The combination of two privileged motifs, that is, indoline and the constrained peptidomimetic piperazine-2,5-dione, within one tricyclic structure resulted in a scaffold that is abundant in nature but surprisingly scarce in the domain of synthetic bioactive molecules. Utilizing the power of the isocyanide-based Joullié–Ugi reaction followed by postcondensation cyclization, we synthesized such compounds with four elements of diversity in good yields from readily available precursors. The compounds are constrained peptidomimetics distinctly encumbered in a steric sense and have a pronounced three-dimensional character, which is a highly desirable feature in modern drug design.