The new starting compounds 5a,b 2-(cyanomethyl)-7-(4-fluorophenyl)-5-(heteroyl-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile, which prepared from α,β-unsaturated carbonyl compounds with 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (4) was reacted with each of aromatic aldehydes, and arenediazonium salts to yield a series of novel fluorinated pyrazolo[1,5-a]pyrimidine derivatives. All the new compounds prepared were supported via spectroscopic tools and elemental analyses. The anticancer activity of some selected compounds was examined in vitro against three lines. Among the other prepared compounds, 7i-l are appeared anticancer activity among the other prepared compounds, additionally, compound 7i is more potent anticancer compound of IC50 = 7.84± 0.6, 5.63± 0.4 and 3.71± 0.1 μg/ml against HepG2, MCF7 and HeLa, respectively. Further, using the molecular docking MOE 2014.10 software, compounds 7i, 7j and 7k were docked with the active site of the 1Y8Y enzyme. The results indicated that there are good hydrogen bond interactions between the target compounds and the Lys 129, lys 89, Lys 33, Asp 89, Gly 8, Gly 13, residues in terms of bond lengths and binding energies. Moreover, ADME study was performed for the selected potent anticancer compounds.