"A3 adenosine receptor is an interesting target that showed controversial roles in cancer. In this work, a structural investigation on the two position of the [1,2,4]triazolo[1,5-c]pyrimidines has been carried out, obtaining potent and selective A3 adenosine receptor antagonists like the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (20, DZ123) that showed a Ki of 0.47 nM and an exceptional selectivity profile against the other adenosine receptor subtypes. Computational studies were able to completely rationalize the affinity and selectivity profile of tested compounds at both A3 adenosine receptor and A1 and A2A adenosine receptors. Compound 20 has been tested on both A3 adenosine receptor positive cancer cell lines (CHO-A3AR transfected, THP1 and HCCT26) and in A3 negative cancer cell lines, showing no effect on the latter and a proliferative effect at a low concentration in the first. These interesting results pave the way to further investigations on both the mechanism involved and the possible therapeutic applications."