Pyridazine derivatives, compositions and methods for treating cognitive impairment

1. A method of treating a central nervous system (CNS) disorder with cognitive impairment in a subject in need thereof, comprising the step of administering to said subject a compound of formula I:

a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing,

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 and B are each independently selected from:

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and

(C3-C10)-heterocyclo-;

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 ) 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:

wherein said CNS disorder with cognitive impairment is selected from the group consisting of age-related cognitive impairment, dementia, and Post Traumatic Stress Disorder (PTSD).

2. The method according to claim 1 , wherein said CNS disorder with cognitive impairment is age-related cognitive impairment.

3. The method according to claim 2 , wherein said age-related cognitive impairment is Age-Associated Memory Impairment (AAMI), Mild Cognitive Impairment (MCI) or Age-Related Cognitive Decline (ARCD).

4. The method according to claim 3 , wherein said Age-Related Cognitive Impairment is Mild Cognitive Impairment (MCI).

5. The method according to claim 1 , wherein said CNS disorder with cognitive impairment is dementia.

6. The method according to claim 5 , wherein said dementia is selected from the group consisting of vascular dementia, dementia with Lewy bodies and frontotemporal dementia.

7. The method according to claim 1 , wherein said CNS disorder with cognitive impairment is Post Traumatic Stress Disorder (PTSD).

8. The method of claim 1 , 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 .

9. The method according to claim 1 , 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 ).

10. The method 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 .

11. The method according to claim 1 , 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-.

12. The method according to claim 1 , 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-.

13. The method according to claim 1 , wherein the compound is selected from:

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