Generation of Polar Semi‐Saturated Bicyclic Pyrazoles for Fragment‐Based Drug‐Discovery Campaigns.

Abstract

Synthesising polar semi-saturated bicyclic heterocycles can lead to better starting points for fragment-based drug discovery (FBDD) programs. We report the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heteroaromatic able to bind effectively to biological targets, is fused to diverse saturated counterparts. The generated fragments can be further developed either after confirmation of their binding pose or early in the process, as their synthetic intermediates. Essential quality control (QC) for selection of small molecules to add to a fragment library is discussed.

A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi‐Saturated Heterobicyclic Fragments

“…Before adding fragments to our library, it was essential to run a quality control (QC) process, which has been extensively discussed elsewhere, to evaluate their purity, stability, solubility and tendency to aggregate. [6a], Following this analysis, compound 32 , 26 and 36 were discarded, since they failed QC due to aggregation, stability and solubility issues, respectively.…”

“…Increasing the sp 3 ‐content has been demonstrated to lead to an enhanced clinical success, although attention should be paid to three dimensional (3D) character that can lead to increased complexity of ligands, diminishing the probability of binding to biological targets . In this regard, as an extension of our previous work,[6a] we aimed to find a compromise by investigating the synthesis of semi‐saturated bicyclic fragments, where some shape to improve physicochemical properties and to increase the number of possible points of growth is delivered by saturated heterocycles, which are fused to an unsaturated counterpart able to perform key interactions (e.g. H‐bonds) with the biological target.…”

“…As an illustration, they reported an emblematic semi‐saturated bicyclic fragment (dihydroisoquinolinone) synthesized in a few steps from a commercial available staring material and presenting polar functionalities, high sp 3 ‐content and accessible vectors to be grown three dimensionally . Concurrently and subsequently to Rees' work, we and others discussed the importance of designing fragments with higher shape diversity ( sp 3 ‐rich molecules) compared to the current “flat” fragment libraries, which prevent an efficient coverage of the theoretical chemical space …”

N‐Formylsaccharin as a CO Source: Applications and Recent Developments

“…Later, Wyatt and coworkers converted 3-Bromopyrazole derivatives (19) into the corresponding carboxylic acids (20) in good yields by this way (Scheme 11). [32]…”