Journal of Medicinal Chemistry
Article
CH), 112.58 (1C, Ar-4″-CH), 110.01 (1C, Ar-2″-CH), 104.46 (1C,
Ar-5-CH), 62.17 (1C, CH2, acetamido), 54.99 (2C, 2CH2,
piperazine), 53.29 (2C, 2CH2, piperazino), 46.23 (1C, CH3); 13C
NMR (75 MHz, DMSO-d6): δ 169.09 (1C, CO), 159.12 (1C, Ar-
4-C), 157.63 (1C, Ar-1″-C), 153.57 (1C, Ar-2-CH), 147.12 (1C, Ar-
6-C), 146.17 (1C, Ar-8a-C), 137.91 (1C, Ar-4′-C), 136.84 (2C, Ar-1′,
3″-C), 131.74 (1C, Ar-5″-CH), 128.87 (1C, Ar-8-CH), 127.86 (1C,
Ar-7-CH), 125.29 (2C, Ar-3′-C, Ar-6″-CH), 125.00 (1C, Ar-5′-CH),
124.10 (2C, Ar-6′, 4″-CH), 122.86 (1C, Ar-2′-CH), 115.76 (1C, Ar-
4a-C), 110.00 (1C, Ar-2″-CH), 104.46 (1C, Ar-5-CH), 62.15 (1C,
CH2, acetamido), 54.98 (2C, 2CH2, piperazino), 53.28 (2C, 2CH2,
piperazino), 46.21 (1C, CH3); HRMS (ES+): m/z calcd for
C27H27ClFN6O2 [M + 1]+, 521.1868; found, 521.1868.
H), 8.03−8.00 (d, J = 9 Hz, 1H, Ar-8-H), 7.92−7.89 (d, 1H, J = 9 Hz,
Ar-7-H), 7.81−7.78 (d, 1H, J = 9, Ar-6′-H), 7.65−7.59 (t, J = 9 Hz,
1H, Ar-5″-H), 7.49−7.46 (d, 1H, J = 9 Hz, Ar-4″-H), 7.35−7.32 (d,
1H, J = 9 Hz, Ar-6″-H), 7.25−7.21 (m, 2H, Ar-2″, 5′), 3.67 (br s, 4H,
2CH2, morpholino) 3.22 (s, 2H, CH2), 2.57 (br s, 4H, 2CH2,
morpholino); 13C DEPT (75 MHz, DMSO-d6): δ 153.58 (1C, Ar-2-
CH), 131.91 (1C, Ar-5″-CH), 128.87 (1C, Ar-8-CH), 128.02 (1C,
Ar-7-CH), 124.12 (1C, Ar-6″-CH), 122.83 (2C, Ar-5′, 6′-CH),
120.67 (1C, Ar-4″-CH), 119.90 (1C, Ar-2′-CH), 113.27 (1C, Ar-2″-
CH), 112.74 (1C, Ar-5-CH), 66.57 (2C, 2CH2, morpholino), 62.41
(1C, CH2), 53.72 (2C, 2CH2, morpholino); 13C NMR (75 MHz,
DMSO-d6): δ 168.90 (1C, CO), 158.12 (1C, Ar-4-C), 157.63 (1C,
Ar-1″-C), 153.57 (1C, Ar-2-CH), 147.16 (1C, Ar-6-C), 145.84 (1C,
Ar-8a-C), 138.15 (1C, Ar-4′-C), 136.83 (2C, Ar-1′, 3″-C), 131.91
(1C, Ar-5″-CH), 128.85 (1C, Ar-8-CH), 128.01 (1C, Ar-7-CH),
125.37 (1C, Ar-3′-C), 125.22 (1C, CF3), 124.12 (1C, Ar-6″-CH),
122.95 (2C, Ar-5′, 6′-CH), 120.69 (1C, Ar-4″-CH), 119.91 (1C, Ar-
2′-CH), 115.76 (1C, Ar-4a-C), 113.26 (1C, Ar-2″-CH), 112.75 (1C,
Ar-5-CH), 66.56 (2C, 2CH2, morpholino), 62.40 (1C, CH2), 53.72
(2C, 2CH2, morpholino); HRMS (ES+): m/z calcd for
C27H24ClF3N5O3 [M + 1]+, 558.1520; found, 558.1528.
