coupled with 3718 to give the final product 12. Alternatively,
amide coupling can be performed by treatment of 36 with
trimethyl aluminum, followed by the addition of ester 3815 at
90oC. The resulting bis-sulfonamide is then de-protected in
aqueous potassium carbonate-methanol at 60oC to give 12.
Scheme 1. Preparation of imidazopyridines: (a) 20% aq. ammonium sulfide, MeOH, reflux, 100%; (b) PhCO2H, POCl3, reflux, 43%; (c) zinc/NH4Cl,
EtOH/water, 60%; (d) EDCI, HOBT, DMF, 30-60%; (e) Me3Al, toluene, 90oC then 2M aqueous K2CO3, methanol, 60oC, 25%.
We have prepared a series of imidazo[4,5-b]pyridine B-Raf
inhibitors with excellent potency and selectivity. X-Ray
D.; Marais, R.; Springer, C.J. Bioorg. Med. Chem. Lett. 2012, 22, 789. (c)
August 7th, 2013.
analysis of compound 4 shows the imidazo core forming contacts
with the hinge binding region of B-Raf, consistent with what has
been observed with related series of inhibitors. Probing into the
exterior of the ATP-cleft with this series led to 23, a potent and
selective inhibitor. Further progress of these compounds will be
reported in due course.
7
Wenglowsky, S., Ren, L.; Ahrendt, K. A.; Laird, E. R.; Aliagas, I.; Alicke,
B.; Buckmelter, A. J.; Choo, E. F.; Dinkel, V.; Feng, B.; Gloor, S. L.; Gould,
S. E.; Gross, S.; Gunzner-Toste, J.; Hansen, J. D.; Hatzivassiliou, G.; Liu, B.;
Malesky. K.; Mathieu, S.; Newhouse, B.; Raddatz, N. J.; Ran, Y.; Rana, S.;
Randolph, N.; Risom, T.; Rudolph, J.; Savage, S.; Selby, L. T.; Shrag, M.;
Song, K.; Sturgis, H. L.; Voegtli, W. C.; Wen. Z.; Willis, B. S.; Woessner, R.
D.; Wu, W.-I.; Young, W. B.; Grina, J. ACS Med. Chem. Lett. 2011, 2, 342.
8
Acknowledgment
Wenglowsky, S., Ahrendt, K. A.; Buckmelter, A. J.; Feng, B.; L Gloor, S.
L.; Gradl, S.; Grina, J.; Hansen, J. D.; Laird, E. R.; Lunghofer, P.; Mathieu,
S.; Moreno, D.; Newhouse, B.; Ren, L.; Risom, T.; Rudolph, J.; Seo, J.;
Sturgis, H. L.; Voegtli, W. C.; Wen. Z. Bioorg. Med. Chem. Lett. 2011, 21,
5533.
Ren, L.; Laird, E.R.; Buckmelter, A.J.; Dinkel, V.; Gloor, S.L.; Grina, J.;
Newhouse, B.; Rasor, K.; Hastings, G.; Gradl, S.; Rudolph, J. Bioorg. Med.
The authors would like to thank Susan Rhodes and Karin Brown
for microsome and hepatocyte stability determinations; Jaimie
Rogan for follow up permeability studies, and Matty Martinson
and Kevin Rasor for follow up enzyme and cell assay studies.
9
Chem. Lett. 2012, 22, 1165.
(a) Tung, Y-S; Coumar, M.S.; Wu, Y-S.; Chang, J-J.; Liou, J-P.; Shukla,
10
References and notes
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