320 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 2
Wendt et al.
560 mg (61%) of 40a as a yellow oil: 1H NMR (CDCl3) δ 8.38
(d, J ) 2.2 Hz, 1H), 8.22 (dd, J ) 8. 5, 2.2 Hz, 1H), 7.39 (d, J
) 8.5 Hz, 1H), 3.74 (t, J ) 7.2 Hz, 2H), 3.32 (m, 1H), 2.77 (t,
J ) 7.2 Hz, 2H), 1.24 (d, J ) 6.6 Hz, 6H); MS (DCI/NH3) m/z
219 (M + H)+.
pared from 46a using the procedure described for the prepa-
ration of 6. The crude product was purified by HPLC to provide
47a : 1H NMR (DMSO-d6) δ 10.61 (s, 1H), 9.50 (s, 2H), 9.35
(s, 1H), 9.22 (s, 2H), 8.69 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H),
8.32 (d, J ) 8.8 Hz, 1H), 8.25 (d, J ) 8.8 Hz, 1H), 8.24 (d, J )
8.8 Hz, 1H), 8.16 (dd, J ) 8.5, 1.7 Hz, 1H), 7.91 (dd, J ) 8.5,
2.0 Hz, 1H), 7.83 (d, J ) 1.7 Hz, 1H), 7.70 (dd, J ) 8.5, 2.0 Hz,
1H), 7.28 (d, J ) 8.5 Hz, 1H), 4.49 (s, 1H), 3.27 (s, 2H), 2.98
(m, 2H), 2.42 (m, 1H), 1.11 (d, J ) 6.8 Hz, 3H), 0.93 (d, J )
6.8 Hz, 3H); MS (DCI/NH3) m/z 387 (M + H)+. Anal.
(C24H26N4O‚3C2HF3O2) C, H, N.
7-Nitro-1-(2-methylpropyl)-3,4-dihydroisoquinoline (40b)
was prepared from 39b using the procedure described for the
preparation of 40a : 1H NMR (CDCl3) δ 8.32 (d, J ) 2.3 Hz,
1H), 8.22 (dd, J ) 8.1, 2.3 Hz, 1H), 7.38 (d, J ) 8.1 Hz, 1H),
3.74 (t, J ) 5.9 Hz, 2H), 2.79 (m, 2H), 2.68 (d, J ) 5.9 Hz,
2H), 2.08-2.11 (m, 1H), 0.98 (d, J ) 6.4 Hz, 6H); MS
(DCI/NH3) m/z 233 (M + H)+.
7-Am in o-1-(2-m et h ylp r op yl)-3,4-d ih yd r oisoq u in olin e
(41b) was prepared from 40b using the procedure described
for the preparation of 41a : 1H NMR (CDCl3) δ 6.99 (d, J )
8.1 Hz, 1H), 6.81 (d, J ) 2.2 Hz, 1H), 6.69 (dd, J ) 8.1, 2.2 Hz,
1H), 3.62 (m, 4H), 2.56 (t, J ) 4.7 Hz, 2H), 2.07 (m, 1H), 0.94
(d, J ) 6.8 Hz, 6H); MS (DCI/NH3) m/z 203 (M + H)+.
6-[N-(1-(2-Meth ylp r op yl)-3,4-d ih yd r o-7-isoqu in olin yl)-
ca r ba m yl]-2-n a p h th a len eca r bon itr ile (42b) was prepared
from 41b using the procedure described for the preparation
of 33d : 1H NMR (DMSO-d6) δ 10.84 (s, 1H), 8.71 (d, J ) 1.8
Hz, 2H), 8.45 (d, J ) 1.1 Hz, 1H), 8.33 (d, J ) 8.5 Hz, 1H),
8.25 (d, J ) 8.5 Hz, 1H), 8.18 (dd, J ) 8.5, 1.1 Hz, 1H), 8.12
(dd, J ) 8. 5, 1.8 Hz, 1H), 7.93 (dd, J ) 8.5, 1.1 Hz, 1H), 7.56
(d, J ) 8.5 Hz, 1H), 3.87 (t, J ) 7.4 Hz, 2H), 3.07 (t, J ) 7.7
Hz, 2H), 2.93 (d, J ) 7.4 Hz, 2H), 2.13 (m, 1H), 0.99 (d, J )
