408
M. Hayakawa et al. / Bioorg. Med. Chem. 15 (2007) 403–412
showed potent p110a inhibitory activity and strong
selectivity for p110a over other PI3K isoforms. Com-
pound 12 also inhibited tumor cell growth both in vitro
and in vivo, suggesting that PI3K p110a is a potential
target in cancer treatment.
J = 9.3 Hz), 8.31–8.37 (2H, m), 8.45–8.51 (2H, m),
8.80 (1H, d, J = 2.9 Hz), 9.07–9.10 (1H, m); FAB
MS m/e (M+H)+ 418; Anal. Calcd for C17H12-
N5O4SCl: C, 48.87; H, 2.89; N, 16.76; S, 7.67; Cl,
8.48. Found: C, 48.90; H, 2.81; N, 16.76; S, 7.65; Cl,
8.45.
5. Experimental
5.1. Chemistry
5.1.4. 6-Chloro-2-methyl-3-{1-[(3-nitrophenyl)sulfonyl]-
1H-pyrazol-3-yl}imidazo[1,2-a]pyridine (2d). Compound
2d was prepared from 4b and 3-nitrobenzenesulfonyl
chloride according to the same procedure as that of 2a.
Compound 2d was obtained as a colorless solid (41%
1H NMR spectra were recorded on a JEOL EX400 or
GX500 spectrometer; chemical shifts are expressed in d
units using tetramethylsilane as the standard (in the
description of the NMR signals, s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; and br, broad peak).
Mass spectra were recorded on a Hitachi M-80 or
JEOL JMS-DX300 spectrometer. Silica gel column
chromatography was performed with Wakogel C-200
or Merck Silica gel 60.
1
yield). Mp: 217–218 ꢁC (pyridine); H NMR (DMSO-
d6) d: 2.54 (3H, s), 7.13 (1H, d, J = 2.9 Hz), 7.45 (1H,
dd, J = 2.0, 9.3 Hz), 7.66 (1H, d, J = 9.3 Hz), 8.02 (1H,
t, J = 8.3 Hz), 8.49–8.54 (1H, m), 8.60–8.65 (1H, m),
8.73–8.76 (1H, m), 8.83 (1H, d, J = 3.0 Hz), 9.09–9.12
(1H, m); FAB MS m/e (M+H)+ 418; Anal. Calcd for
C17H12N5O4SCl: C, 48.87; H, 2.89; N, 16.76; S, 7.67; Cl,
8.48. Found: C, 48.89; H, 2.70; N, 16.80; S, 7.67; Cl, 8.45.
5.1.1. 3-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrazol-3-yl}-
2-methylimidazo[1,2-a] pyridine (2a). To a suspension
of 2-methyl-3-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine
4a (1.8 g, 9.7 mmol) in pyridine (7.1 mL, 88 mmol) was
5.1.5. 6-Chloro-2-methyl-3-{1-[(2-methyl-5-nitrophenyl)-
sulfonyl]-1H-pyrazol-3-yl}imidazo[1,2-a]pyridine (2e).
Compound 2e was prepared from 4b and 2-methyl-5-
nitrobenzenesulfonyl chloride according to the same
procedure as that of 2a. Compound 2e was obtained
as a yellow solid (34% yield). Mp: 207–208 ꢁC (Et2O);
1H NMR (DMSO-d6) d: 2.55 (3H, s), 2.76 (3H, s),
7.13 (1H, d, J = 2.9 Hz), 7.38–7.43 (1H, m), 7.61–7.66
(1H, m), 7.84 (1H, d, J = 8.8 Hz), 8.54 (1H, dd,
J = 2.4, 8.3 Hz), 8.83 (1H, d, J = 2.5 Hz), 8.90 (1H, d,
J = 2.9 Hz), 8.94–8.98 (1H, m); FAB MS m/e (M+H)+
432; Anal. Calcd for C18H14N5O4SCl: C, 50.06; H,
3.27; N, 16.22; S, 7.43; Cl, 8.21. Found: C, 50.07; H,
3.27; N, 16.07; S, 7.54; Cl, 8.19.
added
4-fluorobenzenesulfonyl
chloride
(1.9 g,
9.7 mmol). After stirring at reflux for 1 h, the reaction
mixture was evaporated, diluted with brine, and extract-
ed with CHCl3. The organic layer was dried over MgSO4
and evaporated. The residue was chromatographed on
silica gel eluting with CHCl3/MeOH (100:1–50:1), and
the obtained solid was washed with a mixture of CHCl3
and hexane to give 2a (2.4 g, 78%) as a colorless solid.
