Substituted 5-oxo pyrazoles and [1,2,4]triazoles as antiviral agents

1. A compound of formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein:

X is C(R 8 ) or N;

R 8 is H, halo, CF 3 , C 1 –C 6 alkyl, halo(C 1 –C 6 )alkyl, —OH, —SH, C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, —NH 2 . —NH(C 1 –C 6 alkyl), or —N(C 1 –C 6 alkyl) 2 ;

R 1 is —CO 2 R 9 , —C(O)NR 9 R 10 , —NR 9 SO 2 R 10 , —CN, —C(O)NR 9 CN, or tetrazolyl;

R 2 is cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, or cycloalkylalkyl, wherein each member of R 2 is optionally substituted with 1–4 R 12 moieties;

R 3 is H or C 1 –C 6 alkyl;

R 4 is H, C 1 –C 6 alkyl or C 1 –C 6 alkoxy;

R 5 is H, C 1 –C 6 alkyl or C 1 –C 6 alkoxy;

R 6 is cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, or cycloalkylalkyl, wherein each member of R 6 is optionally substituted with 1–4 R 12 moieties;

R 7 is H or C 1 –C 6 alkyl; or R 6 and R 7 , when attached to the same nitrogen, are optionally taken together with the attached nitrogen to form a five to seven membered ring having 0–1 additional heteroatom selected from N, O or S, wherein said five to seven membered ring is optionally substituted with 1–3 R 18 moieties;

each R 9 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein each member except H is optionally substituted with 1–4 R 12 moieties;

each R 10 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein each member except H is optionally substituted with 1–4 R 12 moieties; or R 9 and R 10 when attached to the same nitrogen are optionally taken together with the attached nitrogen to form a five to sixteen membered monocyclic, bicyclic or tricyclic ring having 0–2 additional heteroatoms selected from N, O or S, wherein said monocyclic, bicyclic or tricyclic ring is optionally substituted with 1–3 R 18 moieties;

each R 12 is independently halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —CN, —CF 3 , —OR 13 , —SR 13 , —C(O)R 13 , —C(S)R 13 , —C(O)OR 13 , —C(S)OR 13 , —OC(O)R 13 , —OC(S)R 13 , —C(O)NR 13 R 14 , —C(S)NR 13 R 14 , —C(O)NR 13 OR 14 , —C(S)NR 13 OR 14 , —C(O)NR 13 NR 13 R 14 , —C(S)NR 13 NR 13 R 14 , —C(S)NR 13 OR 14 , —C(O)SR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(S)R 14 , —NR 13 C(O)OR 14 , —NR 13 C(S)OR 14 , —OC(O)NR 13 R 14 , —OC(S)NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —NR 13 C(S)NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —NR 13 C(S)NR 13 OR 14 , —SO 2 R 13 , —S(O) 1-2 NR 13 R 14 , —N(R 13 )SO 2 R 14 , —N(R 13 )SO 2 NR 13 R 14 , —S(O) 1-2 NR 13 OR 14 , —OCF 3 , —SCF 3 , haloalkyl, ═O, ═S, NO 2 , —C(O)C(O)R 13 , —C(O)CH 2 C(O)R 13 , methylenedioxy, or ethylenedioxy, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is optionally substituted with 1–4 R 5 moieties;

each R 13 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein each member of R 13 except H is optionally substituted with 1–4 R 15 moieties;

each R 14 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein each member of R 14 except H is optionally substituted with 1–4 R 15 moieties; or R 13 and R 14 , when attached to the same nitrogen, are optionally taken together with the attached nitrogen to form a five to seven membered ring having 0–1 additional heteroatom selected from N, O or S, wherein said five to seven membered ring is optionally substituted with 1–3 R 18 moieties;

each R 15 is independently halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —CN, —CF 3 , —OR 16 , —SR 16 , —C(O)R 16 , —C(S)R 16 , —C(O)OR 16 , —C(S)OR 16 , —OC(O)R 16 , —OC(S)R 16 , —C(O)NR 16 R 17 , —C(S)NR 16 R 17 , —C(O)NR 16 OR 17 , —C(S)NR 16 OR 17 , —C(O)NR 16 NR 16 R 17 , —C(S)NR 16 NR 16 R 17 , —C(S)NR 16 OR 17 , —C(O)SR 16 , —NR 16 R 17 , —NR 16 C(O)R 17 , —NR 16 C(S)R 17 , —NR 16 C(O)OR 17 , —NR 16 C(S)OR 17 , —OC(O)NR 16 R 17 , —OC(S)NR 16 R 17 , —NR 16 C(O)NR 16 R 17 , —NR 16 C(S)NR 16 R 17 , —NR 16 C(O)NR 16 OR 17 , —NR 16 C(S)NR 16 OR 17 , —SO 2 R 16 , —S(O) 1-2 NR 16 R 17 , —N(R 18 )SO 2 R 17 , —S(O) 1-2 NR 16 OR 17 , —OCF 3 , —SCF 3 , haloalkyl, ═O, ═S, NO 2 , —C(O)C(O)R 16 , —C(O)CH 2 C(O)R 16 , methylenedioxy, or ethylenedioxy, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is optionally substituted with 1–3 R 18 moieties;

