Journal of Medicinal Chemistry
Article
solvents were removed in vacuo. The solid residue was redissolved in
H2O and the pH was adjusted to 6, using glacial acetic acid. The
precipitate was filtered off, washed with H2O, and dried under vacuum
overnight, affording compound 27f as a solid (183 mg, 0.93 mmol,
60% after 2 steps). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 2.51 (s,
3H, CH3, overlapped with residual solvent signal), 7.02 (d, 1H, J = 8.5
Hz, arom H), 7.39 (d, 1H, J = 8.5 Hz, arom H), 12.73 (br s, 1H, NH),
13.06 (br s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm)
13.40, 115.11, 117.25, 122.52, 146.39, 152.02, 168.83. HRMS (ESI):
m/z [M + H]+ calcd for C7H8N3S2, 198.0160; found, 198.0160.
General Procedure for the Synthesis of Compounds 28a−e.
To a mixture of appropriate 3H-imidazo[4,5-b]pyridine-2-thione 27a−
e (1 mmol) and 2-chloroacetamide 4 (317 mg, 1.3 mmol) in MeOH
(15 mL) was added NaOH (240 mg, 6 mmol). The mixture was
stirred under N2 at room temperature overnight. The solvents were
evaporated, and the crude residue was adsorbed on silica and purified
by flash chromatography on silica. The following compounds were
made according to this procedure
N-(3,4-Dimethoxyphenyl)-2-((5-morpholino-3H-imidazo[4,5-b]-
pyridin-2-yl)thio)acetamide (28a). This compound was prepared
using 27a and was purified using a mixture of cyclohexane and EtOAc
(in a ratio of 6:3), affording the title compound in 23% yield. 1H NMR
(DMSO-d6, 300 MHz): δ (ppm) 3.39 (br s, 4H, 2 × NCH2), 3.7 (br s,
10H, 2 × OCH3, 2 × OCH2), 4.18 (s, 2H, CH2), 6.68 (d, 1H, J = 8.8
Hz, arom H), 6.88 (d, 1H, J = 8.7 Hz, arom H), 7.09 (dd, 1H, J = 8.6
Hz, J = 2.3 Hz, arom H), 7.28 (d, 1H, J = 2.3 Hz, arom H), 7.67 (d,
1H, J = 8.7 Hz, arom H), 10.33 (s, 1H, NH), 12.70 (br s, 1H, NH).
13C NMR (DMSO-d6, 75 MHz): δ (ppm) 35.88, 46.21, 55.32, 55.71,
145.45, 148.27, 148.62, 155.98, 165.79. HRMS (ESI): m/z [M + H]+
calcd for C18H22N5O3S, 388.1443; found, 388.1438.
N-(3,4-Dimethoxyphenyl)-2-((5-(2,2,2-trifluoroethoxy)-3H-
imidazo[4,5-b]pyridin-2-yl)thio)acetamide (28e). This compound
was prepared using 27e and was purified using a mixture of
cyclohexane and EtOAc (in a ratio of 3:7), affording the title
1
compound in 72% yield. H NMR (DMSO-d6, 300 MHz): δ (ppm)
3.71 (s, 6H, 2 × OCH3), 4.24 (s, 2H, CH2), 4.97 (q, 2H, J = 9.2 Hz,
CF3CH2), 6.74 (d, 1H, J = 8.5 Hz, arom H), 6.88 (d, 1H, J = 8.6 Hz,
arom H), 7.09 (d, 1H, J = 8.6 Hz, arom H), 7.29 (d, 1H, J = 1.4 Hz,
arom H), 7.85 (d, 1H, J = 8.4 Hz, arom H), 10.30 (s, 1H, NH), 13.00
(br. s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) 36.01,
55.42, 55.80, 60.91, 61.37, 61.83, 62.30, 104.32, 105.13, 111.09,
111.77, 112.03, 112.21, 122.43, 126.11, 132.58, 145.10, 148.68, 157.39,
165.49. HRMS (ESI): m/z [M + H]+ calcd for C18H18F3N4O4S,
433.1001; found, 433.0995.
