Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors.

A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.