2730
C. H. Jin et al. / Bioorg. Med. Chem. 22 (2014) 2724–2732
148.1, 149.6, 154.1, 158.8, 166.5; HRMS-ESI: m/z [M+H]+ calcd for
24H19N8O: 435.1676, found 435.1686.
mixture was neutralized with 1 N HCl to pH 7–8. The mixture
was extracted with CH2Cl2 (3 ꢁ 20 mL), and the combined organic
extracts were washed with water (20 mL) and brine (20 mL). The
CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using MeOH/CH2Cl2 (1:10) as eluent
to afford the titled compound as a yellow solid. Yield 25%; mp 177–
179 °C; purity by HPLC: 98.8% (13% acetonitrile); IR (KBr) 3351,
C
4.1.6. N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-methyl
pyridin-2-yl)-1H-imidazol-2-yl)methyl)benzothioamide (15a)
A stirred mixture of 14a (0.16 mmol), Lawesson’s reagent
(0.16 mmol), and anhydrous DME (5 mL) in a dry sealed tube
was heated at 85 °C for 12 h. After cooled to room temperature,
the solvent was evaporated to dryness under reduced pressure,
and the residue was purified by MPLC on silica gel using MeOH/
CH2Cl2 (1:20) as eluent to give the titled compound as a white so-
lid. Yield 92%; mp 232–234 °C; purity by HPLC: 99.1% (25% aceto-
nitrile); IR (KBr) 3199, 3072, 2971, 1594, 1252, 1181 cmꢂ1; 1H NMR
(400 MHz, CDCl3) d 2.57 (s, 3H), 5.23 (d, 2H, J = 5.6 Hz), 7.04 (d, 1H,
J = 8.0 Hz), 7.18 (d, 1H, J = 7.6 Hz), 7.34 (t, 2H, J = 7.8 Hz), 7.41–7.45
(m, 1H), 7.46 (t, 1H, overlapped, J = 7.8 Hz), 7.67 (dd, 1H, J = 9.2,
1.6 Hz), 7.71 (d, 1H, J = 9.2 Hz), 7.81 (d, 2H, J = 7.6 Hz), 8.35 (s,
1H), 8.90 (br s, 1H), 9.31 (br s, 1H); 13C NMR (100 MHz, CDCl3) d
24.1, 43.0, 116.7, 118.5, 120.3, 123.0, 127.4 (2C), 128.3, 128.6
(2C), 129.0, 131.1, 131.9, 138.1, 140.2, 141.4, 145.3, 147.1, 150.0,
154.7, 158.7, 200.4; HRMS-ESI: m/z [M+H]+ calcd for C23H20N7S:
426.1495, found 426.1514.
3132, 2917, 1677, 1542 cmꢂ1 1H NMR (400 MHz, CDCl3/CD3OD)
;
d 2.53 (s, 3H), 4.66 (s, 2H), 7.04 (d, 1H, J = 8.0 Hz), 7.12 (br d, 1H,
J = 7.6 Hz), 7.48 (m, 1H), 7.51 (t, 1H, overlapped, J = 7.8 Hz), 7.71
(d, 1H, J = 9.2 Hz), 7.75 (dd, 1H, J = 9.2, 1.6 Hz), 8.00–8.05 (m, 2H),
8.31–8.32 (m, 2H), 8.94 (br s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 23.6, 36.5, 115.1, 118.8, 122.2, 126.9, 128.4, 128.5, 130.2, 130.3,
131.7, 132.3, 132.4, 133.9, 134.4, 134.9, 137.8, 146.4, 148.5,
149.2, 154.4, 157.3, 166.0, 167.4; HRMS-ESI: m/z [M+H]+calcd for
C24H21N8O2: 453.1782, found 453.1799.
