5-Substituted-8-methyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione and its anilines, amino pyridines and hydrazides derivatives were prepared in a good to excellent yields. In the first step 8-methyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione (1) was prepared by reacting 4-methyl-2-aminopyridine, with diethylmalonate. Compounds substituted pyrido[1,2-a]pyrimidine-2,4(3H)-diones (PPMDO) (2)–(17) were prepared by condensing 8-methyl-2H-pyrido[1,2-a] pyrimidine-2,4(3H)-dione in the presence of triethylorthoformte (TEF) and dimethylformamide (DMF), with respective amino components viz. 2-aminoacetophenone, 3-aminoacetophenone, 4-aminoacetophenone, 2,4,6-trimethylaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, 2-aminothiophenol, 2-amino-4-methylpyridine, 2-amino-5-methylpyridine, 2-amino-5-nitropyridine, Benzoic hydrazide, 4-nitrobenzoic hydrazide, 4-bromobenzoic hydrazide, 4-chlorobenzoic hydrazide and 4-hydroxybenzoic hydrazide, respectively. The chemical structures of all the compounds were elucidated by IR, 1 H-NMR, 13C-NMR and elemental analysis data. The synthesized compounds were screened for their in vitro urease inhibition activity, by the phenol hypochlorite method. These compounds were found to exhibit either no or low to moderate or significant activity. The compounds (9) and (14) showed comparatively much higher activity. However, the compound (9) was found to be the most active one.