Design and synthesis of 3,7-diarylimidazopyridines as inhibi of the VEGF-receptor KDR Zhicai Wu,* Mark E. Fraley, Mark T. Bilodeau, Mildred L. Kaufman, Edward S. Tasber, Adrienne E. Balitza, George D. Hartman, Kathleen E. Coll, Keith Rickert, Jennifer Shipman, Bin Shi, Laura Sepp-Lorenzino and Kenneth A. Thomas Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA Received 22 October 2003; revised 24 November 2003; accepted 2 December 2003 Abstract—3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solub # 2004 Elsevier Ltd. All rights reserved. Vascular endothelial growth factor (VEGF) is a regu- lator of vascular permeability and an inducer of endo- thelial cell proliferation, migration, and survival. Activation of the VEGF pathway is a fundamental reg- ulation of angiogenesis, the formation of new capillaries from established blood vessels. In principle, anti-VEGF drugs have potential as new therapy for neovascular- ization-related diseases such asdiabetic retinopathy, 1 rheumatoid arthritis, 2 psoriasis, 3 and cancer. 4 As eluci- dated in molecular mechanisms, the mitogenic signal of VEGF is mediated through the receptor tyrosine kinase KDR (VEGFR-2). 5 Accordingly, the signaling pathway can be terminated by inhibitors against VEGF or its receptor KDR.Indeed,antibodies against VEGF 6 and KDR, 7 soluble VEGF decoy-receptors, 8 and small molecule inhibitors of KDR kinase 9 have been shown to be efficacious in in vivo tumor xenograft models. These results have attracted much attention to develop ther- apeutic reagents from anti-VEGF molecules, especially, the small moleculeKDR kinase inhibitors.Several classes ofKDR kinase inhibitors including indolin-2- ones,phthalazines, and quinazolines have entered clin- ical trials. Most recently,bevacizumab, an antibody againstVEGF was shown to significantlyprolong the time to progression of diseasein patientswith metastatic renal-cell cancer. 10 As part of an effort to develop inhibitors of KDR, 3,6- diarylpyrazolo[1,5-a]pyrimidines (1, Chart 1) have been found to be potentinhibitorsof KDR kinase activ- ity. 11,12 Compounds of this series had been hindered by poor physical properties, including low solubility, high logP and high protein binding. To addressthese limitations,an effort was initiated to exploreother templatesincludingbenzimidazoles 2 and imidazo- pyridines 3. Thesecoresare likely replacements for the pyrazolo[1,5-a]pyrimidine core since they share the same key pharmacophore as 1: N-1 is an important hydrogen bond acceptor and the two aryl substituents form crucialhydrophobic interactions. 11 Indeed,1,5- diarylbenzimidazoles have been identified aspotent inhibitors of KDR kinase. 13 In this communication, we report the development of 3,7-diarylimidazopyridines as a new class of KDR inhibitors. Shown in Scheme 1 is the synthesis of the simple dipheny imidazopyridine 3. The protectedaminopyridine 5 was obtained through theCurtius rearrangement of 0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2003.12.007 Bioorganic & Medicinal Chemistry Letters 14 (2004) 909–912 Chart 1. * Corresponding author. Tel.: +1-215-652-6331; fax: +1-215-652- 7310; e-mail: zhicai_wu@merck.com