Partially Saturated Bicyclic Heteroaromatics as an sp3‐Enriched Fragment Collection. Issue 40 (6th September 2016)

• Record Type: Journal Article
• Authors: Twigg, David G.; Kondo, Noriyasu; Mitchell, Sophie L.; Galloway, Warren R. J. D.; Sore, Hannah F.; Madin, Andrew; Spring, David R.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 40(2016)
• Page Start: 12479
• Page End: 12483
• Publication Date: 2016-09-06
• Subjects: drug design -- drug discovery -- fused-ring systems -- nitrogen heterocycles -- synthetic methods; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201606496
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Fragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp 2 ‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp 3 character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters. Abstract : 2D or not 2D : A collection of partially saturated bicyclic pyridine‐ and pyrazole‐based fragments, derived from a diverse set of readily accessible branch‐point scaffolds, is presented. Their enhanced sp 3 content, compared to typical fragment libraries, allows excellent control of 3D growth vectors in drug development applications.