Synthesis of Aryl-fused Bicyclo[3.1.1]heptanes (BCHeps) and Validation as Naphthyl Bioisosteres

While naphthalene rings are often encountered in drugs, candidates and lead molecules, they can be susceptible to cy-tochrome P450-mediated metabolism in biological systems and exhibit flat, sp2-rich structures, limiting their utility in drug-like candidates. Herein, we report the first library of derivatisable aryl-fused Bicyclo[3.1.1]heptanes (BCHeps) as bioisosteric replacements for (β-)naphthalene and other fused bicyclic aromatics. We incorporate the BCHep-based naphthyl isosteres into the AhR antagonist ezutromid and observe geometrically similar exit vectors while reducing Fsp2, and retainment of biological activity while improving metabolic stability towards CYP metabolism, validating these motifs as ‘true’ bioisosteric replacements for meta-substituted arenes and 2-naphthalenes.