Journal of Medicinal Chemistry
Article
4-Bromo-N-[8-fluoro-3-(1-pyrrolidinylmethyl)-7-quinolinyl]-
benzamide (42). To a solution of 39 (1.31 g, 5.30 mmol) in DMA
(26.6 mL) was added 4-bromobenzoyl chloride (1.29 g, 5.90 mmol),
and the reaction mixture was stirred for 5 h. The solution was poured
into aqueous K2CO3 solution, and the resulting solution was subjected
to extraction with EtOAc The extract was washed with brine and dried
over Na2SO4. The solvent was evaporated in vacuo, and the residue
was chromatographed on NH-silica gel, eluting with EtOAc, to give 42
7.97 (2H, m), 8.13 (2H, d, J = 8.7 Hz), 8.16 (1H, d, J = 1.2 Hz), 8.59
(1H, s), 8.81 (1H, d, J = 2.1 Hz), 10.62 (1H, s). Anal. Calcd for
C27H24ClN3O: C, 73.38; H, 5.47; N, 9.51. Found: C, 73.35; H, 5.45;
N, 9.53.
6-(4-Fluorophenyl)-N-[3-(1-pyrrolidinylmethyl)-7-
quinolinyl]nicotinamide (5f). Compound 5f was prepared in the
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same manner as described for 5b. Yield: 64%. Mp: 218−220 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.76 (2H, s), 7.38
(2H, m), 7.96 (2H, m), 8.18 (2H, m), 8.28 (2H, m), 8.45 (1H, dd, J =
8.4, 2.4 Hz), 8.59 (1H, s), 8.82 (1H, d, J = 2.1 Hz), 9.25 (1H, d, J = 1.5
Hz), 10.76 (1H, s). Anal. Calcd for C26H23FN4O·0.5H2O: C, 71.71; H,
5.55; N, 12.87. Found: C, 71.55; H, 5.59; N, 12.84.
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(1.82 g, 80.0%) as a powder. H NMR (DMSO-d6): δ 1.73 (4H, m),
2.51 (4H, m), 3.81 (2H, s), 7.75−7.83 (4H, m), 7.98 (2H, d, J = 8.4
Hz), 8.30 (1H, s), 8.90 (1H, d, J = 2.1 Hz), 10.54 (1H, s).
4-Bromo-N-[6-fluoro-3-(1-pyrrolidinylmethyl)-7-quinolinyl]-
benzamide (43). Compound 43 was prepared in the same manner as
6-Phenyl-N-[3-(1-pyrrolidinylmethyl)-7-quinolinyl]-
nicotinamide (5g). Compound 5g was prepared in the same manner
as described for 5b. Yield: 32%. Mp: 208−210 °C. 1H NMR (DMSO-
d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.76 (2H, s), 7.55 (3H, m), 7.96
(2H, m), 8.20 (4H, m), 8.45 (1H, dd, J = 8.4, 2.4 Hz), 8.59 (1H, s),
8.82 (1H, d, J = 2.1 Hz), 9.26 (1H, d, J = 1.8 Hz), 10.76 (1H, s). Anal.
Calcd for C26H24N4O·0.5H2O: C, 74.80; H, 6.04; N, 13.42. Found: C,
74.95; H, 5.98; N, 13.35.
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described for 42. Yield: 38%. H NMR (DMSO-d6): δ 1.73 (4H, m),
2.50 (4H, m), 3.78 (2H, s), 7.78 (2H, d, J = 8.4 Hz), 7.89 (1H, d, J =
11.1 Hz), 7.95 (2H, d, J = 8.4 Hz), 8.22 (1H, s), 8.33 (1H, d, J = 7.5
Hz), 8.82 (1H, d, J = 1.8 Hz), 10.47 (1H, s).
4-Bromo-N-[6-chloro-3-(1-pyrrolidinylmethyl)-7-quinolinyl]-
benzamide (44). Compound 44 was prepared in the same manner as
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described for 42. Yield: 64%. H NMR (DMSO-d6): δ 1.73 (4H, m),
2.50 (4H, m), 3.80 (2H, s), 1.98 (2H, s), 7.46 (2H, d, J = 8.1 Hz), 7.63
(2H, d, J = 8.3 Hz), 8.26 (3H, m), 8.88 (1H, d, J = 1.5 Hz), 10.37 (1H,
s).
6-(4-Methoxyphenyl)-N-[3-(1-pyrrolidinylmethyl)-7-
quinolinyl]nicotinamide (5h). Compound 5h was prepared in the
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same manner as described for 5b. Yield: 32%. Mp: 246−248 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.77 (2H, s), 3.85
(3H, s), 7.10 (2H, d, J = 9.3 Hz), 7.96 (2H, m), 8.11 (1H, d, J = 8.1
Hz), 8.19 (3H, m), 8.40 (1H, dd, J = 8.4, 2.1 Hz), 8.58 (1H, s), 8.82
(1H, d, J = 2.1 Hz), 9.21 (1H, d, J = 1.5 Hz), 10.72 (1H, s). Anal.
