Journal of Medicinal Chemistry
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methanol in dichloromethane with 0.5% ammonium hydroxide) to
afford the title compound as a colorless oil. The oil was dissolved in
ethanol and made into its hydrochloride salt (36 mg) as a white solid,
mp 255−257 °C; yield 65%. H NMR (400 MHz, DMSO-d6) δ 1.09
(t, 7.20 Hz, 3H), 1.83 (m, 2H), 1.94 (m, 2H), 3.05−3.09 (m, 4H),
3.27 (m, 2H), 3.37 (m, 2H), 3.59−3.62 (m, 4H), 3.79 (t, J = 5.61 Hz,
2H), 7.66−7.69 (m, 2H), 7.78 (d, J = 8.42 Hz, 2H), 7.90−7.94 (m,
3H), 8.50 (m, 1H), 9.66 (br, 1H). HRMS: calcd for C24H29N3O2 + H+,
392.23325; found (ESI, [M + H]+), 392.2336.
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mp 216−218 °C. H NMR (400 MHz, DMSO-d6) δ 1.82 (m, 2H),
1.96 (m, 2H), 3.00−3.05 (m, H), 3.11 (t, J = 6.72 Hz, 2H), 3.35−3.40
(m, 2H), 3.55−3.60 (m, 2H), 3.63 (t, J = 6.43 Hz, 2H), 3.82 (t, J = 6.26
Hz, 2H), 7.87−7.89 (m, 2H), 7.99 (d, J = 8.70 Hz, 1H), 8.13 (d, J =
6.03 Hz, 2H), 8.84 (d, J = 5.68 Hz, 2H), 10.13 (br, 1H). HRMS: calcd
for C20H23N3O + H+, 322.19139; found (ESI, [M + H]+), 322.1926.
6-[4-(Cyclopropylcarbonyl)phenyl]-2-(2-pyrrolidin-1-yleth-
yl)-3,4-dihydro-isoquinolin-1(2H)-one (31). To a solution of
N-methoxy-N-methyl-4-(1-oxo-2-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tet-
rahydroisoqui-nolin-6-yl)benzamide 70 (0.14 g, 0.34 mmol) in
anhydrous tetrahydrofuran (20 mL) was added cyclopropyl magnesium
bromide (0.5 M solution in tetrahydrofuran solution, 2.0 mL, 1.4
mmol) at 0 °C. The reaction mixture was allowed to warm slowly to
room temperature and stirred overnight. The reaction mixture was
quenched with saturated aqueous ammonium chloride and extracted
with methylene chloride. The aqueous phase was extracted with
methylene chloride (3 × 100 mL). The organic layers were combined,
dried (sodium sulfate), and filtered, and the solvent was concentrated in
vacuo. The residue was purified by ISCO CombiFlash chromatography
(silica, 0−10% methanol in methylene chloride with 0.5% ammonium
hydroxide) to afford 6-[4-(cyclopropylcarbonyl)phenyl]-2-(2-pyrroli-
din-1-ylethyl)-3,4-dihydro-isoquinolin-1(2H)-one as a colorless oil.
The oil was dissolved in ethanol and made into its hydrochloride salt
48.4 mg (33%) as a white solid; mp 244−246 °C. 1H NMR (400 MHz,
DMSO-d6) δ 1.01−1.04 (m, 4H), 1.83 (m, 2H), 1.96 (m,2H), 2.88−
2.92 (m, 1H), 3.02 (m, 2H), 3.09 (t, J = 6.58 Hz, 2H), 3.34−3.38 (m,
2H), 3.57 (m, 2H), 3.62 (t, J = 6.47 Hz, 2H), 3.80 (t, J = 6.22 Hz, 2H),
7.69−7.72 (m, 2H), 7.86 (d, J = 8.54 Hz, 2H), 7.94 (d, J = 7.93 Hz,
1H), 8.11 (d, J = 8.54 Hz, 2H), 10.25 (br, 1H). HRMS: calcd for
C25H28N2O2 + H+, 389.22235; found (ESI, [M + H]+), 389.2228.
