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BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring

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    BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring
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    † Cancer Research UK Centre of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom
    ‡ Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom
    *To whom correspondence should be addressed. Phone: +44 20 87224214. Fax: +44 20 8722 4046. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2010, 53, 5, 1964–1978
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    https://doi.org/10.1021/jm901509a
    Published February 11, 2010
    Copyright © 2010 American Chemical Society
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    Abstract

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    We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A−B−C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

    Copyright © 2010 American Chemical Society

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    Experimental details of the synthesis of compounds 14−30, 32−35, 37−66, 68−77, 79−82, and 84−89 and intermediates; analytical characterization of all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 18 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2010, 53, 5, 1964–1978
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm901509a
    Published February 11, 2010
    Copyright © 2010 American Chemical Society
    Request reuse permissions

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