16
A.K. El-Damasy et al. / European Journal of Medicinal Chemistry 208 (2020) 112756
4.4.4. N-(4-((5-Methoxyquinolin-2-yl)amino)phenyl)quinoline-6-
carboxamide (7d)
[MþH]þ: 405.1118, found: 405.1117.
Column chromatography was performed using 2% MeOH in
4.4.9. N-(3-((5-Methoxyquinolin-2-yl)amino)phenyl)quinoline-6-
carboxamide (8d)
DCM. White solid; yield 73%; 1H NMR (400 MHz, MeOD)
d 8.94 (dd,
J ¼ 4.3, 1.7 Hz, 1H), 8.54 (d, J ¼ 1.9 Hz, 1H), 8.47 (dd, J ¼ 8.6, 0.9 Hz,
1H), 8.28 (dd, J ¼ 9.6, 4.0 Hz, 2H), 8.13 (d, J ¼ 8.8 Hz, 1H), 7.85 (d,
J ¼ 9.0 Hz, 2H), 7.72 (d, J ¼ 9.0 Hz, 2H), 7.61 (q, J ¼ 4.4 Hz,1H), 7.47 (t,
J ¼ 8.0 Hz, 1H), 7.30 (d, J ¼ 8.4 Hz, 1H), 6.91 (d, J ¼ 9.1 Hz, 1H), 6.75
Column chromatography was performed using 35e50% ethyl
acetate in DCM. Yellowish white solid; yield 79.6%; 1H NMR
(300 MHz, DMSO‑d6)
d 10.50 (br. s, 1H), 9.49 (br. s, 1H), 9.02 (dd,
J ¼ 4.1, 1.6 Hz, 1H), 8.66 (s, 1H), 8.56 (d, J ¼ 6.6 Hz, 2H), 8.30e8.23
(m, 2H), 8.16 (d, J ¼ 8.8 Hz, 1H), 7.82 (d, J ¼ 7.4 Hz, 1H), 7.65 (q,
J ¼ 4.2 Hz, 1H), 7.49 (t, J ¼ 8.2 Hz, 1H), 7.36e7.31 (m, 3H), 7.07
(d, J ¼ 9.1 Hz, 1H), 6.79 (d, J ¼ 7.9 Hz, 1H), 3.93 (s, 3H); 13C NMR
(d, J ¼ 7.4 Hz, 1H), 3.97 (s, 3H); 13C NMR (100 MHz, MeOD)
d 166.22,
155.60, 154.85, 151.66, 148.57, 138.00, 137.75, 133.31, 132.76, 132.02,
131.67, 129.62, 128.33, 128.08, 127.78, 122.09, 121.60, 119.75, 117.91,
115.21, 111.62, 101.90, 54.84; HRMS (FABþ) m/z calcd for
(75 MHz, DMSO‑d6) d 165.63, 155.40, 154.92, 152.66, 149.22, 148.41,
C
26H21N4O2 [MþH]þ: 421.1664, found: 421.1663.
142.17, 139.81, 137.64, 133.55, 131.41, 129.98, 129.54, 129.12, 128.88,
128.66, 127.56, 122.71, 119.58, 115.09, 113.94, 113.31, 111.20, 102.68,
56.11; HRMS (FABþ) m/z calcd for C26H21N4O2 [MþH]þ: 421.1664,
found: 421.1663.
4.4.5. N-(4-((5-Methoxyquinolin-2-yl)amino)phenyl)-2,3-
dihydrobenzo[b] [1,4]dioxine-6-carboxamide (7e)
Column chromatography was performed using a mixture of
hexane-ethyl acetate (1:1, v/v). White solid; yield 62.7%; 1H NMR
4.4.10. N-(3-((5-Methoxyquinolin-2-yl)amino)phenyl)-2,3-
dihydrobenzo[b] [1,4]dioxine-6-carboxamide (8e)
(300 MHz, DMSO‑d6)
d 9.98 (br. s, 1H), 9.37 (br. s, 1H), 8.22 (d,
J ¼ 8.9 Hz, 1H), 7.92 (d, J ¼ 8.3 Hz, 2H), 7.71 (d, J ¼ 8.3 Hz, 2H),
7.54e7.45 (m, 3H), 7.28 (d, J ¼ 8.2 Hz, 1H), 6.99 (d, J ¼ 8.0 Hz, 2H),
6.77 (d, J ¼ 7.5 Hz, 1H), 4.31 (s, 4H), 3.93 (s, 3H); 13C NMR (75 MHz,
Column chromatography was performed using a mixture of
hexane-ethyl acetate (1:1, v/v). White solid; yield 70.4%; 1H NMR
(400 MHz, CDCl3)
d
8.27 (d, J ¼ 9.1 Hz, 1H), 8.20 (s, 1H), 7.93 (d,
DMSO‑d6)
d
164.58, 155.43, 154.89, 148.48, 146.67, 143.40, 137.71,
J ¼ 1.9 Hz, 1H), 7.48e7.39 (m, 4H), 7.35 (dd, J ¼ 8.4, 2.2 Hz, 1H),
133.30, 131.36, 130.01, 128.43, 121.57, 121.44, 119.36, 117.27, 117.06,
115.00, 113.17, 102.53, 64.86, 64.50, 56.08; HRMS (FABþ) m/z calcd
for C25H22N3O4 [MþH]þ: 428.1610, found: 428.1613.
