N-hydroxylamino-barbituric acid derivatives
The present disclosure provides N-hydroxylamino-barbituric acid compounds of formulae (1)-(4), pharmaceutical compositions and kits comprising them, and methods of using such compounds or pharmaceutical compositions. The present disclosure provides methods of using such compounds or pharmaceutical compositions for treating heart failure.
1. A compound of formula (1):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently H or (C 1 )alkyl;
R 2 is (C 1 -C 6 )alkyl substituted with a substituent selected from the group consisting of (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 7 )heterocycloalkyl, (5- or 6-membered)heteroaryl and (9- or 10-membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
X is O, NR 7 or S;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl;
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl; and
R 7 is H or (C 1 -C 6 )alkyl.
2. The compound of claim 1 , wherein X is O or S.
3. The compound of claim 1 , wherein at least one of R 1 is H.
4. The compound of claim 1 , wherein at least one of R 1 is (C 1 )alkyl.
5. The compound of claim 1 , wherein each R 1 is (C 1 )alkyl.
6. The compound of claim 1 , wherein X is O.
7. The compound of claim 1 , wherein X is S.
8. The compound of claim 1 , wherein X is NH.
9. The compound of claim 1 , wherein said compound has formula (1a):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 6 )alkyl substituted with (C 6 -C 14 )aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 .
10. The compound of claim 9 , wherein R 2 is (C 1 )alkyl substituted with (C 6 -C 14 )aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
11. The compound of claim 9 , wherein said aryl is phenyl.
12. The compound of claim 9 , wherein R 4 is (C 1 -C 6 )alkyl, —OH, (C 1 -C 3 )alkoxy, —S(O)O(C 1 -C 6 )alkyl or halo.
13. The compound of claim 1 , wherein said compound has formula (1a-1):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is (C 1 )alkyl;
each R 5 is independently selected from the group consisting of H, halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of H, halo and (C 1 -C 6 )alkyl.
14. The compound of claim 13 , wherein one or more of R 5 is selected from the group consisting of H, —OH, (C 1 -C 3 )alkoxy, S(O)O(C 1 -C 6 )alkyl and halo.
15. The compound of claim 13 , wherein one or more of R 5 is methoxy.
16. The compound of claim 13 , wherein one or more of R 5 is Cl.
17. The compound of claim 13 , wherein at least one of R 6 is H.
18. The compound of claim 13 , wherein at least one of R 6 is halo.
19. The compound of claim 13 , wherein at least one of R 6 is methyl.
20. The compound of claim 13 wherein X is O.
21. The compound of claim 13 , wherein X is S.
22. The compound of claim 13 , wherein X is NH.
23. The compound of claim 1 , wherein said compound has formula (1a-2):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is (C 1 )alkyl;
each R 5 is independently selected from the group consisting of H, halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of H, halo and (C 1 -C 6 )alkyl.
24. The compound of claim 23 , wherein one or more of R 5 is selected from the group consisting of H, —OH, (C 1 -C 3 )alkoxy, S(O)O(C 1 -C 6 )alkyl and halo.
25. The compound of claim 23 , wherein one or more of R 5 is methoxy.
26. The compound of claim 23 , wherein one or more of R 5 is Cl.
27. The compound of claim 23 , wherein at least one of R 6 is H.
28. The compound of claim 23 , wherein at least one of R 6 is halo.
29. The compound of claim 23 , wherein at least one of R 6 is methyl.
30. The compound of claim 23 , wherein X is O.
31. The compound of claim 23 , wherein X is S.
32. The compound of claim 23 , wherein X is NH.
33. The compound of claim 1 , wherein said compound has formula (1b):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently H or (C 1 )alkyl;
R 2 is (C 1 -C 6 )alkyl substituted with (C 3 -C 6 )cycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.
34. The compound of claim 33 , wherein R 2 is (C 1 )alkyl substituted with (C 3 -C 6 )cycloalkyl.
35. The compound of claim 33 , wherein said (C 3 -C 6 )cycloalkyl is cyclohexyl.
36. The compound of claim 1 , wherein said compound has formula (1c):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 6 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.
37. The compound of claim 36 , wherein R 2 is (C 1 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl.
38. The compound of claim 1 , wherein said compound has formula (1d):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 6 )alkyl substituted with (5- or 6-membered)heteroaryl or (9- or 10-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′ R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.
39. The compound of claim 38 , wherein R 2 is (C 1 )alkyl substituted with (5- or 6-membered)heteroaryl.
40. The compound of claim 38 , wherein said heteroaryl is selected from the group consisting of furyl, thienyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, thiophenyl, and benzo[d][1,3]dioxolyl.
41. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
43. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
44. A compound of formula (2):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently H or (C 1 )alkyl;
R 2 is selected from the group consisting of a branched C 3 -C 6 alkyl, a branched C 3 -C 6 alkenyl, and a branched C 3 -C 6 alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 ;
X is O, NR 7 or S;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′ R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
R 7 is H or (C 1 -C 6 )alkyl.
45. The compound of claim 44 , wherein X is O or S.
46. The compound of claim 44 , wherein at least one of R 1 is H.
47. The compound of claim 44 , wherein at least one of R 1 is (C 1 )alkyl.
48. The compound of claim 44 , wherein each R 1 is methyl.
49. The compound of claim 44 , wherein R 2 is selected from the group consisting of iso-propyl, methylpropyl, sec-butyl, iso-butyl, tert-butyl, methylbutyl, iso-pentyl, methylpentyl, ethylbutyl, dimethylbutyl, and iso-propylpropyl.
50. The compound of claim 44 , wherein X is O.
51. The compound of claim 44 , wherein X is S.
52. The compound of claim 44 , wherein X is NH.
53. A compound of formula (3):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is H;
R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 1 -C 6 )alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 ;
X is O, NR 7 or S;
each R 4 is independently selected from the group consisting of halo, —OH, —CH 2 OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(NH)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
R 7 is H or (C 1 -C 6 )alkyl.
54. The compound of claim 53 , wherein X is O or S.
55. The compound of claim 53 , wherein R 2 is (C 1 -C 6 )alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 .
56. The compound of claim 53 , wherein R 2 is methyl, ethyl, propylene, iso-propyl, methylbutyl, methylpropyl, iso-pentyl or trifluoroethyl.
57. The compound of claim 53 , wherein R 2 is selected from the group consisting of a branched (C 3 -C 6 )alkyl, branched (C 3 -C 6 )alkenyl, and branched (C 3 -C 6 )alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 .
58. The compound of claim 53 , wherein X is O.
59. The compound of claim 53 , wherein X is S.
60. The compound of claim 53 , wherein X is NH.
61. The compound of claim 53 , wherein said compound has formula (3a):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 4 )alkyl substituted with phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo, —S(O)O(C 1 -C 6 )alkyl and (C 1 -C 6 )alkyl.
62. The compound of claim 61 , wherein R 2 is (C 1 )alkyl substituted with phenyl.
63. The compound of claim 61 , wherein R 4 is (C 1 -C 3 )alkoxy or halo.
64. The compound of claim 61 , wherein X is O.
65. The compound of claim 61 , wherein X is S.
66. The compound of claim 61 , wherein X is NH.
67. The compound of claim 53 , wherein said compound has formula (3a-1):
or a pharmaceutically acceptable salt thereof, wherein:
each R 5 is selected from the group consisting of H, halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of H, halo and (C 1 -C 6 )alkyl.
68. The compound of claim 67 , wherein one or more of R 5 is selected from the group consisting of H, —OH, (C 1 -C 3 )alkoxy, —S(O)O(C 1 -C 6 )alkyl and halo.
69. The compound of claim 67 , wherein one or more of R 5 is methoxy.
70. The compound of claim 67 , wherein one or more of R 5 is Cl.
71. The compound of claim 67 , wherein at least one of R 6 is H.
72. The compound of claim 67 , wherein at least one of R 6 is halo.
73. The compound of claim 67 , wherein at least one of R 6 is methyl.
74. The compound of claim 67 , wherein X is O.
75. The compound of claim 67 , wherein X is S.
76. The compound of claim 67 , wherein X is NH.
77. The compound of claim 53 , wherein said compound has formula (3b):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.
78. The compound of claim 77 , wherein R 2 is (C 1 )alkyl substituted with (C 3 -C 6 )cycloalkyl.
79. The compound of claim 77 , wherein said (C 3 -C 6 )cycloalkyl is cyclohexyl.
80. The compound of claim 77 , wherein X is O.
81. The compound of claim 77 , wherein X is S.
82. The compound of claim 77 , wherein X is NH.
83. The compound of claim 53 , wherein said compound has formula (3c):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 4 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′ R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.
84. The compound of claim 83 , wherein R 2 is (C 1 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl.
85. The compound of claim 83 , wherein said hetercycloalkyl is a (C 6 )heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
86. The compound of claim 83 , wherein X is O.
87. The compound of claim 83 , wherein X is S.
88. The compound of claim 83 , wherein X is NH.
89. The compound of claim 53 , wherein said compound has formula (3d):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9- or 10-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
each R 4 is independently selected from the group consisting of halo, —OH, —CH 2 OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
each R 6 is independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.
