The aim of this work was to synthesize azaspirocyclic derivatives of dihydropyrano[4,3-d]pyrimidine containing aliphatic or aromatic substituents at the second position of the pyrimidine ring. The synthesis was carried out starting from commercially available protected azacyclic ketones by Prins spirocyclization followed by regiospecific condensation with dimethylformamide dimethyl acetal and various amidines. The resulting compound series is characterized by high chemical diversity among the peripheral fragments. The new scaffold appears to be a valuable building block for drug development. The new core advantages were tested in the synthesis of several model compounds with antitubercular potential.