4-[1-Oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tetrahydroisoqui-
nolin-6-yl]benzamide (32). A mixture of thionyl chloride (3 mL)
and 4-(1-oxo-2-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-
6-yl)benzoic acid (68a) (0.10 g, 0.27 mol) was stirred at reflux
temperature for 1 h, cooled to room temperature, and concentrated in
vacuo to afford 4-(1-Oxo-2-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahy-
droiso-quinolin-6-yl)benzoyl chloride (69a) as a desired product. Then
69a was dissolved in THF, cooled to 0 °C, treated with ammonia,
warmed to room temperature, stirred for 1 h at room temperature,
diluted with 1 N NaOH, and extracted with CH2Cl2. The combined
extracts were washed sequentially with saturated NaHCO3 and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by ISCO CombiFlash chromatography (silica, 0−10%
methanol in methylene chloride with 0.5% ammonium hydroxide) to
afford the desired product as a colorless oil. The oil was dissolved in
ethanol, treated with Etheral HCl, stirred, and filtered. The filter cake
was washed with ether, and the desired product was obtained as a
white hydrochloride salt. Yield 67% as a white solid, hydrochloride salt;
N-Isopropyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tetra-
hydroisoquinolin-6-yl]benzamide (35). Using the procedure
described in 32 and employing isopropylamine, the desired product
was obtained as a white hydrochloride salt; mp 257−259 °C; yield
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56%. H NMR (400 MHz, DMSO-d6) δ 1.14 (d, J = 6.59 Hz, 6H),
1.83 (m, 2H), 1.94 (m, 2H), 3.04−3.09 (m, 4H), 3.37 (m, 1H), 3.59−
3.63 (m, 4H), 3.79 (t, J = 6.1 Hz, 2H), 7.66−7.69 (m, 2H), 7.77 (d, J =
8.54 Hz, 2H), 7.92 (m, 3H), 8.25 (d, J = 7.80 Hz, 1H), 9.86 (br, 1H).
HRMS: calcd for C25H31N3O2 + H+, 406.24890; found (ESI, [M +
H]+), 406.2491.
N-Cyclopropyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-
tetrahydroisoquinolin-6-yl]benzamide (36). Using the procedure
described in 32 and employing cyclopropylamine, the desired product
was obtained as a white hydrochloride salt; mp 222−224 °C; yield
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70%. H NMR (400 MHz, DMSO-d6) δ 0.54−0.56 (m, 2H), 0.65−
0.69 (m, 2H), 1.82 (m,2H), 1.94 (m, 2H), 2.81−2.84 (m, 1H), 3.02−
3.08 (m, 4H), 3.37 (m, 2H), 3.58−3.62 (m, 4H), 3.79 (t, J = 6.11 Hz,
2H), 7.66−7.69 (m, 2H), 7.76 (d, J = 8.41 Hz, 2H), 7.88−7.93 (m,
3H), 8.46 (d, J = 4.27 Hz, 1H), 9.65 (br, 1H). HRMS: calcd for
C25H29N3O2 + H+, 404.23325; found (ESI, [M + H]+), 404.2338.
N-Cyclobutyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tet-
rahydroisoquinolin-6-yl]benzamide (37). Using the procedure
described in 32 and employing cyclobutylmine, the desired product
was obtained as a white hydrochloride salt; mp 255−258 °C; yield
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35%. H NMR (400 MHz, DMSO-d6) δ 1.61−1.68 (m, 2H), 1.82−
1.86 (m, 2H), 1.94−2.10 (m, 4H), 2.14−2.21 (m, 2H), 3.04−3.09 (m,
4H), 3.31−3.37 (m, 2H), 3.59−3.65 (m, 4H), 3.79 (t, J = 6.10 Hz,
2H), 4.40 (m, 1H), 7.66−7.70 (m, 2H), 7.77 (d, J = 8.42 Hz, 2H),
7.92 (d, J = 8.42 Hz, 2H), 8.64 (d, J = 7.57 Hz, 1H), 9.82 (br, 1H).
HRMS: calcd for C26H31N3O2 + H+, 418.24890; found (ESI, [M +
H]+), 418.249.
N-Cyclopentyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-
tetrahydroisoquinolin-6-yl]benzamide (38). Using the procedure
described in 32 and employing cyclopentylamine, the desired product
was obtained as a white hydrochloride salt; mp 280−282 °C; yield 44%.
1H NMR (400 MHz, DMSO-d6) δ 1.47−1.53 (m, 4H), 1.63−1.69 (m,
2H), 1.83−1.89 (m, 4H), 1.94−1.97 (m, 2H), 3.04−3.09 (m, 4H), 3.33−
3.38 (m, 2H), 3.59−3.62 (m, 4H), 3.79 (t, J = 6.22 Hz, 2H), 4.18−4.23
(m, 1H), 7.66−7.69 (m, 2H), 7.76 (d J = 8.42 Hz, 2H), 7.90−7.94 (m,
3H), 8.31 (t, J = 7.20 Hz, 1H), 9.82 (br, 1H). HRMS: calcd for
C27H33N3O2 + H+, 432.26455; found (ESI, [M + H]+ calcd), 432.2645.
