Pyridazine derivatives, compositions and methods for treating cognitive impairment

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R′ is —C(O)NR 1 R 2 or a 5-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein the 5-membered heterocyclic or heteroaryl ring has 0-3 substituents selected independently from J;

R 1 and R 2 are independently selected from:

H—,

(C1-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and (C3-C10)-heterocyclo-;

or R 1 and R 2 may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0-3 substituents independently selected from J, and having 0-3 additional heteroatoms independently selected from N, O, S, SO, or SO 2 ;

wherein each of R 1 and R 2 is independently substituted at each substitutable position with 0-3 substituents independently selected from J;

R is H, halogen or (C1-C12)-aliphatic-, wherein said (C1-C12)-aliphatic group is substituted with 0-3 substituents independently selected from J;

A is (C6-C10)-aryl- or (C5-C10)-heteroaryl;

B is (C6-C10)-aryl-;

wherein A and B are each independently substituted with 0-5 substituents independently selected from J;

each J is independently selected from:

halogen, —OR 3 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 3 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, ═N(R 3 ), ═N(OR 3 ), —N(R 3 ) 2 , —SR 3 , —SOR 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —SO 3 R 3 , —C(O)R 3 , —C(O)C(O)R 3 , —C(O)CH 2 C(O)R 3 , —C(S)R 3 , —C(S)OR 3 , —C(O)OR 3 , —C(O)C(O)OR 3 , —C(O)C(O)N(R 3 ) 2 , —OC(O)R 3 , —C(O)N(R 3 ) 2 , —OC(O)N(R 3 ) 2 , —C(S)N(R 3 ) 2 , —(CH 2 ) 0-2 NHC(O)R 3 , —N(R 3 )N(R 3 )COR 3 , —N(R 3 )N(R 3 )C(O)OR 3 , —N(R 3 )N(R 3 )CON(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —N(R 3 )SO 2 N(R 3 ) 2 , —N(R 3 )C(O)OR 3 , —N(R 3 )C(O)R 3 , —N(R 3 )C(S)R 3 , —N(R 3 )C(O)N(R 3 ) 2 , —N(R 3 )C(S)N(R 3 ) 2 , —N(COR 3 )COR 3 , —N(OR 3 )R 3 , —C(═NH)N(R 3 ) 2 , —C(O)N(OR 3 )R 3 , —C(═NOR 3 )R 3 , —OP(O)(OR 3 ) 2 , —P(O)(R 3 ) 2 , —P(O)(OR 3 ) 2 , and —P(O)(H)(OR 3 );

each R 3 is independently selected from:

H—,

(C1-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,

(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,

(C3-C10)-heterocyclyl-,

(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,

(C5-C10)-heteroaryl-, and

(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;

or two R 3 groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1-3 heteroatoms independently selected from N, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl;

provided that said compound of formula I is not:

2. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R′ is —C(O)NR 1 R 2 wherein

R 1 and R 2 are each independently selected from:

H—,

(C1-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and (C3-C10)-hetero-;

or R 1 and R 2 may be taken together with the nitrogen atom to which they are attached form a 3- to 10-membered aromatic or non-aromatic ring having 0-3 additional heteroatoms independently selected from N, O, S, SO, or SO 2 ;

wherein each of R 1 and R 2 is independently substituted at each substitutable position with 0-3 substituents independently selected from J;

or R′ is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein the 5-membered heteroaryl ring has 0-2 substituents selected independently from J;

R is H, halogen or (C1-C12)-aliphatic-, wherein said (C1-C12)-aliphatic group is substituted with 0-3 substituents independently selected from J;

A is (C6-C10)-aryl- or (C5-C10)-heteroaryl;

B is (C6-C10)-aryl-;

wherein A and B are each independently substituted with 0-5 substituents independently selected from J;

each J is independently selected from:

