Immunomodulatory drugs, functioning as cereblon (CRBN) E3 ligase ligands, have been approved for treating various hematological malignancies by hijacking the function of CRBN E3 ligase and inducing the degradation of multiple CRBN-associated substrates. However, the inevitable emergence of drug resistance, resulting from their skeletal similarity, and hematological toxicities pose significant obstacles to their clinical effectiveness. In this study, we report the development of a series of novel CRBN binding moieties, envisioned as a simple deletion of the methylene in isoindole cores of lenalidomide.