Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity

Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy- 3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM), several additional analogues were prepared. Optimization of the C- 4 anilino group of la led to le, which contains a 2,4-dichloro-5-methoxy-su bstituted aniline. Replacement of the methoxy group at C-7 of le with a 3-( morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c, with other trisubstituted anilines at C-4 were also potent Src inhi bitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or p entoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC50 of 1.2 nM in the Src enzymatic assay , an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor gro wth in xenograft models.