Journal of Medicinal Chemistry
Article
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for ∼15 min under nitrogen atmosphere. To this solution was added
the corresponding amine (0.146 mmol), and the solution was stirred
for an additional 12 h. The reaction solution was concentrated and
diluted with diethyl ether, which resulted in the formation of a
precipitate. The precipitate was isolated through vacuum filtration and
purified via reverse-phase chromatography, eluting a gradient of 0−
collected via vacuum filtration. Yield = 0.03 g (42%). H NMR (400
MHz, DMSO-d6): δ 9.49 (t, J = 5.9 Hz, 1H), 9.41 (d, J = 2.1 Hz, 1H),
8.95 (d, J = 2.2 Hz, 1H), 7.94 (s, 1H), 7.86−7.81 (m, 1H), 7.61 (t, J =
7.8 Hz, 1H), 7.41−7.32 (m, 4H), 7.26 (t, J = 7.1 Hz, 1H), 4.58 (d, J =
5.8 Hz, 2H). HR-ESI-MS calcd for [C34H27N4O2S2]+, 587.1570;
found, 587.1571.
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8,8′-Disulfanediylbis(N-(4-fluorobenzyl)quinoline-3-carboxa-
100% acetonitrile in H2O. Yield = 0.065 g (22%). H NMR (400
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mide) (40). Product afforded via method A. Yield = 0.04 g (14%). H
MHz, DMSO-d6): δ 9.32 (d, J = 2 Hz, 1H), 9.04 (t, J = 5.2 Hz, 1H),
8.84 (d, J = 2 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H),
7.61−7.54 (m, 2H), 6.36 (t, J = 2.8 Hz, 1H), 6.21 (d, J = 2.8 Hz, 1H),
3.62 (q, J = 6 Hz, 2H), 2.96 (q, J = 7.2 Hz, 2H). HR-ESI-MS calcd for
[C32H26N4O4S2Na]+, 617.1288; found, 617.1283
NMR (400 MHz, DMSO-d6): δ 9.48 (t, J = 5.6 Hz, 1H), 9.39 (d, J =
1.6 Hz, 1H), 8.92 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84
(d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.44−7.15 (m, 4H), 4.56
(d, J = 5.6 Hz, 2H). HR-ESI-MS calcd for [C34H25F2N4O2S2]+,
623.1382; found, 623.1384.
8,8′-Disulfanediylbis(N-(2-(thiophen-2-yl)ethyl)quinoline-3-car-
boxamide) (34). To a solution of 16b (0.2 g, 0.98 mmol) in DMF (10
mL) was added CDI (0.24 g, 1.46 mmol) and stirred at room
temperature for ∼15 min under nitrogen atmosphere. To this solution
was added the corresponding amine (0.146 mmol), and the solution
was stirred for an additional 12 h. To the resulting solution was added
H2O, which resulted in the formation of a precipitate. The precipitate
was isolated through vacuum filtration and further purified via reverse-
phase chromatography using a gradient of 0−100% acetonitrile in
H2O. Yield = 0.075 g (24%). 1H NMR (400 MHz, DMSO-d6): δ 9.35
(s, 1H), 9.10 (t, J = 5.2 Hz, 1H), 8.87 (s, 1H), 7.95 (d, J = 6.4 Hz,
1H), 7.84 (d, J = 6.4 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.34−6.96 (m,
3H), 3.60 (t, J = 6 Hz, 2H), 3.14 (t, J = 6 Hz, 2H). HR-ESI-MS calcd
for [C32H27N4O2S4]+, 627.1011; found, 627.1013.
8,8′-Disulfanediylbis(N-(4-(trifluoromethyl)benzyl)quinoline-3-
carboxamide) (41). Product afforded via method A. Yield = 0.09 g
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(26%). H NMR (400 MHz, DMSO-d6): δ 9.58 (t, J = 5.6 Hz, 1H),
9.40 (s, 1H), 8.94 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0
Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.62−7.61 (m, 3H), 4.67 (d, J = 5.2
Hz, 2H). ESI-MS(+): m/z 723.25 [M + H]+. HR-ESI-MS calcd for
[C36H24F6N4O2S2Na]+, 745.1137; found, 745.1141
8,8′-Disulfanediylbis(N-(4-methoxybenzyl)quinoline-3-carboxa-
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mide) (42). Product afforded via method A. Yield = 0.15 g (47%). H
NMR (400 MHz, DMSO-d6): δ 9.40−9.38 (m, 2H), 8.91 (d, J = 1.6
Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62 (t, J =
8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.50
(d, J = 5.6 Hz, 2H) 3.72 (s, 3H). HR-ESI-MS calcd for
[C36H30N4O4S2Na]+, 669.1601; found, 669.1603.
