Pyridazine derivatives, compositions and methods for treating cognitive impairment

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)NR1R2, or a 5-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and SO2;
• wherein the 5-membered heterocyclic or heteroaryl ring has 0-3 substituents selected independently from J;
• R1 and R2 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 R1 and R2 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 SO2;
• wherein each of R1 and R2 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, —OR3, —NO2, —CN, —CF3, —OCF3, —R3, oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R3)2, —SR3, —SOR3, —SO2 R3, —SO2N(R3)2, —SO3R3, —C(O)R3, —C(O)C(O)R3, —C(O)CH2C(O)R3, —C(S)R3, —C(S)OR3, —C(O)OR3, —C(O)C(O)OR3, —C(O)C(O)N(R3)2, —OC(O)R3, —C(O)N(R3)2, —OC(O)N(R3)2, —C(S)N(R3)2, —(CH2)0-2NHC(O)R3, —N(R3)N(R3)COR3, —N(R3)N(R3)C(O)OR3, —N(R3)N(R3)CON(R3)2, —N(R3)SO2R3, —N(R3)SO2N(R3)2, —N(R3)C(O)OR3, —N(R3)C(O)R3, —N(R3)C(S)R3, —N(R3)C(O)N(R3)2, —N(R3)C(S)N(R3)2, —N(COR3)COR3, —N(OR3)R3, —C(═NH)N(R3)2, —C(O)N(OR3)R3, —C(═NOR3)R3, —OP(O)(OR3)2, —P(O)(R3)2, —P(O)(OR3)2, and —P(O)(H)(OR3);
• each R3 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 R3 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 SO2, 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).