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Purine can be considered as the most ubiquitous and functional N-heterocyclic compounds in nature. Structural modifications of natural purines, particularly using isosteric ring systems, have been in the focus of many drug discovery programs. Due to the structural similarity between the pyrazolo[1,5-a][1,3,5]triazine scaffold and the purine system, modifications of this scaffold have given rise to a lot of bioactive agents which could interact with targets of biogenic purines. The present review to the best of our knowledge about synthesis of pyrazolo[1,5-a][1,3,5]triazine scaffold as enzyme inhibitors with therapeutic value.