A series of novel 4-azaindolyl-indolyl-maleimides were synthesized and evaluated for their GSK-3beta inhibitory activity. Most compounds exhibited high potency to GSK-3beta. Among them, compound 7c was the most promising GSK-3beta inhibitor. Preliminary structure-activity relationships were discussed based on the experimental data obtained and showed that different substituents on the indole ring and side chains at 1-position of indole had varying degrees of influence on the GSK-3beta inhibitory potency. In a cell-based functional assay, compounds 7c and 15a significantly reduced Abeta-induced Tau hyperphosphorylation by inhibiting GSK-3beta.