7.30e7.23 (m, 2H), 7.19 (br. s, 1H), 6.89e6.84 (m, 2H), 4.24e4.20 (m,
4H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 165.40, 155.42,
154.49, 148.49, 146.68, 143.39, 141.04, 138.83, 132.29, 129.66, 129.51,
128.17, 120.65, 119.27, 117.27, 116.78, 115.93, 115.87, 114.63, 111.89,
111.10, 101.95, 64.51, 64.13, 55.56; HRMS (FABþ) m/z calcd for
4.4.6. 4-Chloro-N-(3-((5-methoxyquinolin-2-yl)amino)phenyl)-3-
(trifluoromethyl)benzamide (8a)
C
25H22N3O4 [MþH]þ: 428.1610, found: 428.1607.
Column chromatography was performed using 5% ethyl acetate
in DCM. White solid; yield 59.6%; 1H NMR (400 MHz, DMSO‑d6)
4.4.11. N-(3-((5-Methoxyquinolin-2-yl)amino)phenyl)-4-(4-
methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide (9a)
Column chromatography was performed using 5e10% MeOH in
DCM. White solid; yield 78.3%; 1H NMR (400 MHz, Acetone-d6)
d
10.53 (br. s,1H), 9.50 (br. s,1H), 8.52 (s,1H), 8.42 (d, J ¼ 2.0 Hz,1H),
8.30 (dd, J ¼ 8.4, 2.0 Hz, 1H), 8.25 (d, J ¼ 9.0 Hz, 1H), 7.95 (d,
J ¼ 8.4 Hz, 1H), 7.80 (m, 1H), 7.51 (t, J ¼ 8.1 Hz, 1H), 7.36e7.31 (m,
3H), 7.07 (d, J ¼ 9.1 Hz, 1H), 6.80 (d, J ¼ 7.4 Hz, 1H), 3.95 (s, 3H); 13
C
d
9.74 (s, 1H), 8.65 (br, 2H), 8.29 (t, J ¼ 4.4 Hz, 2H), 8.25 (d, J ¼ 8.0 Hz,
NMR (100 MHz, DMSO‑d6)
d
163.64, 155.40, 154.87, 148.37, 142.19,
1H), 7.86 (d, J ¼ 8.0 Hz, 1H), 7.55 (d, J ¼ 8.4 Hz, 1H), 7.51e7.40 (m,
3H), 7.32 (t, J ¼ 8.4 Hz,1H), 7.07 (d, J ¼ 9.2 Hz,1H), 6.77 (d, J ¼ 7.6 Hz,
139.34, 134.92, 133.93, 132.37, 131.45, 130.02, 129.15, 127.57, 126.94,
119.54, 115.10, 114.92, 114.04, 113.30, 111.32, 102.70, 56.11; HRMS
(FABþ) m/z calcd for C24H18ClF3N3O2 [MþH]þ: 472.1039, found:
472.1036.
1H), 3.98 (s, 3H), 3.04 (t, J ¼ 4.4 Hz, 4H), 2.59 (s, 4H), 2.34 (s, 3H); 13
C
NMR (400 MHz, Acetone-d6)
d 164.06, 155.45, 155.15, 154.70,
148.56, 142.11, 139.47, 132.43, 131.28, 129.42, 128.73, 127.02, 126.97,
125.52, 125.43, 125.15, 123.58, 122.81, 115.34, 114.60, 113.47, 112.39,
110.83,101.96, 55.17, 55.10, 52.95, 45.36; HRMS (FABþ) m/z calcd for
4.4.7. N-(3-((5-Methoxyquinolin-2-yl)amino)phenyl)-3,5-
bis(trifluoromethyl)benzamide (8b)
C
29H29F3N5O2 [MþH]þ: 536.2273, found: 536.2270.
