766
A.K. El-Damasy et al. / European Journal of Medicinal Chemistry 101 (2015) 754e768
4.10.1. 4-((2-(3-(2,4-Dichlorophenyl)ureido)quinolin-5-yl)oxy)-N-
found: 538.0867.
methylpicolinamide (9a)
White solid; yield 100%; mp 246e248 C; 1H NMR (300 MHz,
ꢀ
4.10.6. 4-((2-(3-(3,4-Dichlorophenyl)ureido)quinolin-5-yl)oxy)-N-
methylpicolinamide (9f)
DMSO-d
6
)
d
12.41 (br. s, 1H), 10.57 (s, 1H), 8.80 (q, J ¼ 4.8 Hz, 1H),
White solid; yield 91.6%; mp 234e236 C; 1H NMR (400 MHz,
ꢀ
8
1
2
.55 (d, J ¼ 5.6 Hz, 1H), 8.45 (d, J ¼ 9.0 Hz, 1H), 8.26 (d, J ¼ 9.1 Hz,
H), 7.85e7.83 (m, 2H), 7.75 (d, J ¼ 2.4 Hz, 1H), 7.46 (dd, J ¼ 8.9,
.3 Hz, 1H), 7.42 (d, J ¼ 2.5 Hz, 1H), 7.34e7.29 (m, 2H), 7.22 (q,
DMSO-d
6
)
d
11.92 (s, 1H), 10.34 (s, 1H), 8.80 (q, J ¼ 4.6 Hz, 1H), 8.57
(dd, J ¼ 5.8, 0.3 Hz, 1H), 8.27 (dd, J ¼ 9.1, 0.5 Hz, 1H), 8.13e8.12 (m,
1H), 8.01 (d, J ¼ 8.5 Hz, 1H), 7.83 (t, J ¼ 7.8 Hz, 1H), 7.62 (s, 2H), 7.47
(d, J ¼ 9.1 Hz, 1H), 7.42 (d, J ¼ 2.5 Hz, 1H), 7.34 (dd, J ¼ 7.7, 0.8 Hz,
13
J ¼ 2.6 Hz,1H), 2.78 (d, J ¼ 4.8 Hz, 3H); C NMR (75 MHz, DMSO-d
6
)
d
165.65, 163.62, 152.60, 151.92, 150.62, 148.97, 146.12, 135.01,
32.89, 131.00, 128.66, 127.80, 126.83, 123.89, 122.92, 122.31, 117.85,
13
1
1H), 7.24 (dd, J ¼ 5.6, 2.6 Hz, 1H), 2.79 (d, J ¼ 4.8 Hz, 3H); C NMR
115.88, 114.37, 114.15, 109.13, 25.97; HRMS (ESI-TOF) m/z calcd for
(75 MHz, DMSO-d
6
) d 166.18, 164.12, 153.12, 152.51, 151.12, 149.32,
þ
C
23
H17Cl
2
N
5
O
3
Na [MþNa] : 504.0606, found: 504.0596.
146.82, 139.35, 133.23, 131.70, 131.18, 131.12, 125.15, 124.84, 120.82,
1
19.98, 118.40, 116.37, 114.83, 114.67, 109.54, 26.47; HRMS (ESI-TOF)
þ
4
.10.2. 4-((2-(3-(2,4-Difluorophenyl)ureido)quinolin-5-yl)oxy)-N-
methylpicolin-amide (9b)
White solid; yield 96%; mp 253e255 C; 1H NMR (400 MHz,
DMSO-d
12.48 (br. s, 1H), 10.46 (s, 1H), 8.79 (q, J ¼ 4.8 Hz, 1H),
.56 (d, J ¼ 5.6 Hz, 1H) 8.37e8.30 (m, 1H), 8.26 (d, J ¼ 9.2 Hz, 1H),
.84 (t, J ¼ 8.0 Hz,1H), 7.76 (d, J ¼ 8.4 Hz,1H), 7.44 (td, J ¼ 8.6, 2.8 Hz,
H), 7.34 (t, J ¼ 8.4 Hz, 2H), 7.23 (dd, J ¼ 5.6, 2.4 Hz, 1H), 7.12 (t,
m/z calcd for C23
H16Cl
2
N
5
O
3
[MꢁH] : 480.0636, found: 480.0627.
