Monosubstitution at the R 1 position in compounds 2-5 led to Kd values below 300 nM, with the methyl derivative 2 exhibiting high potency (Kd = 149 nM). Unsurprisingly, R 1 substitution was well tolerated since this vector is a suitable linker attachment point in VHL-addressing PROTACs. Compounds 10-13 with two residues R 1 and R 3 at the positions adjacent to the benzylic moiety were the weakest binders of this series, which might be due to a reduced molecular flexibility. The introduction of R 2 and R 3 para to one another on the phenylene core in 14-17 revealed a disadvantageous effect of the residues' bulkiness, likely due to a steric clash of R 2 with the methylthiazole preventing the optimal dihedral angle for the bioactive conformation. In general, when two substituents (R 1 and R 3 or R 2 and R 3 ) are located on opposite sides of the arene, one would point inside the protein and would potentially clash with amino acid residues that form the pocket. Actually, when comparing 10-17, the difluoro derivative 16 with the smallest substituents was more tolerated than those ligands with larger substituents.