successfully in other CRBN-recruiting PROTACs. 30-33 Alongside the linkage vector at the 5-C, we wanted to introduce a fluorine atom ortho to the aniline. A fluorine at the 5/6-position of the phthalimide of thalidomide has been shown to increase both binding affinity to CRBN and to help reduce off-target degradation of neosubstrates, Aiolos (IKZF3) and CK1α. 34 Finally, we chose to make two compounds which would be attached to thalidomide via a piperazine at either the 4-C or 5-C of the phthalimide ring. This basic functionality is commonly used to aid in solubility and has also been widely used in CRBN-recruiting degraders (Table ). 32, 33, 35-37 Table . Second generation heterotrivalent PROTAC library .