90. The compound of claim 89 , wherein R 2 is (C 1 )alkyl substituted with (5- or 6-membered)heteroaryl.
91. The compound of claim 89 , wherein said heteroaryl is selected from the group consisting of furyl, thienyl, imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, thiophenyl, 1H-indolyl, 3H-indolyl and benzo[d][1,3]dioxolyl.
92. The compound of claim 89 , wherein X is O.
93. The compound of claim 89 , wherein X is S.
94. The compound of claim 89 , wherein X is NH.
95. The compound of claim 53 having the formula:
or a pharmaceutically acceptable salt thereof.
96. The compound of claim 53 having the formula:
or a pharmaceutically acceptable salt thereof.
97. The compound of claim 53 having the formula:
or a pharmaceutically acceptable salt thereof.
98. The compound of claim 53 having the formula:
s or a pharmaceutically acceptable salt thereof.
99. A compound of formula (4):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently H or (C 1 )alkyl;
R 2 is (C 6 -C 10 )aryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 7 )heterocycloalkyl and (5- or 6-membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 ;
X is O, NR 7 or S;
each R 4 is independently selected from the group consisting of halo, —OH, —NH 2 , —C≡N, —NO 2 , —SH, ═O, ═S, ═N—(C 1 -C 4 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, —C(O)H, —C(O)NH 2 , —C(O)OH, —NH—C(O)—NH 2 , —NH—C(S)—NH 2 , —SC≡N, —SO 2 NH 2 , —COR′, —C(O)OR′, C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —S(O)R′, —S(O)OR′, and —OR′, wherein R′ and R″ are independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl; and
R 7 is H or (C 1 -C 6 )alkyl.
100. The compound of claim 99 , wherein at least one of R 1 is H.
101. The compound of claim 99 , wherein at least one of R 1 is (C 1 )alkyl.
102. The compound of claim 99 , wherein each R 1 is (C 1 )alkyl.
103. The compound of claim 99 , wherein X is O.
104. The compound of claim 99 , wherein X is S.
105. The compound of claim 99 , wherein X is NH.
106. The compound of claim 99 , wherein said compound has formula (4a):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 6 -C 10 )aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
107. The compound of claim 106 , wherein:
R 2 is phenyl unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
108. The compound of claim 107 , wherein:
R 2 is unsubstituted phenyl.
109. The compound of claim 99 , wherein said compound has formula (4b):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
110. The compound of claim 109 , wherein R 2 is cyclohexyl.
111. The compound of claim 99 , wherein said compound has formula (4c):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
112. The compound of claim 111 , wherein R 2 is (C 6 )heterocycloalkyl.
113. The compound of claim 99 , wherein said compound has formula (4d):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
114. A compound of formula (5):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 and X are as defined in claim 1 ; and
R is hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH 2 , —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 , wherein said —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 3 )alkynyl, -(5- or 6-membered)heteroaryl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —NO 2 , —NH 2 , —NH—(C 1 -C 4 )alkyl, —N(—(C 1 -C 4 )alkyl) 2 , —C(O)(C 1 -C 4 )alkyl, —C(O)O(C 1 -C 4 )alkyl, —OC(O)(C 1 -C 4 )alkyl, —OC(O)NH 2 , —S(O)(C 1 -C 4 )alkyl, or —S(O) 2 (C 1 -C 4 )alkyl.
115. A compound of formula (5):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 and X are as defined in claim 44 ; and
R is hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH 2 , —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 , wherein said —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 3 )alkynyl, -(5- or 6-membered)heteroaryl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —NO 2 , —NH 2 , —NH—(C 1 -C 4 )alkyl, —N(—(C 1 -C 4 )alkyl) 2 , —C(O)(C 1 -C 4 )alkyl, —C(O)O(C 1 -C 4 )alkyl, —OC(O)(C 1 -C 4 )alkyl, —OC(O)NH 2 , —S(O)(C 1 -C 4 )alkyl, or —S(O) 2 (C 1 -C 4 )alkyl.
116. A compound of formula (5):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 and X are as defined in claim 53 ; and
R is hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH 2 , —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 , wherein said —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 3 )alkynyl, -(5- or 6-membered)heteroaryl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —NO 2 , —NH 2 , —NH—(C 1 -C 4 )alkyl, —N(—(C 1 -C 4 )alkyl) 2 , —C(O)(C 1 -C 4 )alkyl, —C(O)O(C 1 -C 4 )alkyl, —OC(O)(C 1 -C 4 )alkyl, —OC(O)NH 2 , —S(O)(C 1 -C 4 )alkyl, or —S(O) 2 (C 1 -C 4 )alkyl.