N-(4-((3-Chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-
quinazolin-6-yl)-2-(4-methylpiperazin-1-yl)acetamide (15f). Brown
oil solidifies when kept in the fridge overnight, 0.27 g, yield; 48%: 1H
NMR (300 MHz, DMSO-d6): δ 9.96 (s, 2H, 2NH, exchanged with
D2O), 8.65 (s, 1H, Ar-2-H), 8.59 (s, 1H, Ar-5-H), 8.25 (s, 1H, Ar-2′-
H), 8.06−8.03 (d, J = 9 Hz, 1H, Ar-8-H), 7.92−7.89 (d, 1H, J = 9 Hz,
Ar-7-H), 7.81−7.78 (d, 1H, J = 9, Ar-6′-H), 7.64−7.59 (t, J = 6 Hz,
1H, Ar-5″-H), 7.48−7.46 (d, 1H, J = 6 Hz, Ar-4″-H), 7.34−7.32 (d,
1H, J = 6 Hz, Ar-6″-H), 7.25−7.21 (m, 2H, Ar-2″, 5′), 3.20 (s, 2H,
CH2, acetamido), 2.57 (br s, 4H, 2CH2, piperazino), 2.41 (br s, 4H,
2CH2, piperazine), 2.18 (s, 3H, CH3); 13C DEPT (75 MHz, DMSO-
d6): δ 153.54 (1C, Ar-2-CH), 131.90 (1C, Ar-5″-CH), 128.87 (1C,
Ar-8-CH), 127.85 (1C, Ar-7-CH), 124.12 (1C, Ar-6″-CH), 122.94
(2C, Ar-5′, 6′-CH), 120.66 (1C, Ar-4″-CH), 119.90 (1C, Ar-2′-CH),
113.31 (1C, Ar-2″-CH), 112.54 (1C, Ar-5-CH), 62.15 (1C, CH2,
acetamido), 54.97 (2C, 2CH2, piperazino), 53.26 (2C, 2CH2,
piperazino), 46.18 (1C, CH3); 13C NMR (75 MHz, DMSO-d6): δ
169.08 (1C, CO), 158.12 (1C, Ar-4-C), 157.62 (1C, Ar-1″-C),
153.54 (1C, Ar-2-CH), 147.14 (1C, Ar-6-C), 145.84 (1C, Ar-8a-C),
138.15 (1C, Ar-4′-C), 136.85 (2C, Ar-1′, 3″-C), 131.90 (1C, Ar-5″-
CH), 128.87 (1C, Ar-8-CH), 127.85 (1C, Ar-7-CH), 125.81 (1C, Ar-
3′-C), 125.40 (1C, CF3), 124.12 (1C, Ar-6″-CH), 122.94 (2C, Ar-5′,
6′-CH), 120.67 (1C, Ar-4″-CH), 119.95 (1C, Ar-2′-CH), 115.78
(1C, Ar-4a-C), 113.32 (1C, Ar-2″-CH), 112.54 (1C, Ar-5-CH), 62.15
(1C, CH2, acetamido), 54.97 (2C, 2CH2, piperazino), 53.26 (2C,
2CH2, piperazino), 46.18 (1C, CH3); HRMS (ES+): m/z calcd for
C28H27ClF3N6O2 [M + 1]+, 571.1836; found, 571.1837.
