722 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 2
Kinoyama et al.
chloride and 7 in 26% yield as a colorless solid: mp 225 °C
(AcOEt); H NMR (400 MHz, DMSO-d6) δ 1.14 (3H, d, J ) 6.9
11.28 (1H, br); FAB-MS m/z 420 (M + H+). Anal. (C20H20N5O2F3‚
0.5H2O) C, H, N, F.
1
Hz), 1.21 (3H, d, J ) 6.9 Hz), 3.36-3.50 (2H, m), 3.73 (1H, dd,
J ) 13.2 Hz, 2.0 Hz), 3.81-3.91 (1H, m), 4.30-4.54 (2H, m),
7.20-7.34 (3H, m), 7.85 (1H, d, J ) 8.8 Hz), 8.22 (1H, d, J ) 4.9
Hz), 8.30 (1H, s), 8.38 (1H, br); FAB-MS m/z 418 (M + H+).
Anal. (C21H22N5OF3) C, H, N, F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-dimeth-
yl-N-(5-methylpyridin-3-yl)piperazine-1-carboxamide hydro-
chloride (21). The title compound was prepared from 5-methylni-
cotinic acid hydrochloride and 7 in 65% yield as a colorless solid:
mp 230-233 °C (EtOH/1,4-dioxane); 1H NMR (400 MHz, DMSO-
d6) δ 1.11 (3H, d, J ) 6.3 Hz), 1.22 (3H, d, J ) 6.3 Hz), 2.45 (3H,
s), 3.40 (1H, dd, J ) 13.2 Hz, 3.9 Hz), 3.43-3.53 (1H, m), 3.70-
3.82 (1H, m), 3.98-4.10 (1H, m), 4.33-4.45 (1H, m), 4.53-4.67
(1H, m), 7.24-7.34 (2H, m), 7.86 (1H, d, J ) 9.2 Hz), 8.40 (1H,
br), 8.53 (1H, br), 9.03 (1H, d, J ) 1.9 Hz), 9.86 (1H, br); FAB-
MS m/z 418 (M + H+). Anal. (C21H22N5OF3‚HCl) C, H, N, Cl, F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-dimeth-
yl-N-(6-methylpyridin-3-yl)piperazine-1-carboxamide (22). The
title compound was prepared from 6-methylnicotinic acid and 7 in
21% yield as a colorless solid: mp 233-234 °C (AcOEt); 1H NMR
(400 MHz, DMSO-d6) δ 1.10 (3H, d, J ) 6.3 Hz), 1.18 (3H, d, J
) 6.9 Hz), 2.39 (3H, s), 3.34-3.46 (2H, m), 3.68-3.78 (1H, m),
3.83-3.93 (1H, m), 4.31-4.42 (1H, m), 4.44-4.55 (1H, m), 7.13
(1H, d, J ) 8.3 Hz), 7.23-7.33 (2H, m), 7.78 (1H, dd, J ) 8.3 Hz,
2.5 Hz), 7.85 (1H, d, J ) 8.8 Hz), 8.51 (1H, d, J ) 2.5 Hz), 8.65
(1H, br); FAB-MS m/z 418 (M + H+). Anal. (C21H22N5OF3) C, H,
N, F.
(()-trans-N-(6-Chloropyridin-3-yl)-4-[4-cyano-3-(trifluoro-
methyl)phenyl]-2,5-dimethylpiperazine-1-carboxamide (29). The
title compound was prepared from 6-chloronicotinic acid and 7 in
44% yield as a colorless solid: mp 197-199 °C (AcOEt); 1H NMR
(400 MHz, DMSO-d6) δ 1.10 (3H, d, J ) 6.3 Hz), 1.20 (3H, d, J
) 6.8 Hz), 3.35-3.49 (2H, m), 3.68-3.79 (1H, m), 3.83-3.94
(1H, m), 4.30-4.42 (1H, m), 4.44-4.56 (1H, m), 7.23-7.33 (2H,
m), 7.40 (1H, d, J ) 8.8 Hz), 7.86 (1H, d, J ) 8.8 Hz), 7.99 (1H,
dd, J ) 8.8 Hz, 3.0 Hz), 8.53 (1H, d, J ) 3.0 Hz), 8.90 (1H, br);
FAB-MS m/z 438 (M + H+). Anal. (C20H19N5OClF3) C, H, N, Cl,
F.
