A concise synthesis of biaryl PDE4D allosteric modulators

The optimization and synthesis of biaryl PDE4D allosteric modulator D159687 was achieved on gram scale via a concise two-step process. The synthesis features sequential chemoselective Suzuki coupling reactions taking advantage of different reactivity profiles of benzyl versus aryl halides. The method was then applied to the synthesis of two additional PDE4D allosteric modulators, D159404 and D159153. The efficient synthesis of these PDE4 allosteric modulators will allow for further biological evaluation of these compounds and the method developed will empower rapid analog formation through combinatorial chemical means.