Journal of Medicinal Chemistry
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N-(2-Isopropylphenyl)-4-oxo-1,4-dihydroquinoline-3-car-
boxamide (11). Compound 11 was prepared from 2-isopropylaniline
(67.6 mg, 0.5 mmol) in a similar manner as described for compound 1.
Yield: 16.6 mg, 11%. 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H),
12.35 (s, 1H), 8.90 (s, 1H), 8.36 (dd, J = 8.1, 1.4 Hz, 1H), 8.20 (dd, J
= 8.1, 1.4 Hz, 1H), 7.85−7.79 (m, 1H), 7.76 (d, J = 8.1 Hz, 1H),
7.61−7.46 (m, 1H), 7.35 (dd, J = 7.7, 1.6 Hz, 1H), 7.28−7.18 (m,
1H), 7.18−7.06 (m, 1H), 3.40−3.33 (m, 1H), 1.29 (d, J = 6.7 Hz,
6H). HRMS-ESI (m/z): [M + H]+ calcd for C19H18N2O2, 307.1441;
found, 307.1454.
7.7 Hz, 2H), 3.18 (t, J = 7.7 Hz, 2H). HRMS-ESI (m/z): [M + H]+
calcd for C18H15N3O2, 306.1242; found, 306.1237.
4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid (1-Methyl-
1H-indol-6-yl)amide (18). Compound 18 was prepared from 1-
methyl-1H-indol-6-ylamine (55 mg, 0.3 mmol) in a similar manner as
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described for compound 1. Yield: 30 mg, 32%. H NMR (400 MHz,
DMSO-d6) δ 12.94 (d, J = 5.3 Hz, 1H), 12.51 (s, 1H), 8.89 (d, J = 6.3
Hz, 1H), 8.36 (dd, J = 8.1, 1.1 Hz, 1H), 8.06 (t, J = 0.7 Hz, 1H), 7.85−
7.75 (m, 2H), 7.57−7.51 (m, 2H), 7.28 (d, J = 3.1 Hz, 1H), 7.24 (dd, J
= 8.4, 1.8 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 3.78 (s, 3H).
HRMS-ESI (m/z): [M + H]+ calcd for C19H15N3O2, 318.1242; found,
318.1231.
N-(4-Ethylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxa-
mide (12). Compound 12 was prepared from 4-ethylaniline (60.6 mg,
0.5 mmol) in a similar manner as described for compound 1. Yield: 5.6
4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid (1H-Pyrrolo-
[2,3-b]pyridin-6-yl)amide (19). Compound 19 was prepared from
1H-pyrrolo[2,3-b]pyridin-6-ylamine (53 mg, 0.4 mmol) in a similar
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mg, 4%. H NMR (DMSO-d6, 300 MHz) δ 8.83 (s, 1H), 8.29 (d, J =
7.8 Hz, 1H), 7.78−7.70 (m, 2H), 7.61 (d, J = 7.8 Hz, 2H), 7.51 (t,
1H), 7.17 (d, J = 8.1 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5
Hz,1H), 0.92 (t, J = 7.8 Hz, 3H). HRMS-ESI (m/z): [M + H]+ calcd
for C18H16N2O2, 293.1285; found, 293.1292.
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manner as described for compound 1. Yield: 18 mg, 15%. H NMR
(400 MHz, DMSO-d6) δ 12.79 (s, 1H), 12.02 (s, 1H), 10.46 (s, 1H),
9.00 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.97
(d, J = 8.7 Hz, 1H), 7.82 (m, 2H), 1H), 7.37 (s, 1H), 6.46 (s, 1H).
HRMS-ESI (m/z): [M + H]+ calcd for C17H12N4O2, 305.1038; found,
305.1039.
N-(4-Isopropylphenyl)-4-oxo-1,4-dihydroquinoline-3-car-
boxamide (13). Compound 13 was prepared from 4-isopropylaniline
(67.6 mg, 0.5 mmol) in a similar manner as described for compound 1.
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Yield: 5.5 mg, 3%. H NMR (DMSO-d6, 300 MHz) δ 8.84 (s, 1H),
N-(1H-Indazol-6-yl)-4-oxo-1,4-dihydroquinoline-3-carboxa-
mide (20). Compound 20 was prepared from 1H-indazol-6-amine (26
mg, 0.2 mmol) in a similar manner as described for compound 1.