N-(4-((3-Chloro-4-(3-fluorophenoxy)phenyl)amino)quinazolin-6-
yl)-2-(diethylamino) Acetamide (15c). Brown solid, 0.4 g, yield; 86%,
1
mp 110−115 °C; H NMR (300 MHz, DMSO-d6): δ 9.95 (s, 2H,
2NH, exchanged with D2O), 8.62 (s, 1H, Ar-2-H), 8.59 (s, 1H, Ar-5-
H), 8.24 (s, 1H, Ar-2″-H), 8.21−8.18 (d, J = 9 Hz, 1H, Ar-8-H),
7.92−7.89 (d, 1H, J = 9 Hz, Ar-7-H), 7.81−7.78 (d, 1H, J = 9, Ar-5′-
H), 7.45−7.37 (dd, 1H, Ar-6′-H), 7.30−7.27 (d, 1H, J = 8.8, Ar-2′-
H), 6.98−6.92 (t, J = 9 Hz, 1H, Ar-5″-H), 6.84−6.81 (d, J = 9 Hz,
1H, Ar-4″-H), 6.77−6.74 (d, 1H, J = 9 Hz, Ar-6″-H), 3.23 (s, 2H,
CH2, acetamido), 2.68−2.61 (q, J = 7 Hz, 4H, 2CH2,
(CH3CH2)2N−), 1.09−1.04 (t,
J = 7 Hz, 6H, 2CH3,
(CH3CH2)2N−); 13C DEPT (75 MHz, DMSO-d6): δ 153.53 (1C,
Ar-2-CH), 131.85 (1C, Ar-8-CH), 128.92 (1C, Ar-5″-CH), 127.38
(1C, Ar-7-CH), 124.04 (1C, Ar-5′-CH), 122.79 (1C, Ar-6′-CH),
112.77 (1C, Ar-2′-CH), 112.18 (1C, Ar-6″-CH), 110.28 (1C, Ar-4″-
CH), 104.81 (1C, Ar-2″-CH), 104.46 (1C, Ar-5-CH), 57.78 (1C,
CH2, acetamido), 48.48 (2C, 2CH2, (CH3CH2)2N−), 12.44 (2C,
2CH3, (CH3CH2)2N−); 13C NMR (75 MHz, DMSO-d6): δ 170.98
(1C, CO), 159.06 (1C, Ar-4-C), 158.92 (1C, Ar-3″-C), 157.65
(1C, Ar-1″-C), 153.55 (1C, Ar-2-CH), 146.86 (1C, Ar-6-C), 146.29
(1C, Ar-8a-C), 137.69 (1C, Ar-4′-C), 136.69 (1C, Ar-1′-C), 131.89
(1C, Ar-8-CH), 128.80 (1C, Ar-5″-CH), 127.51 (1C, Ar-7-CH),
125.38 (1C, Ar-3′-C), 124.20 (1C, Ar-5′-CH), 122.83 (1C, Ar-6′-
CH), 115.68 (1C, Ar-4a-C), 112.72 (1C, Ar-2′-CH), 112.05 (1C, Ar-
6″-CH), 110.29 (1C, Ar-4″-CH), 104.67 (1C, Ar-2″-CH), 104.34
(1C, Ar-5-CH), 57.68 (1C, CH2, acetamido), 48.47 (2C, 2CH2,
(CH3CH2)2N−), 12.35 (2C, 2CH3, (CH3CH2)2N−); HRMS (ES+):
m/z calcd for C26H26ClFN5O2 [M + 1]+, 494.1759; found, 494.1756.
N-(4-((3-Chloro-4-(3-fluorophenoxy)phenyl)amino)quinazolin-6-
yl)-2-(dimethylamino)acetamide (15d). Brown solid, 0.3 g, yield:
72%; 1H NMR (300 MHz, DMSO-d6): δ 10.00 (s, 1H, NH,
exchanged with D2O), 9.91 (s, 1H, NH, exchanged with D2O), 8.65
(s, 1H, Ar-2-H), 8.58 (s, 1H, Ar-5-H), 8.23 (s, 1H, Ar-2″-H), 8.13−
8.10 (d, J = 9 Hz, 1H, Ar-8-H), 7.90−7.87 (d, 1H, J = 8.6, Ar-6′-H),
7.80−7.77 (d, J = 9 Hz, 1H, Ar-7-H), 7.44−7.37 (dd, 1H, Ar-4″-H),
7.30−7.27 (d, 1H, J = 8.8, Ar-5′-H), 6.98−6.92 (t, J = 8.5 Hz, 1H, Ar-
5″-H), 6.85−6.75 (m, 2H, Ar-2′,6″-H), 3.16 (s, 2H, CH2, acetamido),
2.33 (s, 6H, 2CH3); 13C DEPT (75 MHz, DMSO-d6): δ 153.46 (1C,
Ar-2-CH), 131.73 (1C, Ar-5″-CH), 128.82 (1C, Ar-8-CH), 127.64
(1C, Ar-7-CH), 123.93 (1C, Ar-5′-CH), 122.79 (1C, Ar-6′-CH),
112.77 (1C, Ar-2′-CH), 110.27 (1C, Ar-6″-CH), 109.98 (1C, Ar-4″-
CH), 104.80 (1C, Ar-2″-CH), 104.46 (1C, Ar-5-CH), 63.69 (1C,
CH2), 45.95 (2C, 2CH3); 13C NMR (75 MHz, DMSO-d6): δ 169.44
(1C, CO), 165.00 (1C, Ar-4-C), 161.76 (1C, Ar-3″-C), 159.14
(1C, Ar-1″-C), 153.50 (1C, Ar-2-CH), 146.11 (1C, Ar-6-C), 136.96
(1C, Ar-8a-C), 131.86 (1C, Ar-4′-C), 131.73 (1C, Ar-5″-CH), 128.82
(1C, Ar-8-CH), 127.65 (1C, Ar-7-CH), 125.31 (1C, Ar-1′-C), 123.94
(1C, Ar-5′-CH), 122.80 (1C, Ar-6′-CH), 122.69 (1C, Ar-3′-C),
112.75 (1C, Ar-2′-CH), 112.45 (1C, Ar-4a-C), 110.27 (1C, Ar-6″-
CH), 109.99 (1C, Ar-4″-CH), 104.79 (1C, Ar-2″-CH), 104.46 (1C,
Ar-5-CH), 63.68 (1C, CH2), 45.94 (2C, 2CH3); HRMS (ES+): m/z
calcd for C24H22ClFN5O2 [M + 1]+, 466.1446; found, 466.1441.