ꢀ
4.10.7. 4-((2-(3-(4-Chlorophenyl)ureido)quinolin-5-yl)oxy)-N-
methylpicolinamide (9g)
6
) d
ꢀ
8
7
2
White solid; yield 85%; mp 248e250 C; 1H NMR (400 MHz,
DMSO-d
6
)
d
11.83 (s, 1H), 10.23 (s, 1H), 8.80 (q, J ¼ 4.4 Hz, 1H), 8.55
(d, J ¼ 5.6 Hz, 1H), 8.24 (d, J ¼ 8.8 Hz, 1H), 7.94 (d, J ¼ 8.4 Hz, 1H),
7.81 (t, J ¼ 8.0 Hz, 1H), 7.73 (d, J ¼ 8.8 Hz, 2H), 7.46e7.40 (m, 4H),
7.32 (d, J ¼ 7.2 Hz, 1H), 7.23 (dd, J ¼ 5.6, 2.8 Hz, 1H), 2.79 (d,
13
J ¼ 8.8 Hz, 1H), 2.80 (d, J ¼ 4.8 Hz, 3H); C NMR (100 MHz, DMSO-
166.14, 164.15, 153.33, 153.13, 152.54, 151.16, 149.49, 146.56,
33.23, 131.39, 124.36, 124.16, 122.10, 118.28, 116.30, 114.79, 111.93,
6
d ) d
1
1
3
J ¼ 4.8 Hz, 3H); C NMR (100 MHz, DMSO-d
6
) d 166.17, 164.13,
111.63, 109.66, 104.72, 104.31, 104.11, 26.49; HRMS (ESI-TOF) m/z
153.28, 153.11, 152.47, 151.10, 149.35, 146.85, 138.18, 133.08, 131.07,
129.27, 129.07, 126.95, 124.95, 121.18, 120.29, 118.31, 116.21, 114.83,
þ
calcd for C23
H F
17 2
N
5
O
3
Na [MþNa] : 472.1197, found: 472.1200.
1
C
14.65, 109.58, 26.47; HRMS (ESI-TOF) m/z calcd for
þ
4
.10.3. 4-((2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)quinolin-5-
yl)oxy)-N-methylpicolinamide (9c)
White solid; yield 89%; mp 258e260 C; 1H NMR (400 MHz,
DMSO-d
11.98 (br. s, 1H), 10.43 (br. s, 1H), 8.80 (q, J ¼ 4.4 Hz, 1H),
.57 (d, J ¼ 5.6 Hz, 1H), 8.36 (s, 2H), 8.28 (d, J ¼ 9.2 Hz, 1H), 8.03 (d,
J ¼ 8.4 Hz, 1H), 7.85 (t, J ¼ 8.0 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J ¼ 9.2 Hz,
H), 7.41 (d, J ¼ 2.4 Hz, 1H), 7.35 (dd, J ¼ 7.8, 0.8 Hz, 1H), 7.25 (q,
23
H18ClN
5
O
3
Na [MþNa] : 470.0996, found: 470.0985.
