Glycans control various biological processes depending on their structures. Particularly, core fucose, formed by a1,6-fucosyltransferase (FUT8), has a substantial influence on multiple biological processes. In this study, we investigated the development of FUT8 inhibitors with structural elements encompassing both the glycosyl donor (GDP-fucose) and acceptor (N-glycan) of FUT8. To efficiently optimize the structure of FUT8 inhibitors, we employed a strategy involving fragmentation of the target structure, followed by the structure optimization using diversity-oriented synthesis approaches. This study proposes an efficient strategy to accelerate the structural optimization of middle molecules.