N-(4-((3-Chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-
quinazolin-6-yl)-2-morpholino-acetamide (15e). Yellow solid, 0.42
g, yield; 77%, mp 105−108; 1H NMR (300 MHz, DMSO-d6): δ 10.05
(s, H, NH, exchanged with D2O), 9.96 (s, H, NH, exchanged with
D2O), 8.67 (s, 1H, Ar-2-H), 8.60 (s, 1H, Ar-5-H), 8.25 (s, 1H, Ar-2′-
N-(4-((3-Chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-
quinazolin-6-yl)-2-(dimethylamino)acetamide (15g). Brown solid,
1
0.42 g, yield; 83%; H NMR (300 MHz, DMSO-d6): δ 9.99 (s, 2H,
2NH, exchanged with D2O), 8.65 (s, 1H, Ar-2-H), 8.59 (s, 1H, Ar-5-
H), 8.25 (s, 1H, Ar-2′-H), 8.13−8.10 (d, J = 9 Hz, 1H, Ar-8-H),
7.92−7.89 (d, 1H, J = 9 Hz, Ar-7-H), 7.80−7.77 (d, 1H, J = 9 Hz, Ar-
6′-H), 7.64−7.59 (t, J = 6 Hz, 1H, Ar-5″-H), 7.48−7.46 (d, 1H, J = 6
Hz, Ar-4″-H), 7.34−7.32 (d, 1H, J = 6 Hz, Ar-6″-H), 7.25−7.21 (m,
2H, Ar-2″, 5′), 3.15 (s, 2H, CH2), 2.33 (s, 6H, 2CH3); 13C DEPT (75
MHz, DMSO-d6): δ 153.45 (1C, Ar-2-CH), 131.89 (1C, Ar-5″-CH),
128.82 (1C, Ar-8-CH), 127.66 (1C, Ar-7-CH), 123.97 (1C, Ar-6″-
CH), 122.95 (1C, Ar-5′-CH), 122.77 (1C, Ar-6′-CH), 120.69 (1C,
Ar-4″-CH), 119.94 (1C, Ar-2′-CH), 113.29 (1C, Ar-2″-CH), 112.44
(1C, Ar-5-CH), 63.68 (1C, CH2), 45.93 (2C, 2CH3); 13C NMR (75
MHz, DMSO): δ 169.41 (1C, CO), 158.13 (1C, Ar-4-C), 157.51
(1C, Ar-1″-C), 153.44 (1C, Ar-2-CH), 147.02 (1C, Ar-6-C), 145.82
(1C, Ar-8a-C), 138.27 (1C, Ar-4′-C), 136.98 (1C, Ar-1′-C), 131.88
(1C, Ar-5″-CH), 131.40 (1C, Ar-3″-C), 130.99 (1C, Ar-3′-C), 128.82
(1C, Ar-8-CH), 127.64 (1C, Ar-7-CH), 125.41 (1C, CF3), 123.97
(1C, Ar-6″-CH), 122.92 (1C, Ar-5′-CH), 122.77 (1C, Ar-6′-CH),
120.69 (1C, Ar-4″-CH), 119.88 (1C, Ar-2′-CH), 115.82 (1C, Ar-4a-
C), 113.28 (1C, Ar-2″-CH), 112.44 (1C, Ar-5-CH), 63.68 (1C,
AA
J. Med. Chem. XXXX, XXX, XXX−XXX