IP Library › Granted Patent US 6,951,889

Granted Patent B2

US 6,951,889 · App. 09/953,049 · Granted Oct 4, 2005

2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives useful as nitric oxide synthase inhibitors

Assignee: Pharmacia Corporation

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Quick Facts

Patent No.: US 6,951,889
App. No.: 09/953,049
Granted: Oct 4, 2005
Kind: B2

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Abstract

The present invention relates to 2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.

Claims (1042)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo.

2. The compound of claim 1 wherein the compound is the Z isomer.

3. The compound of claim 2 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

4. The compound of claim 3 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

5. The compound of claim 3 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl; said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by fluorine or alkoxy.

6. The compound of claim 3 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl optionally substituted by fluorine.

7. The compound of claim 3 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

8. The compound of claim 3 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

9. The compound of claim 8 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and halo; and

R 3 is C 1 -C 3 alkyl.

10. The compound of claim 9 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is C 1 -C 3 alkyl.

11. The compound of claim 10 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is methyl.

12. The compound of claim 11 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methyl.

13. The compound of claim 2 wherein:

R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine; and

R 3 is methyl optionally substituted alkoxy or one or more halo.

14. A compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo.

15. The compound of claim 14 wherein the compound is the Z isomer.

16. The compound of claim 15 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by one or more halo or alkoxy.

17. The compound of claim 15 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl; said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

18. The compound of claim 17 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl optionally substituted by fluorine or alkoxy.

19. The compound of claim 17 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by fluorine.

20. The compound of claim 16 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

21. The compound of claim 16 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

22. The compound of claim 21 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and halo; and

R 3 is C 1 -C 3 alkyl.

23. The compound of claim 22 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is C 1 -C 3 alkyl.

24. The compound of claim 23 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is methyl.

25. The compound of claim 24 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methyl.

26. The compound of claim 15 wherein:

R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine; and

R 3 is methyl optionally substituted by alkoxy or one or more halo.

27. A compound selected from the group consisting of:

(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R/S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R/S,5Z)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R/S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2-ethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2-fluoromethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-5-fluoromethyl-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2,6-dimethyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2,5-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-6-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R/S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R 1 S,5Z)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R, 5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R/S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2R/S,5E)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-2-ethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-2-fluoromethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-5-fluoromethyl-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-2,6-dimethyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2,5-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;

(2S,5E)-2-amino-6-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride; and

28. (2S,5Z)-2-amino-7-(ethanimidoylamino)-2-methylhept-5-enoic acid, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising (2S,5Z)-2-amino-7-(ethanimidoylamino)-2-methylhept-5-enoic acid, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

30. The compound of claim 1 wherein:

R 1 is hydrogen;

R 2 is fluorine; and

R 3 is methyl.

31. The compound of claim 3 wherein:

R 1 is halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

32. The compound of claim 31 wherein:

R 1 is halo;

R 2 is halo; and

R 3 is C 1 -C 3 alkyl.

33. The compound of claim 32 wherein:

R 1 is fluorine;

R 2 is fluorine; and

R 3 is methyl.

34. The compound of claim 31 wherein:

R 1 is fluorine;

R 2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and

R 3 is methyl.

35. The compound of clam 34 wherein:

R 1 is fluorine;

R 2 is hydrogen; and

R 2 is methyl.

36. The compound of claim 3 wherein:

R 1 is methyl;

R 2 is hydrogen; and

R 3 is methyl.

37. The compound of claim 3 wherein:

R 1 is hydrogen;

R 2 is methyl; and

R 3 is methyl.

38. The compound of claim 3 wherein:

R 1 is methyl;

R 2 is methyl; and

R 3 is methyl.

39. The compound of claim 13 wherein:

R 1 is selected from the group consisting of hydrogen and fluorine;

R 2 is C 1 -C 3 alkyl substituted by one or more halo; and

R 3 is methyl.

40. The compound of claim 39 wherein:

R 1 is hydrogen;

R 2 is CH 2 F; and

R 3 is methyl.

41. The compound of claim 13 wherein:

R 1 is CH 2 F;

R 2 is hydrogen; and

R 3 is methyl.

42. The compound of claim 13 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is CH 2 F.

43. The compound of claim 13 wherein:

R 1 is hydrogen;

R 2 is methoxymethyl; and

R 3 is methyl.

44. The compound of claim 13 wherein:

R 1 is methoxymethyl;

R 2 is hydrogen; and

R 3 is methyl.