6.3 Hz, 6H); MS (DCI/NH3) m/z 382 (M + H)+.
6-[N-(1-(2-Meth ylp r op yl)-3,4-d ih yd r o-7-isoqu in olin yl)-
ca r ba m yl]-2-n a p h th a len eca r boxa m id in e (43b) was pre-
pared from 42b using the procedure described for the prepa-
ration of 6. The crude product was purified by HPLC to provide
43b: 1H NMR (DMSO-d6) δ 10.91 (s, 1H), 9.51 (s, 2H), 9.28
(s, 2H), 8.74 (s, 1H), 8.57 (s, 1H), 8.49 (d, J ) 1.7 Hz, 1H),
8.35 (d, J ) 8.8 Hz, 1H), 8.27 (d, J ) 8.5 Hz, 1H), 8.20 (dd, J
) 8.5, 1.7 Hz, 1H), 8.18 (d, J ) 8.8 Hz, 1H), 7.92 (dd, J ) 8.5,
1.7 Hz, 1H), 7.58 (d, J ) 8.5 Hz, 1H), 3.93 (t, J ) 8.0 Hz, 2H),
3.11 (t, J ) 8.0 Hz, 2H), 2.97 (d, J ) 6.5 Hz, 2H), 2.14 (m,
1H), 1.00 (d, J ) 6.8 Hz, 6H); MS (ESI) m/z 399 (M + H)+.
Anal. (C25H26N4O‚2C2HF3O2‚1.5H2O) C, H, N.
1-Isop r op yl-7-a m in o-3,4-d ih yd r oisoq u in olin e (41a ).
Compound 40a (180 mg, 0.82 mmol) was hydrogenated in a
Parr shaker at 4 atm for 48 h with Raney nickel (0.12 g) in
EtOAc (30 mL). The reaction mixture was degassed, filtered
through Celite, and evaporated to afford 155 mg (100%) of
41a : 1H NMR (CDCl3) δ 6.99 (d, J ) 8.0 Hz, 1H), 6.88 (d, J )
2.2 Hz, 1H), 6.70 (dd, J ) 8.0, 2.2 Hz, 1H), 3.63 (t, J ) 7.3 Hz,
2H), 3.20 (sep, J ) 6.8 Hz, 1H), 2.54 (t, J ) 7.3 Hz, 2H), 1.20
(d, J ) 6.8 Hz, 6H); MS (DCI/NH3) m/z 189 (M + H)+.
6-[N-(1-Isop r op yl-3,4-d ih yd r o-7-isoqu in olin yl)ca r ba m -
yl]-2-n a p h th a len eca r bon itr ile (42a ) was prepared from 41a
using the procedure described for the preparation of 33d : 1H
NMR (DMSO-d6) δ 10.86 (s, 1H), 8.71 (s, 2H), 8.56 (s, 1H),
8.32 (d, J ) 8.7 Hz, 1H), 8.25 (d, J ) 8.7 Hz, 1H), 8.18 (dd,
J ) 8.5, 1.8 Hz, 1H), 8.14 (dd, J ) 8.5, 1.8 Hz, 1H), 7.94
(dd, J ) 8.5, 1.1 Hz, 1H), 7.57 (dd, J ) 8.5, 1.1 Hz, 1H), 3.85
(t, J ) 7.4 Hz, 2H), 3.61 (sep, J ) 6.6 Hz, 1H), 3.07 (t, J )
7.4 Hz, 2H), 1.39 (d, J ) 6.6 Hz, 6H); MS (DCI/NH3) m/z 368
(M + H)+.
