Journal of Medicinal Chemistry
Article
the biochemical and cell-based assays reported herein may be found in
the Supporting Information.
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jm300438j. Published online: May 16, 2012.
(37) Prior to commencement of our work, a series of related,
imidazolone-containing compounds had been described as JAK3
inhibitors: (a) Inoue, T.; Tanaka, A.; Nakai, K.; Sasaki, H.; Takahashi,
F.; Shirakami, S.; Hatanaka, K.; Nakajima, Y.; Mukoyoshi, K.;
Hamaguchi, H.; Kunikawa, S.; Higashi, Y. Heterocyclic Janus Kinase
3 Inhibitors. WO2007077949, 2007. More recently, during the course
of or after completion of our work, patent applications have appeared
describing other tricyclic azaindole-containing scaffolds as JAK
inhibitors. These include azaindole annelated by pyrrole: (b) Shir-
akami, S.; Nakajima, Y.; Maeda, J.; Tominaga, H.; Yamagishi, H.;
Hondo, T.; Inami, M.; Morio, H.; Inoue, T.; Mizutani, T.; Ishioka, H.
Fused Pyrrolopyridine Derivative. WO2010119875, 2010. Azaindole
annelated by pyrrole, pyrazole, and isoxazole: (c) Wishart, N.;
Argiriadi, M.; Calderwood, D. J.; Ericsson, A. M.; Fiamengo, B. A.;
Frank, K. E.; Friedman, M.; George, D. M.; Goedken, E. R.;
Josephsohn, N. S.; Li, B. C.; Morytko, M. J.; Stewart, K. D.; Voss, J.
W.; Wallace, G. A.; Wang, L.; Woller, K. R. Novel Tricyclic
Compounds. WO2009152133, 2009. Azaindole annelated by
isothiazole, triazole, and imidazole: (d) Wishart, N.; Argiriadi, M.;
Breinlinger, E. C.; Calderwood, D. J.; Ericsson, A. M.; Fiamengo, B. A.;
Frank, K. E.; Friedman, M.; George, D. M.; Goedken, E. R.;
Josephsohn, N. S.; Li, B. C.; Morytko, M. J.; Mullen, K. D.; Somal, G.;
Stewart, K. D.; Voss, J. W.; Wallace, G. A.; Wang, L.; Woller, K. R.
Novel Tricyclic Compounds. WO2011068899, 2011. Tricyclic
systems related to 3 but having distinct substitution on the core and
probably employing an alternative hinge-binding mode have recently
appeared as JAK2 inhibitors: (e) Purandare, A. V.; Grebinski, J. W.;
Hart, A.; Inghrim, J.; Schroeder, G.; Wan, H. JAK2 Inhibitors and
Their Use for the Treatment of Myeloproliferative Diseases and
Cancer. WO2011028864, 2011.
(38) EC50 values for compounds that do not achieve at least 50%
inhibition at the highest concentration tested (10000 nM) in the cell
based assays are considered to be noncalculable and are reported as
>10000 nM. Because of normal run-to-run variability, some weakly
potent compounds achieve >50% inhibition in some, but not all, of the
replicate runs. In these cases, we report EC50 > X, where X is the
arithmetic mean of all the individual EC50 values, both calculable and
noncalculable. For example, compound 3 displayed replicate EC50
Q
dx.doi.org/10.1021/jm300628c | J. Med. Chem. XXXX, XXX, XXX−XXX