3
48 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Duplantier et al.
S) C,
2
5
.17 (m, 4H), 2.62 (q, 2H), 2.98 (t, 2H), 3.86 (s, 3H), 4.41 (t, 2H),
.63 (quintet, 1H), 7.05 (d, 2H), 7.63 (d, 2H). Anal. (C21 O)
1H), 6.96(d, 1H), 7.03 (s, 1H), 7.29 (d, 1H). Anal. (C19
H, N: calcd, 19.81; found, 18.57.
23 5
H N
25 5
H N
C, H, N.
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-methyl-9H-pyrazolo[3,4-
c]-1,2,4-triazolo[4,3-R]pyridine (23). Procedure B; purified by
9
-Cyclopentyl-5,6-dihydro-7-ethyl-3-(4-methylphenyl)-9H-
pyrazolo[3,4-c]-1,2,4-triazolo[4,3-R]pyridine (12). Procedure B;
purified by chromatography (1:1 ethyl acetate/hexanes); pale yellow
2 2
chromatography (5% methanol/CH Cl ); off-white solid; 55% yield;
1
mp 174-175 °C; MS m/z [M + 1] 272; H NMR (250 MHz,
CDCl ) 1.23 (t, 3H), 1.69 (m, 2H), 1.91 (m, 2H), 2.13 (m, 4H),
2.49 (s, 3H), 2.66 (q, 2H), 2.96 (t, 2H), 4.02 (t, 2H), 5.56 (quintet,
1H). Anal. (C15 ) C, H, N.
1
solid; 94% yield; mp 142-145 °C; MS m/z [M + 1] 348; H NMR
3
3
(250 MHz, CDCl ) δ 1.24 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H),
2
5
.17 (m, 4H), 2.43 (s, 3H), 2.62 (q, 2H), 2.98 (t, 2H), 4.41 (t, 2H),
.63 (quintet, 1H), 7.31 (d, 2H), 7.56 (d, 2H). Anal. (C21 ) C,
21 5
H N
H
25
N
5
9-Cyclopentyl-5,6-dihydro-3,7-diethyl-9H-pyrazolo[3,4-c]-
1,2,4-triazolo[4,3-R]pyridine (24). Procedure B; purified by chro-
matography (ethyl acetate); white solid; 14% yield; mp 118-19
H, N.
9
-Cyclopentyl-5,6-dihydro-7-ethyl-3-(4-chlorophenyl)-9H-
1
°
C; MS m/z [M + 1] 286; H NMR (400 MHz, CDCl
3
) δ 1.22 (t,
pyrazolo[3,4-c]-1,2,4-triazolo[4,3-R]pyridine (13). Procedure B;
purified by chromatography (ethyl acetate); white solid; 72% yield;
J ) 7.7 Hz, 3H), 1.37 (t, J ) 7.7 Hz, 3H), 1.66-1.73 (m, 2H),
1.89-2.03 (m, 2H), 2.05-2.18 (m, 4H), 2.65 (q, J ) 7.7 Hz, 2H),
.81 (q, J ) 7.7 Hz, 2H), 2.94 (t, J ) 7.0 Hz, 2H), 4.01 (t, J ) 7.0
Hz, 2H), 5.54 (quintet, J ) 7.9 Hz, 1H). HRMS calcd for C16
M + 1] 286.2032, found 286.2048. Anal. (C16 ) C, H, N:
calcd, 67.34, 8.12, 24.54; found, 67.84, 8.47, 23.16.
-Cyclopentyl-5,6-dihydro-7-ethyl-3-propyl-9H-pyrazolo[3,4-
1
mp 160-162 °C; MS m/z [M + 1] 364; H NMR (250 MHz,
CDCl ) δ 1.24 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H), 2.17 (m, 4H),
.62 (q, 2H), 2.98 (t, 2H), 4.41 (t, 2H), 5.63 (quintet, 1H), 7.52 (d,
2
3
24 5
H N
2
2
1
[
23 5
H N
H), 7.61 (d, 2H). Anal. (C20
8.20.