8.29 (d, J = 8.1 Hz, 1H), 7.78−7.70 (m, 2H), 7.61 (d, J = 8.4 Hz, 2H),
7.50 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 2.85 (h, J = 6.9 Hz,
1H), 1.19 (d, J = 6.9 Hz, 6H). HRMS-ESI (m/z): [M + H]+ calcd for
C19H18N2O2, 307.1441; found, 307.1439.
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Yield: 27 mg, 44%. H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H),
12.78 (s, 1H), 8.91 (s, 1H), 8.40−8.31 (m, 2H), 7.99 (s, 1H), 7.84−
7.69 (m, 3H), 7.53 (t, J = 7.4 Hz, 1H), 7.09 (dd, J = 8.6, 1.6 Hz, 1H).
HRMS-ESI (m/z): [M + H]+ calcd for C17H12N4O2, 305.1038; found,
305.1031.
N-(1H-Benzo[d]imidazol-6-yl)-4-oxo-1,4-dihydroquinoline-
3-carboxamide (21). Compound 21 was prepared from 1H-
benzo[d]imidazol-6-amine (27 mg, 0.2 mmol) in a similar manner
as described for compound 1. Yield: 28 mg, 46%. 1H NMR (400 MHz,
DMSO-d6) δ 13.05 (d, J = 6.4 Hz, 1H), 12.77 (s, 1H), 9.09 (s, 1H),
8.92 (d, J = 6.7 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 7.4 Hz,
1H), 7.87−7.81 (m, 1H), 7.77 (dd, J = 8.3, 6.1 Hz, 2H), 7.60−7.49
(m, 2H). HRMS-ESI (m/z): [M + H]+ calcd for C17H12N4O2,
305.1038; found, 305.1043.
4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid Naphthalen-
2-ylamide (14). Compound 14 was prepared from 2-naphthylamine
(28 mg, 0.2 mmol) in a similar manner as described for compound 1.
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Yield: 20 mg, 32%. H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H),
8.92 (s, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.37 (dd, J = 8.1, 1.0 Hz, 1H),
7.93 (d, J = 8.8 Hz, 1H), 7.90−7.80 (m, 3H), 7.80−7.72 (m, 2H),
7.60−7.53 (m, 1H), 7.53−7.46 (m, 1H), 7.46−7.39 (m, 1H). HRMS-
ESI (m/z): [M + H]+ calcd for C20H14N2O2, 315.1133; found,
315.1141.
4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid (1H-Indol-5-
yl)amide (15). Compound 15 was prepared from 5-aminoindole (26
mg, 0.2 mmol) in a similar manner as described for compound 1.
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Yield: 31 mg, 50%. H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H),
4-Oxo-N-(2-oxoindolin-6-yl)-1,4-dihydroquinoline-3-carbox-
amide (22). Compound 22 was prepared from 6-aminoindolin-2-one
(60 mg, 0.4 mmol) in a similar manner as described for compound 1.
Yield: 4 mg, 3%. 1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 12.51
(s, 1H), 10.43 (s, 1H), 8.86 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.82 (t, J
= 7.6 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.58−7.50 (m, 2H), 7.17 (d, J
= 8.0 Hz, 1H), 7.06 (dd, J = 8.0, 1.2 Hz, 1H), 3.44 (s, 2H). HRMS-ESI
(m/z): [M + H]+ calcd for C18H13N3O3, 320.1035; found, 320.1041.
1H-Indol-6-yl 4-oxo-1,4-dihydroquinoline 3-Carboxylate
(23). In a round-bottom flask 4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (49, 57 mg, 0.3 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-
phosphonium hexafluorophosphate (133 mg, 0.3 mmol), 1H-indol-6-
ol (40 mg, 0.3 mmol), DMF (1.0 mL), and DIEA (116.3 mg, 0.16 mL,
0.9 mmol) were added and the mixture was stirred at 25 °C for 18 h.
The solvent was evaporated under reduced pressure. The crude
material was dissolved in DMSO, filtered, and purified by reverse-
12.34 (s, 1H), 11.05 (s, 1H), 8.88 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H),
8.08 (s, 1H), 7.81 (dd, J = 11.7, 4.8 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H),
7.54 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.34 (t, J = 2.7 Hz,
1H), 7.29 (dd, J = 8.6, 1.9 Hz, 1H), 6.41 (s, 1H). HRMS-ESI (m/z):
[M + H]+ calcd for C18H13N3O2, 304.1086; found, 304.1086.
