The remaining acids 54 -57 were coupled to VH032-amine ( ) only using the same conditions to yield amides 61 -64. Next, the azides of 59 -63 were reduced with a suspension of 10% Pd/C in methanol, under an atmosphere of hydrogen gas. To synthesise heterotrivalent PROTACs whose linkers are tethered via a piperazine to the CRBN ligand, thalidomide, we required two masked alcohols in the linker to allow for esterification to JQ1, and also for mesylation and subsequent amination with piperazine substituted thalidomide derivatives (Scheme 4). Gratifyingly, all compounds were able to potently degrade all BET proteins, each showing a preference for BRD4 (long and short isoforms) and BRD3 over BRD2. There was no observed degradation of VHL, however, each compound displayed degradation of CRBN to varying extents at the top treatment concentration of 1 µM, and in some cases also at 100 nM (Figure ). Strikingly, fluorinated compounds which were 5-C tethering to the phthalimide ring were an average of 3-fold more potent at degrading each BET protein when compared to their nonfluorinated 4-C tethered matched pairs (26 vs 23, 27 vs 24, 28 vs 25, and 32 vs 31, respectively, Figure , Table ).