halogen, —OR 3 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 3 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, ═N(R 3 ), ═N(OR 3 ), —N(R 3 ) 2 , —SR 3 , —SOR 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —SO 3 R 3 , —C(O)R 3 , —C(O)C(O)R 3 , —C(O)CH 2 C(O)R 3 , —C(S)R 3 , —C(S)OR 3 , —C(O)OR 3 , —C(O)C(O)OR 3 , —C(O)C(O)N(R 3 ) 2 , —OC(O)R 3 , —C(O)N(R 3 ) 2 , —OC(O)N(R 3 ) 2 , —C(S)N(R 3 ) 2 , —(CH 2 ) 0-2 NHC(O)R 3 , —N(R 3 )N(R 3 )COR 3 , —N(R 3 )N(R 3 )C(O)OR 3 , —N(R 3 )N(R 3 )CON(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —N(R 3 )SO 2 N(R 3 ) 2 , —N(R 3 )C(O)OR 3 , —N(R 3 )C(O)R 3 , —N(R 3 )C(S)R 3 , —N(R 3 )C(O)N(R 3 ) 2 , —N(R 3 )C(S)N(R 3 ) 2 , —N(COR 3 )COR 3 , —N(OR 3 )R 3 , —C(═NH)N(R 3 ) 2 , —C(O)N(OR 3 )R 3 , —C(═NOR 3 )R 3 , —OP(O)(OR 3 ) 2 , —P(O)(R 3 ) 2 , —P(O)(OR 3 ) 2 , and —P(O)(H)(OR 3 );

each R 3 is independently selected from:

H—,

(C1-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,

(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,

(C3-C10)-heterocyclyl-,

(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,

(C5-C10)-heteroaryl-, and

(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;

or two R 3 groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1-3 heteroatoms independently selected from N, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl;

provided that said compound of formula I is not:

3. The compound according to claim 1 or 2 , wherein the compound has the Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R, A and B are as defined in claim 1 or 2 .

4. The compound according to claim 3 , wherein at least one of R 1 and R 2 is hydrogen.

5. The compound according to claim 4 , wherein R 1 and R 2 are each independently hydrogen.

6. The compound according to claim 3 , wherein at least one of R 1 and R 2 is (C1-C12)-aliphatic- substituted at each substitutable position with 0-3 substituents independently selected from J.

7. The compound according to claim 6 , wherein R 1 and R 2 are each independently (C1-C12)-aliphatic- substituted at each substitutable position with 0-3 substituents independently selected from J.

8. The compound according to claim 7 , wherein R 1 and R 2 are each independently unsubstituted (C1-C4)-aliphatic.

9. The compound according to claim 8 , wherein R 1 and R 2 are each independently methyl, ethyl or allyl.

10. The compound according to claim 7 , wherein R 1 and R 2 are each independently (C1-C4)-alkyl, and wherein at least one of R 1 and R 2 is substituted with at least one (C6-C10)-aryl.

11. The compound according to claim 10 , wherein R 1 and R 2 are each independently substituted with at least one (C6-C10)-aryl.

12. The compound according to claim 10 or 11 , wherein the at least one (C6-C10)-aryl is phenyl.

13. The compound according to claim 6 , wherein R 1 is H— and R 2 is (C1-C12)-aliphatic-substituted at each substitutable position with 0-3 substituents independently selected from J.

14. The compound according to claim 13 , wherein R 2 is unsubstituted (C1-C4)-alkyl.

15. The compound according to claim 14 , wherein R 2 is methyl or isopropyl.

16. The compound according to claim 13 , wherein R 2 is substituted with at least one (C6-C10)-aryl.

17. The compound according to claim 16 , wherein the at least one (C6-C10)-aryl is phenyl.

18. The compound according to claim 3 , wherein R 1 and R 2 taken together with the atom to which they are attached form a C5-C10 aromatic or non-aromatic ring.

19. The compound according to claim 18 , wherein R 1 and R 2 taken together with the atom to which they are attached form a pyrrolidine ring.

20. The compound according to claim 1 or 2 , wherein the compound has the Formula I-B:

or a pharmaceutically acceptable salt thereof, and

wherein:

X is selected from —N(R 4 )—, —O—, and —S—;

Y is —CR 4 — or —N═;

Z is —CR 4 — or —N═; and

R 4 and R 5 are each independently selected from:

halogen, —OR 3 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 3 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, ═N(R 3 ), ═N(OR 3 ), —N(R 3 ) 2 , —SR 3 , —SOR 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —SO 3 R 3 , —C(O)R 3 , —C(O)C(O)R 3 , —C(O)CH 2 C(O)R 3 , —C(S)R 3 , —C(S)OR 3 , —C(O)OR 3 , —C(O)C(O)OR 3 , —C(O)C(O)N(R 3 ) 2 , —OC(O)R 3 , —C(O)N(R 3 ) 2 , —OC(O)N(R 3 ) 2 , —C(S)N(R 3 ) 2 , —(CH 2 ) 0-2 NHC(O)R 3 , —N(R 3 )N(R 3 )COR 3 , —N(R 3 )N(R 3 )C(O)OR 3 , —N(R 3 )N(R 3 )CON(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —N(R 3 )SO 2 N(R 3 ) 2 , —N(R 3 )C(O)OR 3 , —N(R 3 )C(O)R 3 , —N(R 3 )C(S)R 3 , —N(R 3 )C(O)N(R 3 ) 2 , —N(R 3 )C(S)N(R 3 ) 2 , —N(COR 3 )COR 3 , —N(OR 3 )R 3 , —C(═NH)N(R 3 ) 2 , —C(O)N(OR 3 )R 3 , —C(═NOR 3 )R 3 , —OP(O)(OR 3 ) 2 , —P(O)(R 3 ) 2 , —P(O)(OR 3 ) 2 , and —P(O)(H)(OR 3 ).