6-[N-(1-Isop r op yl-3,4-d ih yd r o-7-isoqu in olin yl)ca r ba m -
yl]-2-n a p h th a len eca r boxa m id in e (43a ) was prepared from
42a using the procedure described for the preparation of 6.
The crude product was purified by HPLC to provide 43a : 1H
NMR (DMSO-d6) δ 10.88 (s, 1H), 9.52 (s, 2H), 9.26 (s, 2H),
8.75 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.34 (d, J ) 8.8 Hz,
1H), 8.27 (d, J ) 8.5 Hz, 1H), 8.19 (dd, J ) 8.5, 1.7 Hz, 1H),
8.14 (d, J ) 8.8 Hz, 1H), 7.94 (dd, J ) 8.3, 1.7 Hz, 1H), 7.55
(d, J ) 8.3 Hz, 1H), 3.84 (t, J ) 8.14 Hz, 2H), 3.60 (sep, J )
6.8 Hz, 1H), 3.04 (t, J ) 8.14 Hz, 2H), 1.38 (d, J ) 6.8 Hz,
6H); MS (DCI/NH3) m/z 385 (M + H)+. Anal. (C24H24N4O‚2C2-
HF3O2‚1.25H2O) C, H, N.
7-Am in o-1-isop r op yl-1,2,3,4-t et r a h yd r oisoq u in olin e
(44a ). NaBH4 (200 mg, 5.3 mmol) was added portionwise to a
0 °C solution of 41a (210 mg, 1.1 mmol) in MeOH (10 mL).
The reaction mixture was refluxed for 30 min and then was
cooled to 0 °C, and acetone (5 mL) was added dropwise. The
solvent was evaporated and water (25 mL) was added to the
residue. The mixture was extracted with ether (3 × 30 mL).
The organic layer was washed with brine, dried (MgSO4),
filtered, and evaporated to afford 200 mg (96%) of 44a : 1H
NMR (CDCl3) δ 6.87 (d, J ) 8.5 Hz, 1H), 6.51 (m, 2H), 3.86
(d, J ) 3.4 Hz, 1H), 3.51 (s, 2H), 3.27 (m, 1H), 2.88 (m, 1H),
2.72 (m, 1H), 2.56 (m, 1H), 2.29 (m, 1H), 1.61 (s, 1H), 1.11
(d, J ) 7.1 Hz, 3H), 0.75 (d, J ) 6.8, 3H); MS (DCI/NH3) m/z
191 (M + H)+.
7-Am in o-2-ter t-bu toxyca r bon yl-1-isop r op yl-1,2,3,4-tet-
r a h yd r oisoqu in olin e (45a ). Di-tert-butyl dicarbonate (250
mg, 1.15 mmol) was added to a 0 °C solution of 44a (200 mg,
1.05 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred
for 2 h at 0 °C, then water (20 mL) was added. The mixture
was extracted with CH2Cl2 (3 × 20 mL). The extracts were
washed with 5% citric acid, saturated NaHCO3, and brine;
dried (MgSO4); filtered; and evaporated to afford 250 mg (82%)
of 45a as a colorless oil: 1H NMR (CDCl3) δ 7.03 (t, J ) 6.8
Hz, 0.5H), 6.92 (t, J ) 7.5 Hz, 0.5H), 6.59-6.40 (m, 3H), 4.80-
4.58 (m, 1H), 3.98 (m, 0.5H), 3.69 (m, 0.5H), 3.47 (m, 0.5H),
3.35 (m, 0.5H), 2.76 (m, 2H), 1.97 (m, 1H), 1.46 (d, J ) 4.4 Hz,
9H), 0.97 (m, 6H); MS (DCI/NH3) m/z 291 (M + H)+.
