Late-stage Functionalization for Improving Drug-like Molecular Properties

The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field of organic synthesis. Over the past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for the drug discovery process to become more efficient. Most reported applications of late-stage C–H functionalization of drugs and drug-like molecules have been to rapidly diversify screening libraries to explore structure–activity relationships. However, there has been a growing trend toward the use of LSF methodologies as an efficient tool for improving drug-like molecular properties of promising drug candidates. In this review, we have comprehensively reviewed recent progress in this emerging area. Particular emphasis is placed on case studies where multiple LSF techniques were implemented to generate a library of novel analogues with improved drug-like properties. We have critically analyzed the current scope of LSF strategies to improve drug-like properties and commented on how we believe LSF can transform drug discovery in the future. Overall, we aim to provide a comprehensive survey of LSF techniques as tools for efficiently improving drug-like molecular properties, anticipating its continued uptake in drug discovery programs.