In an attempt to develop novel targeted anticancer agents, a series of novel substituted phthalazine derivatives has been designed and synthesized as inhibitors of vascular endothelial growth factor receptor (VEGFR) kinase enzyme in accordance to SAR studies of known VEGFR inhibitors. The designed compounds incorporated a biarylamide or biarylurea tail linked to a phthalazine scaffold via an amino or ether linkage or else incorporated an N-substituted piperazine motif at position 1 of the phthalazine core. The prepared compounds were evaluated for their enzymatic inhibition of VEGFR-2 kinase. Furthermore, three of the phthalazines bearing a biarylurea (6b, 6e &7b) exhibited excellent broad spectrum cell growth inhibition against NCI full 60 cell panel with GI₅₀ values between 0.15-5μM. In addition, docking studies were performed through docking of the investigated compounds into VEGFR-2 binding site in order to gain further insight into their binding affinities and binding interactions with the VEGFR-2 kinase.