VHL ligands, we tried to further optimize them with regard to binding affinity by introducing two additional points of diversity. An (S)-methyl group at the benzylic position was added, as respective VHL-based PROTACs have previously shown improved VHL binding affinity and as a result also better target protein degradation potency. Furthermore, at the LHS terminus, besides the cyano group, an α-fluoro substituent at the cyclopropyl moiety has been employed for PROTAC technology, and the cyano-to-fluoro replacement caused a moderate improvement in binding affinity to VHL. Both structural modifications were considered for our second series of VHL ligands and compounds 2 and 8 were used as starting points for the following structural diversification.