45. The compound of claim 13 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methoxymethyl.

46. The compound of claim 1 wherein the compound is the E isomer.

47. The compound of claim 46 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by one or more halo or alkoxy.

48. The compound of claim 47 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl; said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

49. The compound of claim 48 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl optionally substituted by fluorine.

50. The compound of claim 48 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by fluorine or alkoxy.

51. The compound of claim 50 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

52. The compound of claim 47 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

53. The compound of claim 52 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and halo; and

R 3 is C 1 -C 3 alkyl.

54. The compound of claim 53 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is C 1 -C 3 alkyl.

55. The compound of claim 54 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is methyl.

56. The compound of claim 55 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methyl.

57. The compound of claim 55 wherein:

R 1 is hydrogen;

R 2 is fluorine; and

R 3 is methyl.

58. The compound of claim 47 wherein:

R 1 is halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

59. The compound of claim 58 wherein:

R 1 is halo;

R 2 is halo; and

R 3 is C 1 -C 3 alkyl.

60. The compound of claim 59 wherein:

R 1 is fluorine;

R 2 is fluorine; and

R 3 is methyl.

61. The compound of claim 58 wherein:

R 1 is fluorine;

R 2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and

R 3 is methyl.

62. The compound of claim 61 wherein:

R 1 is fluorine;

R 2 is hydrogen; and

R 3 is methyl.

63. The compound of claim 48 wherein:

R 1 is methyl;

R 2 is hydrogen; and

R 3 is methyl.

64. The compound of claim 48 wherein:

R 1 is hydrogen;

R 2 is methyl; and

R 3 is methyl.

65. The compound of claim 48 wherein:

R 1 is methyl;

R 2 is methyl; and

R 3 is methyl.

66. The compound of claim 46 wherein:

R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine; and

R 3 is methyl optionally substituted by alkoxy or one or more halo.

67. The compound of claim 66 wherein:

R 1 is selected from the group consisting of hydrogen and fluorine;

R 2 is C 1 -C 3 alkyl substituted by one or more halo; and

R 3 is methyl.

68. The compound of claim 67 wherein:

R 1 is hydrogen;

R 2 is CH 2 F; and

R 3 is methyl.

69. The compound of claim 66 wherein:

R 1 is CH 2 F;

R 2 is hydrogen; and

R 3 is methyl.

70. The compound of claim 66 wherein:

R 1 is hydrogen,

R 2 is hydrogen; and

R 3 is CH 2 F.

71. The compound of claim 66 wherein:

R 1 is hydrogen;

R 2 is methoxymethyl; and

R 3 is methyl.

72. The compound of claim 66 wherein:

R 1 is methoxymethyl;

R 2 is hydrogen; and

R 3 is methyl.

73. The compound of claim 66 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methoxymethyl.

74. The compound of claim 24 wherein:

R 1 is hydrogen;

R 2 is fluorine; and

R 3 is methyl.

75. The compound of claim 16 wherein:

R 1 is halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

76. The compound of claim 75 wherein:

R 1 is halo;

R 2 is halo; and

R 3 is C 1 -C 3 alkyl.

77. The compound of claim 76 wherein:

R 1 is fluorine;

R 2 is fluorine; and

R 3 is methyl.

78. The compound of claim 76 wherein:

R 1 is fluorine;

R 2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and

R 3 is methyl.

79. The compound of claim 78 wherein:

R 1 is fluorine;

R 2 is hydrogen; and

R 3 is methyl.

80. The compound of claim 16 wherein:

R 1 is methyl;

R 2 is hydrogen; and

R 3 is methyl.

81. The compound of claim 16 wherein:

R 1 is hydrogen;

R 2 is methyl; and

R 3 is methyl.

82. The compound of claim 16 wherein:

R 1 is methyl;

R 2 is methyl; and

R 3 is methyl.

83. The compound of claim 26 wherein:

R 1 is selected from the group consisting of hydrogen and fluorine;

R 2 is C 1 -C 5 alkyl substituted by one or more halo; and

R 3 is methyl.

84. The compound of claim 83 wherein:

R 1 is hydrogen;

R 2 is CH 2 F; and

R 3 is methyl.

85. The compound of claim 26 wherein:

R 1 is CH 2 F;

R 2 is hydrogen; and

R 3 is methyl.

86. The compound of claim 26 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is CH 2 F.

87. The compound of claim 26 wherein:

R 1 is hydrogen;

R 2 is methoxymethyl; and

R 3 is methyl.

