Heterocyclic Merging of Stereochemically Diverse Chiral Piperazines and Morpholines with Indazoles

Abstract

We report a heterocyclic merging approach to construct novel indazolo‐piperazines and indazolo‐morpholines. Starting from chiral diamines and amino alcohols, novel regiochemically (1,3 and 1,4) and stereochemically diverse (relative and absolute) cohorts of indazolo‐piperazines and indazolo‐morpholines were obtained within 6‐7 steps. The key transformations involved are a Smiles rearrangement to generate the indazole core structure and a late stage Michael addition to build the piperazine and morpholine heterocycles. We further explored additional vector diversity by incorporating substitutions on the indazole aromatic ring, generating a total of 20 unique enantiomerically pure heterocyclic scaffolds.

Expanding Complex Morpholines Using Systematic Chemical Diversity

“…Additionally, because all of the compounds are related through their common core scaffold, screening SCD-derived libraries delivers precise structure–activity relationships (SAR), which can be used to guide further optimization of the hits. We have previously documented the application of SCD for generating diverse compounds based on the well-known piperazine scaffold. − Here, we report the synthesis of a collection of morpholines inspired by SCD.…”

“…We elected to extend our previous studies on piperazines − to produce a scaffold family of morpholine-acetic acid esters using SCD. Incorporating the acetic acid moiety into the scaffolds would serve the purposes of facilitating the morpholine ring construction, enhancing solubility for screening, and establishing a handle for further diversification.…”