117. A compound of formula (5):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 and X are as defined in claim 99 ; and
R is hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH 2 , —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 , wherein said —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 3 )alkynyl, -(5- or 6-membered)heteroaryl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —NO 2 , —NH 2 , —NH—(C 1 -C 4 )alkyl, —N(—(C 1 -C 4 )alkyl) 2 , —C(O)(C 1 -C 4 )alkyl, —C(O)O(C 1 -C 4 )alkyl, —OC(O)(C 1 -C 4 )alkyl, —OC(O)NH 2 , —S(O)(C 1 -C 4 )alkyl, or —S(O) 2 (C 1 -C 4 )alkyl.
118. A compound selected from:
5-(N-hydroxylamino)-5-benzyl-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-(4-methoxybenzyl)-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-(4-chlorobenzyl)-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-ethyl-barbituric acid;
5-(N-hydroxylamino)-5-benzyl-barbituric acid;
5-(N-hydroxylamino)-5-(4-methoxybenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-(4-chlorobenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-phenyl-barbituric acid;
5-(N-hydroxylamino)-5-(2-propen-1-yl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-methylpropyl)-barbituric acid;
5-(N-hydroxylamino)-5-(1-methylethyl)-barbituric acid;
5-(N-hydroxylamino)-5-(1-methylbutyl)-barbituric acid;
5-(N-hydroxylamino)-5-phenyl-thiobarbituric acid;
5-(N-hydroxylamino)-5-(2-chlorobenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-furylmethyl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-thienylmethyl)-barbituric acid;
5-(N-hydroxylamino)-5-methyl-barbituric acid;
5-(N-hydroxylamino)-5-(1-methylpropyl)-barbituric acid;
5-(hydroxylamino)-5-(3-methylbutyl) barbituric acid;
5-(hydroxyamino)-2-imino-5-phenyldihydropyrimidine-4,6(1H,5H)-dione;
5-(hydroxylamino)-5-(2,2,2-trifluoroethyl)barbituric acid;
5-(hydroxylamino)-5-(4-(methylsulfonyl)benzyl)barbituric acid
5-(hydroxylamino)-5-(benzo[d][1,3]dioxol-5-ylmethyl)barbituric acid;
5-(hydroxylamino)-5-(pyridin-4-ylmethyl)barbituric acid;
5-(hydroxylamino)-5-(3-ethyl-5-hydroxy-6-methylpyridin-4-ylmethyl)barbituric acid;
5-(hydroxylamino)-5-(3-hydroxy-5-(hydroxylmethyl)-2-methylpyridin-4-ylmethyl)barbituric acid;
5-(hydroxylamino)5-(2-(methylthio)ethyl)barbituric acid;
5-(hydroxyamino)-5-(4-hydroxybenzyl)barbituric acid;
5-((1H-indol-2-yl)methyl)-5-(hydroxyamino)barbituric acid;
2-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetic acid;
3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanoic acid 2-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetamide;
3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanamide;
5-((1H-imidazol-5-yl)methyl)-5-(hydroxyamino)barbituric acid;
5-(4-aminobutyl)-5-(hydroxyamino)barbituric acid;
1-(3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propyl)guanidine;
5-(hydroxylamino)5-(2-(methylthio)ethyl)barbituric acid;
5-(hydroxyamino)-5-(4-hydroxybenzyl)barbituric acid;
5-((1H-indol-2-yl)methyl)-5-(hydroxyamino)barbituric acid;
2-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetic acid;
3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanoic acid
2-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetamide;
3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanamide;
5-((1H-imidazol-5-yl)methyl)-5-(hydroxyamino)barbituric acid;
5-(4-aminobutyl)-5-(hydroxyamino)barbituric acid; and
1-(3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propyl)guanidine.
119. A pharmaceutical composition comprising the compound of and of claims 1 , 44 , 53 , 99 , 114 , 115 , 116 or 117 or 118 and at least one pharmaceutically acceptable excipient.
120. The pharmaceutical composition of claim 119 , wherein said pharmaceutical composition is suitable for intravenous administration.
121. A method of treating a cardiovascular disease selected from the group consisting of coronary obstructions, coronary artery disease, angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, pulmonary congestion, pulmonary edema, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, ventricular hypertrophy, heart valve disease, heart failure, and cardiac hypertrophy comprising administering an effective amount of the compound of and of claims 1 , 44 , 53 , 99 , 114 , 115 , 116 , 117 or 118 or the pharmaceutical composition of claim 119 to a patient in need thereof.
122. The method of claim 121 , wherein said heart failure is selected from the group consisting of diastolic heart failure, systolic heart failure, congestive heart failure, acute congestive heart failure, and acute decompensated heart failure.
123. The method of claim 122 , wherein said heart failure is acute decompensated heart failure.
124. The method of claim 121 , wherein said compound or composition is administered intravenously.