each R 16 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, wherein each member of R 16 is optionally substituted with 1–3 R 18 ;

each R 17 is independently H, alkyl, cycloalkyl, cyoloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, wherein each member of R 16 is optionally substituted with 1–3 R 18; or R 16 and R 17 , when attached to the same nitrogen, are optionally taken together with the attached nitrogen to form a five to seven membered ring having 0–1 additional heteroatom selected from N, O or S, wherein said five to seven membered ring is optionally substituted with 1–3 R 16 moieties;

each R 18 is halo, ═O, ═S, NO 2 , alkyl, —OR 20 , —CN, —NR 19 R 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 19 R 20 , —CF 3 , or —N(R 19 )C(O)R 20;

each R 19 is independently H or alkyl; and

each R 20 is independently H or alkyl.

2. The compound of claim 1 , wherein X is C(R 8 ).

3. The compound of claim 1 , wherein R 8 is H.

4. The compound of claim 1 , wherein X is N.

5. The compound of claim 1 , wherein R 3 is H or CH 3 and R 7 is H or CH 3 .

6. The compound of claim 1 , wherein R 2 is alkyl, cycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1–2 R 12 moieties.

7. The compound of claim 6 , wherein R 2 is i-propyl, t-butyl, phenyl, naphthyl, cyclohexyl, pyridyl, or thienyl, wherein said wherein said phenyl, naphthyl, cyclohexyl, pyridyl, or thienyl is optionally substituted with 1–2 R 12 moieties.

8. The compound of claim 7 , wherein each R 12 is independently —OR 13 , CF 3 , halo, alkyl, 5-membered heteroaryl, —C(O)OR 13 , or aryl, wherein said alkyl is optionally substituted with —SO 2 R 16 and said aryl is optionally substituted with 1–2 R 15 moieties; R 13 is alkyl, aralkyl, or aryl optionally substituted with halo; R 15 is CF 3 , SO 2 R 16 , —OR 16 , —C(O)OR 20 , or halo; and R 16 is alkyl.

9. The compound of claim 8 , wherein each R 12 is —O—(phenyl optionally substituted with halo); CF 3; halo; C 1 –C 4 alkyl; C 1 –C 4 alkoxy; thienyl; —(CH 2 )SO 2 -phenyl; or phenyl optionally substituted with one or two moieties selected from the group consisting of CF 3 , halo, C 1 –C 4 alkoxy, —SO 2 CH 3 , and —CO 2 H.

10. The compound of claim 1 , wherein R 6 is cycloalkyl, aryl, aralkyl or heteroaryl, wherein said cycloalkyl, aryl, aralkyl or heteroaryl is optionally substituted with 1–2 R 12 moieties.

11. The compound of claim 10 , wherein R 6 is cyclohexyl, phenyl, —(CH 2 ) 1-3 -phenyl, or benzothiazolyl, wherein each member of R 6 is optionally substituted with 1–2 R 12 moieties.

12. The compound of claim 11 , wherein R 12 is —OR 13 or —NR 13 R 14 and R 13 is aralkyl.

13. The compound of claim 12 , wherein R 13 is benzyl.

14. The compound of claim 1 , wherein R 1 is —CO 2 R 9 tetrazolyl.

15. The compound of claim 1 , wherein R 1 is —CO 2 H tetrazolyl.

16. The compound of claim 1 , represented by formula II:

17. The compound of claim 16 , wherein R 2 is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1–2 R 12 moieties.

18. The compound of claim 17 , wherein said aryl or heteroaryl is substituted with 1–2 R 12 moieties and one of the R 12 moieties is at the ortho-position.

19. The compound of claim 1 , represented by formula II-a:

20. The compound of claim 1 , represented by formula III:

21. The compound of claim 20 , wherein R 2 is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1–2 R 12 moieties.

22. The compound of claim 21 , wherein said aryl or heteroaryl is substituted with 1–2 R 12 moieties and one of the R 12 moieties is at the ortho-position.

23. The compound of claim 1 selected from Table 1:

TABLE 1

Cpd

Structure

Cpd

Structure

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

24. The compound of claim 23 , wherein the compound is selected from Table 1 compounds 9, 10, 19, 32, 36, 50, 53, 58 and 66.

25. A pharmaceutical composition comprising at least one compound of claim 1 , and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.

26. The pharmaceutical composition of claim 25 , further comprising one or more additional antiviral agent(s).

27. The pharmaceutical composition of claim 26 , wherein said one additional antiviral agent is ribavirin.

28. The pharmaceutical composition of claim 26 , further comprising an interferon or pegylated interferon.

29. The pharmaceutical composition of claim 28 , wherein said additional antiviral agent is ribavirin and said interferon is α-interferon or pegylated interferon.

30. A pharmaceutical composition comprising at least one compound of claim 25 and a pharmaceutically acceptable carrier, adjuvant or vehicle.