Calcd for C27H26N4O2: C, 73.95; H, 5.98; N, 12.78. Found: C, 73.66;
H, 6.04; N, 12.74.
N-[3-(1-Pyrrolidinylmethyl)-7-quinolinyl][1,1′-biphenyl]-4-
carboxamide (5b). To a solution of 38 (150 mg, 0.569 mmol), [1,1′-
biphenyl]-4-carboxylic acid (124 mg, 0.626 mmol), 4-
(dimethylamino)pyridine (70 mg, 0.569 mmol), and triethylamine
(79.1 mL, 0.569 mmol) in DMF (3 mL) was added EDC·HCl (120
mg, 0.626 mmol) with ice-bath cooling, and the mixture was stirred at
room temperature for 16 h. The suspension was diluted with EtOAc,
and the solution was washed with aqueous K2CO3 and brine and dried
over Na2SO4. The solvent was evaporated in vacuo, and the residue
was chromatographed on alumina, eluting with EtOAc, and crystallized
from EtOAc and diisopropyl ether to give 5b (61.5 mg, 26.5%) as a
6-(4-Methylphenyl)-N-[3-(1-pyrrolidinylmethyl)-7-
quinolinyl]nicotinamide (5i). Compound 5i was prepared in the
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same manner as described for 5b. Yield: 64%. Mp: 226−228 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.39 (3H, s), 2.50 (4H, m), 3.77
(2H, s), 7.36 (2H, d, J = 8.1 Hz), 7.96 (2H, m), 8.11 (2H, d, J = 8.1
Hz), 8.17 (2H, m), 8.42 (1H, dd, J = 8.4, 2.4 Hz), 8.59 (1H, s), 8.82
(1H, d, J = 2.1 Hz), 9.23 (1H, m), 10.74 (1H, s). Anal. Calcd for
C27H26N4O: C, 76.75; H, 6.20; N, 13.26. Found: C, 76.47; H, 6.29; N,
13.13.
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powder. Mp: 192−194 °C. H NMR (DMSO-d6): δ 1.73 (4H, m),
2.50 (4H, m), 3.77 (2H, s), 7.44 (1H, m), 7.53 (2H, m), 7.78 (2H, d, J
= 6.9 Hz), 7.88 (2H, d, J = 8.7 Hz), 7.96 (2H, m), 8.14 (3H, m), 8.59
(1H, s), 8.81 (1H, d, J = 2.1 Hz), 10.61 (1H, s). Anal. Calcd for
C27H25N3O·0.9H2O: C, 77.86; H, 6.29; N, 10.09. Found: C, 77.96; H,
6.30; N, 10.21.
6-(4-Chlorophenyl)-N-[3-(1-pyrrolidinylmethyl)-7-
quinolinyl]nicotinamide (5j). Compound 5j was prepared in the
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same manner as described for 5b. Yield: 54%. Mp: 223−225 °C. H
4′-Fluoro-N-[3-(1-pyrrolidinylmethyl)-7-quinolinyl][1,1′-bi-
NMR (DMSO-d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.77 (2H, s), 7.62
(2H, d, J = 9.0 Hz), 7.96 (2H, m), 8.17−8.26 (4H, m), 8.47 (1H, dd, J
= 8.4, 2.4 Hz), 8.59 (1H, s), 8.82 (1H, d, J = 2.1 Hz), 9.26 (1H, d, J =
1.5 Hz), 10.77 (1H, s). Anal. Calcd for C26H23ClN4O: C, 70.50; H,
5.23; N, 12.65; Cl, 8.00. Found: C, 70.28; H, 5.20; N, 12.91.
4-Phenyl-N-[3-(1-pyrrolidinylmethyl)-7-quinolinyl]-1-piperi-
dinecarboxamide (5l). To a solution of 38 (150 mg, 0.569 mmol)
and triethylamine (79.1 μL, 0.569 mmol) in DMA (3 mL) was added
1,1′-carbonyldiimidazole (111 mg, 0.682 mmol) at 0 °C. After this
solution was stirred for 1 h, 4-phenylpiperidine hydrochloride (124
mg, 0.626 mmol) was added, and the reaction mixture was stirred at
room temperature for 2 h. The mixture was diluted with EtOAc, and
the solution was washed with aqueous K2CO3 and brine. The extract
was washed with brine and dried over Na2SO4. The solvent was
evaporated in vacuo, and the residue was chromatographed on
alumina, eluting with EtOAc, and crystallized from EtOAc and
diisopropyl ether to give 5l (18.8 mg, 8%) as a powder. Mp: 222−224
°C. 1H NMR (DMSO-d6): δ 1.59−1.67 (2H, m), 1.71 (4H, m), 1.81−
1.85 (2H, m), 2.50 (4H, m), 2.77 (1H, m), 2.94 (2H, m), 3.73 (2H, s),
4.32−4.36 (2H, m), 7.18−7.34 (5H, m), 7.73−7.82 (2H, m), 8.07
(1H, s), 8.16 (1H, d, J = 2.1 Hz), 8.73 (1H, d, J = 2.4 Hz), 8.87 (1H,
s). Anal. Calcd for C26H30N4O: C, 75.33; H, 7.29; N, 13.52. Found: C,
75.15; H, 7.35; N, 13.47.
