Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest.

在过去十年中，后期功能化 (LSF) 方法的引入极大地推动了分子合成领域的发展。特别是 C–H 功能化方法为新的逆合成断开奠定了基础，同时促进了资源经济性的提高。各种创新技术已成功应用于药物的 C-H 多样化，这些关键发展使药物化学家能够将 LSF 策略整合到他们的药物发现计划中。这篇综述重点介绍了在药物和类药化合物的后期 C-H 功能化方面取得的重大进展，并展示了这些现代策略的实施如何提高药物发现过程的效率。通过涉及定向或先天 C-H 功能化以及新兴反应流形（例如电合成和生物催化等）的机械模式对代表性示例进行检查和分类。还涵盖了小分子以外的结构复杂的生物活性实体，包括新模式领域的多样化。批判性地评估了当前 LSF 方法的挑战和局限性，并讨论了未来改进这一快速扩展领域的途径。我们在此旨在为学术界的化学家和工业从业者提供一个工具箱，并介绍应用 LSF 策略以获得感兴趣的新分子的指导原则。例如电合成和生物催化等。还涵盖了小分子以外的结构复杂的生物活性实体，包括新模式领域的多样化。批判性地评估了当前 LSF 方法的挑战和局限性，并讨论了未来改进这一快速扩展领域的途径。我们在此旨在为学术界的化学家和工业从业者提供一个工具箱，并介绍应用 LSF 策略以获得感兴趣的新分子的指导原则。例如电合成和生物催化等。还涵盖了小分子以外的结构复杂的生物活性实体，包括新模式领域的多样化。批判性地评估了当前 LSF 方法的挑战和局限性，并讨论了未来改进这一快速扩展领域的途径。我们在此旨在为学术界的化学家和工业从业者提供一个工具箱，并介绍应用 LSF 策略以获得感兴趣的新分子的指导原则。讨论了这个迅速发展的领域未来改进的途径。我们在此旨在为学术界的化学家和工业从业者提供一个工具箱，并介绍应用 LSF 策略以获得感兴趣的新分子的指导原则。讨论了这个迅速发展的领域未来改进的途径。我们在此旨在为学术界的化学家和工业从业者提供一个工具箱，并介绍应用 LSF 策略以获得感兴趣的新分子的指导原则。