6-[N-(2-ter t-bu toxycar bon yl-1-isopr opyl-1,2,3,4-tetr ah y-
d r o-7-isoq u in olin yl)ca r b a m yl]-2-n a p h t h a len eca r b on i-
tr ile (46a ) was prepared from 45a using the procedure
described for the preparation of 33d : 1H NMR (CDCl3) δ
8.43 (s, 1H), 8.30 (s, 1H), 8.04 (t, J ) 8.5 Hz, 3H), 7.94 (s, 1H),
7.67 (m, 2H), 7.35 (d, J ) 7.5 Hz, 1H), 4.81 (m, 1H), 4.05
(s, 0.5H), 3.81 (s, 0.5H), 3.50 (s, 0.5H), 3.38 (s, 1H), 2.86
(s, 2H), 2.06 (s, 1H), 1.48 (s, 9H), 1.02 (m, 6H); MS (ESI) m/z
468 (M - 1)-.
7-Am in o-1-(2-m eth ylp r op yl)-1,2,3,4-tetr a h yd r oisoqu in -
olin e (44b) was prepared from 41b using the procedure
described for the preparation of 44a : 1H NMR (CDCl3) δ 6.87
(d, J ) 8.1 Hz, 1H), 6.50 (dd, J ) 8.1, 2.4 Hz, 1H), 6.45 (d, J
) 2.4 Hz, 1H), 3.91 (m, 1H), 3.52 (s, 2H), 3.19 (m, 1H), 2.94
(m, 1H), 2.67 (m, 2H), 1.86 (m, 2H), 1.67 (m, 1H), 1.52 (m,
1H), 1.01 (d, J ) 6.6 Hz, 3H), 0.97 (d, J ) 6.6 Hz, 3H); MS
(DCI/NH3) m/z 205 (M + H)+.
7-Am in o-2-ter t-b u t oxyca r b on yl-1-(2-m et h ylp r op yl)-
1,2,3,4-tetr a h yd r oisoqu in olin e (45b) was prepared from
44b using the procedure described for the preparation of 45a :
1H NMR (CDCl3) δ 6.97 (m, 2H), 6.67 (m, 1H), 6.57 (s, 1H),
4.17 (m, 1H), 3.14 (m, 1H), 2.83 (m, 1H), 2.60 (m, 1H), 1.72
(m, 4H), 1.49 (s, 9H), 1.05 (d, J ) 6.6 Hz, 3H), 0.93 (d, J ) 6.6
Hz, 3H); MS (DCI/NH3) m/z 305 (M + H)+.
6-[N-(2-ter t-Bu toxyca r bon yl-1-(2-m eth ylpr op yl)-1,2,3,4-
t et r a h yd r o-7-isoq u in olin yl)ca r b a m yl]-2-n a p h t h a len e-
ca r bon itr ile (46b) was prepared from 45b using the proce-
dure described for the preparation of 33d :
1H NMR (CDCl3) δ
8.43 (s, 1H), 8.30 (s, 1H), 8.03 (m, 3H), 7.95 (s, 1H), 7.71 (dd,
J ) 8.5, 1.0 Hz, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 7.12 (m, 1H),
4.22 (m, 1H), 4.07 (m, 1H), 3.20 (m, 1H), 2.93 (m, 1H), 2.70
(m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.50 (s, 9H), 1.26 (t, J )
7.1 Hz, 1H), 1.08 (d, J ) 6.1 Hz, 3H), 0.96 (d, J ) 6.4 Hz, 3H);
MS (ESI) m/z 482 (M - 1)-
.
6-[N-(1-(2-Meth ylp r op yl)-1,2,3,4-tetr a h yd r o-7-isoqu in o-
lin yl)ca r ba m yl]-2-n a p h th a len eca r boxa m id in e (47b) was
prepared from 46b using the procedure described for the
6-[N-(1-Isop r op yl-1,2,3,4-t et r a h yd r o-7-isoqu in olin yl)-
ca r ba m yl]-2-n a p h th a len eca r boxa m id in e (47a ) was pre-