ꢀ
4.10.8. 4-((2-(3-(4-Bromophenyl)ureido)quinolin-5-yl)oxy)-N-
methylpicolinamide (9h)
6
) d
ꢀ
8
White solid; yield 93.3%; mp 261e264 C; 1H NMR (400 MHz,
DMSO-d
6
)
d
11.82 (s, 1H), 10.24 (s, 1H), 8.80 (q, J ¼ 4.4 Hz, 1H), 8.57
1
(d, J ¼ 5.6 Hz, 1H), 8.25 (d, J ¼ 9.2 Hz, 1H), 7.96 (d, J ¼ 8.4 Hz, 1H),
7.82 (t, J ¼ 8.0 Hz, 1H), 7.71e7.67 (m, 2H), 7.56e7.54 (m, 2H), 7.47 (d,
J ¼ 9.2 Hz, 1H), 7.43 (d, J ¼ 2.8 Hz, 2H), 7.33 (d, J ¼ 7.4 Hz, 1H), 7.24
13
J ¼ 2.4 Hz, 1H), 2.79 (d, J ¼ 5.2 Hz, 3H); C NMR (100 MHz, DMSO-
166.19, 164.12, 153.11, 152.97, 152.77, 151.12, 149.27, 146.92,
41.22, 133.26, 131.45, 131.13, 125.35, 125.10, 122.39, 119.86, 118.52,
6
d ) d
1
13
(dd, J ¼ 5.6, 2.4 Hz, 1H), 2.79 (d, J ¼ 4.8 Hz, 3H); C NMR (100 MHz,
116.45, 114.84, 114.68, 109.50, 26.47; HRMS (ESI-TOF) m/z calcd for
DMSO-d
6
) d 166.18, 164.12, 153.28, 153.13, 152.46, 151.12, 149.37,
þ
C
H F
25 17 6
N
5
O
3
Na [MþNa] : 572.1134, found: 572.1145.
146.87, 138.62, 132.18, 131.10, 124.97, 121.59, 118.34, 116.25, 114.89,
1
C
14.85, 114.66, 109.58, 26.47; HRMS (ESI-TOF) m/z calcd for
þ
4.10.4. 4-((2-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)
23
H18BrN
5
O
3
Na [MþNa] : 514.0491, found: 514.0490.
quinolin-5-yl)oxy)-N-methylpicolinamide (9d)
White solid; yield 88%; mp 240e242 C; 1H NMR (400 MHz,
DMSO-d
11.97 (br. s, 1H), 10.39 (br. s, 1H), 8.81 (q, J ¼ 4.8 Hz, 1H),
ꢀ
4.10.9. 4-((2-(3-(4-Fluorophenyl)ureido)quinolin-5-yl)oxy)-N-
methylpicolinamide (9i)
6
) d
ꢀ
8
1
1
1
.57 (d, J ¼ 5.6 Hz, 1H), 8.35 (d, J ¼ 2.4 Hz, 1H), 8.28 (d, J ¼ 9.6 Hz,
White solid; yield 86%; mp 241e243 C; 1H NMR (400 MHz,
H), 8.00 (d, J ¼ 8.8 Hz, 1H), 7.90e7.82 (m, 2H), 7.71 (d, J ¼ 8.8 Hz,
H), 7.52 (d, J ¼ 9.2 Hz,1H), 7.42 (d, J ¼ 2.4 Hz,1H), 7.35 (d, J ¼ 7.2 Hz,
DMSO-d
6
)
d
11.75 (s, 1H), 10.20 (s, 1H), 8.81 (q, J ¼ 4.8 Hz, 1H), 8.57
(d, J ¼ 5.6 Hz, 1H), 8.25 (dd, J ¼ 9.2, 0.8 Hz, 1H), 7.96 (d, J ¼ 8.4 Hz,
1H), 7.82 (t, J ¼ 8.0 Hz, 1H), 7.74e7.71 (m, 2H), 7.45 (d, J ¼ 9.2 Hz,
1H), 7.42 (d, J ¼ 2.4 Hz, 1H), 7.33 (dd, J ¼ 7.6, 0.8 Hz, 1H), 7.25-7.23
13
H), 7.25 (dd, J ¼ 5.6, 2.8 Hz, 1H), 2.79 (d, J ¼ 4.8 Hz, 3H); C NMR
(
75 MHz, DMSO-d
6
) d 166.16, 164.12, 153.12, 153.07, 152.59, 151.10,
13
149.33, 146.84, 138.74, 133.18, 132.56, 131.07, 125.07, 124.79, 124.05,
(m, 3H), 2.79 (d, J ¼ 5.2 Hz, 3H); C NMR (100 MHz, DMSO-d
6
)
118.43, 118.17, 116.31, 114.82, 114.66, 109.55, 26.46; HRMS (ESI-TOF)
d 166.20, 164.13, 158.42, 153.39, 153.12, 152.58, 151.12, 149.36,
þ
m/z calcd for
C
24
H17ClF
3
N
5
O
3
Na [MþNa] : 538.0870, found:
146.90, 135.54, 133.07, 131.09, 124.99, 121.46, 118.28, 116.23, 116.09,
5
38.0862.
