The development of novel strained spiro heterocycles (SSHs) as bioisosteres for aromatic or non‐strained aliphatic rings is highly sought after for improving drug design. Their high molecular rigidity and predictable vectorization can enhance drug‐likeness, target selectivity and clinical success. Towards this goal, 1‐oxa‐2,6‐diazaspiro[3.3]heptane (ODASE) is reported as a novel potential SSH‐bioisostere. We demonstrate through theoretical studies the potential of this strained spiro heterocycle to act as a bioisostere for piperazine. We have developed its synthesis from the highly strained azabicyclo[1.1.0]butyl intermediate through a robust and mild flow technology‐assisted two‐step protocol. Its tolerance and stability towards medicinally relevant N‐functionalisation protocols are studied, as well as its mild reduction to the C3‐aminoalkylazetidinol motif found in anti‐cancer drug cobimetinib.

中文翻译：

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1-Oxa-2,6-二氮杂螺[3.3]庚烷作为一种新的潜在哌嗪生物等排体——氮杂双环[1.1.0]丁烷的应变释放的流动辅助制备和衍生化


为了改善药物设计，开发新型应变螺杂环（SSH）作为芳香环或非应变脂肪环的生物等排体受到高度关注。它们的高分子刚性和可预测的矢量化可以增强药物相似性、靶点选择性和临床成功。为了实现这一目标，1-oxa-2,6-diazaspiro[3.3]庚烷（ODASE）被报道为一种新型潜在的 SSH-生物等排体。我们通过理论研究证明了这种应变螺杂环作为哌嗪生物等排体的潜力。我们通过稳健且温和的流动技术辅助的两步方案，从高度紧张的氮杂双环[1.1.0]丁基中间体开发了其合成方法。研究了其对医学相关 N 功能化方案的耐受性和稳定性，以及其对抗癌药物 cobimetinib 中发现的 C3-氨基烷基氮杂环丁醇基序的轻度还原。