88. The compound of claim 26 wherein:

R 1 is methoxymethyl;

R 2 is hydrogen; and

R 3 is methyl.

89. The compound of claim 26 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methoxymethyl.

90. The compound of claim 14 wherein the compound is the E isomer.

91. The compound of claim 90 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by one or more halo or alkoxy.

92. The compound of claim 91 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl; said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

93. The compound of claim 91 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl optionally substituted by fluorine.

94. The compound of claim 91 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by one or more fluorine or alkoxy.

95. The compound of claim 91 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

96. The compound of claim 91 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

97. The compound of claim 96 wherein:

R 1 is hydrogen;

R 1 is selected from the group consisting of hydrogen and halo; and

R 3 is C 1 -C 3 alkyl.

98. The compound of claim 97 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is C 1 -C 3 alkyl.

99. The compound of claim 98 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is methyl.

100. The compound of claim 99 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methyl.

101. The compound of claim 100 wherein:

R 1 is hydrogen;

R 2 is fluorine; and

R 3 is methyl.

102. The compound of claim 91 wherein:

R 1 is halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

103. The compound of claim 102 wherein:

R 1 is halo;

R 2 is halo; and

R 3 is C 1 -C 3 alkyl.

104. The compound of claim 103 wherein:

R 1 is fluorine;

R 2 is fluorine; and

R 3 is methyl.

105. The compound of claim 102 wherein:

R 1 is fluorine;

R 2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and

R 3 is methyl.

106. The compound of claim 105 wherein:

R 1 is fluorine;

R 2 is hydrogen; and

R 3 is methyl.

107. The compound of claim 91 wherein:

R 1 is methyl;

R 2 is hydrogen; and

R 3 is methyl.

108. The compound of claim 91 wherein:

R 1 is hydrogen;

R 2 is methyl; and

R 3 is methyl.

109. The compound of claim 91 wherein:

R 1 is methyl;

R 2 is methyl; and

R 3 is methyl.

110. The compound of claim 90 wherein:

R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine; and

R 3 is methyl optionally substituted by one or more alkoxy or halo.

111. The compound of claim 110 wherein:

R 1 is selected from the group consisting of hydrogen and fluorine;

R 2 is C 1 -C 3 alkyl substituted by one or more halo; and

R 3 is methyl.

112. The compound of claim 111 wherein:

R 1 is hydrogen;

R 2 is CH 2 F; and

R 3 is methyl.

113. The compound of claim 110 wherein:

R 1 is CH 2 F;

R 2 is hydrogen; and

R 3 is methyl.

114. The compound of claim 110 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is CH 2 F.

115. The compound of claim 110 wherein:

R 1 is hydrogen;

R 2 is methoxymethyl; and

R 3 is methyl.

116. The compound of claim 110 wherein:

R 1 is methoxymethyl,

R 2 is hydrogen; and

R 3 is methyl.

117. The compound of claim 110 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methoxymethyl.

118. A compound of Formula V

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo.

119. The compound of claim 118 wherein the compound is the Z isomer.

120. The compound of claim 119 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

121. The compound of claim 120 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl; said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

122. The compound of claim 120 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl optionally substituted by fluorine.

123. The compound of claim 119 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by fluorine or alkoxy.

124. The compound of claim 120 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

125. The compound of claim 120 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

126. The compound of claim 125 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and halo; and

R 3 is C 1 -C 3 alkyl.

127. The compound of claim 126 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is C 1 -C 3 alkyl.

128. The compound of claim 127 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is methyl.

129. The compound of claim 128 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methyl.

130. The compound of claim 128 wherein:

R 1 is hydrogen;

R 2 is fluorine; and

R 3 is methyl.

131. The compound of claim 120 wherein:

R 1 is halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

132. The compound of claim 131 wherein:

R 1 is halo;

R 2 is halo; and

R 3 is C 1 -C 3 alkyl.

133. The compound of claim 132 wherein:

R 1 is fluorine;

R 2 is fluorine; and

R 3 is methyl.

134. The compound of claim 131 wherein:

R 1 is fluorine;

R 2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and

R 3 is methyl.

135. The compound of claim 134 wherein:

R 1 is fluorine;

R 2 is hydrogen; and

R 3 is methyl.

136. The compound of claim 120 wherein:

R 1 is methyl;

R 2 is hydrogen; and

R 3 is methyl.

137. The compound of claim 120 wherein:

R 1 is hydrogen;

R 2 is methyl; and

R 3 is methyl.