115.86, 114.77, 109.56, 26.47; HRMS (ESI-TOF) m/z calcd for
þ
C
23
H18FN
5
O
3
Na [MþNa] : 454.1292, found: 454.1277.
4.10.5. 4-((2-(3-(2-Chloro-5-(trifluoromethyl)phenyl)ureido)
quinolin-5-yl)oxy)-N-methylpicolinamide (9e)
4.10.10. N-Methyl-4-((2-(3-(4-(trifluoromethyl)phenyl)ureido)
quinolin-5-yl)oxy)picolinamide (9j)
ꢀ
1
White solid; yield 90.2%; mp 283e285 C; H NMR (400 MHz,
White solid; yield 95.7%; mp 271e273 C; 1H NMR (400 MHz,
ꢀ
DMSO-d
6
)
d
12.51 (br. s, 1H), 10.57 (s, 1H), 8.84 (d, J ¼ 2.0 Hz, 1H),
8
1
1
.69 (q, J ¼ 4.4 Hz, 1H), 8.56 (d, J ¼ 5.6 Hz, 1H), 8.28 (d, J ¼ 9.2 Hz,
DMSO-d
6
)
d
11.99 (s, 1H), 10.31 (s, 1H), 8.80 (q, J ¼ 4.9 Hz, 1H), 8.57
H), 7.89e7.82 (m, 3H), 7.49 (d, J ¼ 1.6 Hz, 1H), 7.47 (d, J ¼ 2.4 Hz,
H), 7.38 (d, J ¼ 8.8 Hz, 1H), 7.33 (dd, J ¼ 7.2, 1.2 Hz, 1H), 7.23 (dd,
(d, J ¼ 5.6 Hz, 1H), 8.27 (d, J ¼ 9.3 Hz, 1H), 7.97 (d, J ¼ 8.4 Hz, 1H),
7.91 (d, J ¼ 8.5 Hz, 2H), 7.83 (t, J ¼ 7.8 Hz,1H), 7.72 (d, J ¼ 8.6 Hz, 2H),
7.50 (d, J ¼ 9.1 Hz, 1H), 7.43 (d, J ¼ 2.5 Hz, 1H), 7.34 (dd, J ¼ 7.6,
13
J ¼ 5.6, 2.4 Hz, 1H), 2.81 (d, J ¼ 4.8 Hz, 3H); C NMR (100 MHz,
1
3
DMSO-d
6
)
d
166.12, 164.16, 153.24, 153.06, 152.58, 151.09, 149.59,
0.7 Hz, 1H), 7.24 (dd, J ¼ 5.6, 2.6 Hz, 1H), 2.80 (d, J ¼ 4.8 Hz, 3H);
C
146.66, 137.29, 133.40, 131.43, 130.92, 129.03, 128.72, 126.49, 124.35,
6
NMR (100 MHz, DMSO-d ) d 166.17, 164.15, 153.19, 153.12, 152.48,
1
20.62, 118.45, 117.91, 116.28, 114.90, 114.65, 109.75, 26.42; HRMS
151.12, 149.38, 142.90, 133.22, 131.15, 126.70, 126.65, 124.98, 123.61,
123.57, 123.26, 119.52, 118.43, 116.33, 114.84, 114.67, 109.58, 26.46;
þ
(
ESI-TOF) m/z calcd for C24
H17ClF
3
N
5
O
3
Na [MþNa] : 538.0870,