22 5
H N Cl) C, H, N: calcd, 19.04; found,
9
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(4-trifluoromethylphenyl)-
c]-1,2,4-triazolo[4,3-R]pyridine (25). Procedure B; purified by
9
H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-R]pyridine (14). Procedure
chromatography (ethyl acetate); white solid; 28% yield; mp 88-
B; purified by chromatography (1:1 ethyl acetate/hexanes); pale
1
9
2 °C; MS m/z [M + 1] 300; H NMR (250 MHz, CDCl
3
) δ 1.05
yellow solid; 68% yield; mp 134-137 °C; MS m/z [M + 1] 402;
1
(t, J ) 7.4 Hz, 3H), 1.24 (t, J ) 7.6 Hz, 3H), 1.67-2.27 (m, 10
H), 2.66 (q, J ) 7.6 Hz, 2H), 2.78 (t, J ) 7.7 Hz, 2H), 2.95 (t, J
3
H NMR (250 MHz, CDCl ) δ 1.25 (t, 3H), 1.72 (m, 2H), 1.95
(
5
m, 2H), 2.17 (m, 4H), 2.69 (q, 2H), 2.99 (t, 2H), 4.27 (t, 2H),
.61 (quintet, 1H), 7.85 (m, 4H). Anal. (C21 ) C, H, N.
-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-pyridyl)-9H-pyrazolo-
)
7.0 Hz, 2H), 4.03 (t, J ) 7.0 Hz, 2H), 5.56 (quintet, 1H). HRMS
22 5 3
H N F
calcd for C17
+ 0.2H
-Cyclopentyl-5,6-dihydro-7-ethyl-3-butyl-9H-pyrazolo[3,4-
H
26
N
5
[M + 1] 300.2188, found 300.2188. Anal.
9
(C
17
H
25
N
5
2
O) C, H, N: calcd, 23.11; found, 22.19.
[
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (15). Procedure A; purified
9
by chromatography (1:1 ethyl acetate/hexanes); white solid; 74%
c]-1,2,4-triazolo[4,3-R]pyridine (26). Procedure B; purified by
chromatography (1:1 ethyl acetate/hexanes); colorless oil; 49%
1
yield; mp 153-155 °C; MS m/z [M + 1] 335; H NMR (250 MHz,
CDCl ) δ 1.24 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H), 2.17 (m, 4H),
3
1
yield; MS m/z [M + 1] 314; H NMR (400 MHz, CDCl
3
) δ 0.95
2
(
.70 (q, 2H), 2.98 (t, 2H), 4.90 (t, 2H), 5.64 (quintet, 1H), 7.36
dd, 1H), 7.84 (t, 1H), 8.37 (d, 1H), 8.66 (s, 1H).
-Cyclopentyl-5,6-dihydro-7-ethyl-3-(4-pyridyl)-9H-pyrazolo-
(
t, J ) 7.3 Hz, 3H), 1.22 (t, J ) 7.7 Hz, 3H), 1.44 (sextet, J ) 7.5
Hz, 2H), 1.65-1.79 (m, 4H), 1.87-1.97 (m, 2H), 2.04-2.20 (m,
H), 2.65 (q, J ) 7.7 Hz, 2H), 2.78 (t, J ) 7.7 Hz, 2H), 2.93 (t, J
7.0 Hz, 2H), 4.01 (t, J ) 7.0 Hz, 2H), 5.55 (quintet, J ) 7.9 Hz,
H). HRMS calcd for C18
9
4
[
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (17). Procedure A; purified
)
by chromatography (9:1 ethyl acetate/methanol); white solid; 75%
1
H
28
N
5
[M + 1] 314.2345, found 314.2333.
1
yield; mp 198-200 °C; MS m/z [M + 1] 335; H NMR (250 MHz,-
CDCl ) δ 1.24 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H), 2.17 (m, 4H),
3
Anal. (C18
H N
27 5
) C, H, N: calcd, 22.34; found, 19.39.
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-cyclobutyl-9H-pyrazolo-
2
2
.70 (q, 2H), 3.02 (t, 2H), 4.34 (t, 2H), 5.64 (quintet, 1H), 7.79 (d,
H), 8.84 (d, 2H). Anal. (C19 + 0.14H O) C, H, N.
-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-furanyl)-9H-pyrazolo-
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (18). Procedure A; purified
by chromatography (1:1 ethyl acetate/hexanes); yellowish solid;
[
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (27). Procedure B; purified
H
22
N
6
2
by chromatography (1:1 ethyl acetate/hexanes); waxy solid; 28%
yield; mp 116-118 °C; MS m/z [M + 1] 312; H NMR (400 MHz,
CDCl
9
1
[
3
) δ 1.20 (t, J ) 7.7 Hz, 3H), 1.65-1,69 (m, 2H), 1.89-1.93
(
2
m, 2H), 2.01-2.15 (m, 6H), 2.38-2.44 (m, 2H), 2.49-2.56 (m,
1
6
3% yield; mp 95-97 °C; MS m/z [M + 1] 324; H NMR (250
MHz, CDCl ) δ 1.24 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H), 2.17 (m,
H), 2.68 (q, 2H), 2.98 (t, 2H), 4.25 (t, 2H), 5.60 (quintet, 1H),
.6 (d, 1H), 7.14 (d, 1H), 7.61 (d, 1H). Anal. (C18 O) C, H,
H), 2.63 (q, J ) 7.7 Hz, 2H), 2.90 (t, J ) 7.0 Hz, 2H), 3.52-3.57
3
(
m, 1H), 3.92 (t, J ) 7.0 Hz, 2H), 5.53 (quintet, J ) 7.8 Hz, 1H).
