2126
D.-K. Kim et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2122–2127
purified by MPLC on silica gel to afford the titled
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2004, 12, 2013.
compounds 11a–c.
General synthetic procedure for preparation of the 2-
(6-alkylpyridin-2-yl)-1-(quinoxalin-6-yl)ethanones 11d–f.
A stirred solution of pyridine 9a–c (13 mmol) in anhy-
drous THF (100 mL) at À60 ꢁC under Ar atmosphere was
treated dropwise with a solution of n-BuLi in hexanes
(2.0 M, 13 mmol). After 30 min, a solution of Et2AlCl in
hexanes (1.0 M, 14 mmol) was added dropwise to the
reaction mixture, and the reaction mixture was allowed to
warm to room temperature. The reaction mixture was
cooled to À60 ꢁC and transferred via cannula to a stirred
solution of quinoxaline-6-carbonyl chloride (10b)
(10.3 mmol) in anhydrous THF (100 mL) at À60 ꢁC.
Stirring was continued for 20 min, and the reaction
mixture was quenched with saturated aqueous NH4Cl
solution. The mixture was filtered through a pad of Celite,
and the filtered residue was washed with EtOAc (100 mL).
The combined filtrate was concentrated under reduced
pressure, and the residue was purified by MPLC on silica
gel to afford the titled compounds 11d–f as a solid.
General synthetic procedure for preparation of the 2-bromo-
2-(6-alkylpyridin-2-yl)ethanones 12a–f. To
a
stirred
solution of 11a–f (0.78 mmol) in CH2Cl2 at 0 ꢁC was
added N-bromosuccinimide (0.86 mmol), and the mixture
was stirred for an additional 30 min. To the mixture, 5%
aqueous sodium thiosulfate solution (20 mL) was added,
and the mixture was extracted with CH2Cl2 (3· 30 mL).
The CH2Cl2 solution was washed with brine (50 mL),
dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified by
MPLC on silica gel to afford the titled compounds 12a–f
as a solid.
General synthetic procedure for preparation of the 2-amino-
5-(6-alkylpyridin-2-yl)thiazoles 13a–f. A stirred solution
of 12a–f (1.20 mmol) and thiourea (2.52 mmol) in DMF
(6 mL) was heated at 120 ꢁC for 1 h and then cooled to
0 ꢁC. To the mixture, cold water (20 mL) was added, and
the resulting precipitates were collected by filtration and
washed thoroughly with water to afford the titled com-
pounds 13a–f as a powder.
General synthetic procedure for preparation of the 2-
[(cyanophenylmethyl)amino]-5-(pyridin-2-yl)thiazoles 14a–l.
A stirred solution of 13a–f (0.65 mmol), 3- or 4-cyanob-
enzyl bromide (0.78 mmol), and Cs2CO3 (0.85 mmol) in
DMF (16 mL) was heated at 120 ꢁC for 1 h and then
cooled to room temperature and diluted with water
(50 mL). The mixture was extracted with EtOAc
(70 mL), and the EtOAc solution was dried over anhy-
drous Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by MPLC on silica gel
to afford the titled compounds 14a–l as a solid.
17. Moon, J.-A.; Kim, H.-T.; Cho, I.-S.; Sheen, Y. Y.; Kim,
D.-K. Kidney Int. 2006, 70, 1234.
18. Kim, D.-K.; Jang, Y.; Lee, H. S.; Park, H.-J.; Yoo, J.
J. Med. Chem. 2007, 50, 3143.
19. Luo, J.; Ho, P. P.; Buckwalter, M. S.; Hsu, T.; Lee, L. Y.;
Zhang, H.; Kim, D.-K.; Kim, S.-J.; Gambhir, S. S.;
Steinman, L.; Wyss-Coray, T. J. Clin. Invest. 2007, 117,
3306.
20. General synthetic procedure for preparation of the 2-(6-
alkylpyridin-2-yl)-1-(benzo[1,3]dioxol-5-yl)ethanones
11a–c. A stirred solution of pyridine 9a–c (13 mmol) in
anhydrous THF (100 mL) at À60 ꢁC under Ar atmosphere
was treated dropwise with a solution of lithium bis(tri-
methylsilyl)amide in THF (1.0 M, 39 mmol), and then the
solution was transferred via cannula to a stirred solution
General synthetic procedure for preparation of the 2-
[(carboxamidophenylmethyl)amino]-5-(pyridin-2-yl)thia-
zoles 15a–l. To a stirred solution of 14a–l (0.27 mmol) in
MeOH/EtOH/CHCl3 (2:3:2 ratio, 7 mL) were added 1 N
NaOH (0.95 mmol) and 28% H2O2 (1.20 mmol). The
mixture was warmed to 40 ꢁC and stirred overnight, and
to the mixture, 1 N HCl was added to adjust to pH 7 at
0 ꢁC. The mixture was diluted with water and extracted
with CHCl3 (3· 40 mL). The CHCl3 solution was dried
over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified by crystalliza-
tion from hot MeOH/CH2Cl2 to afford the titled com-
pounds 15a–l.
of
methyl
benzo[1,3]dioxole-5-carboxylate
(10a)
(10.3 mmol) in anhydrous THF (100 mL) at À60 ꢁC.
Stirring was continued for 20 min, and the reaction
mixture was quenched with saturated aqueous NH4Cl
solution. The mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was
21. Cellular assays to measure anti-TGF-b activity of ALK5
inhibitors: biological activity of the test compounds was
determined by measuring their ability to inhibit TGF-b-
induced p3TP-luciferase reporter activity, ARE-luciferase
Kim, Dae-Kee
