Journal of Medicinal Chemistry
Article
concentrated hydrochloric acid. The formed precipitated was filtered,
washed with cold water, and dried under vacuum, providing 21a−k.
The obtained compound was dissolved in 2 mL of oxalyl chloride, and
the solution was refluxed for 2 h. The solvent was evaporated, and the
remaining oxalyl chloride was removed by azeotropic distillation with
toluene. After the residue was dissolved in anhydrous dichloro-
methane, corresponding anilines (0.27 mmol) and Et3N (0.90 mmol)
were added to this solution. The reaction was stirred at room
temperature for 2 h. After the reaction was complete, the solution was
washed with brine, dried over anhydrous sodium sulfate, and purified
by flash column chromatography (petroleum/ethyl acetate = 4:1 to
1:1) to provide the desired product.
4-(2,5-Dichlorophenoxy)-N-(2-chlorophenyl)-N-methyl-3-nicotin-
carboxamide (17g). The title compound was obtained as an off-white
solid from 20k and 2-chloro-N-methylaniline according to the general
procedure in 72% yield. 1H NMR (300 MHz, CDCl3): δ 8.54 (s, 1H),
8.26 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.35 (m, 2H), 7.14−
7.25 (m, 3H), 6.92 (d, J = 2.1 Hz, 1H), 6.30 (d, J = 6.0 Hz, 1H), 3.44
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 165.59, 159.15, 151.72,
149.68, 149.31, 140.32, 133.56, 132.48, 131.59, 130.62, 130.19, 129.59,
127.63, 127.13, 125.41, 123.17, 123.00, 109.49, 36.28. HRMS (ESI+)
m/z calcd for C19H14Cl3N2O2 (M + H)+ 407.0121, found 407.0141.
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(3,4-dihydro-2H-quinolin-
1-yl)methanone (22a). The title compound was obtained as an off-
white solid from 20k and tetrahydroquinoline according to the general
procedure in 50% yield. 1H NMR (300 MHz, CDCl3): δ 8.81 (s, 1H),
8.42 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.11 (m, 3H), 6.91
(m, 1H), 6.66 (m, 1H), 6.25 (m, 1H), 5.89 (m, 1H), 2.67 (m, 2H),
2.05 (m, 2H), 1.77 (m, 2H). HRMS (ESI+) m/z calcd for
C21H16Cl2N2O2Na (M + Na)+ 421.0487, found 421.0483.
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(4-isopropyl-3,4-dihydro-
2H-quinoxalin-1-yl)methanone (22e). The title compound was
obtained as a light yellow solid from 20k and 1-isopropyl-1,2,3,4-
tetrahydroquinoxaline according to the general procedure in 59%
1
yield. H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H), 8.42 (d, J = 5.7
Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.02
(t, J = 7.8 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H),
6.30 (m, 2H), 5.76 (d, J = 1.5 Hz, 1H), 4.95 (m, 1H), 3.78 (m, 1H),
3.40 (m, 2H), 3.17 (m, 1H), 1.11 (m, 3H), 0.87 (m, 3H). 13C NMR
(100 MHz, CDCl3): δ 163.45, 158.73, 152.02, 151.52, 149.24, 139.35,
133.07, 130.96, 127.10, 126.56, 124.88, 124.78, 124.15, 123.32, 122.03,
114.15, 111.32, 109.34, 46.88, 41.02, 39.94, 18.44. HRMS (ESI+) m/z
calcd for C23H21Cl2N3O2Na (M + Na)+ 464.0909, found 464.0915.
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(4-allyl-3,4-dihydro-2H-
quinoxalin-1-yl)methanone (22f). The title compound was obtained
as a light yellow solid from 20k and 1-allyl-1,2,3,4-tetrahydroquinoxa-
1
line according to the general procedure in 68% yield. H NMR (300
MHz, CDCl3): δ 8.87 (s, 1H), 8.44 (d, J = 6.3 Hz, 1H), 7.34 (d, J = 8.4
Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.49
(d, J = 7.5 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 6.33 (m, 2H), 5.75 (d, J
= 2.4 Hz, 1H), 5.48 (m, 1H), 5.01 (d, J = 17.4 Hz, 1H), 4.94 (d, J =
10.5 Hz, 1H), 3.16−3.82 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
163.75, 158.29, 152.27, 151.85, 149.25, 139.05, 133.10, 131.76, 130.92,
126.95, 126.31, 124.61, 124.47, 123.84, 123.31, 121.66, 116.33, 114.84,
111.66, 109.55, 52.66, 48.72, 39.96. HRMS (ESI+) m/z calcd for
C23H20Cl2N3O2 (M + H)+ 440.0933, found 440.0929.
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihy-
dro-2H-quinoxalin-1-yl)methanone (22g). The title compound was
obtained as an off-white solid from 20k and 1-cyclopropyl-1,2,3,4-
tetrahydroquinoxaline according to the general procedure in 72%
1
yield. H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.43 (d, J = 5.7
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(2,3-dihydro-2H-benzo-
[1,4]oxazin-4-yl)methanone (22b). The title compound was obtained
as an off-white solid from 20k and benzomorpholine according to the
Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.02 (d, J
= 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.38
(t, J = 7.8 Hz, 1H), 6.32 (d, J = 5.7 Hz, 1H), 5.66 (s, 1H), 4.91 (m,
1H), 3.48 (m, 2H), 3.16 (m, 1H), 2.24 (m, 1H), 0.66 (m, 3H), −0.30
(m, 1H). ESI-MS: 440 [M + H+].
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general procedure in 56% yield. H NMR (300 MHz, CDCl3): δ 8.85
(s, 1H), 8.48 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.13 (d, J =
6.6 Hz, 1H), 7.06 (t, J = 6.6 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.55
(m, 2H), 6.30 (d, J = 3.6 Hz, 1H), 5.85 (s, 1H), 4.94 (m, 1H), 4.37
(m, 2H), 3.40 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 163.81,
158.70, 152.74, 151.62, 148.88, 147.22, 133.44, 131.35, 127.12, 126.66,
125.95, 125.20, 123.21, 122.37, 122.16, 119.56, 117.43, 109.23, 66.76,
40.29, 29.66. HRMS (ESI+) m/z calcd for C20H15Cl2N2O3 (M + H)+
401.0460, found 401.0475.
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(4-ethyl-3,4-dihydro-2H-
quinoxalin-1-yl)methanone (22c). The title compound was obtained
as a brown solid from 20k and 1-ethyl-1,2,3,4-tetrahydroquinoxaline
according to the general procedure in 65% yield. 1H NMR (300 MHz,
CDCl3): δ 8.86 (s, 1H), 8.44 (d, J = 4.5 Hz, 1H), 7.32 (d, J = 6.3 Hz,
1H), 7.09 (dd, J = 6.3, 1.8 Hz, 1H), 7.01 (td, J = 6.3, 0.9 Hz, 1H), 6.48
(d, J = 6.3 Hz, 1H), 6.47 (dd, J = 5.7, 0.9 Hz, 1H), 6.38 (d, J = 4.5 Hz,
1H), 6.30 (t, J = 5.7 Hz, 1H), 5.77 (d, J = 1.8 Hz, 1H), 4.95 (m, 1H),
3.59 (m, 1H), 3.29 (m, 3H), 2.99 (m, 1H), 0.81 (t, J = 5.7 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 163.59, 158.41, 152.05, 151.67,
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(4-cyclobutyl-3,4-dihydro-
2H-quinoxalin-1-yl)methanone (22h). The title compound was
obtained as an off-white solid from 20k and 1-cyclobutyl-1,2,3,4-
tetrahydroquinoxaline according to the general procedure in 68%
1
yield. H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.44 (d, J = 4.5
Hz, 1H), 7.34 (d, J = 6.6 Hz, 1H), 7.11 (dd, J = 6.6, 1.5 Hz, 1H), 7.01
(td, J = 6.6, 0.9 Hz, 1H), 6.49 (t, J = 5.7 Hz, 2H), 6.35 (m, 2H), 5.73
(d, J = 0.9 Hz, 1H), 4.91 (m, 1H), 3.79 (m, 1H), 3.48 (s, 3H), 3.33
(m, 1H), 2.11 (m, 2H), 1.94 (m, 1H), 1.60 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 163.59, 158.58, 152.12, 151.64, 149.23, 139.51,
133.06, 130.94, 126.83, 126.43, 125.30, 124.79, 123.73, 123.28, 121.81,
115.02, 112.21, 109.40, 53.10, 44.21, 40.65, 27.75, 14.82. HRMS (ESI
+) m/z calcd for C24H22Cl2N3O2 (M + H)+ 454.1089, found 454.1092.
(4-Phenoxypyridin-3-yl)-(4-cyclopropyl-3,4-dihydro-2H-quinoxa-
lin-1-yl)methanone (23a). The title compound was obtained as an
off-white solid from 20a according to the general procedure in overall
1
55% yield. H NMR (300 MHz, CDCl3): δ 8.78 (s, 1H), 8.32 (d, J =
149.20, 138.69, 133.02, 130.97, 126.96, 126.38, 124.67, 124.28, 123.93,
123.38, 121.68, 114.32, 111.08, 109.49, 48.09, 44.48, 39.72, 10.33.
HRMS (ESI+) m/z calcd for C22H20Cl2N3O2 (M + H)+ 428.0933,
found 428.0940.
5.4 Hz, 1H), 7.26−7.22 (m, 2H), 7.18−7.15 (m, 1H), 7.01−6.96 (m,
2H), 6.51−6.49 (m, 1H), 6.39−6.36 (m, 1H), 6.31−6.26 (m, 3H),
4.94 (m, 1H), 3.44 (m, 2H), 3.12 (m, 1H), 2.2 (m, 1H), 0.55 (m, 3H),
−0.32 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 164.48, 160.18,
152.69, 151.96, 151.22, 140.39, 129.65, 126.16, 125.47, 123.38, 123.09,
120.37, 115.45, 113.12, 109.21, 48.69, 40.30, 30.78, 7.61. HRMS (ESI
+) m/z calcd for C23H21N3O2Na (M + Na)+ 394.1531, found
394.1521.
[4-(2,5-Dichlorophenoxy)pyridin-3-yl]-(4-propyl-3,4-dihydro-2H-
quinoxalin-1-yl)methanone (22d). The title compound was obtained
as an off-white solid from 20k and 1-propyl-1,2,3,4-tetrahydroquinoxa-
1
line according to the general procedure in 62% yield. H NMR (300
MHz, CDCl3): δ 8.87 (s, 1H), 8.44 (d, J = 6.0 Hz, 1H), 7.32 (d, J = 8.4
Hz, 1H), 7.11 (dd, J = 8.4, 2.1 Hz, 1H), 7.00 (t, J = 8.4 Hz, 1H), 6.46
(m, 2H), 6.34 (d, J = 6.0 Hz, 1H), 6.29 (t, J = 7.8 Hz, 1H), 5.74 (d, J =
2.1 Hz, 1H), 4.94 (m, 1H), 3.62 (m, 1H), 3.41 (m, 1H), 3.22 (m, 2H),
2.84 (m, 1H), 1.26 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 163.51, 158.58, 151.94, 151.53, 149.16, 139.02,
133.11, 130.95, 126.96, 126.50, 124.86, 124.12, 123.92, 123.37, 121.98,
114.28, 111.19, 109.47, 52.25, 49.31, 39.64, 19.07, 11.28. HRMS (ESI
+) m/z calcd for C23H22Cl2N3O2 (M + H)+ 442.1089, found 442.1091.
[4-(2-Chlorophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-
2H-quinoxalin-1-yl)methanone (23b). The title compound was
obtained as an brown solid from 20b according to the general
1
procedure in overall 50% yield. H NMR (300 MHz, CDCl3): δ 8.79
(s, 1H), 8.35 (d, J = 4.5 Hz, 1H), 7.40 (d, J = 5.7 Hz, 1H), 7.09 (m,
2H), 6.96 (m, 2H), 6.53 (d, J = 5.7 Hz, 1H), 6.36 (t, J = 5.7 Hz, 1H),
6.25 (d, J = 4.5 Hz, 1H), 5.88 (d, J = 5.7 Hz, 1H), 4.85 (br, 1H), 3.49
(m, 2H), 3.24 (m, 1H), 2.25 (m, 1H), 0.64 (m, 3H), −0.27 (br, 1H).
13C NMR (100 MHz, CDCl3): δ 163.92, 159.25, 151.92, 151.39,
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dx.doi.org/10.1021/jm301071h | J. Med. Chem. 2012, 55, 10475−10489