4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid (1H-Indol-6-
yl)amide (16). Compound 16 was prepared from 6-aminoindole (45
mg, 0.34 mmol) in a similar manner as described for compound 1.
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Yield: 54 mg, 52%. H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H),
12.47 (s, 1H), 11.08 (s, 1H), 8.90 (s, 1H), 8.35 (dd, J = 8.1, 1.1 Hz,
1H), 8.20 (t, J = 0.8 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7
Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.30 (t, J =
2.7 Hz, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.39 (m, 1H). HRMS-ESI
(m/z): [M + H]+ calcd for C18H13N3O2, 304.1086; found, 304.1078.
4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid (2,3-Dihydro-
1H-indol-6-yl)amide (17). Step 1. 4-Oxo-1,4-dihydroquinoline-3-
carboxylic acid (1-acetyl-2,3-dihydro-1H-indol-6-yl)amide was pre-
pared from 1-(6-amino-2,3-dihydroindol-1-yl)ethanone (70 mg, 0.4
mmol) in a similar manner as described for compound 1. Yield: 43 mg,
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phase HPLC to provide compound 23. Yield: 27 mg, 30%. H NMR
(DMSO-d6, 400 MHz) δ 12.58 (s, 1H), 11.17 (s, 1H), 8.83 (d, J = 3.5
Hz, 1H), 8.21 (dd, J = 8.1, 1.0 Hz, 1H), 7.79−7.72 (m, 1H), 7.69 (d, J
= 7.8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.49−7.43 (m, 1H), 7.39−
7.34 (m, 1H), 7.22 (d, J = 1.7 Hz, 1H), 6.83 (dd, J = 8.5, 2.0 Hz, 1H),
6.49−6.42 (m, 1H). HRMS-ESI (m/z): [M + H]+ calcd for
C18H12N2O3, 305.0926; found, 305.0921.
4-Oxo-1,4-dihydroquinoline-3-sulfonyl Chloride (51). In a
round-bottom flask, 4-hydroxyquinoline (50, 1.13 g, 7.78 mmol) was
treated with chlorosulfonic acid (3.1 mL, 47 mmol), and the mixture
was heated at 125 °C for 3 h. The brownish clear solution was then
poured into ice−water, and a yellow precipitate was formed. The solid
was collected by filtration and washed with cold water (5 × 50 mL).
The solid was lyophilized to provide compound 51 (1.9 g, 100%) as a
beige solid. 1H NMR (300 MH, DMSO-d6,) δ 9.20 (s, 1H), 8.36 (d, J
= 8.4 Hz, 1H), 8.12−8.04 (m, 2H), 7.81 (t, J = 6.9 Hz, 1H).
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30%. H NMR (400 MHz, DMSO-d6) δ 12.75 (d, J = 13.6 Hz, 1H),
8.87 (s, 1H), 8.32−8.28 (m, 2H), 7.76−7.70 (m, 2H), 7.60 (d, J = 7.8
Hz, 1H), 7.49−7.45 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.11 (t, J = 8.3
Hz, 2H), 3.10 (t, J = 7.7 Hz, 2H), 2.18 (s, 3H).
Step 2. 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (1-acetyl-2,3-
dihydro-1H-indol-6-yl)amide (43 mg, 0.12 mmol) was heated at reflux
in a mixture of ethanol (0.5 mL) and 1 N NaOH (0.5 mL) for 48 h.
The reaction mixture was evaporated under reduced pressure, and the
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residue was purified by reverse-phase HPLC. Yield: 10 mg, 27%. H
NMR (400 MHz, DMSO-d6) δ 13.27 (d, J = 6.6 Hz, 1H), 12.73 (s,
1H), 11.36 (s, 1H), 8.87 (d, J = 6.7 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H),
8.15 (s, 1H), 7.83 (q, J = 8.1 Hz, 2H), 7.65−7.29 (m, 3H), 3.75 (t, J =
9786
dx.doi.org/10.1021/jm5012808 | J. Med. Chem. 2014, 57, 9776−9795