phenyl]-4-carboxamide (5a). Compound 5a was prepared in the
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same manner as described for 5b. Yield: 42%. Mp: 210−212 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.77 (2H, s), 7.35
(2H, m), 7.85 (4H, m), 7.97 (2H, m), 8.14 (3H, m), 8.59 (1H, d, J =
1.8 Hz), 8.81 (1H, d, J = 2.1 Hz), 10.61 (1H, s). Anal. Calcd for
C27H24FN3O: C, 76.21; H, 5.69; N, 9.88. Found: C, 75.99; H, 5.78; N,
9.93.
4′-Methoxy-N-[3-(1-pyrrolidinylmethyl)-7-quinolinyl][1,1′-
biphenyl]-4-carboxamide (5c). Compound 5c was prepared in the
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same manner as described for 5b. Yield: 49%. Mp: 202−204 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.76 (2H, s), 3.82
(3H, s), 7.08 (2H, d, J = 8.7 Hz), 7.74 (2H, d, J = 8.7 Hz), 7.83 (2H, d,
J = 8.4 Hz), 7.97 (2H, m), 8.10 (2H, d, J = 8.7 Hz), 8.15 (1H, d, J =
1.2 Hz), 8.59 (1H, d, J = 1.8 Hz), 8.81 (1H, d, J = 2.1 Hz), 10.57 (1H,
s). Anal. Calcd for C28H27N3O2·0.3H2O: C, 75.93; H, 6.28; N, 9.49.
Found: C, 75.99; H, 6.23; N, 9.63.
4′-Methyl-N-[3-(1-pyrrolidinylmethyl)-7-quinolinyl][1,1′-bi-
phenyl]-4-carboxamide (5d). Compound 5d was prepared in the
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same manner as described for 5b. Yield: 30%. Mp: 206−208 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.37 (3H, s), 2.50 (4H, m), 3.77
(2H, s), 7.33 (2H, d, J = 7.8 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.85 (2H, d,
J = 8.4 Hz), 7.97 (2H, m), 8.11 (2H, d, J = 8.7 Hz), 8.16 (1H, d, J =
1.5 Hz), 8.59 (1H, d, J = 1.8 Hz), 8.81 (1H, d, J = 2.1 Hz), 10.59 (1H,
s). Anal. Calcd for C28H27N3O·0.3H2O: C, 78.77; H, 6.52; N, 9.84.
Found: C, 78.77; H, 6.35; N, 9.63.
4-(4-Fluorophenyl)-N-[3-(1-pyrrolidinylmethyl)-7-quinolin-
yl]-1-piperidinecarboxamide (5k). Compound 5k was prepared in
the same manner as described for 5l. Yield: 38%. Mp: 239−241 °C. 1H
NMR (DMSO-d6): δ 1.56−1.64 (2H, m), 1.71 (4H, m), 1.80−1.84
(2H, m), 2.47 (4H, m), 2.78 (1H, m), 2.92 (2H, m), 3.73 (2H, s),
4.31−4.36 (2H, m), 7.12 (2H, m), 7.32 (2H, m), 7.73−7.82 (2H, m),
8.06 (1H, d, J = 1.5 Hz), 8.16 (1H, d, J = 2.1 Hz), 8.72 (1H, d, J = 1.8
4′-Chloro-N-[3-(1-pyrrolidinylmethyl)-7-quinolinyl][1,1′-bi-
phenyl]-4-carboxamide (5e). Compound 5e was prepared in the
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same manner as described for 5b. Yield: 50%. Mp: 217−220 °C. H
NMR (DMSO-d6): δ 1.72 (4H, m), 2.50 (4H, m), 3.77 (2H, s), 7.58
(2H, d, J = 8.7 Hz), 7.82 (2H, d, J = 8.4 Hz), 7.88 (2H, d, J = 8.4 Hz),
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dx.doi.org/10.1021/jm201596h | J. Med. Chem. 2012, 55, 2353−2366