Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor ‘drug-like’ properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp³)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space.

苯是市售小分子药物中最普遍的结构部分，通常与较差的“类药”特性相关，包括代谢不稳定和水溶性差。为了克服这些限制，药物化学的最新发展表明，富含 C( sp ³ ) 的生物等排支架相对于芳烃具有改善的物理化学特征。在过去的二十年中，我们目睹了获取单取代和对位取代苯的饱和生物等排体的合成方法呈指数增长。然而，直到最近的发现，类似的三维邻位取代和间位取代的生物配体仍然未被充分探索，因为它们的环应变和增加的s特征杂交。本综述总结了获取此类饱和基序的新兴合成方法及其对邻位取代、间位取代和多取代苯环生物等排体应用的影响。最后展望了下一代生物等排体的发展，包括新型化学空间内的生物等排体。