4.1.10. 3-(((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-
methylpyridin-2-yl)-1H-imidazol-2-
yl)methyl)carbamothioyl)benzamide (16b)
This compound was prepared according to the same procedure
for 16a using 15c as the starting material. Yield 19%; mp 217–
219 °C; purity by HPLC: 98.2% (18% acetonitrile); IR (KBr) 3464,
4.1.7. N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-methyl
pyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluorobenzothioa
mide (15b)
3383, 3152, 2921, 1668 cmꢂ1 1H NMR (400 MHz, CDCl3/CD3OD)
;
d 2.54 (s, 3H), 5.12 (s, 2H), 7.05 (d, 1H, J = 7.6 Hz), 7.17 (d, 1H,
J = 7.6 Hz), 7.43–7.50 (m, 2H), 7.71–7.76 (m, 2H), 7.94 (dt, 1H,
J = 7.6, 1.6 Hz), 8.07 (ddd, 1H, J = 8.0, 2.0, 1.2 Hz), 8.23 (t, 1H,
J = 1.6 Hz), 8.32 (s, 1H), 8.94 (br s, 1H); 13C NMR (100 MHz, CDCl3/
CD3OD) d 22.6, 41.4, 116.0, 116.7, 119.5, 124.3, 124.8, 128.5, 128.8,
129.1, 129.4, 131.1, 131.4, 132.2, 132.8, 133.1, 139.3, 139.8, 145.4,
149.9, 154.5, 157.9, 169.7, 199.4; HRMS-ESI: m/z [M+H]+ calcd for
This compound was prepared according to the same procedure
for 15a using 14b as the starting material. Yield 71%; mp 364–
365 °C; purity by HPLC: 98.6% (25% acetonitrile); IR (KBr) 3180,
3071, 2969, 1595, 1252, 1182 cmꢂ1 1H NMR (400 MHz, CDCl3) d
;
2.58 (s, 3H), 5.24 (d, 2H, J = 5.2 Hz), 6.70 (br s, 1H), 7.05 (d, 1H,
J = 8.0 Hz), 7.08 (dd, 1H, J = 8.0, 1.2 Hz), 7.17 (td, 1H, J = 8.0,
1.2 Hz), 7.19 (br d, 1H, J = 8.0 Hz), 7.38–7.43 (m, 1H), 7.47 (t, 1H,
J = 7.8 Hz), 7.71 (d, 1H, J = 9.2 Hz), 7.75 (d, 1H, J = 9.2 Hz), 8.09 (t,
1H, J = 7.8 Hz), 8.37 (s, 1H), 8.92 (s, 1H), 9.45 (br s, 1H); 13C NMR
(100 MHz, CDCl3) d 24.1, 42.8, 115.8, 116.0 (d, J = 22.7 Hz), 118.5,
121.3, 122.6, 124.4 (d, J = 2.9 Hz), 128.0, 128.8 (d, J = 11.7 Hz),
129.7, 131.3, 131.8, 132.2, 132.4 (J = 8.8 Hz), 137.6, 144.6, 147.9,
149.5, 153.9, 157.6 (d, J = 249.7 Hz), 158.7, 195.0; HRMS-ESI: m/z
[M+H]+ calcd for C23H19FN7S: 444.1401, found 444.1401.
C24H21N8OS: 469.1554, found 469.1559.
