A series of imines derived from a-aminoglutarimide and alhehydes RCHO was introduced into the In(OTf)3-catalyzed Castagnoli–Cushman reaction with homophthalic anhydrides thus yielding novel glutarimide–tetrahydro-isoquinolone dyads with moderate yields. Carrying out the reaction at room temperature affords isomers with cis-orientation of the R substituent and carboxy group whereas heating to 80 °C promotes conversion into more stable trans-isomers. Some selected compounds were evaluated in vitro, revealing mild or no antiproliferative effects, and tested for cereblon-binding, with the best-performing compound showing an affinity in the range of canonical cereblon ligands.