A series of N-alkylated diaryl pyrazoles has been prepared as inhibitors of Aurora B.  Originally pursued as ErbB+ kinase inhibitors, pyrazolopyridines such as compound 1 were identified as early leads for the Aurora effort.  These compounds displayed good activity against Aurora B in enzymatic and cellular assays.  However, the series suffered from poor developability, which we attributed to high molecular weight and clogP.  In an effort to identify more developable Aurora inhibitors, we have investigated the corresponding pyrazoles, derived from the pyrazolopyridines by removal of the central phenyl ring.  The pyrazoles proved to be excellent Aurora inhibitors, with potent enzymatic and cellular activities, good kinase selectivity and improved developability properties.   This poster will present the various synthetic routes that allowed us to explore the SAR around the pyrazole scaffold.  We will also present the work that allowed us to generate the desired N1-alkyl pyrazole in a regioselective manner on multigram scale.  The in vitro and in vivo data about compound 7  will be presented.

N-Alkylated diaryl pyrazoles: Selective Aurora kinase inhibitors

243rd National Meeting (2012)

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