Anal. (C18 ) C, H, N: calcd, 22.49; found, 20.15.
,9-Dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-
,2,4-triazolo[4,3-R]pyridine (28). Procedure B; purified by chro-
matography (5% methanol/CH Cl ); oily white solid; 30% yield;
MS m/z [M + 1] 326; H NMR (250 MHz, CDCl ) δ 1.23 (t, 3H),
4
6
25 5
H N
21 5
H N
3
N: calcd, 66.85, 6.55, 21.67; found, 67.29, 7.13, 19.56.
1
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(3-chloro-4-methylthien-
2
2
2
-yl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-R]pyridine (20). Pro-
1
3
cedure A; purified by chromatography (1:1 ethyl acetate/hexanes);
1
3
1
.65-2.16 (m, 16H), 2.64 (q, 2H), 2.95 (t, 2H), 3.17 (quintet, 1H),
off-white solid; 78% yield; mp 136-138 °C; MS m/z [M + 1]
.98 (t, 2H), 5.54 (quintet, 1H). HRMS calcd for C19
] 326.2345, found 326.2345.
28 5
H N [M +
1
3
1
2
88; H NMR (250 MHz, CDCl
3
) δ 1.24 (t, 3H), 1.70 (m, 2H)
.94 (m, 2H), 2.15 (m, 4H), 2.28 (s, 3H), 2.66 (q, 2H), 3.00 (t,
22 5
H), 4.32 (t, 2H), 5.58 (quintet, 1H), 7.25 (s, 1H). Anal. (C19H N -
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-cyclohexyl-9H-pyrazolo-
[
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (29). Procedure B; purified
Cl S) C, H, N.
by chromatography (1:1 ethyl acetate/hexanes) followed by recrys-
tallization from a 10:1 mixture of pentane and ether; white solid;
9
-Cyclopentyl-5,6-dihydro-7-ethyl-3-(benzyl)-9H-pyrazolo-
1
[
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (21). Procedure A; purified
20% yield; mp 138-9 °C; MS m/z [M + 1] 340; H NMR (400
by chromatography (1:1 ethyl acetate/hexanes); white solid; 65%
MHz, CDCl ) δ 1.22 (t, J ) 7.7 Hz, 3H), 1.30-1.43 (m, 2H), 1.63-
3
1
yield; mp 116-117 °C; MS m/z [M + 1] 348; H NMR (250 MHz,-
1.80 (m, 6H), 1.87-1.98 (m, 6H), 2.03-2.19 (m, 4H), 2.62-2.73
CDCl
3
) δ 1.19 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H), 2.17 (m, 4H),
(m, including q at 2.65, J ) 7.7 Hz, 3H), 2.92 (t, J ) 6.9 Hz, 2H),
4.03 (t, J ) 6.9 Hz, 2H), 5.55 (quintet, J ) 7.9 Hz, 1H). HRMS
calcd for C H N [M + 1] 340.2501, found 340.2524. Anal.
2
1
3
.60 (q, 2H), 2.83 (t, 2H), 3.84 (t, 2H), 4.25 (s, 2H), 5.56 (quintet,
H), 7.26 (m, 5H). HRMS calcd for C21
47.2109.
25 5
H N [M] 347.2110, found
20
29
5
(C H N ) C, H, N: calcd, 70.76, 8.61, 20.63; found, 71.28, 9.09,
20
29
5
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(3-thenyl)-9H-pyrazolo-
18.79.
[
3,4-c]-1,2,4-triazolo[4,3-R]pyridine (22). Procedure A; purified
9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(4-tetrahydropyranyl)-
9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-R]pyridine (30). Procedure
2 2
B; purified by chromatography (9:1 CH Cl /methanol) followed by
recrystallization from a mixture of isopropylether and hexanes; light
yellow crystalline solid; 26% yield; mp 165-166 °C; MS m/z [M
by chromatography (1:1 ethyl acetate/hexanes); white solid; 32%
yield; mp 134-135 °C; MS m/z [M + 1] 354; H NMR (250 MHz,
CDCl
1
3
) δ 1.19 (t, 3H), 1.72 (m, 2H), 1.95 (m, 2H), 2.17 (m, 4H),
2
.60 (q, 2H), 2.83 (t, 2H), 3.84 (t, 2H), 4.25 (s, 2H), 5.56 (quintet,