The invention relates to a substituted 3-oxygen pyrazine-2-formamide derivative, as well as the preparation method and the medical application thereof. The derivative adopts the chemical structural general formula (I), wherein, R represents any one component of hydrogen atoms, alkyl, naphthene base, heterocyclic alkyl, aryl, and heteroaryl; R<1> represents any one component of hydrogen, halogen, alkoxy, alkyl, alkyl halide base, acyl, carboxyl, aldehyde group, ester group, amide group, hydroxyl, methoxyl, nitro, amino, substituted amino, nitroso, cyan, sulfur cyan, allyl, and alkynyl; Y represents oxygen, sulfur or nitrogen atoms; R2 represents any one component of various substituted and unsubstituted alkoxyl alkyl with hydroxyl at the end, and substituted alkoxyl alkyl with thymidine monophophosphate ester group, diphosphate ester group, and triphosphate at the end; and substituted alkoxyl alkyl with phosphoryl at the end. The invention has the advantages that through a coupling non-cyclic nucleoside analog into substituted 3-oxygen pyrazine-2-formamide and the phosphorylation thereof, the dissolvability is greatly improved, and the antivirus activity can also be improved greatly.