N-(3,4-Dimethoxyphenyl)-2-(5-(methylthio)-3H-imidazo[4,5-
b]pyridin-2-ylthio)acetamide (28f). To the compound 27f (15 mg,
0.08 mmol) in a mixture of 1% aq NaOH solution (304 μL) and
EtOH (200 μL), 2-chloroacetamide 4 (18 mg, 0.08 mmol) was added
in one portion. The resulting mixture was stirred overnight at room
temperature. Then volatiles were removed under reduced pressure and
the crude product was purified on preparative TLC (4% of MeOH in
CH2Cl2), affording compound 28f as a yellowish solid (20 mg, 0.05
1
mmol, 63%). H NMR (DMSO-d6, 300 MHz): δ (ppm) 2.54 (s, 3H,
SCH3), 3.72 (s, 6H, 2 × OCH3), 4.26 (s, 2H, CH2), 6.89 (d, 1H, J =
8.7 Hz, arom H), 7.05 (d, 1H, J = 8.4 Hz, arom H), 7.09 (dd, 1H, J =
8.7 Hz, J = 2.4 Hz, arom H), 7.30 (d, 1H, J = 2.4 Hz, arom H), 7.32 (d,
1H, J = 8.4 Hz, arom H), 10.36 (s, 1H, NH), 13.09 (br s, 1H, NH).
13C NMR (DMSO-d6, 75 MHz): δ (ppm) 13.20, 35.77, 55.32, 55.70,
104.21, 110.98, 112.10, 115.11, 132.48, 144.98, 148.56, 151.64, 165.36.
HRMS (ESI): m/z [M − H]− calcd for C17H17N4O3S2, 389.0742;
found, 389.0746.
6-Methoxypyrimidine-2,4-diamine (30a). 6-Chloropyrimidine
29 (1.0 g, 6.92 mmol) was dissolved in anhydrous MeOH (5.8 mL),
and a 30% solution of NaOMe in MeOH (2 mL, 10.67 mmol of
NaOMe) was added. The resulting reaction mixture was refluxed
overnight. After cooling to room temperature, the mixture was
neutralized using a 6 N HCl solution. The solvents were removed
under reduced pressure, and the crude residue was purified by silicagel
flash chromatography, using 5% of MeOH in CH2Cl2 as mobile phase,
affording compound 30a as a white solid (780 mg, 5.57 mmol, 80%).
1H NMR (DMSO-d6, 300 MHz): δ (ppm) 3.67 (s, 3H, OCH3), 5.04
(s, 1H, arom H), 5.89 (br s, 2H, NH2), 6.01 (br s, 2H, NH2). 13C
NMR (DMSO-d6, 75 MHz): δ (ppm) 52.41, 75.83, 162.98, 165.94,
170.44.
6-Ethoxypyrimidine-2,4-diamine (30b). This compound was
synthesized from 6-chloropyrimidine 29 (1.0 g, 6.92 mmol) using
method described for the synthesis of 6-methoxypyrimidine-2,4-
diamine. A solution of NaOEt in EtOH (21% w/w, 3.98 mL, 10.67
mmol of NaOEt) and EtOH (5.8 mL) was used, affording the title
compound as a white powder (1.03 g, 96%). 1H NMR (DMSO-d6, 300
MHz): δ (ppm) 1.22 (t, 3H, J = 7.2 Hz, CH3), 4.13 (q, 2H, J = 7.2 Hz,
CH2), 5.05 (s, 1H, arom H), 5.99 (br s, 2H, NH2), 6.11 (br s, 2H,
NH2). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) 14.67, 60.44, 76.10,
162.45, 165.50, 169.95.
6-Isopropoxypyrimidine-2,4-diamine (30c). To a solution of 6-
chloropyrimidine 29 (500 mg, 3.46 mmol) in i-PrOH (15 mL) was
added NaH (60% in oil, 277 mg, 6.92 mmol of NaH), and the mixture
was refluxed for 60 h. After cooling to room temperature and
neutralization using a 6 N HCl solution, the solvents were removed
under reduced pressure. The crude residue was purified by silicagel
flash chromatography, using a mixture of MeOH and CH2Cl2 as
mobile phase (in a gradient gradually ranging from 2 to 6% of
MeOH), affording compound 30c as a white solid (571 mg, 98%). 1H
NMR (DMSO-d6, 300 MHz): δ (ppm) 1.23 (d, 6H, J = 6.0 Hz, 2 ×
CH3), 5.05−5.15 (m, 2H, CH and arom H), 6.81 (br s, 2H, NH2),
6.87 (br s, 2H, NH2). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) 21.89,
68.20, 76.48, 159.10, 162.45, 169.05. HRMS (ESI): m/z [M + H]+
calcd for C7H13N4O, 169.1089; found, 169.1080.
