Efforts to further explore the influence of phthaloyl ring modifications on neosubstrate binding, degradation, and antiproliferative activity have led several groups to focus on identifying thalidomide analogs with enhanced potency and specificity. Bristol Myers Squibb (BMS)/Celgene's 2 nd generation compounds CC-122, CC-220 and CC-885 were synthesized as part of various focused combinatorial libraries retaining the main CRBN binding pharmacophore glutarimide ring with variations to the solvent exposed ring. CC-122 (Supplemental Information Table ) was synthesized as part of their quinazolinoneglutarimide derivative library. Compared to lenalidomide, CC-122 shows enhanced proteasome dependent degradation of IKZF1 and IKZF3 with broader and enhanced antiproliferative activity across both ABC-and GCB-DLBCL cell lines. CC-220 (Supplemental Information Table ) was synthesized as part of BMS/ Celgene's 4'-arylmethoxy isoindoline-glutarimide library. Studies show CC-220 binds to CRBN with a higher affinity than lenalidomide and pomalidomide in time-resolved fluorescence energy transfer cereblon binding assays and degrades IKZF1 and IKZF3 with greater potency in cell based chemiluminesence substrate degradation assays. CC-885 (Supplemental Information Table ), synthesized as part of BMS/Celgene's 5-substituted isoindoline-glutarimide library , was identified with strong CRBN-dependent antiproliferative activity in a broad range of tumor cell lines, with enhanced antiproliferative activity compared to lenalidomide and pomalidomide in 12 AML cell lines studied.