Compounds that are ERK inhibitors

1. A compound of formula 1.0:

or the pharmaceutically acceptable salts, esters and solvates thereof, wherein:

Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of:

—CH═, and —CR 9 ═;

z is 1 to 3;

Q is a substituent selected from the group consisting of:

Z 2 is selected from the group consisting of: —N(R 44 )—, —O— and —C(R 46 ) 2 —;

m is 1 to 6;

n is 1 to 6;

p is 0 to 6;

t is 0, 1, or 2;

R 1 is selected from the group consisting of:

(1) —CN,

(2) —NO 2 ,

(3) —OR 10 ,

(4) —SR 10

(5) —N(R 10 ) 2 ,

(6) R 10 ,

(7) —C(O)R 10 ,

(8) —(C(R 30 ) 2 ) n —NR 32 —C(O)—R 10 ,

(9)) —(C(R 30 2 ) n —NR 32 —S(O) t —R 10 ,

(10) —(C(R 30 ) 2 ) n —NR 32 —C(O)—N(R 32 )—R 10 ,

(11)

(12) —CF 3 ,

(13) —C(O)OR 10 ,

(14) —(C(R 30 ) 2 ) n R 13 wherein n is 1, each R 30 is H, and R 13 is selected from the group consisting of: —OH and —N(R 10 ) 2 , wherein each R 10 is independently selected,

(15) alkenyl,

(16) —NR 32 —C(O)—R 14 ,

(17)

wherein each R 10 is independently selected,

(18)

wherein each R 10 is independently selected,

(19)

(20) —C(O)—NR 32 —(C(R 30 2 ) p —OR 10 ,

(21) —C(O)N(R 10 ) 2 wherein each R 10 is independently selected,

(22) —C(O)—NR 32 —C(R 18 ) 3 wherein each R 18 is independently selected from the group consisting of: R 10 and —C(O)OR 19 , and R 19 is selected from the group consisting of: alkyl and substituted arylalkyl,

(23) —C(O)—NR 32 —(C(R 30 2 ) n —C(O)—N(R 10 ) 2 ,

(24) heterocycloalkenyl,

(25)

(26) arylalkenyl-;

R 2 is selected from the group consisting of:

(1) H,

(2) —CN,

(3) halo,

(4) alkyl,

(5) substituted alkyl wherein said substituted alkyl is substituted with 1 to 3 substitutents selected from the group consisting of: (a) —OH, (b) —O-alkyl, (c) —O-alkyl substituted with 1 to 3 F atoms, and (d) —N(R 40 ) 2 wherein each R 40 is independently selected from the group consisting of: (i) H, (ii) C 1 -C 3 alkyl, (iii) —CF 3 , and (e) halo,

(6) alkynyl,

(7) alkenyl,

(8) —(CH 2 ) m R 11 ,

(9) —N(R 26 ) 2 ,

(10) —OR 23 ,

(11) —N(R 26 )C(O)R 42 ,

(12) cycloalkyl,

(13) cycloalkylalkyl,

(14)

(15) —O-(substituted alkyl) wherein said substituted alkyl is substituted with 1 to 3 F atoms,

(16) —S(O) t -alkyl,

(17) —C(O)-alkyl,

(18)

(19)

wherein each alkyl is independently selected,

(20)

which each alkyl is independently selected,

(21)

wherein each alkyl is independently selected,

(22) —N(R 48 )—C(O)—R 48 wherein each R 48 is independently selected from the group consisting of: H and alkyl, and

(23) —C(O)-alkyl;

each R 3 , R 4 , R 5 , R 6 and R 7 is independently selected from the group consisting of:

