISNER, DAVID A.; SLOSS, MARIANNE; ROMANOW, WILLIAM J.; SATOH, YOSHITAKA; TIKHE, JAYASHREE; YOON, WON HYUNG; DELGADO, MERCEDES
To: SIGNAL PHARMACEUTICALS, LLC
Reel/Frame 029108/0827 →
Continuity (3)
Provisional Application 61478076 · Apr 22, 2011
Provisional Application 61555339 · Nov 3, 2011
Related Publication 20130029987A1 · Jan 31, 2013