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Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities

机译：含四元环的螺环：合成策略和机会

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Four-membered rings are witnessing significant prominence in medicinal chemistry discovery programs. For example, a search of the chemical databases shows exponential increase in their representation, which is found principally in the patent literature as a consequence of the stakeholders involved. The various reports that have documented the benefits accompanying their use in discovery candidates are driving the increased visibility. The range of advantages includes structural novelty along with improved physicochemical and pharmaco-kinetic properties. This has led the scientific community to redesign, improve, or invent strategies for their synthesis, and tactics enabling their incorporation into complex structures. A particular class of structures that is of interest to discovery chemists at present is the spirocyclic modules incorporating a four-membered ring. The advantages of these in particular are clear, as they constitute poorly explored regions of chemical space. Their use affords opportunities for the design of new classes of lead candidates that do not impinge on, infringe, or overlap with the dense regions of intellectual property space that have been intensively populated over the last 5 decades. The crowded structural space that has been mined in the context of work emanating from medicinal chemistry programs relies on a widely used portfolio of fragments, including heterocycles, hetarenes, and arenes. It has been pointed out that the impressive advances of modern medicinal chemistry in the last few decades have been fueled by parallel developments in synthetic chemistry and proteomics, in which metal-mediated coupling reactions hand-in-hand with molecular docking have driven the science. However, with the generalization of screening libraries and database tools, pharmaceutical scientists currently face the challenge of identifying and developing new molecules that may include the same toolbox as their colleagues and competitors, thereby limiting the opportunities for creating truly new entities. The identification of novel building blocks, such as spirocyclic modules, opens new avenues, especially when the search for new structures is intimately coupled to assessment of the attendant molecular properties. The new chemical space generated opens new vistas by offering an expanded toolbox to improve, alter, and modulate physicochemical properties, such as the lipophilicity, the acidity or basicity of embedded groups, aqueous solubility, and stability against metabolic degradation.
机译：在药用化学发现计划中，四元环正处于显着地位。例如，对化学数据库的搜索显示其表示形式呈指数增长，这主要是由于所涉利益相关者在专利文献中发现的。记录了在发现候选物中使用它们带来的好处的各种报告正在推动可见性的提高。优势范围包括结构新颖以及改善的物理化学和药物动力学特性。这导致科学界重新设计，改进或发明了它们的合成策略，以及使它们纳入复杂结构的策略。目前，发现化学家感兴趣的一类特殊结构是掺有四元环的螺环模块。这些优点尤其明显，因为它们构成了化学空间探索不充分的区域。它们的使用为设计新类别的潜在候选人提供了机会，这些候选人不会影响，侵犯或重叠过去五年来密集分布的密集知识产权区域。在药物化学程序产生的工作环境中开采的拥挤的结构空间依赖于广泛使用的片段组合，包括杂环，戊烯和芳烃。已经指出，近几十年来现代药物化学的惊人进步是由合成化学和蛋白质组学的并行发展所推动的，其中金属介导的偶联反应与分子对接的结合推动了科学的发展。但是，随着筛选库和数据库工具的普遍应用，药物科学家目前面临识别和开发可能包含与其同事和竞争对手相同的工具箱的新分子的挑战，从而限制了创建真正新实体的机会。新型结构单元（例如螺环模块）的鉴定开辟了新途径，尤其是当对新结构的搜索与对伴随分子特性的评估紧密相关时。产生的新化学空间通过提供扩展的工具箱来改善，改变和调节物理化学特性（例如亲脂性，嵌入基团的酸度或碱性，水溶性和对代谢降解的稳定性），从而打开了新的视野。

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