Pyridinylquinoxalines and pyridinylpyridopyrazines as lead compounds for novel p38 alpha mitogen-activated protein kinase inhibitors.

Various substituted 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines and 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)pyridopyrazines were synthesized as novel p38 alpha MAP kinase inhibitors via different short synthetic strategies with high variation possibilities. The formation of the quinoxaline/pyridopyrazine core was achieved from alpha-diketones and o-phenylenediamines/alpha-diaminopyridines under microwave irradiation. Introduction of an amino moiety at the pyridine C2 position of the 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines led to compounds showing potent enzyme inhibition down to the double-digit nanomolar range (6f; IC(50) = 81 nM). Replacement of the quinoxaline core with pyrido[2,3-b]pyrazine gave compound 9e with superior p38 alpha MAP kinase inhibition (IC(50) = 38 nM).