21. The compound according to claim 20 , wherein X is —O—.

22. The compound according to claim 20 , wherein Z is —N═.

23. The compound according to claim 20 , wherein X is —O— and Z is —N═.

24. The compound according to claim 20 , wherein Y is —CR 4 — and R 4 is H or (C1-C12)-aliphatic.

25. The compound according to claim 24 , wherein R 4 is H.

26. The compound according to claim 24 , wherein R 4 is (C1-C4)-alkyl-.

27. The compound according to claim 20 , wherein R 5 is (C1-C12)-aliphatic- or —C(O)OR 3 .

28. The compound according to claim 27 , wherein R 5 is (C1-C4)-alkyl-.

29. The compound according to claim 28 , wherein R 5 is methyl or ethyl.

30. The compound according to claim 27 , wherein R 5 is —C(O)OR 3 , wherein R 3 is (C1-C12)-aliphatic-.

31. The compound according to claim 30 , wherein R 3 is (C1-C4)-alkyl-.

32. The compound according to claim 31 , wherein R 3 is methyl.

33. The compound according to claim 20 , wherein X is —O—, Z is —N═, Y is —CR 4 — or —N═, and R 5 is (C1-C12)-aliphatic- or —C(O)OR 3 .

34. The compound according to claim 1 , wherein the compound has the Formula I-D:

or a pharmaceutically acceptable salt thereof;

wherein:

X, and Y are independently selected from —C(R 4 ) 2 —, —N(R 4 )—, —O—, and —S—;

Z is —N═; and

each of R 4 and R 5 are independently selected from:

halogen, —OR 3 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 3 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, ═N(R 3 ), ═N(OR 3 ), —N(R 3 ) 2 , —SR 3 , —SOR 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —SO 3 R 3 , —C(O)R 3 , —C(O)C(O)R 3 , —C(O)CH 2 C(O)R 3 , —C(S)R 3 , —C(S)OR 3 , —C(O)OR 3 , —C(O)C(O)OR 3 , —C(O)C(O)N(R 3 ) 2 , —OC(O)R 3 , —C(O)N(R 3 ) 2 , —OC(O)N(R 3 ) 2 , —C(S)N(R 3 ) 2 , —(CH 2 ) 0-2 NHC(O)R 3 , —N(R 3 )N(R 3 )COR 3 , —N(R 3 )N(R 3 )C(O)OR 3 , —N(R 3 )N(R 3 )CON(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —N(R 3 )SO 2 N(R 3 ) 2 , —N(R 3 )C(O)OR 3 , —N(R 3 )C(O)R 3 , —N(R 3 )C(S)R 3 , —N(R 3 )C(O)N(R 3 ) 2 , —N(R 3 )C(S)N(R 3 ) 2 , —N(COR 3 )COR 3 , —N(OR 3 )R 3 , —C(═NH)N(R 3 ) 2 , —C(O)N(OR 3 )R 3 , —C(═NOR 3 )R 3 , —OP(O)(OR 3 ) 2 , —P(O)(R 3 ) 2 , —P(O)(OR 3 ) 2 , and —P(O)(H)(OR 3 );

and A, B and R are as defined in claim 1 .

35. The compound according to claim 34 , wherein X is —O—.

36. The compound according to claim 34 , wherein Y is —C(R 4 ) 2 —.

37. The compound according to claim 36 , wherein at least one R 4 is H or (C1-C12)-aliphatic.

38. The compound according to claim 37 , wherein each is independently R 4 are H.

39. The compound according to claim 37 , wherein at least one R 4 is (C1-C4)-alkyl-.

40. The compound according to claim 34 , wherein R 5 is (C1-C12)-aliphatic- or —C(O)OR 3 .

41. The compound according to claim 40 , wherein R 5 is (C1-C4)-alkyl-.

42. The compound according to claim 41 , wherein R 5 is methyl or ethyl.

43. The compound according to claim 40 , wherein R 5 is —C(O)OR 3 and R 3 is (C1-C12)-aliphatic-.

44. The compound according to claim 43 , wherein R 3 is (C1-C4)-alkyl-.

45. The compound according to claim 44 , wherein R 3 is methyl.

46. The compound according to claim 34 , wherein X is —O—, Z is —N═, Y is —C(R 4 ) 2 —, and R 5 is (C1-C12)-aliphatic- or —C(O)OR 3 .

47. The compound according to claim 1 or 2 , wherein A is (C6-C10)-aryl- or (C5-C10)-heteroaryl-, each of said aryl or heteroaryl being optionally and independently substituted with 1 to 5 substituents independently selected from J.

48. The compound according to claim 47 , wherein A is phenyl, optionally substituted with 1 to 5 substituents independently selected from J.

49. The compound according to claim 48 , wherein the phenyl is unsubstituted or substituted with at least one halogen or —OR 3 .

50. The compound according to claim 49 , wherein the phenyl is substituted with at least one F, Cl, or —OCH 3 .

51. The compound according to claim 47 , wherein A is a 5-membered or 6-membered heteroaryl optionally substituted with 1 to 5 substituents independently selected from J.

52. The compound according to claim 51 , wherein the heteroaryl is pyrazolyl or pyridyl.

53. The compound according to claim 52 , wherein the heteroaryl is unsubstituted or substituted with at least one (C1-C12)-aliphatic group.

54. The compound according to claim 53 , wherein the heteroaryl is substituted with at least one —CH 3 .

55. The compound according to claim 1 or 2 , wherein B is (C6-C10)-aryl-, optionally substituted with 1 to 5 substituents independently selected from J.

56. The compound according to claim 55 , wherein B is phenyl optionally substituted with 1 to 5 substituents independently selected from J.

57. The compound according to claim 56 , wherein A is phenyl, pyrazolyl or pyridyl, optionally substituted with 1 to 3 substituents independently selected from J.

58. The compound according to claim 1 or 2 , wherein:

B is phenyl;

A is phenyl, pyrazolyl or pyridyl, substituted with 0-2 substituents independently selected from —OR 3 wherein R 3 is (C1-C4)alkyl-, halogen and (C1-C4)alkyl-;

R is hydrogen;

R′ is selected from the group consisting of:

(1) —C(O)NR 1 R 2 , wherein

R 1 and R 2 are each independently unsubstituted (C1-C4)-aliphatic-,

or R 1 and R 2 are each independently (C1-C4)-alkyl, wherein at least one of R 1 and R 2 is substituted with at least one phenyl,

or R 1 is H, and R 2 is unsubstituted (C1-C4)-alkyl,

or R 1 and R 2 taken together with the nitrogen atom to which they are bound form a 5-membered non-aromatic ring; and

(2) a 5-membered heterocyclic or heteroaryl ring having one nitrogen atom and one oxygen atom, wherein the 5-membered heterocyclic or heteroaryl ring has 0-2 substituents selected independently from (C1-C4)-alkyl- and —C(O)OR 3 wherein R 3 is (C1-C4)alkyl-.

59. The compound according to claim 1 or 2 , wherein:

B is phenyl;

A is phenyl substituted with 0 or 1 substituent selected from —OR 3 wherein R 3 is (C1-C4)alkyl-, and halogen;

R is hydrogen;

R′ is selected from the group consisting of:

(1) —C(O)NR 1 R 2 , wherein

R 1 and R 2 are each independently (C1-C4)-alkyl-,

or R 1 and R 2 are each independently (C1-C4)-alkyl, wherein at least one of R 1 and R 2 is substituted with one phenyl,

or R 1 is H, and R 2 is (C1-C4)-alkyl; and

(2) a 5-membered heterocyclic or heteroaryl ring having one nitrogen atom and one oxygen atom, wherein the 5-membered heterocyclic or heteroaryl ring has 1 substituent selected from (C1-C4)-alkyl- and —C(O)OR 3 wherein R 3 (C1-C4)alkyl-.

60. The compound according to claim 1 or 2 , wherein the compound is selected from:

Compound

Structure

 1

 2

 4

 5

 7

 8

 9

10

12

14

16

18

19

20

21

22

23

24

25

26

27

28

29

30

61. A pharmaceutical composition comprising a compound according to any one of claims 1 - 60 or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.