N,N-Dimethyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tet-
rahydroisoquinolin-6-yl]benzamide (39). Using the procedure
described in 32 and employing N,N-dimethylamine (1.0 M solution in
THF), the desired product was obtained as a white hydrochloride salt;
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mp 252−254 °C; yield 62%. H NMR (400 MHz, DMSO-d6) δ 1.83
mp 268−270 °C. H NMR (400 MHz, DMSO-d6) δ 1.82−1.85 (m,
(m, 2H), 1.97 (m, 2H), 2.91 (s, 3H), 2.95 (s, 3H), 3.01−3.09 (m, 4H),
3.35−3.39 (m, 2H), 3.59−3.62 (m, 4H), 3.79 (t, J = 6.11 Hz, 2H),
7.47 (d, J = 8.17 Hz, 2H), 7.64−7.67 (m, 2H), 7.74 (d, J = 8.29 Hz,
2H), 7.92 (d, J = 8.05 Hz, 1H), 9.84 (br, 1H). HRMS: calcd for
C24H29N3O2 + H+, 392.23325; found (ESI, [M + H]+), 392.2337.
6-[4-(Pyrrolidin-1-ylcarbonyl)phenyl]-2-(2-pyrrolidin-1-
ylethyl)-3,4-dihydroiso-quinolin-1(2H)-one (40). Using the pro-
cedure described in 32 and employing pyrrolidine, the desired product
was obtained as a white hydrochloride salt; mp 245−248 °C; yield
2H), 1.94−1.99 (m, 2H), 3.01−3.10 (m, 4H), 3.35−3.40 (m, 2H),
3.57−3.63 (m, 4H), 3.80 (t, J = 6.11 Hz, 2H), 7.37 (s, 1H), 7.66−7.70
(m, 2H), 7.77 (d, J = 8.42 Hz, 2H), 7.92−7.96 (m, 3H), 8.01 (br, 1H),
9.97 (br, 1H). HRMS: calcd for C22H25N3O2 + H+, 364.20195; found
(ESI, [M + H]+ obsd), 364.2021.
N-Methyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tetrahy-
droisoquinolin-6-yl]benzamide (33). Using the procedure de-
scribed in 32 and employing methylamine (1.0 M in THF), the desired
product was obtained as a white hydrochloride salt; mp 235−236 °C;
Yield: 56%. 1H NMR (400 MHz, DMSO-d6) δ 1.82 (m, 2H), 1.94 (m,
2H), 2.77 (d, J = 4.51 Hz, 3H), 3.07 (m, 4H), 3.37 (m, 2H), 3.60 (m,
4H), 3.79 (m, 2H), 7.67−7.70 (m, 2H), 7.78 (d, J = 8.54 Hz, 2H),
7.90−7.94 (m, 3H), 8.45−8.48 (m, 1H), 9.55 (br, 1H). HRMS: calcd
for C23H27N3O2 + H+, 378.21760; found (ESI, [M + H]+), 378.2177.
N-Ethyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tetrahy-
droisoquinolin-6-yl]benzamide (34). Using the procedure de-
scribed in 32 and employing ethylamine (1.0 M solution in THF),
the desired product was obtained as a white hydrochloride salt;
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42%. H NMR (400 MHz, DMSO-d6) δ 1.75−1.85 (m, 6H), 1.94−
1.97 (m, 2H), 3.03−3.09 (m, 4H), 3.28−3.32 (m, 4H), 3.38 (t, J =
6.47 Hz, 2H), 3.60−3.63 (m, 4H), 3.80 (t, J = 6.22 Hz, 2H), 7.61 (d,
J = 8.42 Hz, 2H), 7.63−7.67 (m, 2H), 7.74 (d, J = 8.30 Hz, 2H), 7.92
(d, J = 7.93 Hz, 1H), 10.03 (br, 1H). HRMS: calcd for C26H31N3O2 +
H+, 418.24890; found (ESI, [M + H]+), 418.2492.
6-(4-{[(2R)-2-Methylpyrrolidin-1-yl]carbonyl}phenyl)-2-(2-
pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-1(2H)-one (41).
Using the procedure described for 32 and employing
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dx.doi.org/10.1021/jm300011d | J. Med. Chem. 2012, 55, 2452−2468