(()-Methyl 5-[({trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-
2,5-dimethylpiperazin-1-yl}carbonyl)amino]pyridine-2-carboxy-
late (30). The title compound was prepared from 6-(methoxycar-
bonyl)nicotinic acid48 and 7 in 39% yield as a colorless solid: mp
259-260 °C (MeOH/AcOEt/i-Pr2O); 1H NMR (400 MHz, DMSO-
d6) δ 1.11 (3H, d, J ) 6.4 Hz), 1.21 (3H, d, J ) 6.3 Hz), 3.36-
3.52 (2H, m), 3.71-3.79 (1H, m), 3.85 (3H, s), 3.89-3.96 (1H,
m), 4.32-4.43 (1H, m), 4.47-4.59 (1H, m), 7.23-7.34 (2H, m),
7.86 (1H, d, J ) 8.8 Hz), 8.00 (1H, d, J ) 8.8 Hz), 8.13 (1H, dd,
J ) 8.8 Hz, 2.5 Hz), 8.81 (1H, d, J ) 2.5 Hz), 9.15 (1H, br); FAB-
MS m/z 462 (M + H+). Anal. (C22H22N5O3F3) C, H, N, F.
(()-trans-N-(6-Cyanopyridin-3-yl)-4-[4-cyano-3-(trifluoro-
methyl)phenyl]-2,5-dimethylpiperazine-1-carboxamide (32). The
title compound was prepared from 6-cyanonicotinic acid and 7 in
31% yield as a beige solid: mp 182-184 °C (AcOEt/n-hexane);
1H NMR (400 MHz, DMSO-d6) δ 1.11 (3H, d, J ) 6.8 Hz), 1.22
(3H, d, J ) 6.4 Hz), 3.41 (1H, dd, J ) 13.2 Hz, 3.9 Hz), 3.44-
3.53 (1H, m), 3.69-3.81 (1H, m), 3.86-3.98 (1H, m), 4.31-4.44
(1H, m), 4.47-4.58 (1H, m), 7.22-7.36 (2H, m), 7.86 (1H, d, J )
8.8 Hz), 7.91 (1H, d, J ) 8.7 Hz), 8.15 (1H, dd, J ) 8.8 Hz, 2.4
Hz), 8.85 (1H, d, J ) 2.4 Hz), 9.26 (1H, br); FAB-MS m/z 429 (M
+ H+). Anal. (C21H19N6OF3) C, H, N, F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-N-(2-meth-
oxypyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide (23). The
title compound was prepared from 2-methoxynicotinic acid and 7
1
in 52% yield as a colorless solid: mp 174-176 °C (AcOEt); H
NMR (400 MHz, DMSO-d6) δ 1.12 (3H, d, J ) 6.9 Hz), 1.19 (3H,
d, J ) 6.4 Hz), 3.38-3.49 (2H, m), 3.68-3.75 (1H, m), 3.79-
3.85 (1H, m), 3.91 (3H, s), 4.28-4.49 (2H, m), 6.92-6.98 (1H,
m), 7.25 (1H, dd, J ) 8.8 Hz, 2.4 Hz), 7.29 (1H, d, J ) 2.4 Hz),
7.81-7.95 (4H, m); FAB-MS m/z 434 (M + H+). Anal.
(C21H22N5O2F3) C, H, N, F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-dimeth-
yl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxam-
ide (33). The title compound was prepared from 6-(trifluoromethyl)-
nicotinic acid and 7 in 82% yield as a colorless solid: mp 148-
149 °C (AcOEt/i-Pr2O/n-hexane); 1H NMR (400 MHz, DMSO-d6)
δ 1.12 (3H, d, J ) 6.4 Hz), 1.22 (3H, d, J ) 6.4 Hz), 3.35-3.55
(2H, m), 3.68-3.83 (1H, m), 3.86-4.00 (1H, m), 4.30-4.62 (2H,
m), 7.21-7.39 (2H, m), 7.80 (1H, d, J ) 8.8 Hz), 7.86 (1H, d, J
) 9.3 Hz), 8.20 (1H, dd, J ) 8.8 Hz, 2.4 Hz), 8.86 (1H, d, J ) 2.4
Hz), 9.18 (1H, br); FAB-MS m/z 472 (M + H+). Anal. (C21H19N5-
OF6) C, H, N, F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-N-(5-meth-
oxypyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide (25). The
title compound was prepared from 5-methoxynicotinic acid hydro-
chloride47 and 7 in 70% yield as a colorless solid: mp 198-201
°C (AcOEt/Et2O); 1H NMR (400 MHz, DMSO-d6) δ 1.11 (3H, d,
J ) 6.4 Hz), 1.20 (3H, d, J ) 6.8 Hz), 3.35-3.50 (2H, m), 3.75
(1H, dd, J ) 13.2 Hz, 1.5 Hz), 3.80 (3H, s), 3.86-3.94 (1H, m),
4.31-4.43 (1H, m), 4.41-4.57 (1H, m), 7.28 (1H, dd, J ) 8.8 Hz,
2.4 Hz), 7.31 (1H, d, J ) 2.4 Hz), 7.59-7.64 (1H, m), 7.86 (1H,
d, J ) 8.8 Hz), 7.91 (1H, d, J ) 2.9 Hz), 8.32 (1H, d, J ) 2.0 Hz),
8.77 (1H, br); FAB-MS m/z 434 (M + H+). Anal. (C21H22N5O2F3)
C, H, N, F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-dimeth-
yl-N-[6-(methylthio)pyridin-3-yl]piperazine-1-carboxamide (27).