138. The compound of claim 120 wherein:

R 1 is methyl;

R 2 is methyl; and

R 3 is methyl.

139. The compound of claim 119 wherein:

R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine; and

R 3 is C 1 -C 5 alkyl optionally substituted by alkoxy or one or more halo.

140. The compound of claim 139 wherein:

R 1 is selected from the group consisting of hydrogen and fluorine;

R 2 is C 1 -C 3 alkyl substituted by one or more halo; and

R 3 is methyl.

141. The compound of claim 140 wherein:

R 1 is hydrogen;

R 2 is CH 2 F; and

R 3 is methyl.

142. The compound of claim 139 wherein:

R 1 is CH 2 F;

R 2 is hydrogen; and

R 3 is methyl.

143. The compound of claim 139 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is CH 2 F.

144. The compound of claim 139 wherein:

R 1 is hydrogen;

R 2 is methoxymethyl; and

R 3 is methyl.

145. The compound of claim 139 wherein:

R 1 is methoxymethyl;

R 2 is hydrogen; and

R 3 is methyl.

146. The compound of claim 139 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methoxymethyl.

147. The compound of claim 118 wherein the compound is the E isomer.

148. The compound of claim 147 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by one or more halo or alkoxy.

149. The compound of claim 148 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 5 alkyl; said C 1 -C 5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by halo or alkoxy.

150. The compound of claim 148 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl optionally substituted by fluorine.

151. The compound of claim 148 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by fluorine or alkoxy.

152. The compound of claim 148 wherein:

R 1 is selected from the group consisting of hydrogen, halo, and C 1 -C 3 alkyl;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

153. The compound of claim 148 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

154. The compound of claim 153 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and halo; and

R 3 is C 1 -C 3 alkyl.

155. The compound of claim 154 wherein:

R 1 is hydrogen;

R 2 selected from the group consisting of hydrogen and fluorine; and

R 3 is C 1 -C 3 alkyl.

156. The compound of claim 155 wherein:

R 1 is hydrogen;

R 2 is selected from the group consisting of hydrogen and fluorine; and

R 3 is methyl.

157. The compound of claim 155 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methyl.

158. The compound of claim 156 wherein:

R 1 is hydrogen;

R 2 is fluorine; and

R 3 is methyl.

159. The compound of claim 148 wherein:

R 1 is halo;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 3 alkyl; and

R 3 is C 1 -C 3 alkyl.

160. The compound of claim 159 wherein:

R 1 is halo;

R 2 is halo; and

R 3 is C 1 -C 3 alkyl.

161. The compound of claim 160 wherein:

R 1 is fluorine;

R 2 is fluorine; and

R 3 is methyl.

162. The compound of claim 159 wherein:

R 1 is fluorine;

R 2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and

R 3 is methyl.

163. The compound of claim 162 wherein:

R 1 is fluorine;

R 2 is hydrogen; and

R 3 is methyl.

164. The compound of claim 148 wherein:

R 1 is methyl;

R 2 is hydrogen; and

R 3 is methyl.

165. The compound of claim 148 wherein:

R 1 is hydrogen;

R 2 is methyl; and

R 3 is methyl.

166. The compound of claim 148 wherein:

R 1 is methyl;

R 2 is methyl; and

R 3 is methyl.

167. The compound of claim 147 wherein:

R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine;

R 2 is selected from the group consisting of hydrogen, halo and C 1 -C 5 alkyl, said C 1 -C 5 alkyl optionally substituted by alkoxy or one or more fluorine; and

R 3 is methyl optionally substituted by one or more alkoxy or halo.

168. The compound of claim 167 wherein:

R 1 is selected from the group consisting of hydrogen and fluorine;

R 2 is C 1 -C 3 alkyl substituted by one or more halo; and

R 3 is methyl.

169. The compound of claim 168 wherein:

R 1 is hydrogen;

R 2 is CH 2 F, and

R 3 is methyl.

170. The compound of claim 168 wherein:

R 1 is CH 2 F;

R 2 is hydrogen; and

R 3 is methyl.

171. The compound of claim 167 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is CH 2 F.

172. The compound of claim 167 wherein;

R 1 is hydrogen;

R 2 is methoxymethyl; and

R 3 is methyl.

173. The compound of claim 167 wherein:

R 1 is methoxymethyl;

R 2 is hydrogen; and

R 3 is methyl.

174. The compound of claim 167 wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

R 3 is methoxymethyl.

175. A pharmaceutical composition comprising at least one compound selected from the group consisting of:

(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;

(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid