Evaluation of aryl amino-oxetanes as bioisosteres of benzamides and design elements for drug discovery | Poster Board #3163

Bioisosteres represent a powerful tool for medicinal chemists to modulate and improve structural and pharmacokinetic properties of bioactive compounds in the development of pharmaceuticals. Benzamides are an important pharmacophore which is present in over 100 approved drugs. Consequently, bioisosteres thereof are common, but frequently require bespoke synthetic methods. As such, aryl-amino-oxetanes offer promising potential as isosteres due to their comparable polarity, lone pair orientation and previous success to replace ketone functionalities. However, the lack of synthetic methods to access aryl-amino-oxetanes has hampered their use as benzamide isosteres and have thus, rarely been examined.

This poster will describe the synthesis and evaluation of aryl amino-oxetanes as bioisosteres of benzamides through a matched molecular pair (MMP) analysis. The synthesis was achieved through an alternative defluorosulfonylation reaction of bench stable oxetane sulfonyl fluoride reagents and amines. The transformation was employed in the late-stage functionalization of complex amines, synthesis of oxetane analogues of benzamide drugs and application to array chemistry. X-Ray structures and DFT calculations showed amino-oxetanes to adopt a more 3-dimensional conformation than benzamides. Eight MMPs were synthesized and their physiochemical properties compared. The amino-oxetane motif showed a remarkable stability towards acidic and basic conditions and higher aqueous solubility than the amide. Desirable properties such as low LogD and high metabolic stability were maintained, thereby demonstrating the high potential of amino-oxetanes as bioisosteres of benzamides and new design elements for drug discovery.