Column chromatography was performed using 5% ethyl acetate
in DCM. Yellowish white solid; yield 70%; 1H NMR (400 MHz,
4.4.12. N-(3-((5-Methoxyquinolin-2-yl)amino)phenyl)-4-
morpholino-3-(trifluoromethyl)benzamide (9b)
DMSO‑d6)
d 10.67 (br. s, 1H), 9.52 (br. s, 1H), 8.64 (s, 2H), 8.54 (d,
J ¼ 1.9 Hz, 1H), 8.39 (s, 1H), 7.83 (dt, J ¼ 7.3, 1.7 Hz, 1H), 7.52 (t,
Column chromatography was performed using a mixture of
hexane-ethyl acetate (2:1, then 1:1 v/v). White solid; yield 74.5%;
J ¼ 8.1 Hz, 1H), 7.37e7.31 (m, 3H), 7.07 (d, J ¼ 9.1 Hz, 1H), 6.81 (d,
J ¼ 7.4 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, DMSO‑d6)
d
163.04,
1H NMR (400 MHz, DMSO- d6)
d 10.39 (s, 1H), 9.49 (s, 1H), 8.49 (s,
155.41, 154.87, 148.36, 142.23, 139.17, 137.90, 131.46, 130.75, 130.03,
129.18, 129.06, 125.47, 124.99, 122.28, 119.53, 115.12, 114.15, 113.31,
111.43, 102.72, 56.11; HRMS (FABþ) m/z calcd for C25H18F6N3O2
[MþH]þ: 506.1303, found: 506.1306.
1H), 8.28e8.24 (m, 3H), 7.84e7.81 (m, 1H), 7.68 (d, J ¼ 4.5 Hz, 1H),
7.51 (t, J ¼ 8.1 Hz,1H), 7.36e7.31 (m, 3H), 7.07 (d, J ¼ 9.1 Hz,1H), 6.80
(d, J ¼ 7.8 Hz, 1H), 3.95 (s, 3H), 3.76 (t, J ¼ 4.0 Hz, 4H), 2.98 (t,
J ¼ 4.2 Hz, 4H); 13C NMR (100 MHz, DMSO‑d6)
d 164.36, 155.40,
154.90, 154.83, 148.38, 142.14, 139.59, 133.46, 131.53, 130.00, 129.09,
127.46, 127.40, 125.03, 124.74, 124.33, 119.53, 115.08, 114.70, 114.04,
113.31, 111.31, 102.66, 66.91, 56.08, 53.61; HRMS (FABþ) m/z calcd
for C28H26F3N4O3 [MþH]þ: 523.1957, found: 523.1953.
4.4.8. 6-Chloro-N-(3-((5-methoxyquinolin-2-yl)amino)phenyl)
picolinamide (8c)
Column chromatography was performed using a mixture of
hexane-ethyl acetate (1:1, v/v). Yellow solid; yield 24.6%; 1H NMR
(300 MHz, CDCl3)
d
9.70 (s, 1H), 8.34 (d, J ¼ 9.1 Hz, 1H), 8.22 (d,
4.4.13. 3-(4-Ethylpiperazin-1-yl)-N-(3-((5-methoxyquinolin-2-yl)
amino)phenyl)-5-(trifluoromethyl)benzamide (9c)
J ¼ 7.6 Hz, 1H), 8.16 (d, J ¼ 1.9 Hz, 1H), 7.84 (t, J ¼ 7.8 Hz, 1H),
7.53e7.34 (m, 6H), 6.99 (br.s, 1H), 6.95 (d, J ¼ 9.1 Hz, 1H), 6.66 (d,
Column chromatography was performed using 0e50% hexane in
J ¼ 7.4 Hz, 1H), 3.95 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 160.63,
ethyl acetate. White solid; yield 59.3%; 1H NMR (400 MHz, CDCl3)
155.46, 154.36, 150.45, 150.03, 148.61, 141.23, 140.28, 138.11, 132.50,
129.80, 129.76, 127.29, 121.20, 119.46, 116.13, 116.00, 114.14, 111.24,
110.86, 102.07, 55.61; HRMS (FABþ) m/z calcd for C22H18ClN4O2
d
8.48 (s, 1H), 8.28 (d, J ¼ 9.1 Hz, 1H), 8.01 (s, 1H), 7.56 (s, 1H),
7.48e7.42 (m, 3H), 7.38 (d, J ¼ 8.4 Hz, 1H), 7.31e7.26 (m, 2H), 7.18 (s,
1H), 6.90 (d, J ¼ 9.1 Hz, 1H), 6.65 (d, J ¼ 7.4 Hz, 1H), 3.95 (s, 3H), 3.27