8,8′-Disulfanediylbis(N-(benzo[d][1,3]dioxol-5-ylmethyl)-
quinoline-3-carboxamide) (43). Product afforded via method A. Yield
= 0.12 g (37%). 1H NMR (400 MHz, acetone-d6): δ 9.38 (s, 2H), 9.01
(s, 1H), 8.27−8.26 (m, 2H), 7.81 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H),
6.87−6.85 (m, 2H), 5.98 (s, 2H), 4.46 (d, J = 5.6 Hz, 2H). HR-ESI-
MS calcd for [C36H27N4O6S2]+, 675.1372; found, 675.1374.
8,8′-Disulfanediylbis(N-(4-morpholinobenzyl)quinoline-3-carbox-
amide) (44). Product afforded via method A. Yield = 0.18 g (50%). 1H
NMR (400 MHz, DMSO-d6): δ 9.40−9.33 (m, 2H), 8.91 (s, 1H), 7.94
(d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H),
7.26 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.47 (d, J = 5.6 Hz,
2H), 3.72 (t, J = 4.8 Hz, 4H), 3.05 (t, J = 4.8 Hz, 4H). HR-ESI-MS
calcd for [C42H40N6O4S2 Na]+, 779.2445; found, 779.2443.
8,8′-Disulfanediylbis(N-(2-(thiazol-2-yl)ethyl)quinoline-3-carbox-
amide) (35). To a solution of 16b (0.2 g, 0.98 mmol) in DMF (10
mL) was added CDI (0.24 g, 1.46 mmol), and the mixture was stirred
at room temperature for ∼15 min under nitrogen atmosphere. To this
solution was added the corresponding amine (0.15 mmol), and the
solution was stirred for an additional ∼12 h. To the resulting solution
was added H2O, which resulted in the formation of a precipitate. The
precipitate was isolated through vacuum to yield the final product.
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Yield = 0.18 g (57%). H NMR (400 MHz, DMSO-d6): δ 9.33 (s,
1H), 9.11 (t, J = 5.2 Hz, 1H), 8.86 (s, 1H), 7.95 (d, J = 8 Hz, 1H),
7.84 (d, J = 8 Hz, 1H), 7.74 (d, J = 3.2 Hz, 1H), 7.62−7.58 (m, 2H),
3.74 (q, 2H), 3.34 (t, 2H). 13C NMR (100 MHz, DMSO- d6): δ 167.7,
163.3, 148.9, 146.3, 143.0, 136.6, 134.9, 128.6, 128.6, 127.6, 127.5,
126.3, 120.4, 40.1, 32.9. HR-ESI-MS calcd for [C30H25N6O2S4]+,
629.0916; found, 629.0913.
8,8′-Disulfanediylbis(N-(2-morpholinoethyl)quinoline-3-carboxa-
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mide) (45). Product afforded via method A. Yield = 0.07 g (24%). H
8,8′-Disulfanediylbis(N-(pyridin-2-ylmethyl)quinoline-3-carboxa-
NMR (400 MHz, acetone-d6): δ 9.45 (s, 1H), 8.96 (s, 1H), 8.36 (d, J
= 8 Hz, 1H), 8.30 (d, J = 8 Hz, 1H), 7.86 (t, J = 8 Hz, 1H), 3.79−3.75
(m, 6H), 3.06 (t, J = 6 Hz, 2H). HR-ESI-MS calcd for
[C32H37N6O4S2]+, 633.2312; found, 633.2316.
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mide) (36). Product afforded via method B. Yield = 0.06 g (21%). H
NMR (400 MHz, DMSO-d6): δ 9.52 (d, J = 2.4 Hz, 1H), 9.07 (d, J =
2.4 Hz, 1H), 8.77−8.58 (m, 2H), 8.36 (dd, J = 7.2, 1.2 Hz, 1H), 8.32
(dd, J = 7.2, 1.2 Hz, 1H), 7.86−7.82 (m, 2H), 7.55 (d, J = 8 Hz, 1H),
7.36 (t, J = 6 Hz, 3H), 4.82 (d, J = 6 Hz, 2H). HR-ESI-MS calcd for
[C32H25N6O2S2]+, 589.1475; found, 589.1478.
Dibenzyl 2,2′-((2,2′-((8,8′-Disulfanediylbis(quinoline-8,3-diyl-3-
carbonyl))bis(azanediyl))bis(acetyl))bis(azanediyl))diacetate (46).
To a solution of 16b (0.05 g, 0.24 mmol) in dry DMF (5 mL) was
added HATU (0.11 g, 0.29 mmol), HOBT (0.04 g, 0.29 mmol), Et3N
(0.068 mL, 0.48 mmol), and H2N-Gly-Gly-Bz (0.11 g, 0.26 mmol).
The reaction was stirred at room temperature for 4 h. The resulting
mixture was evaporated to dryness, and the crude material was
dissolved in CH2Cl2 and washed with 1 M HCl, H2O, and then brine.
The product, which precipitated out of the organic layer, was filtered
8,8′-Disulfanediylbis(N-(pyridin-3-ylmethyl)quinoline-3-carboxa-
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mide) (37). Product afforded via method B. Yield = 0.11 g (38%). H
NMR (400 MHz, DMSO-d6): δ 9.46 (d, J = 2.4 Hz, 1H), 8.98 (d, J =
2.4 Hz, 1H), 8.70−8.52 (m, 2H), 8.34 (dd, J = 7.2, 1.2 Hz, 1H), 8.27
(dd, J = 7.2, 1.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 (t, J = 7.6 Hz,
1H), 7.43 (dd, J = 7.6, 4.8 Hz, 1H), 4.73 (d, J = 5.6 Hz, 2H). HR-ESI-
MS calcd for [C32H25N6O2S2]+, 589.1475; found, 589.1477.
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off and dried under vacuum. Yield = 0.07 g (69%). H NMR (400
8,8′-Disulfanediylbis(N-(pyridin-4-ylmethyl)quinoline-3-carboxa-
MHz, DMSO-d6): δ 9.40 (d, J = 2.1 Hz, 1H), 9.29 (t, J = 5.9 Hz, 1H),
8.94 (d, J = 2.2 Hz, 1H), 8.51 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 8.0 Hz,
1H), 7.88−7.82 (m, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.37−7.28 (m, 5H),
5.14 (s, 2H), 4.03 (d, J = 5.9 Hz, 2H), 3.95 (d, J = 5.9 Hz, 2H). HR-
ESI-MS calcd for [C42H37N6O8S2]+, 817.2109; found, 817.2106.
8-Hydroxy-N-(2-(thiazol-2-yl)ethyl)quinoline-3-carboxamide
(47). To a solution of 8-hydroxyquinoline-3-carboxylic acid (0.1 g,
0.529 mmol) in DMF (3 mL) was added Et3N (0.088 mL, 0.634
mmol) and HATU (0.24 g, 0.634 mmol), then allowed to stir at room
temperature for ∼15 min. To this was then added 2-(thiazol-2-
yl)ethan-1-amine (0.08 g, 0.634 mmol) and allowed to stir for 18 h.
The resulting solution was concentrated in vacuo and purified via silica
gel chromatography, eluting a gradient of 0−20% MeOH in CH2Cl2.
Yield = 0.04 g (30%). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (t, J =
3.6 Hz, 1H), 9.26 (s, 1H), 9.17 (s, 1H), 7.78 (d, J = 3.2 Hz, 1H),
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mide) (38). Product afforded via method B. Yield = 0.06 g (21%). H
NMR (400 MHz, DMSO-d6): δ 9.88 (t, J = 5.6 Hz, 1H), 9.46 (d, J =
2.4 Hz, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.84−8.74 (m, 2H), 7.99 (d, J =
8 Hz, 1H), 7.92−7.91 (m, 2H), 7.87 (d, J = 8 Hz, 1H), 7.65 (t, J = 8
Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H). HR-ESI-MS calcd for
[C32H25N6O2S2]+, 589.1475; found, 589.1477.
8,8′-Disulfanediylbis(N-benzylquinoline-3-carboxamide) (39). To
a solution of 16b (0.2 g, 0.98 mmol) in DMF (10 mL) was added
HATU (0.56 g, 1.46 mmol) and Et3N (0.204 mL, 1.46 mmol), and the
mixture was stirred at 60 °C for ∼15 min under nitrogen atmosphere.
To this solution was added the corresponding amine (0.146 mmol),
and the solution was stirred for an additional 12 h. The reaction
mixture was concentrated, and the crude material was dissolved in
CH2Cl2. The product, which precipitated out of the organic layer, was
N
J. Med. Chem. XXXX, XXX, XXX−XXX