Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity.

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

Addition of benzylic and allylic organozinc and Grignard reagents to resin-bound imines to provide alpha-branched secondary amines bearing a wide variety of functional groups. Utility in the synthesis of beta-3 adrenergic receptor agonists.

Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.