(1) H,

(2) alkenyl,

(3) substituted alkenyl,

(4) alkyl,

(5) substituted alkyl,

(6) cycloalkyl,

(7) substituted cycloalkyl,

(8) cycloalkylalkyl-,

(9) substituted cycloalkylalkyl-,

(10) heterocycloalkyl,

(11) substituted heterocycloalkyl,

(12) heterocycloalkylalkyl-,

(13) substituted heterocycloalkylalkyl-,

(14) —C(O)R 10 ,

(15) arylheteroaryl-,

(16) substituted arylheteroaryl-,

(17) heteroarylaryl-,

(18) substituted heteroarylaryl-,

(19) aryl,

(20) substituted aryl,

(21) heteroaryl,

(22) substituted heteroaryl,

(23) heteroarylheteroaryl-,

(24) substituted heteroarylheteroaryl-,

(25) arylaminoheteroaryl-,

(26) substituted arylaminoheteroaryl-,

(27) arylalkynyl-,

(28) substituted arylalkynyl-,

(29) heteroarylalkynyl-,

(30) substituted heteroarylalkynyl-, and

(31) benzoheteroaryl,

wherein said R 3 , R 4 , R 5 , R 6 and R 7 substituted groups (7), (9), (11), (13), (16), (18), (20), (22), (24), (26), (28) and (30) are substituted with 1 to 3 substituents independently selected from the group consisting of: —NH 2 , —NHR 20 , —N(R 20 ) 2 wherein each R 20 is independently selected, alkyl, alkenyl, halo, —C(O)—NH—R 28 , —C(O)OR 28 , —C(O)R 28 , and —OR 20 , and

wherein said R 3 , R 4 , R 5 , R 6 and R 7 substituted groups (3) and (5) are substituted with 1 to 3 substituents independently selected from the group consisting of: —NH 2 , halo, —C(O)—NH—R 28 , —C(O)OR 28 , and —C(O)R 28 ;

R 5 A is selected from the group consisting of: halo, —OH, alkyl, and —O-alkyl;

R 8 is selected from the group consisting of: H, —OH, —N(R 10 ) 2 , —NR 10 C(O)R 12 , and alkyl;

each R 9 is independently selected from the group consisting of: halogen, —CN, —NO 2 , —OR 10 , —SR 10 , —N(R 10 ) 2 , and R 10 ;

each R 10 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl-, substituted alkylaryl-, heterocycloalkenyl, and substituted heterocycloalkenyl, and wherein:

said R 10 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: —NH 2 , —NHR 20 , —NO 2 , —CN, —OR 26 , halo, —C(O)—NH—R 26 , —C(O)OR 26 , and —C(O)R 26 , and

said R 10 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) —NH 2 , (2) —NO 2 , (3) —CN, (4) —OH, (5) —OR 20 , (6) —OCF 3 , (7) alkyl substituted with 1 to 3 independently selected halo atoms, (8) —C(O)R 38 , (9) alkyl, (10) alkenyl, (11) halo, (12) —C(O)—NH—R 26 , (13) —C(O)OR 38 , (14) —C(O)—NR 32 —(C(R 30 2 ) n —N(R 38 ) 2 , (15) —S(O) t R 38 , (16) —C(O)—NR 32 —R 38 , (17) —NR 32 —C(O)—R 38 , (18)

(19) —NHR 20 , (20) cycloalkyl, (21) —O-alkyl-O—R 20 , (22) hydroxyalkyl, (23) —N(R 20 ) 2 wherein each R 20 is independently selected, (24) -alkyl-OR 20 , (25) —O-alkyl-OH, (26) —NH(hydroxyalkyl), and (27) oxazolidinone;

R 11 is selected from the group consisting of: F, —OH, —CN, —OR 10 , —NHNR 1 R 10 , —SR 10 and heteroaryl;

R 12 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl;

R 14 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-;

R 15 is selected from the group consisting of: H, —OH, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl and heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-;

R 20 represents alkyl;

R 23 is selected from the group consisting of: H, alkyl, aryl, cycloalkyl, and cycloalkylalkyl-;

each R 26 is independently selected from the group consisting of: H and alkyl;

R 28 is alkyl;

each R 30 is independently selected from the group consisting of: H, alkyl, and F;

each R 32 is independently selected from the group consisting of: H and alkyl, and wherein each R 32 is generally H;

each R 35 is independently selected from the group consisting of: H and C 1 to C 6 alkyl;

R 36 is selected from the group consisting of: H, alkyl, and —O-alkyl;

each R 38 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein:

said R 38 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: —NH 2 , —NO 2 , —CN, —OR 26 , halo, —C(O)—NH—R 28 , —C(O)OR 28 , and —C(O)R 28 , and

said R 38 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) —NH 2 , (2) —NO 2 , (3) —CN, (4) —OH, (5) —OR 20 , (6) —OCF 3 , (7) —CF 3 , (8) —C(O)R 26 , (9) alkyl, (10) alkenyl, (11) halo, (12) —C(O)—NH—R 26 , (13) —C(O)OR 26 , (14) —C(O)—NR 32 —(C(R 30 ) 2 ) n —N(R 26 ) 2 , (15) —S(O) t R 26 , (16) —C(O)N(R 32 )(R 26 ), (17) —NR 32 C(O)R 26 ,

(18)

and

(19) —NHR 20 ;

R 42 is selected from the group consisting of: alkyl, aryl, heteroaryl, and cycloalkyl;

R 44 is selected from the group consisting of: H, alkyl, cycloalkyl, and cycloalkylalkyl; and

Each R 46 is independently selected from the group consisting of: H, alkyl, cycloalkyl, and cycloalkylalkyl.

2. The compound of claim 1 having the formula:

3. The compound of claim 1 having the formula:

4. The compound of claim 1 having the formula:

5. The compound of claim 1 wherein Q is selected from the group consisting of: 2.1, and 2.2.

6. The compound of claim 3 wherein Q is selected from the group consisting of: 2.1, and 2.2.

7. The compound of claim 4 wherein Q is selected from the group consisting of: 2.1, and 2.2.

8. The compound of claim 1 wherein Q is 2.17.

9. The compound of claim 3 wherein Q is 2.17.

10. The compound of claim 4 wherein Q is 2.17.

11. The compound of claim 1 wherein each R 3 , R 4 , R 6 , and R 7 is independently selected from the group consisting of: H and alkyl.

12. The compound of claim 11 wherein each R 3 , R 4 , R 6 , and R 7 is independently selected from the group consisting of: H and methyl.

13. The compound of claim 5 wherein each R 3 , R 4 , R 6 , and R 7 is independently selected from the group consisting of: H and alkyl.

14. The compound of claim 13 wherein each R 3 , R 4 , R 6 , and R 7 is independently selected from the group consisting of: H and methyl.

15. The compound of claim 14 wherein each R 3 , R 4 , R 6 , and R 7 is H.

16. The compound of claim 15 wherein Q is 2.1.

17. The compound of claim 1 wherein Q is 2.17.

18. The compound of claim 1 wherein Q is 2.17 wherein each R 3 , R 4 , R 6 , and R 7 is independently selected from the group consisting of: H and methyl.

19. The compound of claim 1 wherein Q is 2.17 wherein each R 3 , R 4 , R 6 , and R 7 is H.

20. The compound of claim 16 wherein the compound of formula 1.0 is:

21. The compound of claim 4 wherein Q is selected from the group consisting of: 2.1, and 2.2 and R 3 , R 4 , R 6 , and R 7 are each independently selected from the group consisting of: H and alkyl.

22. The compound of claim 21 wherein R 3 , R 4 , R 6 , and R 7 are selected from the group consisting of: H and methyl.

23. The compound of claim 22 wherein Q is 2.1.

24. The compound of claim 23 wherein R 3 , R 4 , R 6 , and R 7 are each H.

25. The compound of claim 1 wherein Q is

substituted with one or two substituents independently selected from the group consisting of R 3 groups, provided that said one or two substitutents are not H.

26. The compound of claim 1 wherein Q is

substituted with one or two alkyl groups.

27. The compound of claim 1 wherein Q is

substituted with one or two methyl groups.

28. The compound of claim 1 wherein Q is

substituted with one methyl group.

29. The compound of claim 1 wherein R 1 is selected from the group consisting of:

30. The compound of claim 7 wherein R 1 is selected from the group consisting of:

31. The compound of claim 1 wherein R 1 is aryl.

32. The compound of claim 1 wherein R 1 is heteroaryl or substituted heteroaryl.

33. The compound of claim 1 wherein R 5 is selected from the group consisting of:

34. The compound of claim 7 wherein R 5 is selected from the group consisting of:

35. The compound of claim 1 wherein R 1 is selected from the group consisting of:

R 5 is selected from the group consisting of:

36. The compound of claim 7 wherein R 1 is selected from the group consisting of:

R 5 is selected from the group consisting of:

37. The compound of claim 36 wherein R 1 is

38. The compound of claim 36 wherein R 1 is

39. The compound of claim 36 wherein R 1 is

40. The compound of claim 1 wherein R 2 is selected from the group consisting of:

41. The compound of claim 36 wherein R 2 is selected from the group consisting of:

42. The compound of claim 36 wherein the R 3 , R 4 , R 6 , and R 7 are each independently selected from the group consisting of: H and alkyl.

43. The compound of claim 42 wherein R 3 , R 4 , R 6 , and R 7 are each H.

44. The compound of claim 43 wherein Q is 2.1.

45. The compound of claim 4 wherein Q is 2.17, R 3 , R 4 , R 6 , and R 7 are each independently selected from the group consisting of: H and alkyl, R 1 is selected from the group consisting of:

R 5 is selected from the group consisting of:

46. The compound of claim 1 wherein Q is

47. The compound of claim 1 wherein Q is:

and R 5A is selected from the group consisting of: halo, —OH, alkoxy, and alkyl.

48. The compound of claim 1 wherein Q is selected from the group consisting of:

49. The compound of claim 1 wherein Q is selected from the group consisting of:

50. The compound of claim 1 wherein Q is selected from the group consisting of:

51. The compound of claim 1 wherein R 1 is selected from the group consisting of:

52. The compound of claim 1 wherein R 5 is selected from the group consisting of:

53. The compound of claim 1 wherein:

R 1 is selected from the group consisting of:

R 5 is selected from the group consisting of:

54. The compound of claim 1 wherein R 2 is selected from the group consisting of: —S(O) 2 -alkyl and —S-alkyl.

55. The compound of claim 1 wherein R 2 is selected from the

group consisting of: —SCH 3 and —S(O) 2 CH 3 .

56. The compound of claim 53 wherein R 2 is selected from the group consisting of: —S(O) 2 -alkyl and —S-alkyl.

57. The compound of claim 53 wherein R 2 is selected from the group consisting of: —SCH 3 and —S(O) 2 CH 3 .

58. The compound of claim 53 wherein R 2 is selected from the group consisting of:

59. The compound of claim 1 wherein said compound is a compound of formula 1.0.

60. The compound of claim 1 wherein said compound is a salt of the compound of formula 1.0.

61. The compound of claim 1 selected from the group consisting of:

62. The compound of claim 1 selected from the group consisting of:

63. The compound of claim 1 selected from the group consisting of:

64. The compound of claim 1 selected from the group consisting of:

65. The compound of claim 1 having the formula:

66. The compound of claim 1 having the formula:

67. The compound of claim 1 having the formula:

68. The compound of claim 1 having the formula:

69. The compound of claim 1 having the formula:

70. The compound of claim 1 having the formula:

71. The compound of claim 1 having the formula:

72. The compound of claim 1 having the formula;

73. The compound of claim 1 having the formula

74. The compound of claim 1 having the formula

75. The compound of claim 1 having the formula

76. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.