4.1.11. 2-(4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-3-(6-methyl
pyridin-2-yl)-1H-pyrazol-1-yl)-N-phenylacetamide (19a) and 2-
(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-
1H-pyrazol-1-yl)-N-phenylacetamide (20a)
To a stirred solution of 6-(3-(6-methylpyridin-2-yl)-1H-pyra-
zol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (17) (0.72 mmol) in
anhydrous DMF (6 ml), a catalytic amount of NaI, 2-chloro-N-
phenylacetamide (18a) (1.08 mmol), and NaH (1.08 mmol) were
added. The mixture was stirred at room temperature for 30 min
and then evaporated to dryness under reduced pressure. The resi-
due was purified by MPLC on silica gel using MeOH/CHCl3 (1:40) as
eluent to give the two positional isomers 19a and 20a as white sol-
ids. Compound 19a: Yield 78%; mp 120–122 °C; purity by HPLC:
99.8% (21% acetonitrile); IR (KBr) 3276, 2985, 1684, 1600,
4.1.8. N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-
methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-3-
cyanobenzothioamide (15c)
This compound was prepared according to the same procedure
for 15a using 14c as the starting material. Yield 68%; mp 188–
189 °C; purity by HPLC: 99.1% (25% acetonitrile); IR (KBr) 3188,
3018, 2976, 2233, 1534, 1252, 1174 cmꢂ1 1H NMR (400 MHz,
;
CDCl3/CD3OD) d 2.55 (s, 3H), 5.10 (s, 2H), 7.07 (d, 1H, J = 7.6 Hz),
7.19 (d, 1H, J = 7.6 Hz), 7.49 (td, 1H, overlapped, J = 8.0, 0.4 Hz),
7.50 (t, 1H, overlapped, J = 7.6 Hz), 7.71 (ddd, 1H, J = 8.0, 1.6,
1.2 Hz), 7.74 (m, 2H), 8.08 (ddd, 1H, J = 8.0, 2.0, 1.2 Hz), 8.18 (dd,
1H, J = 2.0, 1.6 Hz), 8.33 (s, 1H), 8.95 (t, 1H, J = 1.6 Hz); 13C NMR
(100 MHz, CDCl3/CD3OD) d 23.9, 42.6, 112.4, 116.0, 118.1, 118.7,
120.4, 122.9, 128.2, 129.3, 129.6, 130.6, 131.5, 131.6, 131.7,
134.3, 137.9, 141.4, 144.7, 147.4, 149.6, 154.1, 158.6, 197.5;
HRMS-ESI: m/z [M+H]+ calcd for C24H19N8S: 451.1448, found
451.1465.
1558 cmꢂ1 1H NMR (400 MHz, CDCl3) d 2.52 (s, 3H), 5.08 (s, 2H),
;
7.11–7.15 (m, 1H), 7.17 (d, 1H, J = 7.6 Hz), 7.29–7.33 (m, 2H),
7.49–7.52 (m, 2H), 7.57 (d, 1H, overlapped, J = 7.6 Hz), 7.58 (dd,
1H,overlapped, J = 9.2, 1.6 Hz), 7.67 (t, 1H, J = 7.8 Hz), 7.70 (dd,
1H, J = 9.2, 0.8 Hz), 7.79 (s, 1H), 8.35 (s, 1H), 8.68 (br s, 1H), 8.88
(dd, 1H, J = 1.6, 0.8 Hz); 13C NMR (100 MHz, CDCl3) d 24.4, 56.1,
115.5, 118.1, 119.9, 120.1, 120.3 (2C), 123.1, 125.1, 127.7, 129.2
(2C), 130.6, 132.5, 132.8, 137.2, 149.7, 150.3, 150.9, 154.3, 158.6,
164.5; HRMS-ESI: m/z [M+H]+ calcd for C23H20N7O: 410.1724,
found 410.1729. Compound 20a: Yield 3%; mp 187–188 °C; IR
(KBr) 3275, 2924, 1684, 1599, 1555 cmꢂ1 1H NMR (400 MHz,
;
4.1.9. N0-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-
methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)isophthalamide
(16a)
A stirred solution of 14c (0.07 mmol) in EtOH (3 mL) and 1 N
NaOH (0.26 mmol) was cooled to 0 °C, and to it, 28% H2O2
(0.08 mmol) was added dropwise. The mixture was allowed to
warm to room temperature and stirred for 12 h. The reaction
CDCl3) d 2.68 (s, 3H), 5.04 (s, 2H), 7.07 (d, 1H, J = 7.6 Hz), 7.11 (br
t, 1H, J = 7.2 Hz), 7.27 (d, 1H, J = 7.6 Hz), 7.31–7.35 (m, 2H), 7.38
(dd, 1H, J = 9.2, 1.6 Hz), 7.57–7.63 (m, 3H), 7.70 (dd, 1H, J = 9.2,
0.8 Hz), 7.84 (s, 1H), 8.33 (s, 1H), 8.53 (dd, 1H, J = 1.6, 0.8 Hz),
9.67 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 24.6, 55.5, 116.9,
117.6, 120.0 (2C), 120.2, 123.0, 124.2, 124.6, 126.8, 129.2 (2C),
131.4, 137.9, 138.0, 139.7, 139.9, 147.2, 149.7, 154.4, 159.8,