The title compound was prepared from 6-(methylsulfanyl)nicotinic
acid and 7 in 63% yield as a colorless solid: mp 175-177 °C
(AcOEt/n-hexane); 1H NMR (400 MHz, DMSO-d6) δ 1.11 (3H, d,
J ) 6.3 Hz), 1.19 (3H, d, J ) 6.8 Hz), 2.48 (3H, s), 3.35-3.47
(2H, m), 3.67-3.79 (1H, m), 3.81-3.94 (1H, m), 4.27-4.56 (2H,
m), 7.21 (1H, d, J ) 8.8 Hz), 7.25-7.33 (2H, m), 7.79 (1H, dd, J
) 8.8 Hz, 2.4 Hz), 7.85 (1H, d, J ) 8.8 Hz), 8.55 (1H, d, J ) 2.4
Hz), 8.70 (1H, br); FAB-MS m/z 450 (M + H+). Anal. (C21H22N5-
OF3S) C, H, N, F, S.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-dimeth-
yl-N-(1-oxidopyridin-3-yl)piperazine-1-carboxamide (34). To a
solution of trans-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimeth-
yl-N-pyridin-3-ylpiperazine-1-carboxamide (605 mg, 1.5 mmol) in
AcOH (3 mL) was added NaBO3‚4H2O (507 mg, 3.3 mmol) at 40
°C.36 After stirring at 40 °C for 3 days, the reaction mixture was
cooled to ambient temperature, diluted by H2O, and extracted with
CHCl3. The organic layer was washed with saturated, aqueous
NaHCO3, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (CHCl3/
MeOH ) 7/1) and recrystallized from MeOH/AcOEt to give the
title compound (202 mg, 32%) as a pale yellow powder: mp 238
1
°C; H NMR (300 MHz, DMSO-d6) δ 1.10 (3H, d, J ) 6.6 Hz),
1.19 (3H, d, J ) 6.6 Hz), 3.33-3.49 (2H, m), 3.68-3.79 (1H, m),
3.82-3.92 (1H, m), 4.30-4.55 (2H, m), 7.22-7.33 (3H, m), 7.40-
7.47 (1H, m), 7.81-7.88 (2H, m), 8.53-8.58 (1H, m), 8.90 (1H,
br); FAB-MS m/z 420 (M + H+). Anal. (C20H20N5O2F3) C, H, N,
F.
(()-trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-N-(6-hydroxy-
pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide (28). The
title compound was prepared from 6-hydroxynicotinic acid and 7
in 5% yield as a gray solid: mp 160-164 °C (AcOEt/n-hexane);
1H NMR (400 MHz, DMSO-d6) δ 1.09 (3H, d, J ) 6.4 Hz), 1.15
(3H, d, J ) 6.9 Hz), 3.27-3.40 (2H, m), 3.64-3.85 (2H, m), 4.28-
4.47 (2H, m), 6.26-6.33 (1H, m) 7.21-7.32 (2H, m), 7.46 (1H, d,
J ) 2.9 Hz), 7.48 (1H, s), 8.19 (1H, d, J ) 8.8 Hz), 8.24 (1H, br),
(()-5-[({trans-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-di-
methylpiperazin-1-yl}carbonyl)amino]pyridine-2-carboxylic Acid
(35). A mixture of (()-methyl 5-[({trans-4-[4-cyano-3-(trifluo-
romethyl)phenyl]-2,5-dimethylpiperazin-1-yl}carbonyl)amino]-
pyridine-2-carboxylate (30, 5.0 g, 9.73 mmol) and 1 M NaOH. (10.2
mL, 10.2 mmol) in MeOH (100 mL) was stirred at ambient
temperature for 6 h. The reaction mixture was acidified with 1 M