Phosphatidylinositol 3-kinase α (PI3Kα) is an important regulator of intracellular signaling pathways, controlling remarkably diverse arrays of physiological processes. Because the PI3K pathway is frequently up-regulated in human cancers, the inhibition of PI3Kα can be a promising approach to cancer therapy. In this study, we have designed and synthesized a new series of imidazo[1,2-a]pyridine derivatives as PI3Kα inhibitors through the fragment-growing strategy. By varying groups at the 3- and 6-positions of imidazo[1,2-a]pyridines, we studied the structure-activity relationships (SAR) profiles and identified a series of potent PI3Kα inhibitors. Representative derivatives showed good activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity.