Pyridazine derivatives, compositions and methods for treating cognitive impairment

摘要

This invention relates to pyridazine derivatives, compositions comprising therapeutically effective amounts of those pyridazine derivatives and methods of using those derivatives or compositions in treating central nervous system (CNS) disorders with cognitive impairment that are responsive to agonists of α5 subunit containing GABAA receptor, e.g., age-related cognitive impairment, Mild Cognitive Impairment (MCI), dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia and cancer-therapy-related cognitive impairment.

主权项

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, 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 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, —OR3, —NO2, —CN, —CF3, —OCF3, —R3, oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, ═N(R3), ═N(OR3), —N(R3)2, —SR3, —SOR3, —SO2R3, —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: