Nicotinamide biaryl derivatives useful as inhibitors of pde4 isozymes

Abstract

Compounds useful as inhibitors of PDE4 in the treatment of diseases regulated by the activation and degranulation of eosinophils, especially asthma, chronic bronchitis, and chronic obstructuive pulmonary disease, of the formula:where j is 0 or 1 provided that when j is 0, n must be 2; k is 0 or 1; m is 0, 1, or 2; n is 1 or 2; Wis —O—; or —S(═O)—, where t is 0, 1, or 2; or —N(R)—; Wis —O—CRR— or is absent; Y is ═C(R)— or —[N→(O)]— where k is 0 or 1; Rand Rare —H; —F; —CF; —(C-C)alkyl; —(C-C) cycloalkyl; phenyl; or benzyl substituted with 0 to 3 substituents R; or Rand Rare taken together, but only in the case where m is 1, to form a spiro moiety; Rand Rhave the same meaning as Rand Rexcept that one of them must be —H, Rand Rare —H; —F; —Cl; —CN; —NO; —(C-C)alkyl; —(C-C)alkynyl; fluorinated-(C-C)alkyl; —OR; and —C(═O)NRR; Ris —H; —(C-C)alkyl; phenyl; benzyl; or —OR; R, Rand in addition to other meanings may be taken together to form, e.g.,Qis a saturated or unsaturated carbon ring system that is a 3- to 7-membered monocyclic, or that is a 7- to 12-membered, fused polycyclic; provided that Qis not a discontinuous or restricted biaryl moiety as defined under Q; where optionally one carbon atom may be replaced by a heteroatom selected from N, O, and S; where optionally a second carbon atom thereof, and further optionally a third carbon atom thereof may be replaced by N; Qis a discontinuous or restricted biaryl moiety consisting of a saturated or unsaturated carbon ring system that is a 3- to 7-membered monocyclic, or that is a 7- to 12-membered, fused polycyclic; where optionally one carbon atom may be replaced by a heteroatom selected from N, O, and S; where optionally a second carbon atom thereof, and further optionally a third carbon atom thereof may be replaced by N; Z is selected from: