382
Y. Sun et al. / European Journal of Medicinal Chemistry 141 (2017) 373e385
(0.56 g, 45.5%) as yellow solid.
1H NMR (400 MHz, DMSO)
d 10.69 (s, 1H), 9.62 (s, 1H), 8.38 (s, 1H),
8.21e8.16 (m, 1H), 8.11 (d, J ¼ 8.2 Hz, 1H), 8.06 (d, J ¼ 8.7 Hz, 2H),
7.86 (t, J ¼ 8.0 Hz,1H), 7.64 (d, J ¼ 7.7 Hz,1H), 7.60 (d, J ¼ 8.7 Hz, 2H),
7.48 (m, J ¼ 8.0, 1.1 Hz, 1H), 7.32 (m, J ¼ 11.5, 4.2 Hz, 1H), 7.09e7.02
(m, 1H), 6.70 (m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (m, J ¼ 17.0, 1.8 Hz, 1H),
4.1.2.3. N-(6-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)
ureido)
phenyl)pyridin-2-yl)acrylamide (17a). To a mixture of 10 (0.20 g,
0.55 mmol) and triethanolamine (0.31 mL, 2.20 mmol) dissolved in
20 mL of anhydrous THF in ice-bath. After stirring for 30 min,
acryloyl chloride (0.11 mL, 1.33 mmol) was dropped. The reaction
was warmed to the room temperature and stirred overnight. After
the completion of the reaction, the mixture was filtered and the
filtrate distilled by rotary evaporation to remove THF. After filtra-
tion and concentration in vacuo, the residues was purified by silica
gel flash chromatography (PE/AcOEt ¼ 1:1) yielding 17a as white
solid (yield 55.3%), HRMS m/z calcd for C22H16ClF3N4O2 ([M]þ)
460.0914, found 460.9698. m.p. ¼ 165e167 ꢀC, 1H NMR (400 MHz,
5.81 (m, J ¼ 10.2, 1.7 Hz, 1H). 13C NMR (101 MHz, DMSO)
d 164.26,
155.03, 152.49, 152.10, 140.97, 139.64, 136.30, 132.33, 132.12, 129.72,
128.20, 128.08, 127.76, 123.94, 122.53, 121.88, 118.43, 115.65, 112.32.
4.1.2.8. N-(6-(4-(3-(3-isopropylphenyl)ureido)phenyl) pyridin-2-yl)
acrylamide (17f). White solid (yield 76.5%), HRMS m/z calcd for
C
24H24N4O2 ([M]þ) 400.1899, found 400.9910. m.p. ¼ 172e174 ꢀC,
1H NMR (400 MHz, DMSO)
d 10.69 (s, 1H), 8.89 (s, 1H), 8.73 (s, 1H),
8.12 (d, J ¼ 8.2 Hz,1H), 8.03 (d, J ¼ 8.7 Hz, 2H), 7.85 (t, J ¼ 8.0 Hz,1H),
7.63 (d, J ¼ 7.7 Hz, 1H), 7.60 (d, J ¼ 8.7 Hz, 2H), 7.39 (s, 1H), 7.28 (d,
J ¼ 8.2 Hz, 1H), 7.20 (t, J ¼ 7.8 Hz, 1H), 6.88 (d, J ¼ 7.5 Hz, 1H), 6.71
(m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (m, J ¼ 17.0, 1.8 Hz, 1H), 5.81 (m,
J ¼ 10.2, 1.8 Hz, 1H), 2.85 (t, J ¼ 13.8, 6.9 Hz, 1H), 1.21 (d, J ¼ 6.9 Hz,
DMSO)
d
10.69 (s, 1H), 9.24 (s, 1H), 9.06 (s, 1H), 8.15 (d, J ¼ 2.2 Hz,
1H), 8.12 (d, J ¼ 8.2 Hz,1H), 8.05 (d, J ¼ 8.8 Hz, 2H), 7.86 (t, J ¼ 8.0 Hz,
1H), 7.65 (d, J ¼ 1.8 Hz, 2H), 7.63 (d, J ¼ 4.4 Hz, 1H), 7.60 (s, 1H), 6.70
(m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (m, J ¼ 17.0, 1.9 Hz, 1H), 5.81 (m,
J ¼ 10.2, 1.9 Hz, 1H). 13C NMR (101 MHz, DMSO)
d
164.26, 155.01,
6H). 13C NMR (101 MHz, DMSO)
d 164.26, 155.13, 152.88, 152.09,
152.76, 152.11, 140.76, 139.72, 139.62, 132.49, 132.12, 128.18, 127.66,
127.35, 127.04, 123.62, 122.91, 118.82, 117.32, 115.70, 112.37.
The title compounds 17b-17n were prepared from the key in-
termediate 10 and acryloyl chloride with a similar procedure as
described for compounds 17b.
149.53, 141.34, 140.01, 139.58, 132.14, 131.96, 129.16, 128.15, 127.65,
120.51, 118.36, 116.71, 116.37, 115.61, 112.25, 33.98, 24.35.
4.1.2.9. N-(6-(4-(3-(3-chlorophenyl)ureido)phenyl)pyridin-2-yl)
acrylamide (17g). White solid (yield 69.7%), HRMS m/z calcd for
C
21H17ClN4O2 ([M]þ) 392.1040, found 392.9003. m.p. ¼ 214e216 ꢀC,
4.1.2.4. N-(6-(4-(3-(4-chloro-3-methylphenyl)ureido)phenyl)
pyr-
1H NMR (400 MHz, DMSO)
d 10.68 (s, 1H), 8.98 (s, 2H), 8.12 (d,
idin-2-yl)acrylamide (17b). White solid (yield 78.1%), HRMS m/z
calcd for
J ¼ 8.2 Hz, 1H), 8.04 (d, J ¼ 8.7 Hz, 2H), 7.86 (t, J ¼ 8.0 Hz,1H), 7.76 (s,
1H), 7.64 (d, J ¼ 7.6 Hz, 1H), 7.60 (d, J ¼ 8.8 Hz, 2H), 7.33 (d,
J ¼ 8.1 Hz, 1H), 7.30 (d, J ¼ 1.5 Hz, 1H), 7.04 (m, J ¼ 7.3, 1.8 Hz, 1H),
6.70 (m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (m, J ¼ 17.0, 1.8 Hz, 1H), 5.81 (m,
C
22H19ClN4O2 ([M]þ) 406.1197, found 406.9239.
m.p. ¼ 217e219 ꢀC, 1H NMR (400 MHz, DMSO)
d 10.68 (s, 1H), 8.91
(s, 1H), 8.83 (s, 1H), 8.11 (d, J ¼ 8.2 Hz, 1H), 8.04 (d, J ¼ 8.7 Hz, 2H),
7.85 (t, J ¼ 7.9 Hz,1H), 7.73 (d, J ¼ 1.9 Hz,1H), 7.65e7.62 (m,1H), 7.59
(d, J ¼ 8.7 Hz, 2H), 7.26 (d, J ¼ 8.3 Hz, 1H), 7.21 (m, J ¼ 8.3, 2.0 Hz,
1H), 6.70 (m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (m, J ¼ 17.0, 1.8 Hz, 1H),
J ¼ 10.2, 1.8 Hz, 1H). 13C NMR (101 MHz, DMSO)
d 164.26, 155.05,
152.74, 152.10, 141.62, 140.98, 139.61, 133.69, 132.29, 132.13, 130.88,
128.17, 127.67, 122.05, 118.60, 118.12, 117.20, 115.65, 112.31.
5.84e5.77 (m, 1H), 2.27 (s, 3H). 13C NMR (101 MHz, DMSO)
d 164.26,
155.07, 152.78, 152.09, 141.09, 139.59, 139.23, 133.61, 132.13, 131.65,
129.28, 128.85, 128.16, 127.65, 118.68, 118.53, 117.51, 115.63, 112.29,
19.29.
4.1.2.10. N-(6-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)
pyridin-2-yl)acrylamide (17h). White solid (yield 81.3%), HRMS m/z
phenyl)
calcd for
C
22H17F3N4O3 ([M]þ) 442.1253, found 442.9702.
m.p. ¼ 248e250 ꢀC, 1H NMR (400 MHz, DMSO)
d 10.68 (s, 1H), 9.00
4.1.2.5. N-(6-(4-(3-(4-fluorophenyl)ureido)phenyl)pyridin-2-yl)
acrylamide (17c). þWhite solid (yield 81.8%), HRMS m/z calcd for
(s, 1H), 8.97 (s, 1H), 8.12 (d, J ¼ 8.2 Hz, 1H), 8.04 (d, J ¼ 8.7 Hz, 2H),
7.85 (t, J ¼ 8.0 Hz, 1H), 7.63 (d, J ¼ 7.9 Hz, 1H), 7.61 (d, J ¼ 3.1 Hz, 2H),
7.59 (d, J ¼ 3.4 Hz, 2H), 7.31 (d, J ¼ 8.5 Hz, 2H), 6.71 (m, J ¼ 17.0,
10.2 Hz, 1H), 6.34 (m, J ¼ 17.0, 1.9 Hz, 1H), 5.81 (m, J ¼ 10.2, 1.8 Hz,
C
21H17FN4O2 ([M] ) 376.1336, found 376.9211. m.p. ¼ 252e254 ꢀC,
1H NMR (400 MHz, DMSO)
d 10.68 (s, 1H), 8.87 (s, 1H), 8.78 (s, 1H),
8.11 (d, J ¼ 8.2 Hz,1H), 8.03 (d, J ¼ 8.7 Hz, 2H), 7.85 (t, J ¼ 8.0 Hz,1H),
7.63 (d, J ¼ 7.7 Hz, 1H), 7.59 (d, J ¼ 8.7 Hz, 2H), 7.52e7.46 (m, 2H),
7.14 (t, J ¼ 8.9 Hz, 2H), 6.70 (m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (m,
J ¼ 17.0, 1.8 Hz,1H), 5.81 (m, J ¼ 10.2, 1.8 Hz,1H). 13C NMR (101 MHz,
1H). 13C NMR (101 MHz, DMSO)
d 164.26, 155.08, 152.84, 152.10,
143.16, 141.09, 139.59, 139.37, 132.21, 132.13, 128.15, 127.66, 122.20,
119.95, 118.54, 115.64, 112.30.
DMSO)
d
164.25, 159.08, 156.71, 155.10, 152.97, 152.09, 141.25,
4.1.2.11. N-(6-(4-(3-(2,4-dichlorophenyl)ureido)phenyl) pyridin-2-yl)
139.59, 136.37, 132.13, 132.05, 128.17, 127.65, 120.59, 120.52, 118.45,
115.88, 115.66, 112.26.
acrylamide (17i). White solid (yield 62.4%), HRMS m/z calcd for
C
21H16Cl2N4O2
([M]þ)
426.0650,
found
426.8830.
m.p. ¼ 243e245 ꢀC, 1H NMR (400 MHz, DMSO)
d
10.69 (s, 1H), 9.65
4.1.2.6. N-(6-(4-(3-(4-(tert-butyl)phenyl)ureido)phenyl) pyridin-2-
yl)acrylamide (17d). White solid (yield 84.0%), HRMS m/z calcd for
(s, 1H), 8.46 (s, 1H), 8.23 (d, J ¼ 8.9 Hz, 1H), 8.12 (d, J ¼ 8.1 Hz, 1H),
8.06 (d, J ¼ 8.5 Hz, 2H), 7.86 (t, J ¼ 7.9 Hz,1H), 7.64 (d, J ¼ 3.5 Hz,1H),
7.63 (s, 1H), 7.60 (d, J ¼ 8.5 Hz, 2H), 7.41 (m, J ¼ 8.9, 1.8 Hz, 1H), 6.70
(m, J ¼ 17.0, 10.2 Hz, 1H), 6.34 (d, J ¼ 16.9 Hz, 1H), 5.81 (d,
C
25H26N4O2
([MþH]þ)
415.2056,
found
415.0150.
m.p. ¼ 194e196 ꢀC, 1H NMR (400 MHz, DMSO)
d
10.68 (s, 1H), 8.83
(s, 1H), 8.65 (s, 1H), 8.11 (d, J ¼ 8.2 Hz, 1H), 8.03 (d, J ¼ 8.7 Hz, 2H),
7.85 (t, J ¼ 8.0 Hz, 1H), 7.66e7.61 (m, 1H), 7.61 (s, 2H), 7.39 (d,
J ¼ 8.7 Hz, 2H), 7.31 (d, J ¼ 8.7 Hz, 2H), 6.70 (m, J ¼ 17.0, 10.2 Hz, 1H),
6.37e6.31 (m, 1H), 5.81 (m, J ¼ 10.2, 1.8 Hz, 1H), 1.27 (s, 9H). 13C
J ¼ 10.7 Hz,1H). 13C NMR (101 MHz, DMSO)
d 164.26,154.99, 152.36,
152.10, 140.78, 139.63, 135.57, 132.48, 132.11, 129.05, 128.19, 128.13,
127.77, 126.73, 123.22, 122.67, 118.51, 115.67, 112.36.
NMR (101 MHz, DMSO)
d
164.26, 155.13, 152.90, 152.08, 144.77,
4.1.2.12. N-(6-(4-(3-(3-(trifluoromethyl)phenyl)ureido) phenyl) pyr-
idin-2-yl)acrylamide (17j). White solid (yield 71.9%), HRMS m/z
141.38, 139.58, 137.38, 132.13, 131.92, 128.17, 127.66, 125.88, 118.61,
118.32, 115.60, 112.24, 34.36, 31.72.
calcd for
C
22H17F3N4O2 ([M]þ) 426.1304, found 426.9488.
m.p. ¼ 179e180 ꢀC, 1H NMR (400 MHz, DMSO)
d 10.70 (s, 1H), 9.13
4.1.2.7. N-(6-(4-(3-(2-chlorophenyl)ureido)phenyl)pyridin-2-yl)
(s, 1H), 9.02 (s, 1H), 8.13 (d, J ¼ 8.2 Hz, 1H), 8.07 (s, 1H), 8.05 (d,
J ¼ 8.9 Hz, 2H), 7.86 (t, J ¼ 8.0 Hz,1H), 7.64 (d, J ¼ 6.6 Hz, 2H), 7.60 (d,
J ¼ 8.5 Hz, 2H), 7.53 (t, J ¼ 8.0 Hz, 1H), 7.33 (d, J ¼ 7.6 Hz, 1H), 6.71
acrylamide (17e). White solid (yield 46.9%), HRMS m/z calcd for
C
21H17ClN4O2 ([M]þ) 392.1040, found 392.8999. m.p. ¼ 178e180 ꢀC,