65.99, 102.49, 104.20, 110.96, 112.12, 125.34, 132.49, 144.98, 147.68,
148.58, 153.94, 155.95, 165.64. HRMS (ESI): m/z [M + H]+ calcd for
C20H24N5O4S, 430.1549; found, 430.1543.
N-(3,4-Dimethoxyphenyl)-2-((5-(4-methylpiperazin-1-yl)-3H-
imidazo[4,5-b]pyridin-2-yl)thio)acetamide (28b). This compound
was prepared using 27b and was purified using a mixture of MeOH
and EtOAc (in a ratio of 7:3), affording the title compound in 23%
1
yield. H NMR (DMSO-d6, 300 MHz): δ (ppm) 2.20 (s, 3H, CH3),
2.40 (s, 4H, 2 × CH3NCH2), 3.70 (s, 6H, 2 × CH3), 4.16 (s, 2H, 2 ×
NCH2), 6.67 (d, 1H, J = 8.8 Hz, arom H), 6.88 (d, 1H, J = 8.7 Hz,
arom H), 7.08 (dd, 1H, J = 8.6 Hz, J = 2.3, arom H), 7.28 (d, 1H, J =
2.2 Hz, arom H), 7.64 (d, 1H, J = 8.8 Hz, arom H), 10.38 (br s, 1H,
NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) 35.91, 45.66, 45.79,
54.44, 55.33, 55.71, 102.62, 104.21, 110.98, 112.12, 124.84, 126.56,
132.52, 144.99, 147.87, 148.59, 150.02, 155.88, 165.72. HRMS (ESI):
m/z [M + H]+ calcd for C21H27N6O3S, 443.1865; found, 443.1857.
N-(3,4-Dimethoxyphenyl)-2-((5-(piperidin-1-yl)-3H-imidazo[4,5-
b]pyridin-2-yl)thio)acetamide (28c). This compound was prepared
using 27c and was purified using a mixture of cyclohexane and EtOAc
(in a ratio of 6:4), affording the title compound in 70% yield. 1H NMR
(DMSO-d6, 300 MHz): δ (ppm) 1.56 (s, 6H, 3 × CH2), 3.46 (s, 4H, 2
× NCH2), 3.70 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.15 (s, 2H,
CH2), 6.66 (d, 1H, J = 8.9 Hz, arom H), 6.88 (d, 1H, J = 8.8 Hz, arom
H), 7.08 (dd, J = 8.6 Hz, J = 2.1 Hz, 1H, arom H), 7.28 (d, 1H, J = 2.3
Hz, arom H), 7.62 (d, 1H, J = 8.5 Hz, arom H), 10.32 (br s, 1H, NH),
12.64 (br s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm)
24.40, 25.06, 36.00, 46.76, 55.41, 55.80, 102.74, 104.27, 111.03,
112.20, 132.58, 145.06, 147.81, 148.66, 155.84, 156.04, 165.30, 165.79.
HRMS (ESI): m/z [M + H]+ calcd for C21H26N5O3S, 428.1756;
found, 428.1748.
N-(3,4-Dimethoxyphenyl)-2-((5-(dimethylamino)-3H-imidazo-
[4,5-b]pyridin-2-yl)thio)acetamide (28d). This compound was
prepared using 27d and was purified using a mixture of cyclohexane
and EtOAc (in a ratio of 1:9), affording the title compound in 43%
1
yield. H NMR (DMSO-d6, 300 MHz): δ (ppm) 3.01(s, 6H, 2 ×
CH3), 3.70 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.15 (s, 2H, CH2),
6.47 (d, 1H, J = 8.8 Hz, arom H), 6.88 (d, 1H, J = 8.8 Hz, arom H),
7.08 (d, 1H, J = 8.4 Hz, arom H), 7.29 (d, 1H, J = 2.4 Hz, arom H),
7.65 (d, 1H, J = 8.6 Hz, arom H), 10.32 (s, 1H, NH), 12.68 (s, 1H,
NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) 35.95, 38.44, 55.34,
55.72, 101.28, 104.22, 110.99, 112.13, 126.53, 127.21, 132.53, 145.01,
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dx.doi.org/10.1021/jm501434y | J. Med. Chem. XXXX, XXX, XXX−XXX