1
Mp: 159–160 ꢁC; H NMR (DMSO-d6) d: 2.55 (3H, s),
7.06 (1H, d, J = 3.0 Hz), 7.13 (1H, dd, J = 1.0, 6.8 Hz),
7.36–7.42 (1H, m), 7.51–7.64 (3H, m), 8.18–8.25 (2H,
m), 8.70 (1H, d, J = 3.0 Hz), 9.10–9.16 (1H, m); FAB
MS m/e (M+H)+ 357; Anal. Calcd for C17H13N4O2SF:
C, 57.29; H, 3.68; N, 15.72; S, 9.00; F, 5.33. Found: C,
56.96; H, 3.68; N, 15.68; S, 9.00; F, 5.37.
5.1.6. 6-Bromo-2-methyl-3-{1-[(2-methyl-5-nitrophenyl)-
sulfonyl]-1H-pyrazol-3-yl} imidazo[1,2-a]pyridine (2f).
Compound 2f was prepared from 4c and 2-methyl-5-
nitrobenzenesulfonyl chloride according to the same
procedure as that of 2a. Compound 2f was obtained
as a yellow solid (12% yield). Mp: 202–203 ꢁC (Et2O);
1H NMR (DMSO-d6) d: 2.55 (3H, s), 2.76 (3H, s),
7.13 (1H, d, J = 2.9 Hz), 7.47 (1H, dd, J = 1.9, 9.3 Hz),
7.58 (1H, d, J = 9.3 Hz), 7.85 (1H, d, J = 8.3 Hz), 8.55
(1H, dd, J = 2.4, 8.3 Hz), 8.83 (1H, d, J = 2.5 Hz), 8.89
(1H, d, J = 2.9 Hz), 9.06 (1H, d, J = 2.5 Hz); FAB MS
m/e (M+H)+ 476, 478; Anal. Calcd for C18H14N5O4SBr:
C, 45.39; H, 2.96; N, 14.70; S, 6.73; Br, 16.78. Found: C,
45.27; H, 2.84; N, 14.67; S, 6.82; Br, 16.65.
5.1.2. 6-Chloro-3-{1-[(4-fluorophenyl)sulfonyl]-1H-pyra-
zol-3-yl}-2-methylimidazo[1,2-a]pyridine (2b). Compound
2b was prepared from 4b and 4-fluorobenzenesulfonyl
chloride according to the same procedure as that of
2a. Compound 2b was obtained as a colorless solid
1
(84% yield). Mp: 195–196 ꢁC (CHCl3/Et2O); H NMR
(DMSO-d6) d: 2.58 (3H, s), 7.09 (1H, d, J = 2.9 Hz),
7.44 (1H, dd, J = 2.0, 9.8 Hz), 7.54–7.68 (3H, m),
8.14–8.22 (2H, m), 8.73 (1H, d, J = 2.9 Hz), 9.06–9.09
(1H, m); FAB MS m/e (M+H)+ 391; Anal. Calcd for
C17H12N4O2SFCl: C, 52.25; H, 3.09; N, 14.34; S, 8.20;
Cl, 9.07, F, 4.86. Found: C, 51.88; H, 2.98; N, 14.25;
S, 8.20; Cl, 9.05, F, 4.73.
5.1.7. 6-Bromo-3-{1-[(2-methyl-5-nitrophenyl)sulfonyl]-
1H-pyrazol-3-yl}imidazo[1,2-a]pyridine (2g). Compound
2g was prepared from 4d and 2-methyl-5-nitro-
benzenesulfonyl chloride according to the same proce-
dure as that of 2a. Compound 2g was obtained as a
colorless solid (16% yield). Mp: 195–196 ꢁC (AcOEt);
1H NMR (DMSO-d6) d: 2.80 (3H, s), 7.32 (1H, d,
J = 2.9 Hz), 7.55 (1H, dd, J = 1.9, 9.3 Hz), 7.73 (1H, d,
J = 9.3 Hz), 7.84 (1H, d, J = 8.7 Hz), 8.35 (1H, s), 8.53
(1H, dd, J = 2.5, 8.8 Hz), 8.80–8.85 (2H, m), 9.20–9.24
(1H, m); FAB MS m/e (M+H)+ 462, 464; Anal. Calcd
for C17H12N5O4SBr: C, 44.17; H, 2.62; N, 15.15; S, 6.94;
5.1.3. 6-Chloro-2-methyl-3-{1-[(4-nitrophenyl)sulfonyl]-
1H-pyrazol-3-yl}imidazo[1,2-a]pyridine (2c). Compound
2c was prepared from 4b and 4-nitrobenzenesulfonyl
chloride according to the same procedure as that of
2a. Compound 2c was obtained as a yellow solid
(56% yield). Mp: 263–264 ꢁC (pyridine); 1H NMR
(DMSO-d6) d: 2.54 (3H, s), 7.15 (1H, d, J = 2.9 Hz),
7.47 (1H, dd, J = 1.9, 9.7 Hz), 7.67 (1H, d,